Mary Leonard

All Publications

• New BMDCS Body Composition Z-scores Require Caution When Applying to Existing and New Whole Body Scans Kent, K., Leonard, M. B., Strickland, A., Long, J., Zhong, Y., Whalen, J., Zemel, B. S. OXFORD UNIV PRESS. 2024: 168-169

  View details for Web of Science ID 001361790801028

• Fat Mass Adjusted Appendicular Lean Mass Z-score - A Novel Way to Evaluate Muscle Status in Children Zhong, Y., Leonard, M. B., Whalen, J., Kent, K., Zemel, B., Mostoufi-Moab, S., Long, J. OXFORD UNIV PRESS. 2024: 186

  View details for Web of Science ID 001361790801081

• Publisher Correction: Vitamin D supplementation in children and young adults with persistent proteinuria secondary to glomerular disease. Pediatric nephrology (Berlin, Germany) Kogon, A. J., Ballester, L. S., Zee, J., Walker, N., Zaritsky, J. J., Atkinson, M. A., Sethna, C. B., Hoofnagle, A. N., Leonard, M. B., Denburg, M. R. 2024

  View details for DOI 10.1007/s00467-024-06475-6

  View details for PubMedID 39264421

• Responding to the workforce crisis: consensus recommendations from the Second Workforce Summit of the American Society of Pediatric Nephrology. Pediatric nephrology (Berlin, Germany) Soranno, D. E., Amaral, S., Ashoor, I., Atkinson, M. A., Barletta, G. M., Braun, M. C., Carlson, J., Carter, C., Chua, A., Dharnidharka, V. R., Drake, K., Erkan, E., Feig, D., Goldstein, S. L., Hains, D., Harshman, L. A., Ingulli, E., Kula, A. J., Leonard, M., Mannemuddhu, S., Menon, S., Modi, Z. J., Moxey-Mims, M., Nada, A., Norwood, V., Starr, M. C., Verghese, P. S., Weidemann, D., Weinstein, A., Smith, J. 2024

  Abstract

  Pediatric patients with complex medical problems benefit from pediatric sub-specialty care; however, a significant proportion of children live greater than 80 mi. away from pediatric sub-specialty care.To identify current knowledge gaps and outline concrete next steps to make progress on issues that have persistently challenged the pediatric nephrology workforce.Workforce Summit 2.0 employed the round table format and methodology for consensus building using adapted Delphi principles. Content domains were identified via input from the ASPN Workforce Committee, the ASPN's 2023 Strategic Plan survey, the ASPN's Pediatric Nephrology Division Directors survey, and ongoing feedback from ASPN members. Working groups met prior to the Summit to conduct an organized literature review and establish key questions to be addressed. The Summit was held in-person in November 2023. During the Summit, work groups presented their preliminary findings, and the at-large group developed the key action statements and future directions.A holistic appraisal of the effort required to cover inpatient and outpatient sub-specialty care will help define faculty effort and time distribution. Most pediatric nephrologists practice in academic settings, so work beyond clinical care including education, research, advocacy, and administrative/service tasks may form a substantial amount of a faculty member's time and effort. An academic relative value unit (RVU) may assist in creating a more inclusive assessment of their contributions to their academic practice. Pediatric sub-specialties, such as nephrology, contribute to the clinical mission and care of their institutions beyond their direct billable RVUs. Advocacy throughout the field of pediatrics is necessary in order for reimbursement of pediatric sub-specialist care to accurately reflect the time and effort required to address complex care needs. Flexible, individualized training pathways may improve recruitment into sub-specialty fields such as nephrology.The workforce crisis facing the pediatric nephrology field is echoed throughout many pediatric sub-specialties. Efforts to improve recruitment, retention, and reimbursement are necessary to improve the care delivered to pediatric patients.

  View details for DOI 10.1007/s00467-024-06410-9

  View details for PubMedID 38976042

  View details for PubMedCentralID 9346544

• Dependent on our dependents: advancing child health through transdisciplinary team science to sustain social programs. Pediatric research Davis, M. M., Leonard, M. B., Chamberlain, L. 2024

  View details for DOI 10.1038/s41390-024-03344-8

  View details for PubMedID 38961166

• Correction to: Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial. Diabetologia Kobayashi, Y., Long, J., Dan, S., Johannsen, N. M., Talamoa, R., Raghuram, S., Chung, S., Kent, K., Basina, M., Lamendola, C., Haddad, F., Leonard, M. B., Church, T. S., Palaniappan, L. 2024

  View details for DOI 10.1007/s00125-024-06135-2

  View details for PubMedID 38689057

  View details for PubMedCentralID 2844943

• PEDSQL, EXERCISE CAPACITY, AND ENDOTHELIAL FUNCTION IN PEDIATRIC FONTAN PATIENTS Jose, J., Bernstein, D., Palaniappan, L. P., Leonard, M., Long, J., Desai, M., Lui, M., Davila, T., Cooke, J. P., Olson, I. L., Myers, J. N., Schneider, L., Tierney, E. ELSEVIER SCIENCE INC. 2024: 2407

  View details for Web of Science ID 001324901502441

• Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies AMERICAN JOURNAL OF NEPHROLOGY Pfaff, M., Denburg, M. R., Meyers, K. E., Brady, T. M., Leonard, M. B., Hoofnagle, A. N., Sethna, C. B. 2024; 55 (2): 187-195

  Abstract

  Fibroblast growth factor 23 (FGF23) has direct effects on the vasculature and myocardium, and high levels of FGF23 are a risk factor for cardiovascular disease (CVD); however, the impact of FGF23 on CVD in primary proteinuric glomerulopathies has not been addressed.The associations of baseline plasma intact FGF23 levels with resting blood pressure (BP) and lipids over time among adults and children with proteinuric glomerulopathies enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were analyzed using generalized estimating equation regression analyses. Models were adjusted for age, sex, glomerular diagnosis, follow-up time, estimated glomerular filtration rate, urine protein/creatinine ratio, obesity, and serum phosphorous levels.Two hundred and four adults with median FGF23 77.5 (IQR 51.3-119.3) pg/mL and 93 children with median FGF23 62.3 (IQR 44.6-83.6) pg/mL were followed for a median of 42 (IQR 20.5-54) months. In adjusted models, each 1 µg/mL increase in FGF23 was associated with a 0.3 increase in systolic BP index at follow-up (p < 0.001). Greater baseline FGF23 was associated with greater odds of hypertensive BP (OR = 1.0003; 95% CI 1.001-1.006, p = 0.03) over time. Compared to tertile 1, tertile 2 (OR = 2.1; 95% CI 1.12-3.99, p = 0.02), and tertile 3 (OR = 3; 95% CI 1.08-8.08, p = 0.04), FGF23 levels were associated with greater odds of hypertensive BP over time. Tertile 2 was associated with greater triglycerides compared to tertile 1 (OR = 48.1; 95% CI 4.4-91.9, p = 0.03).Overall, higher baseline FGF23 was significantly associated with hypertensive BP over time in individuals with proteinuric glomerulopathies. Further study of FGF23 as a therapeutic target for reducing CVD in proteinuric glomerular disease is warranted.

  View details for DOI 10.1159/000535092

  View details for Web of Science ID 001197887100002

  View details for PubMedID 38128487

  View details for PubMedCentralID PMC10987260

• Projecting the Future Pediatric Subspecialty Workforce: Summary and Recommendations. Pediatrics Orr, C. J., McCartha, E., Vinci, R. J., Mink, R. B., Leonard, M. B., Bissell, M., Gaona, A. R., Leslie, L. K. 2024; 153 (Suppl 2)

  Abstract

  This article summarizes the findings of a Pediatrics supplement addressing the United States workforce for 15 pediatric subspecialties. It includes results from a microsimulation model projecting supply through 2040; growth is forecasted to be uneven across the subspecialties with worsening geographic maldistribution. Although each subspecialty has unique characteristics, commonalities include (1) the changing demographics and healthcare needs of children, including mental health; (2) poor outcomes for children experiencing adverse social drivers of health, including racism; and (3) dependence on other subspecialties. Common healthcare delivery challenges include (1) physician shortages for some subspecialties; (2) misalignment between locations of training programs and subspecialists and areas of projected child population growth; (3) tension between increasing subsubspecialization to address rare diseases and general subspecialty care; (4) the need to expand clinical reach through collaboration with other physicians and advanced practice providers; (5) the lack of parity between Medicare, which funds much of adult care, and Medicaid, which funds over half of pediatric subspecialty care; and (6) low compensation of pediatric subspecialists compared with adult subspecialists. Overall, subspecialists identified the lack of a central authority to monitor and inform child healthcare provided by pediatric subspecialists as a challenge. Future research on the pediatric subspecialty workforce and the children it serves will be necessary to ensure these children's needs are met. Together, these articles provide overarching and subspecialty-specific recommendations to improve training, recruitment, and retention of a diverse workforce, implement innovative models of care, drive policy changes, and advise future research.

  View details for DOI 10.1542/peds.2023-063678T

  View details for PubMedID 38300012

• Child Health Needs and the Pediatric Endocrinology Workforce: 2020-2040. Pediatrics Aye, T., Boney, C. M., Orr, C. J., Leonard, M. B., Leslie, L. K., Allen, D. B. 2024; 153 (Suppl 2)

  Abstract

  The pediatric endocrinology (PE) workforce in the United States is struggling to sustain an adequate, let alone optimal, workforce capacity. This article, one of a series of articles in a supplement to Pediatrics, focuses on the pediatric subspecialty workforce and furthers previous evaluations of the US PE workforce to model the current and future clinical PE workforce and its geographic distribution. The article first discusses the children presenting to PE care teams, reviews the current state of the PE subspecialty workforce, and presents projected headcount and clinical workforce equivalents at the national, census region, and census division level on the basis of a subspecialty workforce supply model through 2040. It concludes by discussing the educational and training, clinical practice, policy, and future workforce research implications of the data presented. Data presented in this article are available from the American Board of Pediatrics, the National Resident Matching Program, and the subspecialty workforce supply model. Aging, part-time appointments, and unbalanced geographic distribution of providers diminish the PE workforce capacity. In addition, limited exposure, financial concerns, and lifestyle perceptions may impact trainees. Additional workforce challenges are the subspecialty's increasingly complex cases and breadth of conditions treated, reliance on international medical graduates to fill fellowship slots, and high relative proportion of research careers. The recent limitations on pediatric endocrinologists providing gender-affirming care may also impact the geographic distribution of the subspecialty's workforce. Deliberate actions need to be taken now to continue serving the needs of children.

  View details for DOI 10.1542/peds.2023-063678J

  View details for PubMedID 38300000

• Child Health and the US Pediatric Subspecialty Workforce: Planning for the Future. Pediatrics Leslie, L. K., Orr, C. J., Turner, A. L., Mink, R., Leonard, M. B., Sabadosa, K. A., Vinci, R. J. 2024; 153 (Suppl 2)

  Abstract

  This article opens a multi-article Pediatrics supplement that provides a rigorous analysis of the projected pediatric subspecialty workforce in the United States. Congenital variations, epigenetics, exposures, lifestyle, preventive care, and medical interventions from conception through young adulthood set the stage for health and wellbeing in adulthood. Although care provided by pediatric subspecialists is associated with better outcomes and lower costs compared with adult providers, the authors of recent articles in the lay and medical literature have questioned the capacity of pediatric subspecialists to meet children's health care needs. This article highlights that, despite numerous advances in prevention, diagnosis, and treatment, the last decade has witnessed increasing numbers of children with acute or chronic physical and mental health disorders, including medical complexity, obesity, type 2 diabetes, anxiety, depression, and suicidality, all of which are exacerbated by poverty, racism, and other social drivers of health. In this article, we then describe the variability in the demographics, practice characteristics, and geographic distribution of the 15 core pediatric subspecialties certified by the American Board of Pediatrics. We then discuss the rationale and approach to the development of a pediatric subspecialty workforce model that forecasts subspecialist supply from 2020 to 2040 for 14 subspecialties at the national and subnational levels (not including the newest subspecialty, pediatric hospital medicine), accounting for US Census Bureau child population projections. The model does not account for the unique physical and mental needs of individual children, nor does it address the increasingly precarious commitment to, and financing of, pediatric subspecialty care in the US health care system impacting market demand.

  View details for DOI 10.1542/peds.2023-063678B

  View details for PubMedID 38299999

• Child Health Needs and the Pediatric Nephrology Subspecialty Workforce: 2020-2040. Pediatrics Weidemann, D. K., Orr, C. J., Norwood, V., Brophy, P., Leonard, M. B., Ashoor, I. 2024; 153 (Suppl 2)

  Abstract

  Pediatric nephrology is dedicated to caring for children with kidney disease, a unique blend of acute care and chronic longitudinal patient relationships. Though historically a small field, trainee interest has declined over the past 2 decades. This has led to growing alarm about the health of the pediatric nephrology workforce, although concerns have been hampered by a lack of available data to enable feasible projections. This article is part of a supplement that anticipates the future pediatric subspecialty workforce supply. It draws on existing literature, data from the American Board of Pediatrics, and findings from a model that estimates the future supply of pediatric subspecialists developed by the Carolina Health Workforce Research Center at the University of North Carolina Chapel Hill's Cecil G. Sheps Center for Health Services Research and Strategic Modeling Analytics & Planning Ltd. The workforce projections from 2020 to 2040 incorporate population growth, clinical effort, and geographic trends and model alternate scenarios adjusting for changes in trainee interest, clinical efforts, and workforce attrition. The baseline model predicts growth of clinical work equivalents by 26% by 2040, but further widening geographic disparities worsen the existing mismatch between supply, clinical need, and market demand. The worst-case scenario projects 13% growth by 2040 which, at best, maintains the status quo of an already strained workforce. The models do not account for many factors expected to heighten demand over the coming decades. Urgent reforms are necessary now. Proposed solutions require multipronged changes in education and training pathways, remuneration, clinical practice models, and government policy.

  View details for DOI 10.1542/peds.2023-063678P

  View details for PubMedID 38300004

• Child Health Needs and the Pediatric Rheumatology Workforce: 2020-2040. Pediatrics Correll, C. K., Klein-Gitelman, M. S., Henrickson, M., Battafarano, D. F., Orr, C. J., Leonard, M. B., Mehta, J. J. 2024; 153 (Suppl 2)

  Abstract

  The Pediatric Rheumatology (PRH) workforce supply in the United States does not meet the needs of children. Lack of timely access to PRH care is associated with poor outcomes for children with rheumatic diseases. This article is part of a Pediatrics supplement focused on anticipating the future pediatric subspecialty workforce supply. It draws on information in the literature, American Board of Pediatrics data, and findings from a model that estimates the future supply of pediatric subspecialists developed by the Sheps Center for Health Services Research at the University of North Carolina at Chapel Hill, Strategic Modeling and Analysis Ltd., and the American Board of Pediatrics Foundation. PRH has a smaller workforce per capita of children than most other pediatric subspecialties. The model demonstrates that the clinical workforce equivalent of pediatric rheumatologists in 2020 was only 0.27 per 100 000 children, with a predicted increase to 0.47 by 2040. Although the model predicts a 72% increase in providers, this number remains inadequate to provide sufficient care given the number of children with rheumatic diseases, especially in the South and West regions. The likely reasons for the workforce shortage are multifactorial, including lack of awareness of the field, low salaries compared with most other medical specialties, concerns about working solo or in small group practices, and increasing provider retirement. Novel interventions are needed to increase the workforce size. The American College of Rheumatology has recognized the dire consequences of this shortage and has developed a workforce solutions initiative to tackle these problems.

  View details for DOI 10.1542/peds.2023-063678R

  View details for PubMedID 38300008

• Derivation of paediatric blood pressure percentiles from electronic health records. EBioMedicine Mitsnefes, M. M., Maltenfort, M., Denburg, M. R., Flynn, J. T., Schuchard, J., Dixon, B. B., Patel, H. P., Claes, D., Dickinson, K., Chen, Y., Gluck, C., Leonard, M., Verghese, P. S., Forrest, C. B. 2023; 98: 104885

  Abstract

  Identification of abnormal blood pressure (BP) in children requires normative data. We sought to examine the feasibility of using "real-world" office BP data obtained from electronic health records (EHR) to generate age-, sex- and height-specific BP percentiles for children.Using data collected 01/01/2009-8/31/2021 from eight large children's healthcare organisations in PEDSnet, we applied a mixed-effects polynomial regression model with random slopes to generate Z-scores and BP percentiles and compared them with currently used normative BP distributions published in the 2017 American Academy of Paediatrics (AAP) Clinical Practise Guidelines (CPG).We identified a study sample of 292,412 children (1,085,083 BP measurements), ages 3-17 years (53% female), with no chronic medical conditions, who were not overweight/obese and who were primarily seen for general paediatric care in outpatient settings. Approximately 45,000-75,000 children contributed data to each age category. The PEDSnet systolic BP percentile values were 1-4 mmHg higher than AAP CPG BP values across age-sex-height groups, with larger differences observed in younger children. Diastolic BP values were also higher in younger children; starting with age 7 years, diastolic BP percentile values were 1-3 mmHg lower than AAP CPG values. Cohen's Kappa was 0.90 for systolic BP, 0.66 for diastolic BP, and 0.80 overall indicating excellent agreement between PEDSnet and 2017 AAP CPG data for systolic BP and substantial agreement for diastolic BP.Our analysis indicates that real-word EHR data can be used to generate BP percentiles consistent with current clinical practise on BP management in children.Funding for this work was provided by the Preserving Kidney Function in Children with Chronic Kidney Disease (PRESERVE) study; Patient-Centred Outcomes Research Institute (PCORI) RD-2020C2020338 (Principal Investigator: Dr. Forrest; Co-Principal Investigator: Dr. Denburg).

  View details for DOI 10.1016/j.ebiom.2023.104885

  View details for PubMedID 37988770

• Reliable Quantification of Bone Microstructure from HR-pQCT During Growth Requires Density-Independent Segmentation Burghardt, A., Kent, K., Long, J., Strickland, A., Aye, T., Leonard, M. OXFORD UNIV PRESS. 2023: 244

  View details for Web of Science ID 001266167001182

• Raising the Bar: The Need for Increased Financial Support to Sustain and Expand the Community of Pediatric Subspecialists. The Journal of pediatrics Lakshminrusimha, S., Cheng, T. L., Leonard, M. B., Devaskar, S. U., Vinci, R. J., Degnon, L., St Geme, J. W. 2023: 113758

  View details for DOI 10.1016/j.jpeds.2023.113758

  View details for PubMedID 37748730

• Comparisons of body composition and muscle strength between transgender adolescents and cisgender controls Misakian, A., Long, J., Kent, K., Leonard, M. B., Aye, T. KARGER. 2023: 378-381

  View details for Web of Science ID 001050468900215

• Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial. Diabetologia Kobayashi, Y., Long, J., Dan, S., Johannsen, N. M., Talamoa, R., Raghuram, S., Chung, S., Kent, K., Basina, M., Lamendola, C., Haddad, F., Leonard, M. B., Church, T. S., Palaniappan, L. 2023

  Abstract

  AIMS/HYPOTHESIS: Type 2 diabetes in people in the healthy weight BMI category (<25 kg/m2), herein defined as 'normal-weight type 2 diabetes', is associated with sarcopenia (low muscle mass). Given this unique body composition, the optimal exercise regimen for this population is unknown.METHODS: We conducted a parallel-group RCT in individuals with type 2 diabetes (age 18-80 years, HbA1c 47.5-118.56 mmol/mol [6.5-13.0%]) and BMI <25 kg/m2). Participants were recruited in outpatient clinics or through advertisements and randomly assigned to a 9 month exercise programme of strength training alone (ST), aerobic training alone (AER) or both interventions combined (COMB). We used stratified block randomisation with a randomly selected block size. Researchers and caregivers were blinded to participants' treatment group; however, participants themselves were not. Exercise interventions were conducted at community-based fitness centres. The primary outcome was absolute change in HbA1c level within and across the three groups at 3, 6 and 9 months. Secondary outcomes included changes in body composition at 9 months. Per adherence to recommended exercise protocol (PP) analysis included participants who completed at least 50% of the sessions.RESULTS: Among 186 individuals (ST, n=63; AER, n=58; COMB, n=65) analysed, the median (IQR) age was 59 (53-66) years, 60% were men and 83% were Asian. The mean (SD) HbA1c level at baseline was 59.6 (13.1) mmol/mol (7.6% [1.2%]). In intention-to-treat analysis, the ST group showed a significant decrease in HbA1c levels (mean [95% CI] -0.44 percentage points [-0.78, -0.12], p=0.002), while no significant change was observed in either the COMB group (-0.35 percentage points, p=0.13) or the AER group (-0.24 percentage points, p=0.10). The ST group had a greater improvement in HbA1c levels than the AER group (p=0.01). Appendicular lean mass relative to fat mass increased only in the ST group (p=0.0008), which was an independent predictor of HbA1c change (beta coefficient -7.16, p=0.01). Similar results were observed in PP analysis. Only one adverse event, in the COMB group, was considered to be possibly associated with the exercise intervention.CONCLUSIONS/INTERPRETATION: In normal-weight type 2 diabetes, strength training was superior to aerobic training alone, while no significant difference was observed between strength training and combination training for HbA1c reduction. Increased lean mass relative to decreased fat mass was an independent predictor of reduction in HbA1c level.TRIAL REGISTRATION: ClinicalTrials.gov NCT02448498.FUNDING: This study was funded by the National Institutes of Health (NIH; R01DK081371).

  View details for DOI 10.1007/s00125-023-05958-9

  View details for PubMedID 37493759

• Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study. Journal of the American Heart Association Hsu, S., Zelnick, L. R., Bansal, N., Brown, J., Denburg, M., Feldman, H. I., Ginsberg, C., Hoofnagle, A. N., Isakova, T., Leonard, M. B., Lidgard, B., Robinson-Cohen, C., Wolf, M., Xie, D., Kestenbaum, B. R., de Boer, I. H. 2023: e028561

  Abstract

  Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

  View details for DOI 10.1161/JAHA.122.028561

  View details for PubMedID 37421259

• Cystatin C and Creatinine Concentrations are Uninformative Biomarkers of Sarcopenia: A Cross-Sectional NHANES Study. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation Shah, L. N., Leonard, M. B., Ziolkowski, S. L., Grimm, P., Long, J. 2023

  Abstract

  Differences in creatinine and cystatin C-based estimates of glomerular filtration rate (eGFRDiff = eGFRCr - eGFRCysC) may reflect differences in muscle mass. We sought to determine if eGFRDiff (1) reflects lean mass, (2) identifies sarcopenic individuals beyond estimates based on age, BMI, and sex; and (3) demonstrates associations differently in those with and without chronic kidney disease (CKD).This cross-sectional study included 3,754 participants, ages 20-85 years, with creatinine and cystatin C concentration levels, and DXA scans from NHANES data (1999 to 2006). DXA appendicular lean mass index (ALMI) estimated muscle mass. Non-race-based CKD EPI equations estimated GFR using creatinine (eGFRCr), cystatin C (eGFRCysC), and both biomarkers (eGFRCysC&Cr). CKD was defined as eGFRCysC&Cr < 60 mL/min/1.73m2. ALMI sex-specific T-scores (compared with young adult) < -2.0 defined sarcopenia. In estimating ALMI, we compared the coefficient of determination (R2) values from: 1) eGFRDiff, 2) clinical characteristics (age, BMI, and sex), and 3) clinical characteristics plus eGFRDiff. Using logistic regression, we evaluated each model's C-statistic to diagnose sarcopenia.eGFRDIFF was negatively and weakly associated with ALMI (No CKD: R2 = 0.006, p-value 0.002; CKD: R2 = 0.001, p-value 0.9). Clinical characteristics explained most of the variation in ALMI (No CKD: R2 = 0.851, CKD: R2 = 0.828), and provided strong discrimination of sarcopenia (No CKD C-statistic: 0.950; CKD C-statistic: 0.943). Adding eGFRDiff improved the R2 by 0.025, and the C-statistic by 0.003. Tests for interaction between eGFRDiff and CKD were not significant (all p-values > 0.05).Although eGFRDiff has statistically significant associations with ALMI and sarcopenia in univariate analyses, multivariate analyses demonstrate that eGFRDiff does not capture more information beyond routine clinical characteristics (age, BMI, and sex).

  View details for DOI 10.1053/j.jrn.2023.01.012

  View details for PubMedID 36796503

• Design and Rationale of RE-ENERGIZE FONTAN: RandomizEd Exercise iNtERvention desiGned to maximIZE fitness in FONTAN patients. American heart journal Tierney, E. S., Palaniappan, L., Leonard, M., Long, J., Myers, J., Dávila, T., Lui, M. C., Kogan, F., Olson, I., Punn, R., Desai, M., Schneider, L. M., Wang, C. H., Cooke, J. P., Bernstein, D. 2023

  Abstract

  In this manuscript, we describe the design and rationale of a randomized controlled trial in pediatric Fontan patients to test the hypothesis that a live-video-supervised exercise (aerobic+resistance) intervention will improve cardiac and physical capacity; muscle mass, strength, and function; and endothelial function. Survival of children with single ventricles beyond the neonatal period has increased dramatically with the staged Fontan palliation. Yet, long-term morbidity remains high. By age 40, 50% of Fontan patients will have died or undergone heart transplantation. Factors that contribute to onset and progression of heart failure in Fontan patients remain incompletely understood. However, it is established that Fontan patients have poor exercise capacity which is associated with a greater risk of morbidity and mortality. Furthermore, decreased muscle mass, abnormal muscle function, and endothelial dysfunction in this patient population is known to contribute to disease progression. In adult patients with two ventricles and heart failure, reduced exercise capacity, muscle mass, and muscle strength are powerful predictors of poor outcomes, and exercise interventions can not only improve exercise capacity and muscle mass, but also reverse endothelial dysfunction. Despite these known benefits of exercise, pediatric Fontan patients do not exercise routinely due to their chronic condition, perceived restrictions to exercise, and parental overprotection. Limited exercise interventions in children with congenital heart disease have demonstrated that exercise is safe and effective; however, these studies have been conducted in small, heterogeneous groups, and most had few Fontan patients. Critically, adherence is a major limitation in pediatric exercise interventions delivered on-site, with adherence rates as low as 10%, due to distance from site, transportation difficulties, and missed school or workdays. To overcome these challenges, we utilize live-video conferencing to deliver the supervised exercise sessions. Our multidisciplinary team of experts will assess the effectiveness of a live-video-supervised exercise intervention, rigorously designed to maximize adherence, and improve key and novel measures of health in pediatric Fontan patients associated with poor long-term outcomes. Our ultimate goal is the translation of this model to clinical application as an "exercise prescription" to intervene early in pediatric Fontan patients and decrease long-term morbidity and mortality.

  View details for DOI 10.1016/j.ahj.2023.02.006

  View details for PubMedID 36796574

• Trabecular Bone Score (TBS) varies with correction for tissue thickness versus body mass index; Implications when using pediatric reference norms. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Valenzuela Riveros, L. F., Long, J., Bachrach, L. K., Leonard, M. B., Kent, K. 2023

  Abstract

  Trabecular bone score (TBS) derived from secondary analysis of lumbar spine DXA scans improves fracture prediction independent of BMD in adults. The utility of TBS to assess fracture risk in younger patients has not been established because pediatric norms have been lacking. Robust TBS reference data from the Bone Mineral Density in Childhood Study (BMDCS) have been published. TBS values for the BMDCS study were derived using an algorithm that accounts for tissue thickness (TBSTH ) rather than the commercially-available algorithm that adjusts for BMI (TBSBMI ). We examined the magnitude of differences in TBSTH and TBSBMI in a cohort of 189 healthy youth. TBS values using both algorithms increased with age and pubertal development in a similar pattern. However,TBSBMI values were systematically and significantly higher than TBSTH (mean=0.06, p<0.0001). The difference between calculated TBSBMI and TBSTH was not uniform. Differences were greater at lower TBS values, in males, in older individuals, in those at later Tanner stages and in those with a greater BMI Z-score. These systematic differences preclude the development of a simple formula to allow conversion of TBSBMI to TBSTH "equivalents". Because of these systematic differences in these two algorithms, using an individual's TBSBMI to calculate a Z-score using the BMDCS TBSTH reference values results in a falsely higher TBS Z-score (differences mean=0.73, IQR=0.3 to 1.6). Until TBSTH software for Hologic DXA equipment becomes commercially available, BMDCS TBS reference norms should not be used. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.4786

  View details for PubMedID 36779634

• Challenging obesity and sex based differences in resting energy expenditure using allometric modeling, a sub-study of the DIETFITS clinical trial. Clinical nutrition ESPEN Haddad, F., Li, X., Perelman, D., Santana, E. J., Kuznetsova, T., Cauwenberghs, N., Busque, V., Contrepois, K., Snyder, M. P., Leonard, M. B., Gardner, C. 2023; 53: 43-52

  Abstract

  BACKGROUND & AIMS: Resting energy expenditure (REE) is a major component of energy balance. While REE is usually indexed to total body weight (BW), this may introduce biases when assessing REE in obesity or during weight loss intervention. The main objective of the study was to quantify the bias introduced by ratiometric scaling of REE using BW both at baseline and following weight loss intervention.DESIGN: Participants in the DIETFITS Study (Diet Intervention Examining The Factors Interacting with Treatment Success) who completed indirect calorimetry and dual-energy X-ray absorptiometry (DXA) were included in the study. Data were available in 438 participants at baseline, 340at 6 months and 323at 12 months. We used multiplicative allometric modeling based on lean body mass (LBM) and fat mass (FM) to derive body size independent scaling of REE. Longitudinal changes in indexed REE were then assessed following weight loss intervention.RESULTS: A multiplicative model including LBM, FM, age, Black race and the double product (DP) of systolic blood pressure and heart rate explained 79% of variance in REE. REE indexed to [LBM0.66*FM0.066] was body size and sex independent (p=0.91 and p=0.73, respectively) in contrast to BW based indexing which showed a significant inverse relationship to BW (r=-0.47 for female and r=-0.44 for male, both p<0.001). When indexed to BW, significant baseline differences in REE were observed between male and female (p<0.001) and between individuals who are overweight and obese (p<0.001) while no significant differences were observed when indexed to REE/[LBM0.66*FM0.066], p>0.05). Percentage predicted REE adjusted for LBM, FM and DP remained stable following weight loss intervention (p=0.614).CONCLUSION: Allometric scaling of REE based on LBM and FM removes body composition-associated biases and should be considered in obesity and weight-based intervention studies.

  View details for DOI 10.1016/j.clnesp.2022.11.015

  View details for PubMedID 36657929

• Transgender Females on Gonadotropin Agonist Have Lower BMD Scores But Muscle Strength Remained Similar to Controls Aye, T., Long, J., Kent, K., Burghardt, A., Leonard, M. WILEY. 2023: 230-231

  View details for Web of Science ID 001008985201229

• Contribution of local density variation to micro-finite element analysis in pediatric HR-pQCT Burghardt, A., Long, J., Aye, T., Kent, K., Strickland, A., Leonard, M. WILEY. 2023: 193-194

  View details for Web of Science ID 001008985201102

• Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis. Kidney international reports Lalayiannis, A. D., Crabtree, N. J., Ferro, C. J., Wheeler, D. C., Duncan, N. D., Smith, C., Popoola, J., Varvara, A., Mitsioni, A., Kaur, A., Sinha, M. D., Biassoni, L., McGuirk, S. P., Mortensen, K. H., Milford, D. V., Long, J., Leonard, M. D., Fewtrell, M., Shroff, R. 2023; 8 (2): 265-273

  Abstract

  Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification.Methods: This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores.Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P= 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P= 0.09). Median cIMTz and PWVz showed nonsignificant increase (P= 0.23 and P= 0.19, respectively). The annualized increase in TrabBMDz (DeltaTrabBMDz) was an independent predictor of cIMTz increase (R 2= 0.48, beta= 0.40, P= 0.03). Young people who demonstrated statural growth (n= 33) had lower DeltaTrabBMDz and also attenuated vascular changes compared with those with static growth (n= 24).Conclusion: This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

  View details for DOI 10.1016/j.ekir.2022.10.023

  View details for PubMedID 36815116

• Improving Quality of Care and Outcomes for Pediatric Patients With End-stage Kidney Disease The Importance of Pediatric Nephrology Expertise JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Leonard, M. B., Grimm, P. C. 2022; 328 (5): 427-429

  View details for Web of Science ID 000840708300007

• Improving Quality of Care and Outcomes for Pediatric Patients With End-stage Kidney Disease: The Importance of Pediatric Nephrology Expertise. JAMA Leonard, M. B., Grimm, P. C. 2022; 328 (5): 427-429

  View details for DOI 10.1001/jama.2022.11603

  View details for PubMedID 35916864

• Vitamin D supplementation in children and young adults with persistent proteinuria secondary to glomerular disease. Pediatric nephrology (Berlin, Germany) Kogon, A. J., Ballester, L. S., Zee, J., Walker, N., Zaritsky, J. J., Atkinson, M. A., Sethna, C. B., Hoofnagle, A. N., Leonard, M. B., Denburg, M. R. 2022

  Abstract

  BACKGROUND: Vitamin D deficiency is common in glomerular disease. Supplementation may be ineffective due to ongoing urinary losses of vitamin D binding protein. We sought to determine if daily cholecalciferol supplementation would increase vitamin D concentrations in children with glomerular disease and persistent proteinuria, without adverse effects.METHODS: Eighteen participants at least 5years of age with primary glomerular disease and urine protein:creatinine ratio≥0.5 were enrolled from four pediatric nephrology practices to receive cholecalciferol supplementation: 4,000IU or 2,000IU per day for serum 25 hydroxyvitamin vitamin D (25OHD) concentrations<20ng/mL and 20ng/mL to<30ng/mL, respectively. Measures of vitamin D and mineral metabolism were obtained at baseline and weeks 6 and 12. Multivariable generalized estimating equation (GEE) regression estimated mean percent changes in serum 25OHD concentration.RESULTS: Median baseline 25OHD was 12.8ng/mL (IQR 9.3, 18.9) and increased to 27.8ng/mL (20.5, 36.0) at week 6 (p<0.001) without further significant increase at week 12. A total of 31% of participants had a level≥30ng/mL at week 12. Supplementation was stopped in two participants at week 6 for mildly elevated calcium and phosphorus, respectively, with subsequent declines in 25OHD of>20ng/mL. In the adjusted GEE model, 25OHD was 102% (95% CI: 64, 141) and 96% (95% CI: 51, 140) higher versus baseline at weeks 6 and 12, respectively (p<0.001).CONCLUSION: Cholecalciferol supplementation in vitamin D deficient children with glomerular disease and persistent proteinuria safely increases 25OHD concentration. Ideal dosing to fully replete 25OHD concentrations in this population remains unknown.CLINICAL TRIAL: NCT01835639. A higher resolution version of the Graphical abstract is available as Supplementary information.

  View details for DOI 10.1007/s00467-022-05660-9

  View details for PubMedID 35852656

• Bone accrual and structural changes over one year in youth with cystic fibrosis. Journal of clinical & translational endocrinology Bass, R. M., Zemel, B. S., Stallings, V. A., Leonard, M. B., Tsao, J., Kelly, A. 2022; 28: 100297

  Abstract

  Background: Pediatric bone accrual governs peak bone mass and strength. Longitudinal studies of bone health in youth with cystic fibrosis (CF) may provide insight into CF-related bone disease (CFBD), a prevalent co-morbidity in adults with CF.Methods: This one-year longitudinal study of youth with pancreatic insufficient CF, enrolled in a nutrition intervention study [n = 62 (36 M/26F)] 1) examined dual-energy x-ray absorptiometry (DXA)-defined lumbar spine (LS) and total body less head (TBLH) bone accrual and 2) compared their changes in peripheral quantitative computed tomography (pQCT) cortical and trabecular tibial bone density and geometry to those of a healthy reference group [n = 143 (68 M/75F)].Main outcome measures were 1) DXA: lumbar spine areal bone mineral density (LSaBMD) and total body less head bone mineral content (TBLH-BMC), sex- and pubertal status-specific, height velocity (HV)-adjusted or HV and lean body mass velocity (HV-LBMV)-adjusted annualized velocity-Z scores and 2) pQCT: age, sex, pubertal status and, when appropriate, tibial length adjusted Z-scores for bone architecture measures.DXA velocity-Z were compared to expected mean of 0 and correlations with clinical parameters (age, BMI-Z and FEV1%-predicted) tested. Within-subject comparisons of HV-adjusted and LBMV-HV-adjusted DXA velocity-Z were conducted in CF.pQCT Z-scores were compared between the two groups over one year using longitudinal models. Longitudinal relationships between measures of bone health and clinical parameters (age, BMI-Z and FEV1%-predicted) were examined in individuals with CF.Results: DXA velocity-Z were higher than normal in females (p < 0.05) but not males with CF. HV-adjusted and LBMV-HV-adjusted velocity-Z did not differ for LSaBMD or TBLH-BMC.In males with CF, both HV-adjusted and LBMV-HV-adjusted LSaBMD velocity-Z scores correlated negatively with age (HV rho: -0.35; p = 0.045 and LBMV-HV rho: -0.47; p = 0.0046). In males with CF BMI-Z correlated positively with HV-adjusted LSaBMD velocity-Z (rho: 0.37; p = 0.034), but this relationship did not persist for LBMV-HV (rho: 0.14; p = 0.42). In females with CF, no correlations between LSaBMD velocity-Z scores and age or BMI-Z were found (all p > 0.05). No correlations between LSaBMD velocity-Z scores and FEV1%-predicted were seen in either sex (all p > 0.12). TBLH-BMC velocity Z-scores were not correlated with clinical parameters in either sex (all p > 0.1).At baseline, multiple pQCT parameters were lower in CF (p < 0.05). pQCT Z-scores did not differ between baseline and one-year in either CF or reference group. In a longitudinal model comparing pQCT-Z changes in CF and reference, multiple pQCT-Z outcomes remained lower in CF, but the changes in parameters did not differ in CF vs reference (all p > 0.26). Lower pQCT outcomes in CF were largely restricted to males (CF group*female sex interaction beta coefficients > 0). In this combined longitudinal model, of both CF and reference, BMI-Z was positively associated with pQCT-Z parameters(p < 0.001).Multiple pQCT-Z outcomes positively correlated with both BMI-Z and FEV1%-predicted in males with CF, and with FEV1%-predicted in females with CF (p < 0.05). Age was negatively associated with section modulus (p = 0.001) in males and with cortical density-Z in females (p < 0.001).Conclusions: With improved longevity, bone health in CF is of increasing importance. On average, bone accrual was preserved in youth with CF, and while deficits in bone geometry and strength were found, these deficits did not worsen over the one-year study. Lower LS bone accrual with increasing age suggests emerging adulthood is a period of vulnerability in CF while the role of LBM in bone health is underscored by the lack of relationship between LBMV-adjusted accrual and BMI. These findings may be useful in targeting screening practices and interventions.

  View details for DOI 10.1016/j.jcte.2022.100297

  View details for PubMedID 35433270

• Achieving equity through science and integrity: dismantling race-based medicine. Pediatric research Wright, J. L., Freed, G. L., Hendricks-Munoz, K. D., Jarvis, J. N., Maldonado, Y. A., Raphael, J. L., Schnadower, D., Sims, B., Bogue, C. W., Leonard, M. B., Coyne-Beasley, T. D., Committee on Diversity, I. a., Wright, J. L., Freed, G. L., Hendricks-Munoz, K. D., Jarvis, J. N., Maldonado, Y. A., Raphael, J. L., Schnadower, D., Sims, B., Bogue, C. W., Leonard, M. B., Coyne-Beasley, T. D. 2022

  View details for DOI 10.1038/s41390-022-02041-8

  View details for PubMedID 35383261

• Comparison of Cortical Bone Outcomes in the Metaphysis and Diaphysis During Growth and Development Kent, K., Strickland, A., Whalen, J., Burghardt, A., Leonard, M., Long, J. WILEY. 2022: 243-244

  View details for Web of Science ID 000778074501163

• Comparison of Cortical Bone Outcomes in the Metaphysis and Diaphysis During Growth and Development Kent, K., Strickland, A., Whalen, J., Burghardt, A., Leonard, M., Long, J. WILEY. 2022: 12

  View details for Web of Science ID 000778074500030

• Guidelines for HR-pQCT Motion Scoring in the Cortical Diaphysis Strickland, A., Long, J., Kent, K., Whalen, J., Leonard, M. B., Burghardt, A. WILEY. 2022: 133

  View details for Web of Science ID 000778074500399

• Persistent Musculoskeletal Deficits in Pediatric, Adolescent and Young Adult Survivors of Allogeneic Hematopoietic Stem-Cell Transplantation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Kindler, J. M., Guo, M., Baker, J., McCormack, S., Armenian, S. H., Zemel, B. S., Leonard, M. B., Mostoufi-Moab, S. 1800

  Abstract

  Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common therapy for pediatric hematologic malignancies. With improved supportive care, addressing treatment-related late effects is at the forefront of survivor long-term health and quality of life. We previously demonstrated that alloHSCT survivors had increased adiposity, decreased lean mass, and lower bone density and strength, 7years (median) from alloHSCT compared to their healthy peers. Yet it is unknown whether these deficits persist. Our longitudinal study characterized changes in muscle and bone over a period of 3.4 (range 2.0 to 4.9) years in 47 childhood alloHSCT survivors, age 5-26years at baseline (34% female). Tibia cortical bone geometry and volumetric density and lower leg muscle cross-sectional area (MCSA) were assessed via peripheral quantitative computed tomography (pQCT). Anthropometric and pQCT measurements were converted to age, sex, and ancestry-specific standard deviation scores, adjusted for leg length. Muscle-specific force was assessed as strength relative to MCSA adjusted for leg length (strength Z-score). Measurements were compared to a healthy reference cohort (n=921), ages 5 to 30years (52% female). At baseline and follow up, alloHSCT survivors demonstrated lower height-, weight-, and leg length Z-scores compared to the healthy reference cohort. Deficits in MCSA, trabecular volumetric bone density, and cortical bone size and estimated strength (section modulus) were evident in survivors (all p<0.05). Between the two study time points, anthropometric, muscle, and bone Z-scores did not change significantly in alloHSCT survivors. Approximately 15% and 17% of alloHSCT survivors had MCSA and section modulus Z-score less than -2.0, respectively, at baseline and follow up. Furthermore, those with a history of total body irradiation compared to those without demonstrated lower MCSA at follow up. The persistent muscle and bone deficits in pediatric alloHSCT survivors support the need for strategies to improve bone and muscle health in this at-risk population. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.4513

  View details for PubMedID 35080067

• The importance of trustworthiness: lessons from the COVID-19 pandemic. Pediatric research Leonard, M. B., Pursley, D. M., Robinson, L. A., Abman, S. H., Davis, J. M. 2021

  View details for DOI 10.1038/s41390-021-01866-z

  View details for PubMedID 34853429

• Deficits in the Functional Muscle-Bone Unit in Youth With Fontan Physiology. The Journal of pediatrics Vaikunth, S. S., Leonard, M. B., Whitehead, K. K., Goldberg, D. J., Rychik, J., Zemel, B. S., Avitabile, C. M. 2021

  Abstract

  OBJECTIVE: To determine whether dual energy X-ray absorptiometry (DXA), a clinically available tool, mirrors the magnitude of deficits in trabecular and cortical bone mineral density (BMD) demonstrated on peripheral quantitative computed tomography in youth with Fontan physiology. We aimed to describe DXA-derived BMD at multiple sites and investigate the relationship between BMD and leg lean mass, a surrogate for skeletal muscle loading.STUDY DESIGN: Fontan participants (n= 46; 5-20y) underwent DXA in a cross-sectional study of growth, bone and muscle health as previously described. Data from the Bone Mineral Density in Childhood Study were used to calculate age-, sex-, and race-specific BMD Z-scores of the whole body, lumbar spine, hip, femoral neck, distal 1/3 radius, ultradistal radius and leg lean mass Z-scores (LLMZ).RESULTS: Fontan BMD Z-scores were significantly lower than reference at all sites: whole body: -0.34±0.85, p=0.01, spine: -0.41±0.96, p=0.008, hip: -0.75±1.1, p<0.001, femoral neck: -0.73±1.0, P < .001, distal 1/3 radius: -0.87±1.1, p<0.001, ultradistal radius: -0.92±1.03, p<0.001, as was LLMZ: -0.93 ± 1.1, p<0.001. Lower LLMZ was associated with lower BMD of the whole body (R2 = 0.40, p<0.001), lumbar spine (R2 = 0.16, p=0.005), total hip (R2 = 0.32, p<0.001), femoral neck (R2 = 0.47, p<0.001), and ultradistal radius (R2 = 0.35, p <0.001).CONCLUSIONS: Fontan patients have marked deficits in both cortical (hip, distal 1/3 radius) and trabecular (lumbar spine, femoral neck, ultradistal radius) BMD. Lower LLMZ is associated with lower BMD and may reflect inadequate skeletal muscle loading. Interventions to increase muscle mass may improve bone accrual.

  View details for DOI 10.1016/j.jpeds.2021.06.068

  View details for PubMedID 34214589

• Sarcopenia and preserved bone mineral density in paediatric survivors of high-risk neuroblastoma with growth failure. Journal of cachexia, sarcopenia and muscle Guo, M., Zemel, B. S., Hawkes, C. P., Long, J., Kelly, A., Leonard, M. B., Jaramillo, D., Mostoufi-Moab, S. 2021

  Abstract

  BACKGROUND: Survival from paediatric high-risk neuroblastoma (HR-NBL) has increased, but cis-retinoic acid (cis-RA), the cornerstone of HR-NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR-NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR-NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR-NBL survivors compared with controls.METHODS: This prospective cross-sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual-energy X-ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex-specific standard deviation scores (Z-scores) included aBMD (adjusted for height Z-score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole-body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength-Z). Muscle-specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR-NBL survivors and controls using Student's t-test or Mann-Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes.RESULTS: We enrolled 20 survivors of HR-NBL treated with cis-RA [13 male; mean age: 12.4±1.6years; median (range) age at therapy initiation: 2.6 (0.3-9.1) years] and 20 age-, sex- and race-matched controls. Height-Z was significantly lower in HR-NBL survivors compared with controls (-1.73±1.38 vs. 0.34±1.12, P<0.001). Areal BMD-Z, BMAD-Z, FMI-Z, visceral adipose tissue and subcutaneous adipose tissue were not significantly different in HR-NBL survivors compared with controls. Compared with controls, HR-NBL survivors had lower leg lean mass-Z (-1.46±1.35 vs. -0.17±0.84, P<0.001) and strength-Z (-1.13±0.86 vs. -0.15±0.71, P<0.001). Muscle-specific force was lower in HR-NBL survivors compared with controls (P<0.05).CONCLUSIONS: Bone mineral density and adiposity are not severely impacted in HR-NBL survivors with growth failure, but significant sarcopenia persists years after treatment. Future studies are needed to determine if sarcopenia improves with muscle-specific interventions in this population of cancer survivors.

  View details for DOI 10.1002/jcsm.12734

  View details for PubMedID 34184837

• Establishing a Data Science Unit in an Academic Medical Center: An Illustrative Model. Academic medicine : journal of the Association of American Medical Colleges Desai, M., Boulos, M., Pomann, G. M., Steinberg, G. K., Longo, F. M., Leonard, M., Montine, T., Blomkalns, A. L., Harrington, R. A. 2021

  Abstract

  The field of data science has great potential to address critical questions relevant for academic medical centers. Data science initiatives are consequently being established within academic medicine. At the cornerstone of such initiatives are scientists who practice data science. These scientists include biostatisticians, clinical informaticians, database and software developers, computational scientists, and computational biologists. Too often, however, those involved in the practice of data science are viewed by academic leadership as providing a noncomplex service to facilitate research and further the careers of other academic faculty. The authors contend that the success of data science initiatives relies heavily on the understanding that the practice of data science is a critical intellectual contribution to the overall science conducted at an academic medical center. Further, careful thought by academic leadership is needed for allocation of resources devoted to the practice of data science. At the Stanford University School of Medicine, the authors have developed an innovative model for a data science collaboratory based on 4 fundamental elements: an emphasis on collaboration over consultation; a subscription-based funding mechanism that reflects commitment by key partners; an investment in the career development of faculty who practice data science; and a strong educational component for data science members in team science and for clinical and translational investigators in data science. As data science becomes increasingly essential to learning health systems, centers that specialize in the practice of data science are a critical component of the research infrastructure and intellectual environment of academic medical centers.

  View details for DOI 10.1097/ACM.0000000000004079

  View details for PubMedID 33769342

• Assessment of the Association of Leadership Behaviors of Supervising Physicians With Personal-Organizational Values Alignment Among Staff Physicians. JAMA network open Shanafelt, T. D., Wang, H., Leonard, M., Hawn, M., McKenna, Q., Majzun, R., Minor, L., Trockel, M. 2021; 4 (2): e2035622

  Abstract

  Importance: Although misalignment of values between physicians and their organization is associated with increased risk of burnout, actionable organizational factors that contribute to perceived values alignment are poorly understood.Objective: To evaluate the association between the leadership behaviors of immediate supervisors and physicians' perception of personal-organizational values alignment.Design, Setting, and Participants: This survey study of faculty physicians and physician leaders at Stanford University School of Medicine was conducted from April 1 to May 13, 2019. The survey included assessments of perceived personal-organizational values alignment, professional fulfillment, and burnout. Physicians also evaluated the leadership behaviors of their immediate supervisor (eg, division chief) using a standardized assessment. Data analysis was performed from May to December 2020.Main Outcomes and Measures: Association between mean leadership behavior score (range, 0-10) of each supervisor and the mean personal-organizational values alignment scores (range, 0-12) for the physicians in their work unit.Results: Of 1924 physicians eligible to participate, 1285 (67%) returned surveys. Among these, 651 (51%) were women and 729 (57%) were aged 40 years or older. Among the 117 physician leaders evaluated, 66 (56%) had their leadership behavior independently evaluated by at least 5 physicians and were included in analyses. The mean (SD) personal-organizational values alignment score on the 0 to 12 scale was 6.19 (3.21). As the proportion of work effort devoted to clinical care increased, values alignment scores decreased. Personal-organizational values alignment scores demonstrated an inverse correlation with burnout (r=-0.39; P<.001) and a positive correlation with professional fulfillment (r=0.52; P<.001). The aggregate leader behavior score of the 66 leaders evaluated correlated with the mean values alignment score for physicians in their work unit (r=0.53; P<.001). Aggregate leader behavior score was associated with 21.6% of the variation in personal-organizational values alignment scores between work units. After adjusting for age, gender, academic rank, work hours, physician-leader gender concordance, and time devoted to clinical care, each 1-point increase in leadership score of immediate supervisor was associated with a 0.56-point (95% CI, 0.46-0.66; P<.001) increase in personal-organizational values alignment score.Conclusions and Relevance: This survey study's results suggest that physicians experience their organization through the prism of their work unit leader. Organizational efforts to improve values alignment should attend to the development of first-line physician leaders.

  View details for DOI 10.1001/jamanetworkopen.2020.35622

  View details for PubMedID 33560424

• Sarcopenic Obesity in Rheumatoid Arthritis: Prevalence and Impact on Physical Functioning. Rheumatology (Oxford, England) Baker, J. F., Giles, J. T., Weber, D., George, M. D., Leonard, M. B., Zemel, B. S., Long, J., Katz, P. 2021

  Abstract

  We determined the prevalence of sarcopenic obesity in patients with rheumatoid arthritis (RA) using multiple methods and assessed associations with physical functioning.This study evaluated data from three RA cohorts. Whole-body dual-energy absorptiometry (DXA) measures of appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI) were converted to age, sex, and race-specific Z-Scores and categorized using a recently validated method and compared it to a widely-used existing method. The prevalence of body composition abnormalities in RA was compared with two reference populations. In the RA cohorts, associations between body composition and change in the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB) in follow-up were assessed using linear and logistic regression, adjusting for age, sex, race, and study.The prevalence of low lean mass and sarcopenic obesity were higher in patients with RA (14.2; 12.6%, respectively) compared with the reference population cohorts (7-10%; 4-4.5%, respectively, all p< 0.05). There was only moderate agreement among methods of sarcopenic obesity categorization (Kappa 0.45). The recently validated method categorized fewer subjects as obese, and many of these were categorized as low lean mass only. Low lean mass, obesity, and sarcopenic obesity were each associated with higher HAQ and lower SPPB at baseline and numerically greater worsening.RA patients had higher rates of low lean mass and sarcopenic obesity than the general population. The recently validated methods characterized body composition changes differently from traditional methods and were more strongly associated with physical function.

  View details for DOI 10.1093/rheumatology/keab710

  View details for PubMedID 34559201

• Risk of Potentially Inappropriate Medications in Adults With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study. American journal of kidney diseases : the official journal of the National Kidney Foundation Hall, R. K., Blumenthal, J. B., Doerfler, R. M., Chen, J., Diamantidis, C. J., Jaar, B. G., Kusek, J. W., Kallem, K., Leonard, M. B., Navaneethan, S. D., Sha, D., Sondheimer, J. H., Wagner, L. A., Yang, W., Zhan, M., Fink, J. C. 2021

  Abstract

  Adults with chronic kidney disease (CKD) may be at increased risk of adverse effects from use of potentially inappropriate medications (PIMs). Our objective was to assess whether PIM exposure has an independent association with CKD progression, hospitalizations, mortality, or falls.Retrospective observational study.Chronic Renal Insufficiency Cohort (CRIC) study; 3929 adults with CKD enrolled 2003-2008; followed prospectively until December 2011.PIM exposure was defined as prescriptions for any medications to be avoided in older adults as defined by the 2015 American Geriatrics Society Beers Criteria.Hospitalization count, death, a composite kidney disease endpoint of CKD progression or initiation of kidney replacement therapy (KRT), KRT, and fall events assessed one year after PIM exposure.Logistic regression and Poisson regression to estimate the associations of PIM exposure with each outcome.The most commonly prescribed PIMs were proton pump inhibitors and alpha blockers. In unadjusted models any PIM exposure (compared to none) was associated with hospitalizations, death, and fall events. After adjustment, exposure to 1, 2, or >3 PIMs had a graded association with a higher hospitalization rate: RR 1.09, 95% CI:1.01-1.17, RR 1.18, 95% CI:1.07-1.30, and RR 1.35, 95% CI:1.19-1.53, respectively, and higher odds of mortality: OR 1.19, 95% CI: 0.91-1.54, OR 1.62, 95% CI:1.21-2.17 and OR 1.65, 95% CI:1.14-2.41, respectively. In a cohort subset reporting falls (n=1109), prescriptions for ≥3 PIMs was associated with and increased risk of falls (adjusted OR 2.85, 95% CI:1.54-5.26). PIMs were not associated with CKD progression or KRT. Age did not modify the association between PIM count and outcomes.Measurement bias; confounding by indication.Adults of any age with CKD who are prescribed PIMs have an increased risk of hospitalization, mortality, and falls with the greatest risk occurring after more than one PIM prescription.

  View details for DOI 10.1053/j.ajkd.2021.03.019

  View details for PubMedID 34029681

• Changes in Body Composition, Muscle Strength, and Fat Distribution Following Kidney Transplantation. American journal of kidney diseases : the official journal of the National Kidney Foundation Dienemann, T., Ziolkowski, S. L., Bender, S., Goral, S., Long, J., Baker, J. F., Shults, J., Zemel, B. S., Reese, P. P., Wilson, F. P., Leonard, M. B. 2021

  Abstract

  Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined following transplantation. We studied how measures of body composition change after receipt of a kidney allograft.Prospective longitudinal cohort study.60 kidney transplant recipients (ages 20-60 years) at the University of Pennsylvania.Kidney transplantation.DXA measures of fat mass index (FMI) and appendicular lean mass index (ALMI; representing muscle mass), CT measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALMFMI) is an established index of relative sarcopenia.Measures expressed as age, sex, and race-specific Z-scores for transplant recipients were compared to 327 healthy controls. Regression models were used to identify correlates of change in outcome Z-scores and compare transplant recipients to controls.At transplantation, ALMI, ALMIFMI, muscle strength and muscle density Z-scores were lower vs. controls (all p≤0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18 to 45%. Although ALMI increased following transplantation (p<0.001) and was comparable to controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMIFMI deficits (mean Z-score -0.31 at 24 months, p=0.02 vs controls). Muscle density improved following transplantation despite gains in FMI (p = 0.02). Muscle strength relative to ALMI also improved (p = 0.04) but remained low compared with controls (p=0.01). Exercise increased in the early months following transplantation (p<0.05) but remained lower than controls (p=0.02).Lack of muscle biopsies precluded assessment of muscle histology and metabolism.The two-year interval following kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass resulting in persistent relative sarcopenia.

  View details for DOI 10.1053/j.ajkd.2020.11.032

  View details for PubMedID 34352286

• Effect of Low Intensity Vibration on Bone Strength, Microstructure, and Adiposity in Pre-Osteoporotic Postmenopausal Women: A Randomized Placebo-Controlled Trial. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Rajapakse, C. S., Johncola, A. J., Batzdorf, A. S., Jones, B. C., Al Mukaddam, M., Sexton, K., Shults, J., Leonard, M. B., Snyder, P. J., Wehrli, F. W. 2020

  Abstract

  There has been evidence that cyclical mechanical stimulation may be osteogenic, thus providing opportunities for non-pharmacological treatment of degenerative bone disease. Here, we applied this technology to a cohort of postmenopausal women with varying bone mineral density (BMD) T-scores at the total hip (-0.524±0.843) and spine (-0.795±1.03) to examine the response to intervention after one year of daily treatment with ten minutes of vibration therapy in a randomized double-blinded trial. The device operates either in an active mode (30Hz and 0.3g) or placebo. Primary endpoints were changes in bone stiffness at the distal tibia and marrow adiposity of the vertebrae, based on 3 Tesla high-resolution MRI and spectroscopic imaging, respectively. Secondary outcome variables included distal tibial trabecular microstructural parameters and vertebral deformity determined by MRI, volumetric and areal bone densities derived using peripheral quantitative computed tomography (pQCT) of the tibia, and dual-energy X-ray absorptiometry (DXA)-based BMD of the hip and spine. Device adherence was 83% in the active group (n=42) and 86% in the placebo group (n=38), and did not differ between groups (p=0.7). The mean 12-month changes in tibial stiffness in the treatment group and placebo group were+1.31±6.05 and-2.55±3.90%, respectively (group difference 3.86%, p=0.0096). In the active group, marrow fat fraction significantly decreased after 12months of intervention (p=0.0003), while no significant change was observed in the placebo group (p=0.7; group difference-1.59%, p=0.029). Mean differences of the changes in trabecular bone volume fraction (p=0.048) and erosion index (p=0.044) were also significant, as was pQCT-derived trabecular volumetric BMD (vBMD; p=0.016) at the tibia. The data are commensurate with the hypothesis that vibration therapy is protective against loss in mechanical strength, and further, that the intervention minimizes the shift from the osteoblastic to the adipocytic lineage of mesenchymal stem cells. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.4229

  View details for PubMedID 33314313

• Type 1 Diabetes is Associated with Bone and Muscle Deficiencies in Children and Adolescents Long, J., Seeley, H., Whalen, J., Strickland, A., Kent, K., Aye, T., Bachrach, L., Leonard, M. WILEY. 2020: 76

  View details for Web of Science ID 000593119300207

• Classification of Motion Artifact Severity in High-Resolution Peripheral Quantitative Computed Tomography Using Deep Convolutional Neural Network Long, J., Whalen, J., Yang, D., Strickland, A., Kent, K., Seyyedi, S., Leonard, M., Burghardt, A. WILEY. 2020: 208

  View details for Web of Science ID 000593119300631

• Optimization of a High-Resolution Peripheral Quantitative Computed Tomography(HR-pQCT) Protocol in the Distal Tibia and Radius in Children and Adolescents Kent, K., Long, J., Leonard, M., Strickland, A., Whalen, J., Zemel, B., Brown, K., Burghardt, A. WILEY. 2020: 75

  View details for Web of Science ID 000593119300204

• Associations of Sex, Sexual maturation, IGF1 and Muscle Mass with Bone Failure Load in the Tibia and Radius Metaphysis and Diaphysis dining Development Aye, T., Long, J., Kent, K., Whalen, J., Strickland, A., Burghardt, A., Leonard, M. WILEY. 2020: 76

  View details for Web of Science ID 000593119300206

• Serum Calcification Propensity in Children on Chronic Hemodialysis KIDNEY INTERNATIONAL REPORTS Kakajiwala, A., Pasch, A., Rogers, R., Hoofnagle, A., Meloni, S., Furth, S. L., Leonard, M. B., Copelovitch, L., Denburg, M. R. 2020; 5 (9): 1528–31

  View details for DOI 10.1016/j.ekir.2020.06.022

  View details for Web of Science ID 000568662700019

  View details for PubMedID 32954079

  View details for PubMedCentralID PMC7486188

• Bone Geometry and Microarchitecture Deficits in Children with Alagille Syndrome. Bone Kindler, J. M., Mitchell, E. L., Piccoli, D. A., Grimberg, A., Leonard, M. B., Loomes, K. M., Zemel, B. S. 2020: 115576

  Abstract

  Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n=247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p<0.05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p<0.05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p<0.05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [rho]=-0.82, p=0.023) and greater trabecular separation (rho=0.82, p=0.023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (rho=-0.78, p=0.041) and lower serum insulin-like growth factor-1 (rho=-0.86, p=0.002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.

  View details for DOI 10.1016/j.bone.2020.115576

  View details for PubMedID 32791330

• Racism and social injustice as determinants of child health: the American Pediatric Society Issue of the Year. Pediatric research Abman, S. H., Bogue, C. W., Baker, S. n., Carlo, W. n., Daniels, S. R., Debaun, M. R., Fike, C. n., Gordon, C. M., Leonard, M. B., Steinhorn, R. H., Walker-Harding, L. R. 2020

  View details for DOI 10.1038/s41390-020-01126-6

  View details for PubMedID 32987397

• Association of Burnout, Professional Fulfillment, and Self-care Practices of Physician Leaders With Their Independently Rated Leadership Effectiveness. JAMA network open Shanafelt, T. D., Makowski, M. S., Wang, H. n., Bohman, B. n., Leonard, M. n., Harrington, R. A., Minor, L. n., Trockel, M. n. 2020; 3 (6): e207961

  Abstract

  Although leadership behavior of physician supervisors is associated with the occupational well-being of the physicians they supervise, the factors associated with leadership behaviors are poorly understood.To evaluate the associations between burnout, professional fulfillment, and self-care practices of physician leaders and their independently assessed leadership behavior scores.This survey study of physicians and physician leaders at Stanford University School of Medicine (n = 1924) was conducted from April 1 to May 13, 2019. The survey included assessments of professional fulfillment, self-valuation, sleep-related impairment, and burnout. Physicians also rated the leadership behaviors of their immediate physician supervisors using a standardized assessment. Leaders' personal well-being metrics were paired with their leadership behavior scores as rated by the physicians they supervised. All assessment scores were converted to a standardized scale (range, 0-10). Data were analyzed from October 20, 2019, to March 10, 2020.Association between leaders' own well-being scores and their independently assessed leadership behavior.Of 1924 physicians invited to participate, 1285 (66.8%) returned surveys, including 67 of 117 physician leaders (57.3%). Among these respondents, 651 (50.7%) were women and 729 (56.7%) were 40 years or older. Among the 67 leaders, 57 (85.1%) had their leadership behaviors evaluated by at least 5 physicians (median, 11 [interquartile range, 9-15]) they supervised. Overall, 9.8% of the variation in leaders' aggregate leadership behavior scores was associated with their own degree of burnout. In models adjusted for age and sex, each 1-point increase in burnout score of the leaders was associated with a 0.19-point decrement in leadership behavior score (β = -0.19; 95% CI, -0.35 to -0.03; P = .02), whereas each 1-point increase in their professional fulfillment and self-valuation scores was associated with a 0.13-point (β = 0.13; 95% CI, 0.01-0.26; P = .03) and 0.15-point (β = 0.15; 95% CI, 0.02-0.29; P = .03) increase in leadership behavior score, respectively. Each 1-point increase in leaders' sleep-related impairment was associated with a 0.15-point increment in sleep-related impairment among those they supervised (β = 0.15; 95% CI, 0.02-0.29; P = .03). The associations between leaders' well-being scores in other dimensions and the corresponding well-being measures of those they supervised were not significant.In this survey study, burnout, professional fulfillment, and self-care practices of physician leaders were associated with their independently assessed leadership effectiveness. Training, skill building, and support to improve leader well-being should be considered a dimension of leadership development rather than simply a dimension of self-care.

  View details for DOI 10.1001/jamanetworkopen.2020.7961

  View details for PubMedID 32543700

• Validation of a description of sarcopenic obesity defined as excess adiposity and low lean mass relative to adiposity. Journal of cachexia, sarcopenia and muscle Baker, J. F., Harris, T. n., Rapoport, A. n., Ziolkowski, S. L., Leonard, M. B., Long, J. n., Zemel, B. n., Weber, D. R. 2020

  Abstract

  This study aims to assess the construct validity of a body composition-defined definition of sarcopenic obesity based on low appendicular lean mass relative to fat mass (ALMIFMI ) and high fat mass index (FMI) and to compare with an alternative definition using appendicular lean mass index (ALMI) and percent body fat (%BF).This is a secondary analysis of two cohort studies: the National Health and Examination Survey (NHANES) and the Health, Aging, and Body Composition study (Health ABC). Sarcopenic obesity was defined as low ALMIFMI combined with high FMI and was compared with a widely used definition based on ALMI and %BF cut-points. Body composition Z-scores, self-reported disability, physical functioning, and incident disability were compared across body composition categories using linear and logistic regression and Cox proportional hazards models.Among 14, 850 participants from NHANES, patients with sarcopenic obesity defined by low ALMIFMI and high FMI (ALMIFMI -FMI) had above-average FMI Z-scores [mean (standard deviation): 1.00 (0.72)]. In contrast, those with sarcopenic obesity based on low ALMI and high %BF (ALMI-%BF) had below-average FMI Z-scores. A similar pattern was observed for 2846 participants from Health ABC. Participants with sarcopenic obesity based on ALMIFMI -FMI had a greater number of disabilities, worse physical function, and a greater risk of incident disability compared with those defined based on ALMI-%BF.Body composition-defined measures of sarcopenic obesity defined as excess adiposity and lower-than-expected ALMI relative to FMI are associated with functional deficits and incident disability and overcome the limitations of using %BF in estimating obesity in this context.

  View details for DOI 10.1002/jcsm.12613

  View details for PubMedID 32931633

• Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Lalayiannis, A. D., Crabtree, N. J., Ferro, C. J., Askiti, V. n., Mitsioni, A. n., Biassoni, L. n., Kaur, A. n., Sinha, M. D., Wheeler, D. C., Duncan, N. D., Popoola, J. n., Milford, D. V., Long, J. n., Leonard, M. B., Fewtrell, M. n., Shroff, R. n. 2020

  Abstract

  Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk.This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis.Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = -0.44, P < 0.0001) and alkaline phosphatase (ALP; r = -0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below -2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (β = -0.43 , P < 0.0001), ALP (β = -0.36, P < 0.0001) and Ca (β = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model.Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4-5D.

  View details for DOI 10.1093/ndt/gfaa199

  View details for PubMedID 33094322

• Serial Fibroblast Growth Factor 23 Measurements and Risk of Requirement for Kidney Replacement Therapy: The CRIC (Chronic Renal Insufficiency Cohort) Study. American journal of kidney diseases : the official journal of the National Kidney Foundation Mehta, R., Cai, X., Lee, J., Xie, D., Wang, X., Scialla, J., Anderson, A. H., Taliercio, J., Dobre, M., Chen, J., Fischer, M., Leonard, M., Lash, J., Hsu, C., de Boer, I. H., Feldman, H. I., Wolf, M., Isakova, T., CRIC Study Investigators, Appel, L. J., Go, A. S., He, J., Rao, P. S., Rahman, M., Townsend, R. R. 2019

  Abstract

  RATIONALE & OBJECTIVE: Studies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levelsare associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changesin FGF-23 levels as kidney disease progresses.STUDY DESIGN: Case-cohort study.SETTING & PARTICIPANTS: To evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort.EXPOSURE: Serial FGF-23 measurements and FGF-23 trajectory group membership.OUTCOMES: Incident KRT.ANALYTICAL APPROACH: To handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure.RESULTS: In our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log-transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with 3- and 21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group.LIMITATIONS: Residual confounding and lack of intact FGF-23 values.CONCLUSIONS: Increasing FGF-23 levels are independently associated with increased risk for incident KRT.

  View details for DOI 10.1053/j.ajkd.2019.09.009

  View details for PubMedID 31864822

• Vitamin D Metabolic Ratio and Risks of Death and CKD Progression. Kidney international reports Bansal, N., Katz, R., Appel, L., Denburg, M., Feldman, H., Go, A. S., He, J., Hoofnagle, A., Isakova, T., Kestenbaum, B., Kusek, J., Lash, J., Leonard, M., Rahman, M., Robinson-Cohen, C., Wolf, M., Xie, D., Zelnick, L., de Boer, I. H. 2019; 4 (11): 1598-1607

  Abstract

  Assessment of impaired vitamin D metabolism is limited by lack of functional measures. CYP24A1-mediated vitamin D clearance, calculated as the ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (the vitamin D metabolic ratio, VDMR), is induced by 1,25-dihydroxyvitamin D and may assess tissue-level activity. We tested associations of the VDMR with risks of death and progression to end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD).We studied participants from the Chronic Renal Insufficiency Cohort (CRIC), which included a random subset of 1080 CRIC participants plus additional participants who experienced ESRD or died (case cohort study design). Serum 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 was measured 1 year after enrollment. The primary outcomes included death and progression to ESRD. Using inverse probability weighting, we tested associations of VDMR (24,25[OH]2D3/25[OH]D3) with risks of death and ESRD, adjusting for demographics, comorbidity, and kidney function (estimated glomerular filtration rate [eGFR] and urine protein-to-creatinine ratio [PCR]).There were a total of 708 ESRD events and 650 deaths events over mean (SD) follow-up periods of 4.9 (2.9) years and 6.5 (2.5) years, respectively. Lower VDMR was associated with increased risk of ESRD prior to adjusting for kidney function (hazard ratio [HR], 1.80 per 20 pg/ng lower VDMR; 95% confidence interval [CI], 1.56-2.08), but not with adjustment for kidney function (HR, 0.94 per 20 pg/ng; 95% CI, 0.81-1.10). Lower VDMR was associated with modestly increased mortality risk, including adjustment for kidney function (HR, 1.18 per 20 pg/ng; 95% CI, 1.02-1.36).Lower VDMR, a measure of CYP24A1-mediated vitamin D clearance, was significantly associated with all-cause mortality but not with progression to ESRD in patients with CKD.

  View details for DOI 10.1016/j.ekir.2019.08.014

  View details for PubMedID 31891001

  View details for PubMedCentralID PMC6933450

• Chronic Kidney Disease and the Adiposity Paradox: Valid or Confounded? JOURNAL OF RENAL NUTRITION Ziolkowski, S. L., Long, J., Baker, J. F., Chertow, G. M., Leonard, M. B. 2019; 29 (6): 521–28

  View details for DOI 10.1053/j.jrn.2018.11.011

  View details for Web of Science ID 000493897600010

• Vitamin D Metabolic Ratio and Risks of Death and CKD Progression KIDNEY INTERNATIONAL REPORTS Bansal, N., Katz, R., Appel, L., Denburg, M., Feldman, H., Go, A. S., He, J., Hoofnagle, A., Isakova, T., Kestenbaum, B., Kusek, J., Lash, J., Leonard, M., Rahman, M., Robinson-Cohen, C., Wolf, M., Xie, D., Zelnick, L., de Boer, I. H., CRIC Study Investigators 2019; 4 (11): 1598–1607

  View details for DOI 10.1016/j.ekir.2019.08.014

  View details for Web of Science ID 000494963400010

• Serum Calcification Propensity and Clinical Events in CKD. Clinical journal of the American Society of Nephrology : CJASN Bundy, J. D., Cai, X., Mehta, R. C., Scialla, J. J., de Boer, I. H., Hsu, C., Go, A. S., Dobre, M. A., Chen, J., Rao, P. S., Leonard, M. B., Lash, J. P., Block, G. A., Townsend, R. R., Feldman, H. I., Smith, E. R., Pasch, A., Isakova, T., CRIC Study Investigators 2019

  Abstract

  BACKGROUND AND OBJECTIVES: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T50 with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality.RESULTS: The mean T50 was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T50 was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T50, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T50, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T50, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T50, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T50 was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality.CONCLUSIONS: Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function.PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.

  View details for DOI 10.2215/CJN.04710419

  View details for PubMedID 31658949

• Associations between exercise, bone mineral density, and body composition in adolescents with anorexia nervosa EATING AND WEIGHT DISORDERS-STUDIES ON ANOREXIA BULIMIA AND OBESITY Nagata, J. M., Carlson, J. L., Golden, N. H., Murray, S. B., Long, J., Leonard, M. B., Peebles, R. 2019; 24 (5): 939–45

  View details for DOI 10.1007/s40519-018-0521-2

  View details for Web of Science ID 000496976600017

• Impact of Adrenal Hormone Supplementation on Bone Geometry in Growing Teens With Anorexia Nervosa. The Journal of adolescent health : official publication of the Society for Adolescent Medicine DiVasta, A. D., Feldman, H. A., O'Donnell, J. M., Long, J., Leonard, M. B., Gordon, C. M. 2019

  Abstract

  PURPOSE: Adolescents with anorexia nervosa (AN) have decreased dehydroepiandrosterone (DHEA) and estrogen concentrations that may contribute to skeletal deficits. We sought to determine whether DHEA+ estrogen replacement (ERT) prevented bone loss in young adolescents with AN.METHODS: We recruited females with AN (n= 70, ages 11-18years) into a 12-month, randomized, double-blind placebo-controlled trial. Participants were randomized to oral micronized DHEA 50mg+ 20 mcg ethinyl estradiol/.1mg levonorgestrel daily (n= 35) or placebo (n= 35). Outcomes included serial measures of bone mineral density (BMD) by dual-energy X-ray absorptiometry (total body, hip, spine) and peripheral quantitative computed tomography (pQCT; tibia). Magnetic resonance imaging of T1-weighted images of the left knee determined physeal status (open/closed).RESULTS: Sixty-two subjects completed the trial. Physeal closure status was the strongest predictor of aBMD changes. Among girls with open physes, those who received DHEA+ERT showed a decline in BMD Z-scores compared with those receiving placebo, whereas there was no effect in those with at least one closed physis. Treatment did not affect any pQCT measures, regardless of physeal closure status.CONCLUSIONS: Combined DHEA+ ERT did not significantly improve dual-energy X-ray absorptiometry or pQCT BMD measurements in young adolescent girls with AN, in contrast to an earlier trial showing benefit in older adolescents and young women. In girls with open physes, the mean change in the placebo arm was greater than that of the DHEA+ERT group. We conclude that DHEA+ERT is ineffective for preserving bone health in growing young adolescents with AN at the dose and route of administration described in this report.

  View details for DOI 10.1016/j.jadohealth.2019.04.003

  View details for PubMedID 31227390

• Serum Calcification Propensity and Coronary Artery Calcification Among Patients with CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study AMERICAN JOURNAL OF KIDNEY DISEASES Bundy, J. D., Cai, X., Scialla, J. J., Dobre, M. A., Chen, J., Hsu, C., Leonard, M. B., Go, A. S., Rao, P. S., Lash, J. P., Townsend, R. R., Feldman, H., de Boer, I. H., Block, G. A., Wolf, M., Smith, E. R., Pasch, A., Isakova, T., Appel, L. J., He, J., Rahman, M., CRIC Study Investigators 2019; 73 (6): 806–14

  View details for DOI 10.1053/j.ajkd.2019.01.024

  View details for Web of Science ID 000468407400010

• Poor glycemic control is associated with impaired bone accrual in the year following a diagnosis of type 1 diabetes. The Journal of clinical endocrinology and metabolism Weber, D. R., Gordon, R. J., Kelley, J. C., Leonard, M. B., Willi, S. M., Hatch-Stein, J., Kelly, A., Kosacci, O., Kucheruk, O., Kaafarani, M., Zemel, B. S. 2019

  Abstract

  CONTEXT: Type 1 diabetes (T1D) is associated with an increased fracture risk across the life course. The effects on bone accrual early in the disease are unknown.OBJECTIVE: To characterize changes in bone density and structure over the year following diagnosis of T1D and to identify contributors to impaired bone accrual.DESIGN: Prospective cohort study.SETTING: Academic children's hospital.PARTICIPANTS: 36 children, ages 7-17 years, enrolled at diagnosis of T1D.OUTCOMES: Whole body and regional DXA and tibia peripheral quantitative computed tomography obtained at baseline and 12 months. The primary outcome was bone accrual assessed by bone mineral content (BMC) and areal bone mineral density (aBMD) velocity Z-score.RESULTS: Participants had low total body less head (TBLH) BMC (Z= -0.46 ± 0.76), femoral neck aBMD (Z= -0.57 ± 0.99), and tibia cortical volumetric BMD (Z= -0.44 ± 1.11) at diagnosis, compared to reference data, p<0.05. TBLH BMC velocity in the year following diagnosis was lower in participants with poor (hemoglobin A1c ≥ 7.5%) versus good (hemoglobin A1c < 7.5%) glycemic control at 12-months, Z= -0.36 ± 0.84 vs 0.58 ± 0.71, p=0.003. TBLH BMC velocity was correlated with gains in tibia cortical area (R=0.71, p=0.003) and periosteal circumference (R=0.67, p=0.007) Z-scores in participants with good, but not poor control.CONCLUSIONS: Our results suggest that the adverse effects of T1D on BMD develop early in the disease. Bone accrual following diagnosis was impaired in participants with poor glycemic control and appeared to be mediated by diminished bone formation on the periosteal surface.

  View details for DOI 10.1210/jc.2019-00035

  View details for PubMedID 31034056

• Relative sarcopenia and mortality and the modifying effects of chronic kidney disease and adiposity JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE Ziolkowski, S. L., Long, J., Baker, J. F., Chertow, G. M., Leonard, M. B. 2019; 10 (2): 338–46

  View details for DOI 10.1002/jcsm.12396

  View details for Web of Science ID 000465092100008

• Serum Calcification Propensity and Coronary Artery Calcification Among Patients With CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study. American journal of kidney diseases : the official journal of the National Kidney Foundation Bundy, J. D., Cai, X., Scialla, J. J., Dobre, M. A., Chen, J., Hsu, C., Leonard, M. B., Go, A. S., Rao, P. S., Lash, J. P., Townsend, R. R., Feldman, H. I., de Boer, I. H., Block, G. A., Wolf, M., Smith, E. R., Pasch, A., Isakova, T., CRIC Study Investigators 2019

  Abstract

  RATIONALE & OBJECTIVE: Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to4.STUDY DESIGN: Prospective cohort study.SETTING & PARTICIPANTS: Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements.PREDICTORS: Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications.OUTCOMES: CAC prevalence, severity, incidence, and progression.ANALYTICAL APPROACH: Multivariable-adjusted generalized linear models.RESULTS: At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase≥100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression.LIMITATIONS: Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification.CONCLUSIONS: Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.

  View details for PubMedID 30935773

• Relative sarcopenia and mortality and the modifying effects of chronic kidney disease and adiposity. Journal of cachexia, sarcopenia and muscle Ziolkowski, S. L., Long, J., Baker, J. F., Chertow, G. M., Leonard, M. B. 2019

  Abstract

  BACKGROUND: Conventional definitions of sarcopenia based on lean mass may fail to capture low lean mass relative to higher fat mass, that is, relative sarcopenia. The objective of this study is to determine the associations of sarcopenia and relative sarcopenia with mortality independent of co-morbidities, and whether chronic kidney disease (CKD) and adiposity alter these associations.METHODS: Dual energy X-ray absorptiometry-derived appendicular lean mass index (ALMI, kg/m2 ) and fat mass index (FMI, kg/m2 ) were assessed in 14850 National Health and Nutrition Examination Survey participants from 1999 to 2006 and were linked to death certificate data in the National Death Index with follow-up through 2011. Sarcopenia was defined using sex-specific and race/ethnicity-specific standard deviation scores compared with young adults (T-scores) as an ALMI T-score<-2 and relative sarcopenia as fat-adjusted ALMI (ALMIFMI ) T-score<-2. Glomerular filtration rate (GFR) was estimated using creatinine-based (eGFRCr ) and cystatin C-based (eGFRCys ) regression equations.RESULTS: Three (3.0) per cent of National Health and Nutrition Examination Survey participants met criteria for sarcopenia and 8.7% met criteria for relative sarcopenia. Sarcopenia and relative sarcopenia were independently associated with mortality (HR sarcopenia 2.20, 95% CI 1.69 to 2.86; HR relative sarcopenia 1.60, 95% CI 1.31 to 1.96). The corresponding population attributable risks were 5.2% (95% CI 3.4% to 6.4%) and 8.4% (95% CI 4.8% to 11.2%), respectively. Relative sarcopenia remained significantly associated with mortality (HR 1.32, 95% CI 1.08 to 1.61) when limited to the subset who did not meet the criteria for sarcopenia. The risk of mortality associated with relative sarcopenia was attenuated among persons with higher FMI (P for interaction <0.01) and was not affected by CKD status for either sarcopenia or relative sarcopenia.CONCLUSIONS: Sarcopenia and relative sarcopenia are significantly associated with mortality regardless of CKD status. Relative sarcopenia is nearly three-fold more prevalent amplifying its associated mortality risk at the population level. The association between relative sarcopenia and mortality is attenuated in persons with higher FMI.

  View details for PubMedID 30784237

• The Adiponectin Paradox in the Elderly: Associations With Body Composition, Physical Functioning, and Mortality JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Baker, J. F., Newman, A. B., Kanaya, A., Leonard, M. B., Zemel, B., Miljkovic, I., Long, J., Weber, D., Harris, T. B. 2019; 74 (2): 247–53

  Abstract

  To determine if adiponectin levels are associated with weight loss, low muscle mass, and physical functioning among the elderly and to determine independent associations with incident disability and death.Included were 3,044 participants from the Health, Aging and Body Composition Study, who had whole-body dual energy absorptiometry performed to evaluate appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2), computed tomography measures of thigh muscle density, weight histories, estimates of physical functioning, and adiponectin levels at enrollment. Associations between adiponectin levels and body composition, weight loss, and physical functioning were assessed in multivariable linear regression models. Associations between adiponectin and incident disability and mortality were assessed in mediation analyses, adjusting for other factors.Greater adiponectin at baseline was independently associated with low FMI Z-score, lower waist circumference, low ALMI Z-score, low muscle density, a history of weight loss, and poor physical functioning (all p < .05). Greater adiponectin levels (per SD) were associated with incident disability [HR: 1.14 (1.08, 1.20), p < .001] and greater mortality [HR: 1.17 (1.10, 1.25), p < .001] in models adjusting for demographic factors, adiposity, and comorbid conditions. The association was completely attenuated and no longer significant (all p > 0.05) when adjusting for body composition, muscle density, weight loss, and physical functioning at baseline.Greater serum adiponectin levels are associated with historical weight loss, low skeletal muscle mass, low muscle density, and poor physical functioning. High adiponectin is associated with a greater risk of incident disability and death, but not independently of these factors.

  View details for PubMedID 29438496

  View details for PubMedCentralID PMC6333931

• Chronic Kidney Disease and the Adiposity Paradox: Valid or Confounded? Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation Ziolkowski, S. L., Long, J., Baker, J. F., Chertow, G. M., Leonard, M. B. 2019

  Abstract

  OBJECTIVE: Obesity, defined by body mass index (BMI), is associated with lower mortality risk in patients with chronic kidney disease (CKD). BMI and % body fat (%BF) are confounded by muscle mass, while DXA derived fat mass index (FMI) overcomes this limitation. We compared the associations between obesity and mortality in persons with CKD using multiple estimates of adiposity, and determined whether muscle mass, inflammation and weight loss modify these associations.METHODS: Obesity was defined using BMI and DXA-derived FMI and %BF cut-offs in 2,852 NHANES participants with CKD from 1999-2006 and linked to the National Death Index with follow up through 2011. Cox proportional hazards models assessed associations between mortality and measures of obesity.RESULTS: Obesity based on FMI and continuous variables, FMI, BMI and %BF were associated with lower mortality. The protective association of obesity was less pronounced among participants with higher muscle mass and was no longer significant after adjustment for prior weight loss. Inflammation did not modify these associations.CONCLUSIONS: We observed lower mortality associated with higher fat mass, particularly among persons with lower muscle mass. The prevalence of >10% weight loss was half as common among obese compared to non-obese participants and confounded these associations.

  View details for PubMedID 30709713

• Effects of Weight History on the Association Between Directly-Measured Adiposity and Mortality in Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences Baker, J. F., Ziolkowski, S. L., Long, J. n., Leonard, M. B., Stokes, A. n. 2019

  Abstract

  It is controversial whether an altered relationship between adiposity and mortality occurs with aging. We evaluated associations between adiposity and mortality in younger and older participants before and after considering historical weight loss.This study utilized whole-body Dual Energy Absorptiometry (DXA) data from the National Health and Nutrition Examination Survey (NHANES) in adults ≥20 years of age. Fat Mass Index (FMI), determined by DXA, was converted to age-, sex-, and race-specific Z-Scores. Percent change in weight from the maximum reported weight was determined and categorized. Cox proportional hazards models assessed associations between quintile of FMI Z-Score and mortality. Sequential models adjusted for percent weight change since the maximum weight.Participants with lower FMI were more likely to have lost weight from their maximum, particularly among older participants with lower FMI. Substantially greater risk of mortality was observed for the highest quintile of FMI Z-Score compared to the second quintile among younger individuals [HR 2.50 (1.69,3.72) p<0.001]. In contrast, a more modest association was observed among older individuals in the highest quintile [HR 1.23 (0.99,1.52) p=0.06] (p for interaction <0.001). In both the younger and older participants, the risks of greater FMI Z-Score were magnified when adjusting for percent weight change since maximum reported weight.Older people with low fat mass report greater historical weight loss, potentially explaining substantially altered relationships between fat mass and mortality in older individuals. As a result, epidemiologic studies performed in older populations will likely underestimate the causal risks of excess adiposity.

  View details for DOI 10.1093/gerona/glz144

  View details for PubMedID 31168573

• Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study. American journal of kidney diseases : the official journal of the National Kidney Foundation Isakova, T. n., Cai, X. n., Lee, J. n., Mehta, R. n., Zhang, X. n., Yang, W. n., Nessel, L. n., Anderson, A. H., Lo, J. n., Porter, A. n., Nunes, J. W., Negrea, L. n., Hamm, L. n., Horwitz, E. n., Chen, J. n., Scialla, J. J., de Boer, I. H., Leonard, M. B., Feldman, H. I., Wolf, M. n. 2019

  Abstract

  The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD.Retrospective analysis nested in a cohort study.Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847).Years before ESKD.Serial FGF-23, PTH, serum phosphate, and serum calcium levels.To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD.Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased.Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied.Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

  View details for DOI 10.1053/j.ajkd.2019.07.022

  View details for PubMedID 31668375

• Serum Calcification Propensity and Cardiovascular Disease Events Among Patients With Chronic Kidney Disease: the CRIC Study Bundy, J. D., Cai, X., Mehta, R., Scialla, J. J., Block, G. A., Feldman, H. I., de Boer, I. H., Lash, J. P., Chen, J., Hsu, C., Dobre, M. A., Leonard, M. B., Rao, P. S., Go, A. S., Townsend, R. R., Smith, E. R., Pasch, A., Isakova, T. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for DOI 10.1161/circ.139.suppl_1.P063

  View details for Web of Science ID 000478079000496

• Low Muscle Density is Associated with Deteriorations in Muscle Strength and Physical Functioning in Rheumatoid Arthritis. Arthritis care & research Baker, J. F., Mostoufi-Moab, S. n., Long, J. n., Taratuta, E. n., Leonard, M. B., Zemel, B. n. 2019

  Abstract

  Rheumatoid arthritis (RA) is associated with low muscle density due to accumulation of intramuscular fat. This study identified predictors of changes in muscle density and determined whether low muscle density predicted changes in strength and physical function.Patients with RA, ages 18-70, completed whole-body DXA and peripheral quantitative CT (pQCT) to quantify lean and fat mass indices and muscle density. Dynamometry was used to measure strength at the hand, knee, and lower leg. Disability and physical function were measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). Assessments were performed at baseline and at follow-up. Regression analyses assessed associations between patient characteristics, muscle density, and deteriorations in strength and function.Muscle density was assessed at baseline in 107 patients with RA. Seventy-nine (74%) returned for a follow-up assessment at a median follow-up time of 2.71 years (IQR: 2.35-3.57). Factors associated with declines in muscle density included female sex, higher disease activity, smoking, and lower IGF-1 levels. Greater muscle density Z-Score at baseline (per 1 SD) was associated with less worsening per year of HAQ, SPPB, and 4-meter walk time and a lower risk of a clinically important worsening in HAQ [OR 1.90 (1.06,3.42) p=0.03] and walking speed [OR 2.87 (1.05,7.89) p=0.04].Worsening of skeletal muscle density occurred in patients with higher disease activity, smokers, and those with lower IGF-1. Low muscle density was associated with worsening of physical function. Interventions addressing reductions in muscle quality might prevent functional decline.

  View details for DOI 10.1002/acr.24126

  View details for PubMedID 31841259

• A multi-imaging modality study of bone density, bone structure and the muscle - bone unit in end-stage renal disease. Bone Leonard, M. B., Wehrli, F. W., Ziolkowski, S. L., Billig, E. n., Long, J. n., Nickolas, T. L., Magland, J. F., Nihtianova, S. n., Zemel, B. S., Herskovitz, R. n., Rajapakse, C. S. 2019

  Abstract

  End stage renal disease (ESRD) is associated with sarcopenia and skeletal fragility. The objectives of this cross-sectional study were to (1) characterize body composition, bone mineral density (BMD) and bone structure in hemodialysis patients compared with controls, (2) assess whether DXA areal BMD (aBMD) correlates with peripheral quantitative CT (pQCT) measures of volumetric BMD (vBMD), cortical dimensions and MRI measures of trabecular microarchitecture, and (3) determine the magnitude of bone deficits in ESRD after adjustment for muscle mass. Thirty ESRD participants, ages 25 to 64 years, were compared with 403 controls for DXA and pQCT outcomes and 104 controls for MRI outcomes; results were expressed as race- and sex- specific Z-scores relative to age. DXA appendicular lean mass index (ALMI kg/m2) and total hip, femoral neck, ultradistal and 1/3rd radius aBMD were significantly lower in ESRD, vs. controls (all p < 0.01). pQCT trabecular vBMD (p < 0.01), cortical vBMD (p < 0.001) and cortical thickness (due to a greater endosteal circumference, p < 0.02) and MRI measures of trabecular number, trabecular thickness, and whole bone stiffness were lower (all p < 0.01) in ESRD, vs. controls. ALMI was positively associated with total hip, femoral neck, ultradistal radius and 1/3rd radius aBMD and with tibia cortical thickness (R = 0.46 to 0.64). Adjustment for ALMI significantly attenuated bone deficits at these sites: e.g. mean femoral neck aBMD was 0.79 SD lower in ESRD, compared with controls and this was attenuated to 0.33 with adjustment for ALMI. In multivariate models within the dialysis participants, pQCT trabecular vBMD and cortical area Z-scores were significant and independently (all p < 0.02) associated with DXA femoral neck, total hip, and ultradistal radius aBMD Z-scores. Cortical vBMD (p = 0.01) and cortical area (p < 0.001) Z-scores were significantly and independently associated with 1/3rd radius areal aBMD Z-scores (R2 = 0.62). These data demonstrate that DXA aBMD captures deficits in trabecular and cortical vBMD and cortical area. The strong associations with ALMI, as an index of skeletal muscle, highlight the importance of considering the role of sarcopenia in skeletal fragility in patients with ESRD.

  View details for DOI 10.1016/j.bone.2019.05.022

  View details for PubMedID 31158505

• Intramuscular Fat Accumulation and Associations With Body Composition, Strength, and Physical Functioning in Patients With Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Baker, J. F., Mostoufi-Moab, S., Long, J., Zemel, B., Ibrahim, S., Taratuta, E., Leonard, M. B. 2018; 70 (12): 1727–34

  Abstract

  Rheumatoid arthritis (RA) is associated with adverse body composition profiles and low muscle density due to the accumulation of intramuscular fat. Linear regression was used to assess differences between RA patients and controls and to determine associations between muscle density, strength, and physical functioning.Patients with RA, ages 18-70 years, and healthy control subjects underwent whole-body dual x-ray absorptiometry and peripheral quantitative computed tomography, in order to quantify the appendicular lean mass index (ALMI) and the fat mass index (FMI), visceral fat area, and muscle density. Dynamometry was used to measure hand grip strength and muscle strength at the knee and lower leg. Disability and physical functioning were measured using the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). Linear regression analyses were performed to assess differences related to RA and associations between muscle density, strength, and function.The study group included 103 patients with RA (51 men) and 428 healthy control subjects. Among patients with RA, low muscle density was associated with higher disease activity, C-reactive protein and interleukin-6 levels, greater total and visceral fat area, lower ALMI Z scores, physical inactivity, and long-term use of glucocorticoids (>1 year). Patients with low ALMI Z scores had lower muscle density Z scores compared with reference participants with similarly low ALMI scores. Low muscle density was independently associated with lower muscle strength, higher HAQ scores, and lower SPPB scores, after adjustment for ALMI and FMI Z scores.The low muscle density observed in patients with RA was associated with low muscle mass, excess adiposity, poor strength, and greater disability. Interventions to address poor muscle quality could potentially affect important functional outcomes.

  View details for PubMedID 29481721

  View details for PubMedCentralID PMC6109612

• Impact of Sex and Maturation on Trabecular and Cortical Microarchitecture in Children and Young Adults Aye, T., Kent, K., Long, J., Whalen, J., Strickland, A., Burghardt, A., Leonard, M. B. WILEY. 2018: 209–10

  View details for Web of Science ID 000450475401168

• Multimodality Study of Glucocorticoid Induced Osteoporosis in Pediatric Crohn's Disease Long, J., Lee, D., Herskovitz, R., Zemel, B., Leonard, M. WILEY. 2018: 212

  View details for Web of Science ID 000450475401175

• Pediatric Bone Mineral Accrual Z-Score Calculation Equations and Their Application in Childhood Disease. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Kelly, A., Shults, J., Mostoufi-Moab, S., McCormack, S. E., Stallings, V. A., Schall, J. I., Kalkwarf, H. J., Lappe, J. M., Gilsanz, V., Oberfield, S. E., Shepherd, J. A., Winer, K. K., Leonard, M. B., Zemel, B. S. 2018

  Abstract

  Annual gains in BMC and areal bone mineral density (aBMD) in children vary with age, pubertal status, height-velocity, and lean body mass accrual (LBM velocity). Evaluating bone accrual in children with bone health-threatening conditions requires consideration of these determinants. The objective of this study was to develop prediction equations for calculating BMC/aBMD velocity SD scores (velocity-Z) and to evaluate bone accrual in youth with health conditions. Bone and body compositions via DXA were obtained for up to six annual intervals in healthy youth (n=2014) enrolled in the Bone Mineral Density in Childhood Study (BMDCS) . Longitudinal statistical methods were used to develop sex- and pubertal-status-specific reference equations for calculating velocity-Z for total body less head-BMC and lumbar spine (LS), total hip (TotHip), femoral neck, and 1/3-radius aBMD. Equations accounted for (1) height velocity, (2) height velocity and weight velocity, or (3) height velocity and LBM velocity. These equations were then applied to observational, single-center, 12-month longitudinal data from youth with cystic fibrosis (CF; n=65), acute lymphoblastic leukemia (ALL) survivors (n=45), or Crohn disease (CD) initiating infliximab (n=72). Associations between BMC/aBMD-Z change (conventional pediatric bone health monitoring method) and BMC/aBMD velocity-Z were assessed. The BMC/aBMD velocity-Z for CF, ALL, and CD was compared with BMDCS. Annual changes in the BMC/aBMD-Z and the BMC/aBMD velocity-Z were strongly correlated, but not equivalent; LS aBMD-Z=1 equated with LS aBMD velocity-Z=-3. In CF, BMC/aBMD velocity-Z was normal. In posttherapy ALL, BMC/aBMD velocity-Z was increased, particularly at TotHip (1.01 [-.047; 1.7], p<0.0001). In CD, BMC/aBMD velocity-Z was increased at all skeletal sites. LBM-velocity adjustment attenuated these increases (eg, TotHip aBMD velocity-Z: 1.13 [0.004; 2.34] versus 1.52 [0.3; 2.85], p<0.0001). Methods for quantifying the BMC/aBMD velocity that account for maturation and body composition changes provide a framework for evaluating childhood bone accretion and may provide insight into mechanisms contributing to altered accrual in chronic childhood conditions. © 2018 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.3589

  View details for PubMedID 30372552

• Children with Crohn's Disease Frequently Consume Select Food Additives DIGESTIVE DISEASES AND SCIENCES Lee, D., Swan, C., Suskind, D., Wahbeh, G., Vanamala, J., Baldassano, R. N., Leonard, M. B., Lampe, J. W. 2018; 63 (10): 2722–28

  Abstract

  Certain food additives may promote the pathogenesis of Crohn's disease (CD), but thus far the evaluation of food additive exposures in humans has been limited. The objective of this study was to quantify food additive exposures in children with CD.In a trial for bone health in CD, children were followed over 24 months with evaluation of disease characteristics, dietary intake, and body composition. At baseline, participants completed three 24-h dietary recalls. Foods were categorized, and the ingredient list for each item was evaluated for the presence of select food additives: polysorbate-80, carboxymethylcellulose, xanthan gum, soy lecithin, titanium dioxide, carrageenan, maltodextrin, and aluminosilicates. The frequency of exposures to these food additives was described for study participants and for food categories.At study baseline, 138 participants, mean age 14.2 ± 2.8 years, 95% having inactive or mild disease, were enrolled and dietary recalls were collected. A total of 1325 unique foods were recorded. Mean exposures per day for xanthan gum was 0.96 ± 0.72, carrageenan 0.58 ± 0.63, maltodextrin 0.95 ± 0.77, and soy lecithin 0.90 ± 0.74. The other additives had less than 0.1 exposures per day. For the 8 examined food additives, participants were exposed to a mean (SD) of 3.6 ± 2.1 total additives per recall day and a mean (SD) of 2.4 ± 1.0 different additives per day.Children with CD frequently consume food additives, and the impact on disease course needs further study.

  View details for PubMedID 29862484

• Changes in pediatric DXA measures of musculoskeletal outcomes and correlation with quantitative CT following treatment of acute lymphoblastic leukemia BONE Mostoufi-Moab, S., Kelly, A., Mitchell, J. A., Baker, J., Zemel, B. S., Brodsky, J., Long, J., Leonard, M. B. 2018; 112: 128–35

  Abstract

  We previously reported significant gains in pQCT measures of tibia trabecular bone mineral density (BMD) and cortical structure following completion of therapy in children and adolescents with acute lymphoblastic leukemia (ALL). The objective of this study was to examine changes in DXA measures used in clinical practice and expressed as Z-scores using robust national reference data. Children and adolescents, ages 5 to 18 years were enrolled within 2 (median 0.8) years of completing ALL therapy. DXA total-body less-head bone mineral content (TBLH-BMC), and spine, total hip, femoral neck, and 1/3rd radius areal BMD (aBMD) were assessed in 45 participants at enrollment and 12-months later. Linear regression models examined correlates of changes in DXA Z-scores. Changes in DXA outcomes were compared to changes in tibia pQCT trabecular and cortical volumetric BMD (vBMD) and cortical area. At enrollment, DXA TBLH-BMC, spine and radius aBMD Z-scores were not significantly reduced in ALL survivors; however, total hip [median -0.74 (IQ range -1.51 to -0.04)] and femoral neck [-0.51 (-1.24 to 0.14)] aBMD Z-scores were lower (both p < 0.01) compared to reference data. DXA Z-scores at all skeletal sites increased over 12 months. Despite improvement, total hip Z-score remained lower at -0.55 (-1.05 to 0.18). The increases in TBLH-BMC, total hip and femoral neck aBMD Z-scores were more pronounced in those enrolled within 6 months of completing ALL therapy, compared to those enrolled at >6 months. Gains in TBLH-BMC, total hip, femoral neck and radius aBMD Z-scores were significantly associated with gains in tibia cortical area Z-scores (R = 0.56 to 0.67, p ≤ 0.001). Changes in TBLH and proximal femur sites were associated with gains in trabecular vBMD Z-scores (R = 0.37 to 0.40; p ≤ 0.01); these associations were not significant when adjusted for gains in cortical area. In summary, gains in DXA measures were most pronounced in total hip and femoral neck following ALL therapy. The gains in all DXA measures, with the exception of lumbar spine, reflected gains in cortical area. Overall, ALL survivors demonstrate skeletal recovery following completion of therapy; a small sub-group continue to demonstrate deficits and benefit from continued observation to ensure improvement over time.

  View details for PubMedID 29679731

  View details for PubMedCentralID PMC5970089

• Estimation of Skeletal Muscle Mass Relative to Adiposity Improves Prediction of Physical Performance and Incident Disability JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES Baker, J. F., Long, J., Leonard, M. B., Harris, T., Delmonico, M. J., Santanasto, A., Satterfield, S., Zemel, B., Weber, D. R. 2018; 73 (7): 946–52

  Abstract

  We assessed the discrimination of lean mass estimates that have been adjusted for adiposity for physical functioning deficits and prediction of incident disability.Included were 2,846 participants from the Health, Aging and Body Composition Study with available whole-body dual energy absorptiometry measures of appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Age-, sex-, and race-specific Z-Scores and T-Scores were determined by comparison to published reference ranges. ALMI values were adjusted for FMI (ALMIFMI) using a novel published method. Sex-stratified analyses assessed associations between lean mass estimates and the physical performance score, ability to complete a 400-meter walk, grip strength, and incident disability. Dichotomized definitions of low lean for age and sarcopenia were examined and their performance compared to the ALM-to-BMI ratio.Compared to ALMI T-Scores and Z-Scores, the ALMIFMI scores demonstrated stronger associations with physical functioning, and were similarly associated with grip strength. Greater FMI Z-Scores and T-Scores were associated with poor physical functioning and incident disability. Definitions of low lean for age and sarcopenia using ALMIFMI (compared to ALMI) better discriminated those with poor physical functioning and a greater risk of incident disability. The ALM-to-BMI ratio was modestly associated with grip strength and physical performance, but was not associated with completion of the 400-meter walk or incident disability, independent of adiposity and height.Estimation of skeletal muscle mass relative to adiposity improves correlations with physical performance and prediction of incident disability suggesting it is an informative outcome for clinical studies.

  View details for PubMedID 28958026

  View details for PubMedCentralID PMC6001879

• Associations between exercise, bone mineral density, and body composition in adolescents with anorexia nervosa. Eating and weight disorders : EWD Nagata, J. M., Carlson, J. L., Golden, N. H., Murray, S. B., Long, J., Leonard, M. B., Peebles, R. 2018

  Abstract

  OBJECTIVE: To identify the effect of duration of weight-bearing exercise and team sports participation on bone mineral density (BMD) and body composition among adolescents with anorexia nervosa (AN).METHOD: We retrospectively reviewed electronic medical records of all patients 9-20years old with a DSM-5 diagnosis of AN evaluated by the Stanford Eating Disorders Program (1997-2011) who underwent dual-energy X-ray absorptiometry.RESULTS: A total of 188 adolescents with AN were included (178 females and 10 males). Using multivariate linear regression, duration of weight-bearing exercise (B=0.15, p=0.005) and participation in team sports (B=0.53, p=0.001) were associated with higher BMD at the hip and team sports (B=0.39, p=0.006) were associated with higher whole body BMC, controlling for covariates. Participation in team sports (B=-1.06, p=0.007) was associated with greater deficits in FMI Z-score. LBMI Z-score was positively associated with duration of weight-bearing exercise (B=0.10, p=0.018) and may explain the relationship between exercise and bone outcomes.CONCLUSION: Duration of weight-bearing exercise and team sports participation may be protective of BMD at the hip and whole body BMC, while participation in team sports was associated with greater FMI deficits among adolescents with AN.LEVEL OF EVIDENCE: Level V, descriptive retrospectivestudy.

  View details for PubMedID 29949128

• The Association of Diet and Exercise With Body Composition in Pediatric Crohn's Disease INFLAMMATORY BOWEL DISEASES Lee, D., Lewis, J. D., Shults, J., Baldassano, R. N., Long, J., Herskovitz, R., Zemel, B., Leonard, M. B. 2018; 24 (6): 1368–75

  Abstract

  In pediatric Crohn's disease, fat mass improves over time with treatment, but lean mass deficits persist. This observational study of the associations of physical activity and dietary intake with lean mass and muscle strength in children with Crohn's disease was ancillary to a previously reported randomized clinical trial of an intervention to improve bone health.In this study, 138 participants were followed at baseline and at 6, 12, and 24 months with evaluation of lean and fat mass using DXA, muscle strength (peak torque), Crohn's characteristics, dietary intake, time in moderate to vigorous physical activity (MVPA), and serum insulin-like growth factor-1 (IGF-1) and tumor necrosis factor-alpha (TNF-α). Race- and sex-specific Z-scores for leg lean mass and whole body fat mass were generated. Quasi least square regression evaluated determinants of changes in body composition and muscle strength.Leg lean mass and muscle strength were positively associated with time in MVPA (P < 0.05) and negatively associated with increasing clinical disease activity (P < 0.05). Both leg lean mass and strength were positively associated with IGF-1 Z-score (P ≤ 0.03) but negatively associated with serum TNF-α (P ≤ 0.04). Neither lean mass nor muscle strength was associated with caloric or protein intake.Persistence of lean mass deficits was related to ongoing Crohn's disease activity but improved with greater time spent in moderate to vigorous physical activity. Future trials are needed to evaluate the efficacy of physical activity in improving lean mass in pediatric Crohn's disease.

  View details for PubMedID 29718224

• Leg lean mass correlates with exercise systemic output in young Fontan patients HEART Avitabile, C. M., Goldberg, D. J., Leonard, M. B., Wei, Z., Tang, E., Paridon, S. M., Yoganathan, A. P., Fogel, M. A., Whitehead, K. K. 2018; 104 (8): 680–84

  Abstract

  We previously described lower leg lean mass Z-scores (LLMZ) in Fontan patients associated with worse peak oxygen consumption on metabolic exercise testing. We hypothesised that LLMZ correlates with indexed systemic flow (Qsi) and cardiac index (CI) on exercise cardiac magnetic resonance (eCMR).Thirteen patients had LLM measured by dual-energy X-ray absorptiometry within mean 40 (range 0-258) days of eCMR. LLM was converted to sex and race-specific Z-scores based on healthy reference data. Ventricular volumes and flow measurements of the ascending and descending (DAO) aorta and superior vena cava (SVC) were obtained by CMR at rest and just after supine ergometer exercise to a heart rate associated with anaerobic threshold on prior exercise test. Baseline and peak exercise measures of Qsi (SVC+DAO/BSA) and CI, as well as change in Qsi and CI with exercise, were compared with LLMZ by linear regression.LLMZ was not correlated with resting flows, stroke volume or CI. There was a strong linear correlation between LLMZ and change in both CI (r=0.77, p=0.002) and Qsi (r=0.73, p=0.005) from rest to exercise. There was also a significant correlation between LLMZ and Qsi at exercise (r=0.70, p=0.008). The correlation between LLMZ and CI at exercise did not reach significance (r=0.3, p=0.07).In our cohort, there was a strong linear correlation between LLMZ and change in both CI and Qsi from rest to exercise, suggesting that Fontan patients with higher LLMZ may be better able to augment systemic output during exercise, improving performance.

  View details for PubMedID 28988207

• Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update ANNALS OF INTERNAL MEDICINE Ketteler, M., Block, G. A., Evenepoel, P., Fukagawa, M., Herzog, C. A., McCann, L., Moe, S. M., Shroff, R., Tonelli, M. A., Toussaint, N. D., Vervloet, M. G., Leonard, M. B. 2018; 168 (6): 422-+

  Abstract

  The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis.Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations.The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

  View details for PubMedID 29459980

• Increases in IGF-1 After Anti-TNF-alpha Therapy Are Associated With Bone and Muscle Accrual in Pediatric Crohn Disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM DeBoer, M. D., Lee, A. M., Herbert, K., Long, J., Thayu, M., Griffin, L. M., Baldassano, R. N., Denson, L. A., Zemel, B. S., Denburg, M. R., Herskovitz, R., Leonard, M. B. 2018; 103 (3): 936–45

  Abstract

  Low levels of insulinlike growth factor 1 (IGF-1) in pediatric and adolescent Crohn disease (CD) likely contribute to bone and muscle deficits.Assess changes in IGF-1 levels and associations with bone and muscle accrual following initiation of anti-tumor necrosis factor α (TNF-α) therapy in pediatric and adolescent CD.Participants (n = 75, age 5 to 21 years) with CD were enrolled in a prospective cohort study; 63 completed the 12-month visit.IGF-1 levels at baseline and 10 weeks, as well as dual-energy x-ray absorptiometry (DXA) and tibia peripheral quantitative computed tomography (pQCT) measures of bone and muscle at baseline and 12 months after initiation of anti-TNF-α therapy. Outcomes were expressed as sex-specific z scores.IGF-1 z scores increased from a median (interquartile range) of -1.0 (-1.58 to -0.17) to -0.36 (-1.04 to 0.36) over 10 weeks (P < 0.001). Lesser disease severity and systemic inflammation, as well as greater estradiol z scores (in girls), was significantly associated with greater IGF-1 z scores over time. DXA whole-body bone mineral content, leg lean mass, and total hip and femoral neck bone mineral density (BMD) z scores were low at baseline (P < 0.0001 vs reference data) and increased significantly (P < 0.001) over 12 months. Greater increases in IGF-1 z scores over 10 weeks predicted improvement in DXA bone and muscle outcomes and pQCT trabecular BMD and cortical area. Adjustment for changes in muscle mass markedly attenuated the associations between IGF-1 levels and bone outcomes.Short-term improvements in IGF-1 z scores predicted recovery of bone and muscle outcomes following initiation of anti-TNF-α therapy in pediatric CD. These data suggest that disease effects on growth hormone metabolism contribute to musculoskeletal deficits in CD.

  View details for PubMedID 29329430

• Longitudinal FGF23 Trajectories and Mortality in Patients with CKD JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Isakova, T., Cai, X., Lee, J., Xie, D., Wang, X., Mehta, R., Allen, N. B., Scialla, J. J., Pencina, M. J., Anderson, A. H., Talierco, J., Chen, J., Fischer, M. J., Steigerwalt, S. P., Leonard, M. B., Hsu, C., de Boer, I. H., Kusek, J. W., Feldman, H. I., Wolf, M., CRIC Study Investigators 2018; 29 (2): 579–90

  Abstract

  Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.

  View details for PubMedID 29167351

  View details for PubMedCentralID PMC5791067

• Effects of a Randomized Weight Loss Intervention Trial in Obese Adolescents on Tibia and Radius Bone Geometry and Volumetric Density JOURNAL OF BONE AND MINERAL RESEARCH Kelley, J. C., Stettler-Davis, N., Leonard, M. B., Hill, D., Wrotniak, B. H., Shults, J., Stallings, V. A., Berkowitz, R., Xanthopoulos, M. S., Prout-Parks, E., Klieger, S. B., Zemel, B. S. 2018; 33 (1): 42–53

  Abstract

  Obese adolescents have increased fracture risk, but effects of alterations in adiposity on bone accrual and strength in obese adolescents are not understood. We evaluated 12-month changes in trabecular and cortical volumetric bone mineral density (vBMD) and cortical geometry in obese adolescents undergoing a randomized weight management program, and investigated the effect of body composition changes on bone outcomes. Peripheral quantitative computed tomography (pQCT) of the radius and tibia, and whole-body dual-energy X-ray absorptiometry (DXA) scans were obtained at baseline, 6 months, and 12 months in 91 obese adolescents randomized to standard care versus behavioral intervention for weight loss. Longitudinal models assessed effects of body composition changes on bone outcomes, adjusted for age, bone length, and African-American ancestry, and stratified by sex. Secondary analyses included adjustment for physical activity, maturation, vitamin D, and inflammatory biomarkers. Baseline body mass index (BMI) was similar between intervention groups. Twelve-month change in BMI in the standard care group was 1.0 kg/m2 versus -0.4 kg/m2 in the behavioral intervention group (p < 0.01). Intervention groups were similar in bone outcomes, so they were combined for subsequent analyses. For the tibia, BMI change was not associated with change in vBMD or structure. Greater baseline lean body mass index (LBMI) associated with higher cortical vBMD in males, trabecular vBMD in females, and polar section modulus (pZ) and periosteal circumference (Peri-C) in both sexes. In females, change in LBMI positively associated with gains in pZ and Peri-C. Baseline visceral adipose tissue (VFAT) was inversely associated with pZ in males and cortical vBMD in females. Change in VFAT did not affect bone outcomes. For the radius, BMI and LBMI changes positively associated with pZ in males. Thus, in obese adolescents, weight loss intervention with modest changes in BMI was not detrimental to radius or tibia bone strength, and changes in lean, but not adiposity, measures were beneficial to bone development. © 2017 American Society for Bone and Mineral Research.

  View details for PubMedID 28884881

• Changes in Hepcidin and Hemoglobin After Anti-TNF-alpha Therapy in Children and Adolescents With Crohn Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Atkinson, M. A., Leonard, M. B., Herskovitz, R., Baldassano, R. N., Denburg, M. R. 2018; 66 (1): 90–94

  Abstract

  Anemia is the most common systemic complication of inflammatory bowel disease, is more common in affected children than in adults, and is mediated in large part by chronic inflammation. Inflammation increases levels of the iron-regulatory protein hepcidin, which have been elevated in adults with Crohn disease.We measured serum hepcidin-25 and hemoglobin (Hgb) in 40 children and adolescents with Crohn disease at baseline and 10 weeks after initiation of anti-tumor necrosis factor (TNF)-α therapy. Measures of disease activity, inflammatory markers, and cytokines were obtained in all subjects. Anemia was defined by World Health Organization criteria.At baseline hepcidin and C-reactive protein levels were correlated, and 95% of subjects were anemic. After anti-TNF-α therapy, median (interquartile range) hepcidin concentrations decreased significantly and the distribution narrowed (27.9 [16.2, 52.9] vs 23.2 [11.1, 37.7] ng/mL, P = 0.01). Mean (standard deviation) Hgb also increased significantly (10.6 ± 1.2 to 10.9 ± 1.1 g/dL, P = 0.02), and the increase was sustained at 12 months, although 90% of participants continued to meet anemia criteria at 10 weeks. Disease activity and markers of inflammation also decreased and albumin levels increased. In generalized estimating equation analyses, higher TNF-α, interleukin 6, erythrocyte sedimentation rate, and C-reactive protein were associated with higher hepcidin concentrations (P = 0.04, P = 0.03, P = 0.003, and P < 0.001, respectively), and increased levels of disease activity were associated with higher hepcidin.In children with Crohn disease, anti-TNF-α therapy is associated with decreased levels of hepcidin and increased Hgb 10 weeks after induction. Improvement in anemia may be a secondary benefit for children who receive this therapy.

  View details for PubMedID 28604512

  View details for PubMedCentralID PMC5723254

• Bone Strength and Microarchitectural Deficits in Children with Cystinosis. Burghardt, A., Kent, K., Long, J., Whalen, J., Leonard, M. WILEY. 2017: S124

  View details for Web of Science ID 000418869201178

• Variability in measures of mineral metabolism in children on hemodialysis: impact on clinical decision-making PEDIATRIC NEPHROLOGY Kakajiwala, A., Jemielita, T. O., Copelovitch, L., Leonard, M. B., Furth, S. L., York, A., Benton, M., Hoofnagle, A. N., Windt, K., Merrigan, K., Lederman, A., Denburg, M. R. 2017; 32 (12): 2311–18

  Abstract

  Variability in measures of mineral metabolism has not been studied in pediatric end stage kidney disease. We sought to determine the intra-individual variability in measures of mineral metabolism in children on hemodialysis (HD) and its impact on clinical decision-making.We conducted a prospective single-center study of children (3.6-17.3 years old) on chronic HD. Serial twice weekly measures of serum calcium, phosphate and intact parathyroid hormone (PTH), as well as weekly measures of fibroblast growth factor 23 (FGF23) and vitamin D metabolites, were obtained over a 12-week period in 10 children. Samples (n = 226) were assayed in a single batch at the end of the study.The median intra-individual coefficient of variation (CV) calculated by 4-week blocks was 5.1-6.5% for calcium, 9.5-14.9% for phosphate and 32.7-33.4% for PTH. The median overall CV for FGF23 was 44.4%. Using the first value of each block as a reference, subsequent values would dictate a discrepant management decision 33-56%, 19-28%, and 30-33% of the time for calcium, phosphate, and PTH, respectively. Adjusting for sex and age, most of the variability in phosphate and PTH was attributable to within-participant variability. For calcium, 49% of the variability was attributable to day of blood collection (Monday vs. Friday). The median (range) of an individual participant's values within clinical target ranges was 55% (26-86%) for calcium, 58% (0-96%) for phosphate, and 21% (0-64%) for PTH.There is considerable intra-individual variability in measures of mineral metabolism that serve as surrogate markers for bone health in children on HD. Within a 4-week period, at least 20-30% of measures would dictate a discrepant decision from the referent measure of that month. These findings have important implications for clinical decision-making and underscore the need to base therapeutic decisions on trends rather than single measurements.

  View details for PubMedID 28667458

• Declining Rates of Hip Fracture in End-Stage Renal Disease: Analysis From the 2003-2011 Nationwide Inpatient Sample JOURNAL OF BONE AND MINERAL RESEARCH Kim, S., Liu, S., Long, J., Montez-Rath, M. E., Leonard, M. B., Chertow, G. M. 2017; 32 (11): 2297–2303

  Abstract

  The incidence of hip fracture in patients with end-stage renal disease (ESRD) is considerably higher than that in the general age- and sex-matched population. Although medical therapy for chronic kidney disease mineral bone disorder (CKD-MBD) has changed considerably over the last decade, rates of hip fracture in the entire ESRD population have not been well-characterized. Herein, we evaluated temporal trends in rates of hip fracture, in-hospital mortality, and costs of associated hospital stay in ESRD. We identified hospitalizations for hip fracture from 2003 to 2011 using the Nationwide Inpatient Sample, a representative national database inclusive of all ages and payers. We incorporated data from the United States Renal Data System and the US Census to calculate population-specific rates. Between 2003 and 2011, we identified 47,510 hip fractures in the ESRD population. The overall rate of hip fracture was 10.04/1000 person-years. The rate was 3.73/1000 person-years in patients aged less than 65 years, and 20.97/1000 person-years in patients aged 65 or older. Age- and sex-standardized rates decreased by 12.6% from 2003 (10.23/1000 person-years; 95% confidence interval [CI], 7.99/1000 to 12.47/1000) to 2011 (8.94/1000 person-years; 95% CI, 7.12/1000 to 10.75/1000). Hip fracture rates over time were virtually identical in patients aged less than 65 years; however, rates decreased by 15.3% among patients aged 65 years or older; rates declined more rapidly in older women compared with older men (p for interaction = 0.047). In-hospital mortality rate after hip fracture operation declined by 26.7% from 2003 (8.6%; 95% CI, 6.8 to 10.4) to 2011 (6.3%; 95% CI, 4.9 to 7.7). In ESRD, age- and sex-standardized hip fracture rates and associated in-hospital mortality have declined substantially over the last decade. © 2017 American Society for Bone and Mineral Research.

  View details for PubMedID 28639740

• Acid Load and Phosphorus Homeostasis in CKD AMERICAN JOURNAL OF KIDNEY DISEASES Khairallah, P., Isakova, T., Asplin, J., Hamm, L., Dobre, M., Rahman, M., Sharma, K., Leonard, M., Miller, E., Jaar, B., Brecklin, C., Yang, W., Wang, X., Feldman, H., Wolf, M., Scialla, J. J., Chronic Renal Insufficiency Cohort 2017; 70 (4): 541–50

  Abstract

  The kidneys maintain acid-base homeostasis through excretion of acid as either ammonium or as titratable acids that primarily use phosphate as a buffer. In chronic kidney disease (CKD), ammoniagenesis is impaired, promoting metabolic acidosis. Metabolic acidosis stimulates phosphaturic hormones, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) in vitro, possibly to increase urine titratable acid buffers, but this has not been confirmed in humans. We hypothesized that higher acid load and acidosis would associate with altered phosphorus homeostasis, including higher urinary phosphorus excretion and serum PTH and FGF-23.Cross-sectional.980 participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.Net acid excretion as measured in 24-hour urine, potential renal acid load (PRAL) estimated from food frequency questionnaire responses, and serum bicarbonate concentration < 22 mEq/L.24-hour urine phosphorus and calcium excretion and serum phosphorus, FGF-23, and PTH concentrations.Using linear and log-linear regression adjusted for demographics, kidney function, comorbid conditions, body mass index, diuretic use, and 24-hour urine creatinine excretion, we found that 24-hour urine phosphorus excretion was higher at higher net acid excretion, higher PRAL, and lower serum bicarbonate concentration (each P<0.05). Serum phosphorus concentration was also higher with higher net acid excretion and lower serum bicarbonate concentration (each P=0.001). Only higher net acid excretion associated with higher 24-hour urine calcium excretion (P<0.001). Neither net acid excretion nor PRAL was associated with FGF-23 or PTH concentrations. PTH, but not FGF-23, concentration (P=0.2) was 26% (95% CI, 13%-40%) higher in participants with a serum bicarbonate concentration <22 versus ≥22 mEq/L (P<0.001). Primary results were similar if stratified by estimated glomerular filtration rate categories or adjusted for iothalamate glomerular filtration rate (n=359), total energy intake, dietary phosphorus, or urine urea nitrogen excretion, when available.Possible residual confounding by kidney function or nutrition; urine phosphorus excretion was included in calculation of the titratable acid component of net acid excretion.In CKD, higher acid load and acidosis associate independently with increased circulating phosphorus concentration and augmented phosphaturia, but not consistently with FGF-23 or PTH concentrations. This may be an adaptation that increases titratable acid excretion and thus helps maintain acid-base homeostasis in CKD. Understanding whether administration of base can lower phosphorus concentrations requires testing in interventional trials.

  View details for PubMedID 28645705

  View details for PubMedCentralID PMC5804342

• Muscle Deficits in Rheumatoid Arthritis Contribute to Inferior Cortical Bone Structure and Trabecular Bone Mineral Density. The Journal of rheumatology Baker, J. F., Long, J., Mostoufi-Moab, S., Denburg, M., Jorgenson, E., Sharma, P., Zemel, B. S., Taratuta, E., Ibrahim, S., Leonard, M. B. 2017

  Abstract

  OBJECTIVE: Rheumatoid arthritis (RA) is associated with muscle loss, osteoporosis, and fracture. We examined associations between skeletal muscle mass, strength, and quality and trabecular and cortical bone deficits in patients with RA and healthy controls.METHODS: Participants, ages 18-75 years, completed whole-body dual-energy x-ray absorptiometry and peripheral quantitative computed tomography (pQCT) of the tibia to quantify appendicular lean mass and fat mass indices (ALMI, FMI), muscle density at the lower leg, trabecular bone density, and cortical bone thickness. Age-, sex-, and race-specific Z scores were calculated based on distributions in controls. Associations between body composition and pQCT bone outcomes were assessed in patients with RA and controls. Linear regression analyses assessed differences in bone outcomes after considering differences in body mass index (BMI) and body composition.RESULTS: The sample consisted of 112 patients with RA (55 men) and 412 controls (194 men). Compared to controls, patients with RA had greater BMI Z score (p < 0.001), lower ALMI Z score after adjustment for FMI (p = 0.02), lower muscle strength Z score (p = 0.01), and lower muscle density Z score (p < 0.001). Among RA, ALMI Z scores were positively associated with trabecular density [beta: 0.29 (0.062-0.52); p = 0.01] and cortical thickness [beta: 0.33 (0.13-0.53; p = 0.002]. Associations were similar in controls. Bone outcomes were inferior in patients with RA after adjusting for BMI, but similar to controls when adjusting for body composition. Radiographic damage and higher adiponectin levels were independently associated with inferior bone outcomes.CONCLUSION: Patients with RA exhibit deficits in cortical bone structure and trabecular density at the tibia and a preserved functional muscle-bone unit. A loss of mechanical loading may contribute to bone deficits.

  View details for PubMedID 28916544

• Oral glucocorticoid use and osteonecrosis in children and adults with chronic inflammatory diseases: a population-based cohort study. BMJ open Horton, D. B., Haynes, K., Denburg, M. R., Thacker, M. M., Rose, C. D., Putt, M. E., Leonard, M. B., Strom, B. L. 2017; 7 (7): e016788

  Abstract

  We studied oral glucocorticoids and osteonecrosis, a rare but serious bone disease, in individuals with various chronic inflammatory diseases. We hypothesised that we would find stronger associations in adults versus children and in people with autoimmune diseases.Retrospective cohort study.Population-representative data (1994-2013) from general practices in the UK.Children and adults diagnosed with asthma; inflammatory bowel disease; juvenile, psoriatic or rheumatoid arthritis; psoriasis; or systemic lupus.Oral glucocorticoid patterns.Diagnosed osteonecrosis (primary) and osteonecrosis plus clinical features (eg, symptoms, pain medication, surgical repair) (secondary). Discrete time failure models estimated the adjusted hazard ratio (aHR) of incident osteonecrosis following oral glucocorticoid exposure. Hypothesis testing was one sided (with corresponding 90% CI) since glucocorticoids were unlikely protective.After adjusting for demographic, disease-related and health utilisation factors, glucocorticoid exposure was associated with osteonecrosis in adults (ages 18-49, aHR 2.1 (90% CI 1.5 to 2.9); ages ≥50, aHR 1.3 (90% CI 1.01 to 1.7)). However, low-dose glucocorticoids, corresponding to average doses <7.5 mg prednisolone daily and maximum doses <30 mg daily, were not associated with osteonecrosis in adults. Furthermore, even at high glucocorticoid doses, there was no evidence of increased osteonecrosis among glucocorticoid-exposed children (p=0.04 for interaction by age) (any glucocorticoid exposure, ages 2-9: aHR 1.1 (90% CI 0.7 to 1.7); ages 10-17: aHR 0.6 (90% CI 0.3 to 1.6)). Arthritis, inflammatory bowel disease and lupus were independently associated with osteonecrosis, but there was a similar dose relationship between glucocorticoids and osteonecrosis among adults with low-risk and high-risk diseases.Glucocorticoid use was clearly associated with osteonecrosis in a dose-related fashion in adults, especially young adults, but this risk was not detectable in children. The absolute risk of glucocorticoid-associated osteonecrosis in the general paediatric population and in adults taking low glucocorticoid doses is at most extremely small.

  View details for DOI 10.1136/bmjopen-2017-016788

  View details for PubMedID 28733303

  View details for PubMedCentralID PMC5642748

• Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney international Ketteler, M., Block, G. A., Evenepoel, P., Fukagawa, M., Herzog, C. A., McCann, L., Moe, S. M., Shroff, R., Tonelli, M. A., Toussaint, N. D., Vervloet, M. G., Leonard, M. B. 2017; 92 (1): 26-36

  Abstract

  The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease.

  View details for DOI 10.1016/j.kint.2017.04.006

  View details for PubMedID 28646995

• Assessment of muscle mass relative to fat mass and associations with physical functioning in rheumatoid arthritis. Rheumatology Baker, J. F., Giles, J. T., Weber, D., Leonard, M. B., Zemel, B. S., Long, J., Ibrahim, S., Katz, P. P. 2017; 56 (6): 981-988

  Abstract

  To determine whether a novel measure of appendicular lean mass relative to fat mass is associated with physical functioning in RA.In a cross-sectional design, three independent RA cohorts were retrospectively analysed. Whole-body DXA measures of appendicular lean mass index (ALMI, kg/m 2 ) and fat mass index (FMI, kg/m 2 ) were converted to age, sex and race-specific Z-scores using published National Health and Nutrition Examination Survey reference ranges. Adiposity-adjusted ALMI Z-scores (ALMI FMI ) were determined using a published method to adjust for normal associations between ALMI and FMI Z-scores. Associations between ALMI Z-scores, ALMI FMI Z-scores and physical functioning were assessed after adjusting for age, sex and study. Functional outcomes assessed included the HAQ, Valued Life Activities assessment and Short Physical Performance Battery. Low lean for age was defined as a Z-score of -1 or less.Our sample consisted of 442 patients with RA. The combined cohort had a mean ALMI Z-score of - 0.51 (1.08) and a mean ALMI FMI Z-score of - 0.58 (1.53), suggesting muscle mass deficits compared with a nationally representative sample. Greater ALMI FMI Z-scores demonstrated stronger associations with better functional outcomes compared with ALMI Z-scores. Associations were not attenuated with adjustment for systemic inflammation or pain. The FMI Z-score was independently associated with physical functioning, with a stronger association seen among patients with greater FMI Z-score. Adiposity-adjusted definitions of low lean mass more clearly identified those with functional impairment.Estimates of appendicular lean mass that are adjusted for adiposity demonstrate stronger positive associations with functional outcomes compared with unadjusted estimates.

  View details for DOI 10.1093/rheumatology/kex020

  View details for PubMedID 28340012

• Assessment of Sex Differences in Fracture Risk Among Patients With Anorexia Nervosa: A Population-Based Cohort Study Using The Health Improvement Network JOURNAL OF BONE AND MINERAL RESEARCH Nagata, J. M., Golden, N. H., Leonard, M. B., Copelovitch, L., Denburg, M. R. 2017; 32 (5): 1082-1089

  Abstract

  Though previous studies have demonstrated an increased fracture risk in females with anorexia nervosa (AN), fracture risk in males is not well characterized. The objective of this study was to examine sex differences in fracture risk and site-specific fracture incidence in AN. We performed a population-based retrospective cohort study using The Health Improvement Network (THIN; a large database of anonymized electronic medical records collected at primary care clinics throughout the United Kingdom). The median calendar year for the start of the observation period was 2004-2005. We identified 9239 females and 556 males <60 years of age with AN, and 97,889 randomly selected sex-, age-, and practice-matched participants without eating disorders (92,329 females and 5560 males). Multivariable Cox regression was used to estimate the hazard ratio (HR) for incident fracture. Median age at start of observation was 29.8 years in females and 30.2 years in males. The HR for fracture associated with AN differed by sex and age (interaction p = 0.002). Females with AN had an increased fracture risk at all ages (HR, 1.59; 95% confidence interval [CI], 1.45 to 1.75). AN was associated with a higher risk of fracture among males >40 years of age (HR, 2.54; 95% CI, 1.32 to 4.90; p = 0.005) but not among males ≤40 years. Females with AN had a higher risk of fracture at nearly all anatomic sites. The greatest excess fracture risk was noted at the hip/femur (HR, 5.59; 95% CI, 3.44 to 9.09) and pelvis (HR, 4.54; 95% CI, 2.42 to 8.50) in females and at the vertebrae (HR, 7.25; 95% CI, 1.21 to 43.45) for males with AN. AN was associated with higher incident fracture risk in females across all age groups and in males >40 years old. Sites of highest fracture risk include the hip/femur and pelvis in females and vertebrae in males with AN. © 2016 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.3068

  View details for Web of Science ID 000400590900021

• Assessment of sex differences in bone deficits among adolescents with anorexia nervosa INTERNATIONAL JOURNAL OF EATING DISORDERS Nagata, J. M., Golden, N. H., Peebles, R., Long, J., Leonard, M. B., Chang, A. O., Carlson, J. L. 2017; 50 (4): 352-358

  Abstract

  The objective of this study was to compare sex differences in bone deficits among adolescents with anorexia nervosa (AN) and to identify other correlates of bone health.Electronic medical records of all patients 9-20 years of age with a DSM-5 diagnosis of AN who were evaluated by the eating disorders program at Stanford with dual-energy X-ray absorptiometry (DXA) between March 1997 and February 2011 were retrospectively reviewed. Whole body bone mineral content Z-scores and bone mineral density (BMD) Z-scores at multiple sites were recorded using the Bone Mineral Density in Childhood Study (BMDCS) reference data.A total of 25 males and 253 females with AN were included, with median age 15 years (interquartile range [IQR] 14-17) and median duration of illness 9 months (IQR 5-13). Using linear regression analyses, no significant sex differences in bone deficits were found at the lumbar spine, total hip, femoral neck, or whole body when controlling for age, %mBMI, and duration of illness. Lower %mBMI was significantly associated with bone deficits at all sites in adjusted models.This is the first study to evaluate sex differences in bone health among adolescents with AN, using novel DSM-5 criteria for AN and robust BMDCS reference data. We find no significant sex differences in bone deficits among adolescents with AN except for a higher proportion of females with femoral neck BMD Z-scores <-1. Degree of malnutrition was correlated with bone deficits at all sites. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016).

  View details for DOI 10.1002/eat.22626

  View details for Web of Science ID 000398841500004

• Commercially available lifestyle modification program: randomized controlled trial addressing heart and bone health in BRCA1/2+ breast cancer survivors after risk-reducing salpingo-oophorectomy. Journal of cancer survivorship : research and practice Sturgeon, K. M., Dean, L. T., Heroux, M., Kane, J., Bauer, T., Palmer, E., Long, J., Lynch, S., Jacobs, L., Sarwer, D. B., Leonard, M. B., Schmitz, K. 2017; 11 (2): 246-255

  Abstract

  The goal of this RCT was to examine the efficacy and safety of a web-based program to improve cardiovascular and bone health outcomes, among 35 BRCA1/2+ breast cancer survivors who underwent prophylactic oophorectomy and thus experienced premature surgical menopause.A 12-month commercially available web-based lifestyle modification program (Precision Nutrition Coaching) was utilized. Cardiovascular fitness, dietary intake, leisure time activity, body composition, bone mineral density, bone structure, and muscle strength were assessed.Average adherence to all program components was 74.8 %. Women in the intervention group maintained their cardiovascular fitness level over the 12 months (1.1 ± 7.9 %), while the control group significantly decreased fitness capacity (-4.0 ± 7.5 %). There was a significant difference between groups in percent change of whole body bone area (-0.8 ± 2.5 control and 0.5 ± 1.30 intervention). We also observed decreased BMI (-4.7 ± 6.2 %) and fat mass (-8.6 ± 12.7 %) in the intervention group due to significant concomitant decreases in caloric intake and increases in caloric expenditure. The control group demonstrated decreased caloric intake and decreased lean tissue mass.In this population at high risk for detrimental cardiovascular and bone outcomes, a commercially available lifestyle intervention program mitigated a decline in cardiovascular health, improved bone health, and decreased weight through fat loss.Precision Nutrition Coaching has shown benefit in breast cancer survivors for reduced risk of deleterious cardiovascular and bone outcomes.

  View details for DOI 10.1007/s11764-016-0582-z

  View details for PubMedID 27873046

  View details for PubMedCentralID PMC5386323

• Commercially available lifestyle modification program: randomized controlled trial addressing heart and bone health in BRCA1/2+breast cancer survivors after risk-reducing salpingo-oophorectomy JOURNAL OF CANCER SURVIVORSHIP Sturgeon, K. M., Dean, L. T., Heroux, M., Kane, J., Bauer, T., Palmer, E., Long, J., Lynch, S., Jacobs, L., Sarwer, D. B., Leonard, M. B., Schmitz, K. 2017; 11 (2): 246-255

  Abstract

  The goal of this RCT was to examine the efficacy and safety of a web-based program to improve cardiovascular and bone health outcomes, among 35 BRCA1/2+ breast cancer survivors who underwent prophylactic oophorectomy and thus experienced premature surgical menopause.A 12-month commercially available web-based lifestyle modification program (Precision Nutrition Coaching) was utilized. Cardiovascular fitness, dietary intake, leisure time activity, body composition, bone mineral density, bone structure, and muscle strength were assessed.Average adherence to all program components was 74.8 %. Women in the intervention group maintained their cardiovascular fitness level over the 12 months (1.1 ± 7.9 %), while the control group significantly decreased fitness capacity (-4.0 ± 7.5 %). There was a significant difference between groups in percent change of whole body bone area (-0.8 ± 2.5 control and 0.5 ± 1.30 intervention). We also observed decreased BMI (-4.7 ± 6.2 %) and fat mass (-8.6 ± 12.7 %) in the intervention group due to significant concomitant decreases in caloric intake and increases in caloric expenditure. The control group demonstrated decreased caloric intake and decreased lean tissue mass.In this population at high risk for detrimental cardiovascular and bone outcomes, a commercially available lifestyle intervention program mitigated a decline in cardiovascular health, improved bone health, and decreased weight through fat loss.Precision Nutrition Coaching has shown benefit in breast cancer survivors for reduced risk of deleterious cardiovascular and bone outcomes.

  View details for DOI 10.1007/s11764-016-0582-z

  View details for Web of Science ID 000398471600008

  View details for PubMedCentralID PMC5386323

• Body composition estimation using skinfolds in children with and without health conditions affecting growth and body composition. Annals of human biology Wendel, D., Weber, D., Leonard, M. B., Magge, S. N., Kelly, A., Stallings, V. A., Pipan, M., Stettler, N., Zemel, B. S. 2017; 44 (2): 108-120

  Abstract

  Body composition prediction equations using skinfolds are useful alternatives to advanced techniques, but their utility across diverse paediatric populations is unknown.To evaluate published and new prediction equations across diverse samples of children with health conditions affecting growth and body composition.Anthropometric and dual-energy X-ray absorptiometry (DXA) body composition measures were obtained in children with Down syndrome (n = 59), Crohn disease (n = 128), steroid-sensitive nephrotic syndrome (n = 67) and a healthy reference group (n = 835). Published body composition equations were evaluated. New equations were developed for ages 3-21 years using the healthy reference sample and validated in other groups and national survey data.Fat mass (FM), fat-free mass (FFM) and percentage body fat (%BF) from published equations were highly correlated with DXA-derived measures (r = 0.71-0.98), but with poor agreement (mean difference = 2.4 kg, -1.9 kg and 6.3% for FM, FFM and %BF). New equations produced similar correlations (r = 0.85-1.0) with improved agreement for the reference group (0.2 kg, 0.4 kg and 0.0% for FM, FFM and %BF, respectively) and in sub-groups.New body composition prediction equations show excellent agreement with DXA and improve body composition estimation in healthy children and those with selected conditions affecting growth.

  View details for DOI 10.3109/03014460.2016.1168867

  View details for PubMedID 27121656

• Effect of Exercise and Antidepressants on Skeletal Outcomes in Adolescent Girls With Anorexia Nervosa. journal of adolescent health DiVasta, A. D., Feldman, H. A., O'Donnell, J. M., Long, J., Leonard, M. B., Gordon, C. M. 2017; 60 (2): 229-232

  Abstract

  We examined the relationships between malnutrition, lifestyle factors, and bone health in anorexia nervosa (AN) via dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT).Seventy adolescent girls with AN and 132 normal-weighted controls underwent pQCT tibial measures including trabecular volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness. Participants with AN underwent DXA measures of the axial skeleton. We assessed the association of DXA and pQCT measures with clinical and lifestyle variables.Body mass index Z-score and ideal body weight percentage were positively correlated with trabecular vBMD, cortical CSA, and section modulus (p < .04). Exercise was associated with all pQCT measures but only with hip BMD by DXA. In AN, the use of antidepressants was associated with lower pQCT measures (p < .03).Antidepressants may negatively, and exercise positively, influence BMD in adolescents with eating disorders. These findings offer a provocative look at two longstanding questions.

  View details for DOI 10.1016/j.jadohealth.2016.10.003

  View details for PubMedID 27939877

• Assessment of Sex Differences in Body Composition Among Adolescents With Anorexia Nervosa. journal of adolescent health Nagata, J. M., Golden, N. H., Peebles, R., Long, J., Murray, S. B., Leonard, M. B., Carlson, J. L. 2017

  Abstract

  To compare deficits in fat mass (FM) and lean body mass (LM) among male and female adolescents with anorexia nervosa (AN) and to identify other covariates associated with body composition.We retrospectively reviewed electronic medical records of all subjects aged 9-20 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of AN and dual-energy x-ray absorptiometry scans after initial evaluation at Stanford between March 1997 and February 2011. From the dual-energy x-ray absorptiometry scans, LM and FM results were converted to age-, height-, sex-, and race-specific Z-scores for age using the National Health and Nutrition Examination Survey reference data.A total of 16 boys and 119 girls with AN met eligibility criteria. The FM Z-score in girls with AN (-3.24 ± 1.50) was significantly lower than that in boys with AN (-2.41 ± .96) in unadjusted models (p = .007). LM was reduced in both girls and boys with AN, but there was no significant sex difference in LM Z-scores. In multivariate models, lower percentage median body mass index was significantly associated with lower FM Z-scores (β = .08, p < .0001) and lower LM Z-score (β = .03, p = .0002), whereas lower whole body bone mineral content Z-score was significantly associated with lower LM Z-score (β = .21, p = .0006).FM deficits in girls were significantly greater than those in boys with AN in unadjusted models; however, the degree of malnutrition appeared to be the primary factor accounting for this difference. There were no significant sex differences in FM or LM in adjusted models.

  View details for DOI 10.1016/j.jadohealth.2016.11.005

  View details for PubMedID 28087266

• ) on bone and body composition in children and young adults with HIV infection: a randomized, double-blind, placebo-controlled trial. Osteoporosis international Rovner, A. J., Stallings, V. A., Rutstein, R., Schall, J. I., Leonard, M. B., Zemel, B. S. 2017; 28 (1): 201-209

  Abstract

  It is unknown whether vitamin D supplementation positively impacts body composition and bone outcomes in children and young adults with HIV. This RCT found that despite increasing 25(OH)D concentrations, high dose vitamin D3 supplementation did not impact bone or body composition in children and young adults with HIV infection.The objective of this paper was to determine the impact of high-dose daily cholecalciferol (vitamin D3) supplementation on body composition and bone density, structure, and strength in children and young adults with perinatally acquired (PHIV) or behaviorally acquired (BHIV) HIV infection.Participants were randomized to receive vitamin D3 supplementation (7000 IU/day) or placebo for 12 months. Serum 25-hydroxyvitamin D [25(OH)D] concentrations, dual energy X-ray absorptiometry (DXA) of the whole body and lumbar spine, and peripheral quantitative computed tomography (pQCT) of tibia sites were acquired at 0, 6, and 12 months. DXA and pQCT outcomes were expressed as sex- and population-ancestry specific Z-scores relative to age and adjusted for height or tibia length, as appropriate.Fifty-eight participants (5.0 to 24.9 years) received vitamin D3 supplements (n = 30) or placebo (n = 28). At enrollment, groups were similar in age, sex, population ancestry, growth status, serum 25(OH)D concentrations, body composition, and size-adjusted bone measures. Median 25(OH)D concentrations were similar (17.3 ng/mL in the vitamin D3 supplementation group vs 15.6 ng/mL in the placebo group), and both groups had mild bone deficits. At 12 months, 25(OH)D rose significantly in the vitamin D supplementation group but not in the placebo group (26.4 vs 14.8 ng/mL, respectively, p < 0.008). After adjusting for population ancestry, sex, antiretroviral therapy use, and season, there were no significant treatment group differences in bone or body composition outcomes.Despite increasing 25(OH)D concentrations, 12 months of high-dose vitamin D3 supplementation did not impact bone or body composition in children and young adults with HIV infection.

  View details for DOI 10.1007/s00198-016-3826-x

  View details for PubMedID 27837268

• Risk of Urolithiasis in Anorexia Nervosa: A Population-Based Cohort Study Using the Health Improvement Network. European eating disorders review : the journal of the Eating Disorders Association Denburg, M. R., Leonard, M. B., Jemielita, T. O., Golden, N. H., Tasian, G. n., Copelovitch, L. n. 2017

  Abstract

  This population-based retrospective cohort study sought to determine if anorexia nervosa (AN) is associated with a higher risk of urolithiasis. Nine thousand three hundred two females with AN were compared to 92 959 randomly selected age-matched and practice-matched females. Cox regression was used to estimate the hazard ratio (HR) for urolithiasis and evaluate effect modification by age. Twenty-three participants with AN (0.25%) developed urolithiasis compared with 154 unexposed participants (0.17%) over a median of 4 years of observation. The risk of urolithiasis varied significantly with age (interaction p = 0.02). AN was associated with a more than threefold higher risk of urolithiasis in females ≤25 years of age (HR 3.49, 95% CI: 1.56-7.81; p = 0.002), but not in females over 25 years (HR 1.18, 95% CI: 0.69-2.02; p = 0.54). The distribution of diagnosis codes for urolithiasis differed between groups (p = 0.04), with a higher proportion of codes for uric acid urolithiasis in the AN (16.2%) versus unexposed group (5.0%). Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

  View details for PubMedID 28660717

• Effect of high-dose cholecalciferol (vitamin D-3) on bone and body composition in children and young adults with HIV infection: a randomized, double-blind, placebo-controlled trial OSTEOPOROSIS INTERNATIONAL Rovner, A. J., Stallings, V. A., Rutstein, R., Schall, J. I., Leonard, M. B., Zemel, B. S. 2017; 28 (1): 201-209

  View details for DOI 10.1007/s00198-016-3826-x

  View details for Web of Science ID 000391390100020

• Assessment of Sex Differences in Fracture Risk Among Patients With Anorexia Nervosa: A Population-Based Cohort Study Using The Health Improvement Network. Journal of bone and mineral research Nagata, J. M., Golden, N. H., Leonard, M. B., Copelovitch, L., Denburg, M. R. 2016

  Abstract

  Though previous studies have demonstrated an increased fracture risk in females with anorexia nervosa (AN), fracture risk in males is not well characterized. The objective of this study was to examine sex differences in fracture risk and site-specific fracture incidence in AN. We performed a population-based retrospective cohort study using The Health Improvement Network (THIN; a large database of anonymized electronic medical records collected at primary care clinics throughout the United Kingdom). The median calendar year for the start of the observation period was 2004-2005. We identified 9239 females and 556 males <60 years of age with AN, and 97,889 randomly selected sex-, age-, and practice-matched participants without eating disorders (92,329 females and 5560 males). Multivariable Cox regression was used to estimate the hazard ratio (HR) for incident fracture. Median age at start of observation was 29.8 years in females and 30.2 years in males. The HR for fracture associated with AN differed by sex and age (interaction p = 0.002). Females with AN had an increased fracture risk at all ages (HR, 1.59; 95% confidence interval [CI], 1.45 to 1.75). AN was associated with a higher risk of fracture among males >40 years of age (HR, 2.54; 95% CI, 1.32 to 4.90; p = 0.005) but not among males ≤40 years. Females with AN had a higher risk of fracture at nearly all anatomic sites. The greatest excess fracture risk was noted at the hip/femur (HR, 5.59; 95% CI, 3.44 to 9.09) and pelvis (HR, 4.54; 95% CI, 2.42 to 8.50) in females and at the vertebrae (HR, 7.25; 95% CI, 1.21 to 43.45) for males with AN. AN was associated with higher incident fracture risk in females across all age groups and in males >40 years old. Sites of highest fracture risk include the hip/femur and pelvis in females and vertebrae in males with AN. © 2016 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.3068

  View details for PubMedID 28019700

• Skeletal outcomes by peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in adolescent girls with anorexia nervosa OSTEOPOROSIS INTERNATIONAL DiVasta, A. D., Feldman, H. A., O'Donnell, J. M., Long, J., Leonard, M. B., Gordon, C. M. 2016; 27 (12): 3549-3558

  Abstract

  We conducted the first comparison of dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) outcomes in adolescent girls with anorexia nervosa. We observed deficits in bone density by both tools. pQCT assessments were associated with many of the same clinical parameters as have been previously established for DXA.Adolescents with anorexia nervosa (AN) commonly exhibit bone loss, but effects on bone geometry are less clear. We compared measures obtained by DXA and pQCT in girls with AN.Seventy females (age 15.5 ± 1.9 years ) with AN and 132 normal-weighted controls underwent tibial measures by pQCT including trabecular volumetric bone mineral density (vBMD) at the 3 % site, cortical vBMD and dimensions at the 38 % site, and muscle cross-sectional area (CSA) at the 66 % site. Participants with AN also underwent standard DXA measures. Independent t tests compared the pQCT results, while Pearson coefficient assessed correlations among DXA and pQCT measures.Trabecular vBMD Z-scores were lower in AN compared to controls (AN -0.31 ± 1.42 vs +0.11 ± 1.01, p = 0.01) and cortical vBMD Z-scores were higher (AN +0.18 ± 0.92 vs -0.50 ± 0.88, p < 0.001). Trabecular vBMD and cortical CSA Z-scores positively correlated with DXA BMD Z-scores (r range 0.57-0.82, p < 0.001). Markers of nutritional status positively correlated with Z-scores for trabecular vBMD, cortical CSA, section modulus, and muscle CSA (p < 0.04 for all).This study is the first to compare DXA and pQCT measurements in adolescent girls with AN. We observed deficits in BMD by both DXA and pQCT. pQCT assessments correlated well with DXA bone and body composition measures and were associated with many of the same clinical parameters and disease severity markers as have been previously established for DXA. The differences in cortical vBMD merit further study.

  View details for DOI 10.1007/s00198-016-3685-5

  View details for PubMedID 27392467

• The Determinants of Peak Bone Mass. journal of pediatrics Gordon, C. M., Zemel, B. S., Wren, T. A., Leonard, M. B., Bachrach, L. K., Rauch, F., Gilsanz, V., Rosen, C. J., Winer, K. K. 2016

  View details for DOI 10.1016/j.jpeds.2016.09.056

  View details for PubMedID 27816219

• Development of Novel Methods to Define Deficits in Appendicular Lean Mass Relative to Fat Mass PLOS ONE Weber, D., Long, J., Leonard, M. B., Zemel, B., Baker, J. F. 2016; 11 (10)

  Abstract

  Recent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity.Whole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMIFMI) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z-Score <-1.0. Correlations with physical function were assessed in an at-risk population.Positive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z-score on ALMI Z-score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z-scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not.Adjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data.

  View details for DOI 10.1371/journal.pone.0164385

  View details for Web of Science ID 000385504100053

  View details for PubMedID 27723820

  View details for PubMedCentralID PMC5056731

• Children with lower respiratory tract infections and serum 25-hydroxyvitamin D-3 levels: A case-control study PEDIATRIC PULMONOLOGY Velarde Lopez, A. A., Gerber, J. S., Leonard, M. B., Xie, D., Schinnar, R., Strom, B. L. 2016; 51 (10): 1080-1087

  Abstract

  Pneumonia is the leading cause of death in children under age of 5 years worldwide. The role of vitamin D in respiratory infections including pneumonia is unclear; therefore, we aimed to determine if children with lower respiratory tract infections had low serum 25-hydroxyvitamin D3 .We performed a case-control study of children ages 3-60 months from the Guatemala City metropolitan area, hospitalized with community-acquired pneumonia between September and December 2012. Controls were selected from the well-baby/care immunization clinics serving the population from which cases emerged. We analyzed serum 25-hydroxyvitamin D3 levels and conducted parental interviews to assess subject age, sex, race, feeding type, vitamin D supplementation, frequency of sun exposure, and maternal education. Height and weight were ascertained from medical records. Complete information was available for 70 (83%) of 84 eligible cases and 68 (60%) of 113 eligible controls.The median (IQR) serum 25-hydroxyvitamin D3 concentration for cases was 23.2 ng/ml (14.4-29.9) compared to 27.5 ng/ml (21.4-32.3) in controls (P = 0.006). Multiple regression analysis using an a priori cut-point for vitamin D of <20 ng/ml showed that children with lower respiratory tract infections were more likely to have low 25-hydroxyvitamin D3 levels than controls (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.2, P = 0.02).Children with lower respiratory tract infections in Guatemala had low 25-hydroxyvitamin D3 levels. Pediatr Pulmonol. 2016;51:1080-1087. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ppul.23439

  View details for Web of Science ID 000384681100012

  View details for PubMedID 27133156

• Reply. The Journal of pediatrics DeBoer, M. D., Leonard, M. B. 2016; 177: 334

  View details for DOI 10.1016/j.jpeds.2016.06.041

  View details for PubMedID 27449365

• Hip Fracture in Patients With Non-Dialysis-Requiring Chronic Kidney Disease. Journal of bone and mineral research Kim, S. M., Long, J., Montez-Rath, M., Leonard, M., Chertow, G. M. 2016; 31 (10): 1803-1809

  Abstract

  Patients with end-stage renal disease (ESRD) are at a high risk for hip fracture. Little is known about the risk for, and consequences of, hip fracture among patients with non-dialysis-requiring chronic kidney disease (CKD). We examined the incidence of hip fracture, in-hospital mortality, length of stay, and costs among patients with ESRD, non-dialysis-requiring CKD, and normal or near normal kidney function. Using the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, a nationally representative database, we identified hospitalizations for hip fracture in 2010. We incorporated data from the United States Renal Data System (USRDS) and the US census to calculate population-specific rates. Age-standardized incidence of hip fracture was highest among patients with ESRD (3.89/1000 person-years), followed by non-dialysis-requiring CKD (1.81/1000 persons) and patients with normal or near normal kidney function (1.18/1000 persons). In-hospital mo rtality (odds ratio [OR] = 1.69, 95% confidence interval [CI] 1.46 to 1.96), lengths of stay (median [10th, 90th percentiles] 5 [3 to 11] versus 5 [3 to 10] days) and costs (median $14,807 versus $13,314) were significantly higher in patients with non-dialysis-requiring CKD relative to patients with normal or near normal kidney function. In summary, non-dialysis-requiring CKD is associated with higher age-standardized rates of hip fracture and post-hip fracture mortality and higher resource utilization. © 2016 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.2862

  View details for PubMedID 27145189

• Assessment of sex differences in bone deficits among adolescents with anorexia nervosa. International journal of eating disorders Nagata, J. M., Golden, N. H., Peebles, R., Long, J., Leonard, M. B., Chang, A. O., Carlson, J. L. 2016

  Abstract

  The objective of this study was to compare sex differences in bone deficits among adolescents with anorexia nervosa (AN) and to identify other correlates of bone health.Electronic medical records of all patients 9-20 years of age with a DSM-5 diagnosis of AN who were evaluated by the eating disorders program at Stanford with dual-energy X-ray absorptiometry (DXA) between March 1997 and February 2011 were retrospectively reviewed. Whole body bone mineral content Z-scores and bone mineral density (BMD) Z-scores at multiple sites were recorded using the Bone Mineral Density in Childhood Study (BMDCS) reference data.A total of 25 males and 253 females with AN were included, with median age 15 years (interquartile range [IQR] 14-17) and median duration of illness 9 months (IQR 5-13). Using linear regression analyses, no significant sex differences in bone deficits were found at the lumbar spine, total hip, femoral neck, or whole body when controlling for age, %mBMI, and duration of illness. Lower %mBMI was significantly associated with bone deficits at all sites in adjusted models.This is the first study to evaluate sex differences in bone health among adolescents with AN, using novel DSM-5 criteria for AN and robust BMDCS reference data. We find no significant sex differences in bone deficits among adolescents with AN except for a higher proportion of females with femoral neck BMD Z-scores <-1. Degree of malnutrition was correlated with bone deficits at all sites. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016).

  View details for DOI 10.1002/eat.22626

  View details for PubMedID 27611361

• Rates and Outcomes of Parathyroidectomy for Secondary Hyperparathyroidism in the United States CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Kim, S. M., Long, J., Montez-Rath, M. E., Leonard, M. B., Norton, J. A., Chertow, G. M. 2016; 11 (7): 1260-1267

  Abstract

  Secondary hyperparathyroidism is common among patients with ESRD. Although medical therapy for secondary hyperparathyroidism has changed dramatically over the last decade, rates of parathyroidectomy for secondary hyperparathyroidism across the United States population are unknown. We examined temporal trends in rates of parathyroidectomy, in-hospital mortality, length of hospital stay, and costs of hospitalization.Using the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, a representative national database on hospital stay regardless of age and payer in the United States, we identified parathyroidectomies for secondary hyperparathyroidism from 2002 to 2011. Data from the US Renal Data System reports were used to calculate the rate of parathyroidectomy.We identified 32,971 parathyroidectomies for secondary hyperparathyroidism between 2002 and 2011. The overall rate of parathyroidectomy was approximately 5.4/1000 patients (95% confidence interval [95% CI], 5.0/1000 to 6.0/1000). The rate decreased from 2003 (7.9/1000 patients; 95% CI, 6.2/1000 to 9.6/1000), reached a nadir in 2005 (3.3/1000 patients; 95% CI, 2.6/1000 to 4.0/1000), increased again through 2006 (5.4/1000 patients; 95% CI, 4.4/1000 to 6.4/1000), and remained stable since that time. Rates of in-hospital mortality decreased from 1.7% (95% CI, 0.8% to 2.6%) in 2002 to 0.8% (95% CI, 0.1% to 1.6%) in 2011 (P for trend <0.001). In-hospital mortality rates were significantly higher in patients with heart failure (odds ratio [OR], 4.23; 95% CI, 2.59 to 6.91) and peripheral vascular disease (OR, 4.59; 95% CI, 2.75 to 7.65) and lower among patients with prior kidney transplantation (OR, 0.20; 95% CI, 0.06 to 0.65).Despite the use of multiple medical therapies, rates of parathyroidectomy of secondary hyperparathyroidism have not declined in recent years.

  View details for DOI 10.2215/CJN.10370915

  View details for PubMedID 27269300

• Effect of Low-Magnitude Mechanical Stimuli on Bone Density and Structure in Pediatric Crohn's Disease: A Randomized Placebo-Controlled Trial JOURNAL OF BONE AND MINERAL RESEARCH Leonard, M. B., Shults, J., Long, J., Baldassano, R. N., Brown, J. K., Hommel, K., Zemel, B. S., Mahboubi, S., Whitehead, K. H., Herskovitz, R., Lee, D., Rausch, J., Rubin, C. T. 2016; 31 (6): 1177-1188

  Abstract

  Pediatric Crohn's Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low-magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12-month randomized double-blind placebo-controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak-to-peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual-energy X-ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex-specific Z-scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12-month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention-to-treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z-score was +0.22 in the active arm and -0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z-score. Treatment response did not vary according to baseline body mass index (BMI) Z-score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites. © 2016 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.2799

  View details for Web of Science ID 000377269200008

  View details for PubMedCentralID PMC4891301

• Effect of Low-Magnitude Mechanical Stimuli on Bone Density and Structure in Pediatric Crohn's Disease: A Randomized Placebo-Controlled Trial. Journal of bone and mineral research Leonard, M. B., Shults, J., Long, J., Baldassano, R. N., Brown, J. K., Hommel, K., Zemel, B. S., Mahboubi, S., Howard Whitehead, K., Herskovitz, R., Lee, D., Rausch, J., Rubin, C. T. 2016; 31 (6): 1177-1188

  Abstract

  Pediatric Crohn's Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low-magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12-month randomized double-blind placebo-controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak-to-peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual-energy X-ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex-specific Z-scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12-month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention-to-treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z-score was +0.22 in the active arm and -0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z-score. Treatment response did not vary according to baseline body mass index (BMI) Z-score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites. © 2016 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.2799

  View details for PubMedID 26821779

• Comparison of Two ELISA Methods and Mass Spectrometry for Measurement of Vitamin D-Binding Protein: Implications for the Assessment of Bioavailable Vitamin D Concentrations Across Genotypes JOURNAL OF BONE AND MINERAL RESEARCH Denburg, M. R., Hoofnagle, A. N., Sayed, S., Gupta, J., de Boer, I. H., Appel, L. J., Durazo-Arvizu, R., Whitehead, K., Feldman, H. I., Leonard, M. B. 2016; 31 (6): 1128-1136

  Abstract

  Studies using vitamin D-binding protein (DBP) concentrations to estimate free and bioavailable vitamin D have increased dramatically in recent years. Combinations of two single-nucleotide polymorphisms (SNPs) produce three major DBP isoforms (Gc1f, Gc1s, and Gc2). A recent study showed that DBP concentrations quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) did not differ by race, whereas a widely used monoclonal enzyme-linked immunosorbent assay (ELISA) quantified DBP differentially by isoform, yielding significantly lower DBP concentrations in black versus white individuals. We compared measurements of serum DBP using a monoclonal ELISA, a polyclonal ELISA, and LC-MS/MS in 125 participants in the Chronic Renal Insufficiency Cohort (CRIC). Serum free and bioavailable 25OHD were calculated based on DBP concentrations from these three assays in homozygous participants, and race differences were compared. We confirmed that the monoclonal ELISA quantifies DBP differentially by isoform and showed that the polyclonal ELISA is not subject to this bias. Whereas ≤9% of the variability in DBP concentrations quantified using either LC-MS/MS or the polyclonal ELISA was explained by genotype, 85% of the variability in the monoclonal ELISA-based measures was explained by genotype. DBP concentrations measured by the monoclonal ELISA were disproportionately lower than LC-MS/MS-based results for Gc1f homozygotes (median difference -67%; interquartile range [IQR] -71%, -64%), 95% of whom were black. In contrast, the polyclonal ELISA yielded consistently and similarly higher measurements of DBP than LC-MS/MS, irrespective of genotype, with a median percent difference of +50% (IQR +33%, +65%). Contrary to findings using the monoclonal ELISA, DBP concentrations did not differ by race, and free and bioavailable 25OHD were significantly lower in black versus white participants based on both the polyclonal ELISA and LC-MS/MS, consistent with their lower total 25OHD. Future studies of DBP and free or bioavailable vitamin D metabolites should employ DBP assays that are not biased by DBP genotype. © 2016 American Society for Bone and Mineral Research.

  View details for DOI 10.1002/jbmr.2829

  View details for PubMedID 27250744

• Serum Infliximab, Antidrug Antibodies, and Tumor Necrosis Factor Predict Sustained Response in Pediatric Crohn's Disease INFLAMMATORY BOWEL DISEASES Stein, R., Lee, D., Leonard, M. B., Thayu, M., Denson, L. A., Chuang, E., Herskovitz, R., Kerbowski, T., Baldassano, R. N. 2016; 22 (6): 1370-1377

  Abstract

  Serum infliximab (s-IFX) levels, antibodies to IFX (ATI), and inflammatory markers are important in predicting clinical outcomes in adults, but their roles in pediatric Crohn's disease (CD) require further study. The primary aim of this study was to determine the association between serologic parameters during induction and ongoing IFX therapy at 12 months in pediatric CD.S-IFX, ATI, serum tumor necrosis factor alpha (s-TNF-α), and C-reactive protein were measured at IFX initiation, 10 weeks, 6 months, and 12 months in a prospective cohort study of children with CD at a single tertiary care center.At 12 months, 60 of 77 participants (78%) remained on IFX. Participants who completed 12 months of IFX had higher 10-week median s-IFX levels (20.40 μg/mL; interquartile range [IQR], 11.20-35.00] versus 8.70 μg/mL; IQR 0.90-16.90; P = 0.01), a greater proportion with undetectable 10-week ATI (P = 0.008), and a greater median change in s-TNF-α between baseline and week 10 (-5.96 pg/mL; IQR, -8.73 to -4.17 versus -1.76 pg/mL; IQR, -5.60 to 0.30; P = 0.006). Receiver operating characteristic analysis to predict ongoing IFX at 12 months showed area under the curve (95% confidence interval) for 10-week s-IFX and change in s-TNF-α from baseline to 10 weeks to be 0.71 (0.54-0.88) and 0.74 (0.58-0.91), respectively. C-reactive protein was not associated with ongoing therapy.ATI, s-IFX, and s-TNF-α during IFX induction are associated with 12-month clinical outcomes in pediatric CD. Future studies are needed to further define the clinical role of s-TNF-α measurement and to compare the clinical utility of 10 and 14-week ATI and s-IFX levels.

  View details for DOI 10.1097/MIB.0000000000000769

  View details for Web of Science ID 000377379500018

  View details for PubMedID 27057683

• Increases in Sex Hormones during Anti-Tumor Necrosis Factor a Therapy in Adolescents with Crohn's Disease. journal of pediatrics DeBoer, M. D., Thayu, M., Griffin, L. M., Baldassano, R. N., Denson, L. A., Zemel, B. S., Denburg, M. R., Agard, H. E., Herskovitz, R., Long, J., Leonard, M. B. 2016; 171: 146-152 e2

  Abstract

  To evaluate children with Crohn's disease for inverse relationships between systemic inflammatory cytokines and sex hormone regulation in the context of anti-tumor necrosis factor α (TNF-α) therapy.An observational study design was used to assess sex hormone and gonadotropin levels at the time of initiation of anti-TNF-α therapy and 10 weeks and 12 months later in 72 adolescents (Tanner stage 2-5) with Crohn's disease. Mixed-model linear regression was used to evaluate relationships between hormone levels, systemic inflammation, and dual-energy x-ray absorptiometry whole-body fat mass Z scores over the study interval.Sex hormone Z scores increased significantly during the 10-week induction interval: testosterone Z scores in male patients increased from a median of -0.36 to 0.40 (P < .05) and estradiol Z scores in females increased from -0.35 to -0.02 (P < .01). In mixed model regression, the pediatric Crohn's disease activity index score, cytokine levels, and measures of inflammation were significantly and negatively associated with sex hormone Z scores and with luteinizing hormone and follicle-stimulating hormone levels, adjusted for sex and Tanner stage. Sex hormone and gonadotropin levels were not associated with body mass index or fat mass Z-scores.Crohn's disease is associated with delayed maturation, and initiation of anti-TNF-α therapy was associated with significant and rapid increases in sex hormone and gonadotropin levels, in association with improvements in disease activity and measures of inflammation. These data are consistent with preclinical studies of the effects of inflammation on sex hormone regulation.

  View details for DOI 10.1016/j.jpeds.2016.01.003

  View details for PubMedID 26873656

  View details for PubMedCentralID PMC4808610

• Increases in Sex Hormones during Anti-Tumor Necrosis Factor a Therapy in Adolescents with Crohn's Disease JOURNAL OF PEDIATRICS DeBoer, M. D., Thayu, M., Griffin, L. M., Baldassano, R. N., Denson, L. A., Zemel, B. S., Denburg, M. R., Agard, H. E., Herskovitz, R., Long, J., Leonard, M. B. 2016; 171: 146-?

  Abstract

  To evaluate children with Crohn's disease for inverse relationships between systemic inflammatory cytokines and sex hormone regulation in the context of anti-tumor necrosis factor α (TNF-α) therapy.An observational study design was used to assess sex hormone and gonadotropin levels at the time of initiation of anti-TNF-α therapy and 10 weeks and 12 months later in 72 adolescents (Tanner stage 2-5) with Crohn's disease. Mixed-model linear regression was used to evaluate relationships between hormone levels, systemic inflammation, and dual-energy x-ray absorptiometry whole-body fat mass Z scores over the study interval.Sex hormone Z scores increased significantly during the 10-week induction interval: testosterone Z scores in male patients increased from a median of -0.36 to 0.40 (P < .05) and estradiol Z scores in females increased from -0.35 to -0.02 (P < .01). In mixed model regression, the pediatric Crohn's disease activity index score, cytokine levels, and measures of inflammation were significantly and negatively associated with sex hormone Z scores and with luteinizing hormone and follicle-stimulating hormone levels, adjusted for sex and Tanner stage. Sex hormone and gonadotropin levels were not associated with body mass index or fat mass Z-scores.Crohn's disease is associated with delayed maturation, and initiation of anti-TNF-α therapy was associated with significant and rapid increases in sex hormone and gonadotropin levels, in association with improvements in disease activity and measures of inflammation. These data are consistent with preclinical studies of the effects of inflammation on sex hormone regulation.

  View details for DOI 10.1016/j.jpeds.2016.01.003

  View details for Web of Science ID 000372753600032

  View details for PubMedCentralID PMC4808610

• Fracture Burden and Risk Factors in Childhood CKD: Results from the CKiD Cohort Study. Journal of the American Society of Nephrology Denburg, M. R., Kumar, J., Jemielita, T., Brooks, E. R., Skversky, A., Portale, A. A., Salusky, I. B., Warady, B. A., Furth, S. L., Leonard, M. B. 2016; 27 (2): 543-550

  Abstract

  Childhood chronic kidney disease (CHD) poses multiple threats to bone accrual; however, the associated fracture risk is not well characterized. This prospective cohort study included 537 CKD in Children (CKiD) participants. Fracture histories were obtained at baseline, at years 1, 3, and 5 through November 1, 2009, and annually thereafter. We used Cox regression analysis of first incident fracture to evaluate potential correlates of fracture risk. At enrollment, median age was 11 years, and 16% of patients reported a prior fracture. Over a median of 3.9 years, 43 males and 24 females sustained incident fractures, corresponding to 395 (95% confidence interval [95% CI], 293-533) and 323 (95% CI, 216-481) fractures per 10,000 person-years, respectively. These rates were 2- to 3-fold higher than published general population rates. The only gender difference in fracture risk was a 2.6-fold higher risk in males aged ≥15 years (570/10,000 person-years, adjusted P=0.04). In multivariable analysis, advanced pubertal stage, greater height Z-score, difficulty walking, and higher average log-transformed parathyroid hormone level were independently associated with greater fracture risk (all P≤0.04). Phosphate binder treatment (predominantly calcium-based) was associated with lower fracture risk (hazard ratio, 0.37; 95% CI, 0.15-0.91; P=0.03). Participation in more than one team sport was associated with higher risk (hazard ratio, 4.87; 95% CI, 2.21-10.75; P<0.001). In conclusion, children with CKD have a high burden of fracture. Regarding modifiable factors, higher average parathyroid hormone level was associated with greater risk of fracture, whereas phosphate binder use was protective in this cohort.

  View details for DOI 10.1681/ASN.2015020152

  View details for PubMedID 26139439

  View details for PubMedCentralID PMC4731126

• Association of 25-hydroxyvitamin D with areal and volumetric measures of bone mineral density and parathyroid hormone: impact of vitamin D-binding protein and its assays. Osteoporosis international Jemielita, T. O., Leonard, M. B., Baker, J., Sayed, S., Zemel, B. S., Shults, J., Herskovitz, R., Denburg, M. R. 2016; 27 (2): 617-626

  Abstract

  A comparison of the association of different forms of 25-hydroxyvitamin D [25(OH)D] with parathyroid hormone (PTH) and with areal and volumetric bone mineral density (BMD) demonstrated that bioavailable and free 25(OH)D do not provide a better index of vitamin D status in terms of bone health compared to total 25(OH)D.This study aims to compare measures of vitamin D-binding protein (DBP) using a monoclonal versus polyclonal ELISA and assess correlations of total versus estimated free and bioavailable 25(OH)D with BMD and PTH concentrations.DXA and peripheral quantitative CT (pQCT) scans were obtained in 304 adults (158 black, 146 white), ages 21-80 years. Free and bioavailable 25(OH)D were calculated from total 25(OH)D, DBP, and albumin concentrations. Multivariable linear regression with standardized beta coefficients was used to evaluate associations of bone measures and PTH with total, free, and bioavailable 25(OH)D.Measures of DBP obtained using a monoclonal versus polyclonal ELISA were not correlated (r s = 0.02, p = 0.76). Free and bioavailable 25(OH)D based on the polyclonal assay were lower in black versus white participants (p < 0.0001); this race difference was not evident using the monoclonal assay. Adjusted for age, sex, calcium intake, and race, all forms of 25(OH)D were negatively associated with PTH, but the absolute coefficient was greatest for total 25(OH)D (-0.34, p < 0.001) versus free/bioavailable 25(OH)D (-0.18/-0.24 depending on DBP assay, p ≤ 0.003). In analyses stratified on race, none of the measures of 25(OH)D were associated with BMD across DXA and pQCT sites.The monoclonal versus polyclonal ELISA yielded highly discrepant measures of DBP, particularly among black individuals, likely related to established race differences in DBP polymorphisms. Contrary to prior studies, our findings indicate that using DBP to estimate bioavailable and free 25(OH)D does not provide a better index of vitamin D status in terms of bone health.

  View details for DOI 10.1007/s00198-015-3296-6

  View details for PubMedID 26359185

• Declining Rates of Inpatient Parathyroidectomy for Primary Hyperparathyroidism in the US. PloS one Kim, S. M., Shu, A. D., Long, J., Montez-Rath, M. E., Leonard, M. B., Norton, J. A., Chertow, G. M. 2016; 11 (8)

  Abstract

  Parathyroidectomy is the only curative therapy for patients with primary hyperparathyroidism. However, the incidence, correlates and consequences of parathyroidectomy for primary hyperparathyroidism across the entire US population are unknown. We evaluated temporal trends in rates of inpatient parathyroidectomy for primary hyperparathyroidism, and associated in-hospital mortality, length of stay, and costs. We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) from 2002-2011. Parathyroidectomies for primary hyperparathyroidism were identified using International Classification of Diseases, Ninth Revision codes. Unadjusted and age- and sex- adjusted rates of inpatient parathyroidectomy for primary hyperparathyroidism were derived from the NIS and the annual US Census. We estimated 109,583 parathyroidectomies for primary hyperparathyroidism between 2002 and 2011. More than half (55.4%) of patients were younger than age 65, and more than three-quarters (76.8%) were female. The overall rate of inpatient parathyroidectomy was 32.3 cases per million person-years. The adjusted rate decreased from 2004 (48.3 cases/million person-years) to 2007 (31.7 cases/million person-years) and was sustained thereafter. Although inpatient parathyroidectomy rates declined over time across all geographic regions, a steeper decline was observed in the South compared to other regions. Overall in-hospital mortality rates were 0.08%: 0.02% in patients younger than 65 years and 0.14% in patients 65 years and older. Inpatient parathyroidectomy rates for primary hyperparathyroidism have declined in recent years.

  View details for DOI 10.1371/journal.pone.0161192

  View details for PubMedID 27529699

• Quantification of skeletal growth, modeling, and remodeling by in vivo micro computed tomography BONE Altman, A. R., Tseng, W., de Bakker, C. M., Chandra, A., Lan, S., Huh, B. K., Luo, S., Leonard, M. B., Qin, L., Liu, X. S. 2015; 81: 370-379

  View details for DOI 10.1016/j.bone.2015.07.037

  View details for PubMedID 26254742

• Response to Comment on Weber et al. Type 1 Diabetes is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN). Diabetes Care 2015;38:1913-1920. Diabetes care Weber, D. R., Haynes, K., Leonard, M. B., Willi, S. M., Denburg, M. R. 2015; 38 (12): e205-6

  View details for DOI 10.2337/dci15-0019

  View details for PubMedID 26604284

  View details for PubMedCentralID PMC5321239

• Increased risk of hip fracture associated with dually treated HIV/hepatitis B virus coinfection JOURNAL OF VIRAL HEPATITIS Byrne, D. D., Newcomb, C. W., Carbonari, D. M., Nezamzadeh, M. S., Leidl, K. B., Herlim, M., Yang, Y. X., Hennessy, S., Kostman, J. R., Leonard, M. B., Localio, A. R., Lo Re, V. 2015; 22 (11): 936-947

  View details for DOI 10.1111/jvh.12398

  View details for Web of Science ID 000362450600009

  View details for PubMedID 25754215

• Insulin-like Growth Factor 1 and Adiponectin and Associations with Muscle Deficits, Disease Characteristics, and Treatments in Rheumatoid Arthritis. journal of rheumatology Baker, J. F., Von Feldt, J. M., Mostoufi-Moab, S., Kim, W., Taratuta, E., Leonard, M. B. 2015; 42 (11): 2038-2045

  Abstract

  Rheumatoid arthritis (RA) is associated with low muscle mass and density. The objective of our study was to evaluate associations between 2 serum biomarkers [insulin-like growth factor 1 (IGF-1) and adiponectin] and skeletal muscle in RA.Whole-body dual energy X-ray absorptiometry measures of the appendicular lean mass index (ALMI; kg/m(2)) and total fat mass index (kg/m(2)), as well as the peripheral quantitative computed tomography measures of the lower leg muscle and fat cross-sectional area (CSA; cm(2)) and muscle density (an index of fat infiltration) were obtained from 50 participants with RA, ages 18-70 years. Multivariable linear regression analyses evaluated associations between body composition and levels of adiponectin and IGF-1, adjusted for age, sex, and adiposity.Greater age was associated with higher adiponectin (p = 0.06) and lower IGF-1 (p = 0.004). Eight subjects had IGF-1 levels below the reference range for their age and sex. These subjects had significantly lower ALMI and muscle CSA in multivariable models. Lower IGF-1 levels were associated with greater clinical disease activity and severity, as well as low ALMI, muscle CSA, and muscle density (defined as 1 SD below normative mean). After adjusting for age and sex, greater adiponectin levels were associated with lower BMI (p = 0.02) as well as lower ALMI, and lower muscle CSA, independent of adiposity (p < 0.05). Only greater Health Assessment Questionnaire scores were significantly associated with lower adiponectin levels.Low IGF-1 and greater adiponectin levels are associated with lower muscle mass in RA. Lower IGF-1 levels were seen in subjects with greater disease activity and severity.

  View details for DOI 10.3899/jrheum.150280

  View details for PubMedID 26329340

  View details for PubMedCentralID PMC4809051

• Use of proton pump inhibitors is associated with fractures in young adults: a population-based study. Osteoporosis international Freedberg, D. E., Haynes, K., Denburg, M. R., Zemel, B. S., Leonard, M. B., Abrams, J. A., Yang, Y. 2015; 26 (10): 2501-2507

  Abstract

  Proton pump inhibitors (PPIs) are associated with risk for fracture in osteoporotic adults. In this population-based study, we found a significant association between PPIs and fracture in young adults, with evidence of a dose-response effect. Young adults who use PPIs should be cautioned regarding risk for fracture.Proton pump inhibitors (PPIs) are associated with fracture in adults with osteoporosis. Because PPI therapy may interfere with bone accrual and attainment of peak bone mineral density, we studied the association between use of PPIs and fracture in children and young adults.We conducted a population-based, case-control study nested within records from general medical practices from 1994 to 2013. Participants were 4-29 years old with ≥1 year of follow-up who lacked chronic conditions associated with use of long-term acid suppression. Cases of fracture were defined as the first incident fracture at any site. Using incidence density sampling, cases were matched with up to five controls by age, sex, medical practice, and start of follow-up. PPI exposure was defined as 180 or more cumulative doses of PPIs. Conditional logistic regression was used to estimate the odds ratio and confidence interval for use of PPIs and fracture.We identified 124,799 cases and 605,643 controls. The adjusted odds ratio for the risk of fracture associated with PPI exposure was 1.13 (95 % CI 0.92 to 1.39) among children aged <18 years old and 1.39 (95 % CI 1.26 to 1.53) among young adults aged 18-29 years old. In young adults but not children, we observed a dose-response effect with increased total exposure to PPIs (p for trend <0.001).PPI use was associated with fracture in young adults, but overall evidence did not support a PPI-fracture relationship in children. Young adults who use PPIs should be cautioned regarding potentially increased risk for fracture, even if they lack traditional fracture risk factors.

  View details for DOI 10.1007/s00198-015-3168-0

  View details for PubMedID 25986385

  View details for PubMedCentralID PMC4575851

• Bone Mineral Accrual Is Associated With Parathyroid Hormone and 1,25-Dihydroxyvitamin D Levels in Children and Adolescents. journal of clinical endocrinology & metabolism DeBoer, M. D., Weber, D. R., Zemel, B. S., Denburg, M. R., Herskovitz, R., Long, J., Leonard, M. B. 2015; 100 (10): 3814-3821

  Abstract

  Rapid bone accrual and calcium demands during puberty may result in compensatory increases in PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels; however, these relations have not been established in longitudinal studies.To determine whether greater bone accrual velocity is associated with greater PTH and 1,25(OH)2D levels in healthy children and adolescents.Prospective cohort study with baseline PTH, 25-hydroxyvitamin D [25(OH)D], and 1,25(OH)2D levels and dual-energy x-ray absorptiometry whole-body bone mineral content (BMC) accrual over 12 months. Secondary analyses examined bone biomarkers and tibia quantitative computed tomography midshaft cortical-BMC.A total of 594 healthy participants, ages 5-21 years, with longitudinal measures in a subset of 145 participants.PTH and 1,25(OH)2D levels.PTH levels were higher during Tanner stages 3 and 4 compared to Tanner 1 (P < .05) in males and females and were inversely and significantly associated with 25(OH)D levels and dietary calcium intake. In multivariable analyses, greater bone accrual [measured directly as change in dual-energy x-ray absorptiometry-BMC (P < .001) or quantitative computed tomography-BMC (P < .05), or indirectly as growth velocity (P < .05) or greater bone-formation biomarker level (P < .01)] was associated with higher PTH levels, independent of 25(OH)D level and dietary calcium intake. Similar associations were observed between these direct and indirect indices of bone accrual and 1,25(OH)2D levels.PTH levels rise in midpuberty, in association with multiple measures of bone accrual. This is consistent with compensatory increases in PTH to drive 1,25(OH)2D production and calcium absorption during periods of increased calcium demands. Additional studies are needed to address PTH effects on bone modeling and remodeling during growth and development.

  View details for DOI 10.1210/jc.2015-1637

  View details for PubMedID 26241322

  View details for PubMedCentralID PMC4596042

• Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN) DIABETES CARE Weber, D. R., Haynes, K., Leonard, M. B., Willi, S. M., Denburg, M. R. 2015; 38 (10): 1913-1920

  View details for DOI 10.2337/dc15-0783

  View details for PubMedID 26216874

• Structural Bone Deficits in HIV/HCV-Coinfected, HCV-Monoinfected, and HIV-Monoinfected Women JOURNAL OF INFECTIOUS DISEASES Lo Re, V., Lynn, K., Stumm, E. R., Long, J., Nezamzadeh, M. S., Baker, J. F., Hoofnagle, A. N., Kapalko, A. J., Mounzer, K., Zemel, B. S., Tebas, P., Kostman, J. R., Leonard, M. B. 2015; 212 (6): 924-933

  Abstract

  Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is associated with reduced bone mineral density (BMD) and increased fracture rates, particularly in women. The structural underpinnings for skeletal fragility in coinfected women have not been characterized. We used tibial peripheral quantitative computed tomography to evaluate skeletal parameters in women, by HIV/HCV status.We conducted a cross-sectional study among 50 HIV/HCV-coinfected, 51 HCV-monoinfected, and 50 HIV-monoinfected women. Tibial volumetric BMD and cortical dimensions were determined with peripheral quantitative computed tomography. Race-specific z scores for age were generated using 263 female reference participants without HIV infection or liver disease.Coinfected participants had lower mean z scores for trabecular volumetric BMD (-0.85), cortical volumetric BMD (-0.67), cortical area (-0.61), and cortical thickness (-0.77) than reference participants (all P < .001). The smaller cortical dimensions were due to greater mean z scores for endosteal circumference (+0.67; P < .001) and comparable z scores for periosteal circumference (+0.04; P = .87). Trabecular volumetric BMD was lower in coinfected than in HCV- or HIV-monoinfected participants. HCV-infected women with stage 3-4 liver fibrosis had lower mean z scores for trabecular volumetric BMD, cortical thickness, and total hip BMD those with stage 0-2 fibrosis.Compared with healthy reference patients, HIV/HCV-coinfected women had decreased tibial trabecular volumetric BMD, diminished cortical dimensions, and significant endocortical bone loss.

  View details for DOI 10.1093/infdis/jiv147

  View details for Web of Science ID 000361285600012

  View details for PubMedID 25754980

  View details for PubMedCentralID PMC4548465

• Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and Insulin Resistance in Long-Term Survivors of Pediatric Hematopoietic Stem Cell Transplantation JOURNAL OF BONE AND MINERAL RESEARCH Mostoufi-Moab, S., Magland, J., Isaacoff, E. J., Sun, W., Rajapakse, C. S., Zemel, B., Wehrli, F., Shekdar, K., Baker, J., Long, J., Leonard, M. B. 2015; 30 (9): 1657-1666

  View details for DOI 10.1002/jbmr.2512

  View details for Web of Science ID 000359866800013

• Deficits in bone density and structure in children and young adults following Fontan palliation BONE Avitabile, C. M., Goldberg, D. J., Zemel, B. S., Brodsky, J. L., Dodds, K., Hayden-Rush, C., Whitehead, K. K., Goldmuntz, E., Rychik, J., Leonard, M. B. 2015; 77: 12-16

  Abstract

  Survival of patients with congenital heart disease has improved such that there are now more adults than children living with these conditions. Complex single ventricle congenital heart disease requiring Fontan palliation is associated with multiple risk factors for impaired bone accrual. Bone density and structure have not been characterized in these patients.Tibia peripheral quantitative computed tomography (pQCT) was used to assess trabecular and cortical volumetric bone mineral density (vBMD), cortical dimensions, and calf muscle area in 43 Fontan participants (5-33 years old), a median of 10 years following Fontan palliation. pQCT outcomes were converted to sex- and race-specific Z-scores relative to age based on >700 healthy reference participants. Cortical dimensions and muscle area were further adjusted for tibia length.Height Z-scores were lower in Fontan compared to reference participants (mean ± SD: -0.29 ± 1.00 vs. 0.25 ± 0.93, p < 0.001); BMI Z-scores were similar (0.16 ± 0.88 vs. 0.35 ± 1.02, p = 0.1). Fontan participants had lower trabecular vBMD Z-scores (-0.85 ± 0.96 vs. 0.01 ± 1.02, p < 0.001); cortical vBMD Z-scores were similar (-0.17 ± 0.98 vs. 0.00 ± 1.00, p = 0.27). Cortical dimensions were reduced with lower cortical area (-0.59 ± 0.84 vs. 0.00 ± 0.88, p<0.001) and periosteal circumference (-0.50 ± 0.82 vs. 0.00 ± 0.84, p < 0.001) Z-scores, compared to reference participants. Calf muscle area Z-scores were lower in the Fontan participants (-0.45 ± 0.98 vs. 0.00 ± 0.96, p = 0.003) and lower calf muscle area Z-scores were associated with smaller periosteal circumference Z-scores (R = 0.62, p < 0.001). Musculoskeletal deficits were not associated with age, Fontan characteristics, parathyroid hormone or vitamin D levels.Children and young adults demonstrate low trabecular vBMD, cortical structure and muscle area following Fontan. Muscle deficits were associated with smaller periosteal dimensions. Future studies should determine the fracture implications of these deficits and identify interventions to promote musculoskeletal development.

  View details for DOI 10.1016/j.bone.2015.04.012

  View details for Web of Science ID 000355717800003

  View details for PubMedID 25882907

• Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure BONE Streeten, E. A., Ramirez, S., Eliades, M., Jaimungal, S., Chandrasekaran, S., Kathleen, R., Morton, D. H., Puffenberger, E. G., Herskovitz, R., Leonard, M. B. 2015; 77: 17-23

  View details for DOI 10.1016/j.bone.2015.04.007

  View details for Web of Science ID 000355717800004

  View details for PubMedID 25892485

• Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure. Bone Streeten, E. A., Ramirez, S., Eliades, M., Jaimungal, S., Chandrasekaran, S., Kathleen, R., Holmes Morton, D., Puffenberger, E. G., Herskovitz, R., Leonard, M. B. 2015; 77: 17-23

  Abstract

  Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of childhood osteoporosis and blindness due to inactivating mutations in LDL receptor-like protein 5 (LRP5). We and others have reported improvement in areal bone mineral density (aBMD) by DXA in OPPG on short term bisphosphonates. Long-term data on bisphosphonate use in OPPG and measures of volumetric BMD (vBMD) and cortical structure are not available. In addition, no long-term DXA data on untreated OPPG is available. The aims of this study were to: (1) record low trauma fractures and longitudinal aBMD by DXA in 5 OPPG patients on chronic bisphosphonate treatment, and in 4 OPPG patients never treated (2) to perform tibia peripheral quantitative CT (pQCT) to evaluate volumetric bone mineral density (vBMD), cortical structure and calf muscle area in 6 OPPG patients and 14 unaffected first degree family members. pQCT results were converted to sex-specific Z-scores for age and adjusted for tibia length based on data in >700 reference participants. We observed 4 fractures (3 femoral shafts) in 3 OPPG patients while on bisphosphonates, after each achieved significant improvement in aBMD. OPPG participants had significantly lower mean trabecular vBMD (-1.51 vs. 0.17, p = 0.002), cortical area (-2.36 vs. 0.37; p < 0.001) and periosteal circumference (-1.86 vs. -0.31, p = 0.001) Z-scores, compared with unaffected participants and had a trend toward lower muscle area Z-score (-0.69 vs. 0.47, p = 0.12). These data demonstrate substantial bone fragility despite improvements in aBMD. The pQCT data provide insight into the fragility with substantial deficits in trabecular vBMD and cortical dimensions, consistent with OPPG effects of bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG.

  View details for DOI 10.1016/j.bone.2015.04.007

  View details for PubMedID 25892485

  View details for PubMedCentralID PMC4480984

• Improvements in Bone Density and Structure during Anti-TNF-a Therapy in Pediatric Crohn's Disease. journal of clinical endocrinology & metabolism Griffin, L. M., Thayu, M., Baldassano, R. N., DeBoer, M. D., Zemel, B. S., Denburg, M. R., Denson, L. A., Shults, J., Herskovitz, R., Long, J., Leonard, M. B. 2015; 100 (7): 2630-2639

  Abstract

  Pediatric Crohn's Disease (CD) is associated with deficits in trabecular bone mineral density (BMD) and cortical structure, potentially related to TNF-α effects to decrease bone formation and promote bone resorption.This study aimed to examine changes in bone density and structure in children and adolescents with CD following initiation of anti-TNF-α therapy.Participants (n = 74; age 5-21 years) with CD completed a 12-month prospective cohort study.Tibia peripheral quantitative computed tomography scans were obtained at initiation of anti-TNF-α therapy and 12 months later. Musculoskeletal outcomes were expressed as sex-and race-specific z scores relative to age, based on >650 reference participants.At baseline, CD participants had lower height, trabecular BMD, cortical area (due to smaller periosteal and larger endocortical circumferences), and muscle area z scores, compared with reference participants (all P < .01). Pediatric CD activity index decreased during the 10-week induction (P < .001), in association with subsequent gains in height, trabecular BMD, cortical area (due to recovery of endocortical bone), and muscle area z scores over 12 months (height P < .05; others P < .001). Bone-specific alkaline phosphatase levels, a biomarker of bone formation, increased a median of 75% (P < .001) during induction with associated 12-month improvements in trabecular BMD and cortical area z scores (both P < .001). Younger age was associated with greater increases in trabecular BMD z scores (P < .001) and greater linear growth with greater recovery of cortical area (P < .001).Anti-TNF-α therapy was associated with improvements in trabecular BMD and cortical structure. Improvements were greater in younger and growing participants, suggesting a window of opportunity for treatment of bone deficits.

  View details for DOI 10.1210/jc.2014-4152

  View details for PubMedID 25919459

  View details for PubMedCentralID PMC4490303

• The impact of vitamin D-3 supplementation on muscle function among HIV-infected children and young adults: a randomized controlled trial JOURNAL OF MUSCULOSKELETAL & NEURONAL INTERACTIONS Brown, J. C., Schall, J. I., Rutstein, R. M., Leonard, M. B., Zemel, B. S., Stallings, V. A. 2015; 15 (2): 145-153

  Abstract

  We tested the hypothesis that daily vitD3 supplementation increases neuromuscular motor skills, jump power, jump energy, muscular force, and muscular strength.This was a secondary analysis of a randomized controlled trial of 12-months of oral 7,000 IU/day vitD3 supplementation or placebo among 56 persons living with HIV aged 9-25 years. Neuromuscular motor skills were quantified using the Bruininks-Oseretsky Test of Motor Proficiency. Power was quantified using peak jump power, and energy was quantified using peak jump height. Muscular force was quantified using isometric ankle plantar- and dorsiflexion, isokinetic knee flexion and extension. Muscular strength was quantified using isometric handgrip strength.After 12-months, serum 25-hydroxyvitamin D [25(OH)D] was higher with supplementation versus placebo (β=12.1 ng/mL; P<0.001). In intention-to-treat analyses, supplementation improved neuromuscular motor skills versus placebo (β=1.14; P=0.041). We observed no effect of supplementation on jump power, jump energy, muscular force, or muscular strength outcomes versus placebo.Among HIV-infected children and young adults supplementation with daily high-dose vitD3 increased concentration of serum 25(OH)D and improved neuromuscular motor skills versus placebo.

  View details for Web of Science ID 000356001800004

  View details for PubMedID 26032206

  View details for PubMedCentralID PMC4533987

• Tibia and radius bone geometry and volumetric density in obese compared to non-obese adolescents. Bone Leonard, M. B., Zemel, B. S., Wrotniak, B. H., Klieger, S. B., Shults, J., Stallings, V. A., Stettler, N. 2015; 73: 69-76

  Abstract

  Childhood obesity is associated with biologic and behavioral characteristics that may impact bone mineral density (BMD) and structure. The objective was to determine the association between obesity and bone outcomes, independent of sexual and skeletal maturity, muscle area and strength, physical activity, calcium intake, biomarkers of inflammation, and vitamin D status. Tibia and radius peripheral quantitative CT scans were obtained in 91 obese (BMI>97th percentile) and 51 non-obese adolescents (BMI>5th and <85th percentiles). Results were converted to sex- and race-specific Z-scores relative to age. Cortical structure, muscle area and muscle strength (by dynamometry) Z-scores were further adjusted for bone length. Obese participants had greater height Z-scores (p<0.001), and advanced skeletal maturity (p<0.0001), compared with non-obese participants. Tibia cortical section modulus and calf muscle area Z-scores were greater in obese participants (1.07 and 1.63, respectively, both p<0.0001). Tibia and radius trabecular and cortical volumetric BMD did not differ significantly between groups. Calf muscle area and strength Z-scores, advanced skeletal maturity, and physical activity (by accelerometry) were positively associated with tibia cortical section modulus Z-scores (all p<0.01). Adjustment for muscle area Z-score attenuated differences in tibia section modulus Z-scores between obese and non-obese participants from 1.07 to 0.28. After multivariate adjustment for greater calf muscle area and strength Z-scores, advanced maturity, and less moderate to vigorous physical activity, tibia section modulus Z-scores were 0.32 (95% CI -0.18, 0.43, p=0.06) greater in obese, vs. non-obese participants. Radius cortical section modulus Z-scores were 0.45 greater (p=0.08) in obese vs. non-obese participants; this difference was attenuated to 0.14 with adjustment for advanced maturity. These findings suggest that greater tibia cortical section modulus in obese adolescents is attributable to advanced skeletal maturation and greater muscle area and strength, while less moderate to vigorous physical activities offset the positive effects of these covariates. The impact of obesity on cortical structure was greater at weight bearing sites.

  View details for DOI 10.1016/j.bone.2014.12.002

  View details for PubMedID 25497572

• Tibia and radius bone geometry and volumetric density in obese compared to non-obese adolescents BONE Leonard, M. B., Zemel, B. S., Wrotniak, B. H., Klieger, S. B., Shults, J., Stallings, V. A., Stettler, N. 2015; 73: 69-76

  View details for DOI 10.1016/j.bone.2014.12.002

  View details for Web of Science ID 000350532800009

  View details for PubMedID 25497572

• Usefulness of Insulin like Growth Factor 1 as a Marker of Heart Failure in Children and Young Adults After the Fontan Palliation Procedure AMERICAN JOURNAL OF CARDIOLOGY Avitabile, C. M., Leonard, M. B., Brodsky, J. L., Whitehead, K. K., Ravishankar, C., Cohen, M. S., Gaynor, J. W., Rychik, J., Goldberg, D. J. 2015; 115 (6): 816-820

  Abstract

  Growth hormone and its mediator, insulinlike growth factor 1 (IGF-1), are key determinants of growth in children and young adults. As patients with Fontan physiology often experience diminished longitudinal growth, we sought to describe IGF-1 levels in this population and to identify factors associated with IGF-1 deficiency. Forty-one Fontan subjects ≥5 years were evaluated in this cross-sectional study. Age- and gender-specific height Z scores were generated using national data. Laboratory testing included IGF-1 and brain natriuretic peptide (BNP) levels. IGF-1 levels were converted to age-, gender-, and Tanner stage-specific Z scores. BNP levels were log transformed to achieve a normal distribution (log-BNP). Medical records were reviewed for pertinent clinical variables. Predictors of IGF-1 Z score were assessed through the Student t test and Pearson's correlation. Median age was 11.1 years (range 5.1 to 33.5 years), and time from Fontan was 8.2 years (1.1 to 26.7). Mean height Z score was -0.2 ± 0.9 with a mean IGF-1 Z score of -0.1 ± 1.3. There was no association between IGF-1 Z score and height Z score. Longer interval since Fontan (R = -0.32, p = 0.04), higher log-BNP (R = -0.40; p = 0.01), and lower indexed systemic flow on cardiac magnetic resonance (R = 0.55, p = 0.02) were associated with lower IGF-1 Z scores. In conclusion, in this cohort with Fontan physiology, higher BNP and lower systemic flow were associated with lower IGF-1 Z score. Longitudinal studies are needed to determine if these relations represent a mechanistic explanation for diminished growth in children with this physiology and with other forms of congenital heart disease.

  View details for DOI 10.1016/j.amjcard.2014.12.041

  View details for Web of Science ID 000351482700018

  View details for PubMedID 25616534

• Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference KIDNEY INTERNATIONAL Ketteler, M., Elder, G. J., Evenepoel, P., Ix, J. H., Jamal, S. A., Lafage-Proust, M., Shroff, R., Thadhani, R. I., Tonelli, M. A., Kasiske, B. L., Wheeler, D. C., Leonard, M. B. 2015; 87 (3): 502-508

  Abstract

  A new definition and classification of chronic kidney disease-mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.Kidney International advance online publication, 4 February 2015; doi:10.1038/ki.2014.425.

  View details for DOI 10.1038/ki.2014.425

  View details for Web of Science ID 000350533300006

  View details for PubMedID 25651364

• Muscle Torque Relative to Cross-Sectional Area and the Functional Muscle-Bone Unit in Children and Adolescents With Chronic Disease JOURNAL OF BONE AND MINERAL RESEARCH Lee, D. Y., Wetzsteon, R. J., Zemel, B. S., Shults, J., Organ, J. M., Foster, B. J., Herskovitz, R. M., Foerster, D. L., Leonard, M. B. 2015; 30 (3): 563-571

  View details for Web of Science ID 000350066900020

• Muscle Torque Relative to Cross-Sectional Area and the Functional Muscle-Bone Unit in Children and Adolescents With Chronic Disease JOURNAL OF BONE AND MINERAL RESEARCH Lee, D. Y., Wetzsteon, R. J., Zemel, B. S., Shults, J., Organ, J. M., Foster, B. J., Herskovitz, R. M., Foerster, D. L., Leonard, M. B. 2015; 30 (3): 575-583

  Abstract

  Measures of muscle mass or size are often used as surrogates of forces acting on bone. However, chronic diseases may be associated with abnormal muscle force relative to muscle size. The muscle-bone unit was examined in 64 children and adolescents with new-onset Crohn's disease (CD), 54 with chronic kidney disease (CKD), 51 treated with glucocorticoids for nephrotic syndrome (NS), and 264 healthy controls. Muscle torque was assessed by isometric ankle dynamometry. Calf muscle cross-sectional area (CSA) and tibia cortical section modulus (Zp) were assessed by quantitative CT. Log-linear regression was used to determine the relations among muscle CSA, muscle torque, and Zp, adjusted for tibia length, age, Tanner stage, sex, and race. Muscle CSA and muscle torque-relative-to-muscle CSA were significantly lower than controls in advanced CKD (CSA -8.7%, p = 0.01; torque -22.9%, p < 0.001) and moderate-to-severe CD (CSA -14.1%, p < 0.001; torque -7.6%, p = 0.05), but not in NS. Zp was 11.5% lower in advanced CKD (p = 0.005) compared to controls, and this deficit was attenuated to 6.7% (p = 0.05) with adjustment for muscle CSA. With additional adjustment for muscle torque and body weight, Zp was 5.9% lower and the difference with controls was no longer significant (p = 0.09). In participants with moderate-to-severe CD, Zp was 6.8% greater than predicted (p = 0.01) given muscle CSA and torque deficits (R(2)  = 0.92), likely due to acute muscle loss in newly-diagnosed patients. Zp did not differ in NS, compared with controls. In conclusion, muscle torque relative to muscle CSA was significantly lower in CKD and CD, compared with controls, and was independently associated with Zp. Future studies are needed to determine if abnormal muscle strength contributes to progressive bone deficits in chronic disease, independent of muscle area. © 2014 American Society for Bone and Mineral Research.

  View details for Web of Science ID 000350066900023

  View details for PubMedID 25264231

• Obesity Is Associated with Greater Valgus Knee Alignment in Pubertal Children, and Higher Body Mass Index Is Associated with Greater Variability in Knee Alignment in Girls JOURNAL OF RHEUMATOLOGY Bout-Tabaku, S., Shults, J., Zemel, B. S., Leonard, M. B., Berkowitz, R. I., Stettler, N., Burnham, J. M. 2015; 42 (1): 126-133

  Abstract

  In adults, osteoarthritis (OA) is associated with obesity and knee alignment. Whether knee alignment differences develop during childhood and are associated with obesity is unknown. We assessed the distribution of knee alignment in children and adolescents, and determined how knee alignment differs between obese and nonobese children.This cross-sectional study examined knee alignment in 155 healthy weight and 165 obese subjects. Knee alignment [metaphyseal-diaphyseal angle (MDA) and anterior tibiofemoral angle (ATFA)] and fat mass were measured using whole body dual-energy X-ray absorptiometry (DEXA). National reference data were used to generate age- and sex-specific body mass index (BMI, kg/m(2)) Z-scores. Multivariable linear regression was used to identify independent factors associated with ATFA and MDA.The mean MDA and ATFA were similar between obese and nonobese subjects. In stratified analyses, females had greater variability in MDA and ATFA values (p < 0.001 and p = 0.04, respectively) at higher BMI Z-scores. Compared with healthy weight controls, obese subjects had less valgus of the MDA prior to the onset of puberty (+ 2.0°, p = 0.001), but had greater valgus at later pubertal stages (-1.9°, p = 0.01).We found significantly greater variability in knee alignment among females at higher BMI Z-scores, and greater valgus alignment in obese adolescents in late puberty. The major limitation is the use of DEXA for assessment of alignment, which needs validation against longstanding radiographs. Longitudinal studies are needed to determine whether childhood obesity is a risk factor for progressive malalignment that may predispose to pain and risk of early osteoarthritis.

  View details for DOI 10.3899/jrheum.131349

  View details for Web of Science ID 000347127300022

  View details for PubMedID 25362652

• Are Men at Greater Risk of Lean Mass Deficits in Rheumatoid Arthritis? ARTHRITIS CARE & RESEARCH Baker, J. F., Long, J., Ibrahim, S., Leonard, M. B., Katz, P. 2015; 67 (1): 112-119

  Abstract

  We aimed to determine if there were sex differences in lean body mass (LBM) in patients with rheumatoid arthritis (RA) when compared with sex- and race-specific National Health and Nutrition Examination Survey (NHANES) reference data, and to investigate the impact of sex differences in risk factors for LBM deficits.Dual x-ray absorptiometry measures of whole body LBM and appendicular LBM (arms and legs, appendicular lean mass [ALM]) were obtained on a total of 190 subjects from 2 independent cohorts (141 from San Francisco [SF], 49 from Philadelphia [PA]), expressed as indices adjusted for height (LBM index and ALM index, kg/m(2) ), and converted to sex- and race-specific Z scores relative to age and based on NHANES data. Sarcopenia was defined using 4 different sex-specific definitions. Multivariable linear and logistic regression analyses adjusted for disease activity, disease duration, physical activity, anti-cyclic citrullinated peptide seropositivity, fat mass index, and glucocorticoid use.While there were significant differences between the 2 cohorts, ALM index Z scores were significantly lower in men compared to women in both (SF: -1.43 versus -0.43, P < 0.0001; PA: -0.83 versus -0.06, P = 0.03). Observed sex differences were significant after adjustment in multivariable analyses within both cohorts. Odds of sarcopenia were 3 to 8 times greater in men in the SF cohort. Men in the PA cohort also had a higher, but nonsignificant, risk of sarcopenia.RA is associated with significant LBM deficits, with greater deficits observed in men. Future study may help elucidate the mechanisms driving greater deficits among men.

  View details for DOI 10.1002/acr.22396

  View details for Web of Science ID 000346917200016

  View details for PubMedID 25048740

• Risk of Fracture in Urolithiasis: A Population-Based Cohort Study Using the Health Improvement Network CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Denburg, M. R., Leonard, M. B., Haynes, K., Tuchman, S., Tasian, G., Shults, J., Copelovitch, L. 2014; 9 (12): 2133-2140

  Abstract

  Studies have shown decreased bone mineral density in individuals with urolithiasis, but their burden of fracture remains unclear. This study sought to determine whether urolithiasis is associated with increased fracture risk across the lifespan and to delineate sex effects.A population-based retrospective cohort study using The Health Improvement Network was performed. The median calendar year for the start of the observation period was 2004 (1994-2012). This study identified 51,785 participants with ≥1 of 87 diagnostic codes for urolithiasis and 517,267 randomly selected age-, sex-, and practice-matched participants. Cox regression was used to estimate the hazard ratio (HR) for first fracture. Fractures identified using diagnostic codes were classified by anatomic site.Median age was 53 years, and 67% of participants were men, confirming their greater urolithiasis burden. Median time from urolithiasis diagnosis to fracture was 10 years. The HR for fracture associated with urolithiasis differed by sex and age (P for interactions, P≤0.003). In men, the adjusted HR was greatest in adolescence (1.55; 95% confidence interval [95% CI], 1.07 to 2.25) with an overall HR of 1.10 (95% CI, 1.05 to 1.16). Urolithiasis was associated with higher fracture risk in women aged 30-79 years (HR, 1.17-1.52), and was highest in women aged 30-39 years (HR, 1.52; 95% CI, 1.23 to 1.87). Peak background fracture rates were highest in boys aged 10-19 years and in women aged 70-79 years. The incidence per 10,000 person-years in participants with versus without urolithiasis was 392 versus 258 in male participants aged 10-19 years, and 263 versus 218 in women aged 70-79 years. Distribution of fracture site within sex did not differ between participants with versus without urolithiasis.Urolithiasis was associated with higher incident fracture risk. The significantly higher risk at times of peak background fracture incidence in adolescent boys and elderly women has profound public health implications.

  View details for DOI 10.2215/CJN.04340514

  View details for Web of Science ID 000345947800018

  View details for PubMedID 25341724

• Urinary Creatinine Excretion, Bioelectrical Impedance Analysis, and Clinical Outcomes in Patients with CKD: The CRIC Study CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Wilson, F. P., Xie, D., Anderson, A. H., Leonard, M. B., Reese, P. P., Delafontaine, P., Horwitz, E., Kallem, R., Navaneethan, S., Ojo, A., Porter, A. C., Sondheimer, J. H., Sweeney, H. L., Townsend, R. R., Feldman, H. I. 2014; 9 (12): 2095-2103

  Abstract

  Previous studies in chronic disease states have demonstrated an association between lower urinary creatinine excretion (UCr) and increased mortality, a finding presumed to reflect the effect of low muscle mass on clinical outcomes. Little is known about the relationship between UCr and other measures of body composition in terms of the ability to predict outcomes of interest.Using data from the Chronic Renal Insufficiency Cohort (CRIC), the relationship between UCr, fat free mass (FFM) as estimated by bioelectrical impedance analysis, and (in a subpopulation) whole-body dual-energy x-ray absorptiometry assessment of appendicular lean mass were characterized. The associations of UCr and FFM with mortality and ESRD were compared using Cox proportional hazards models.A total of 3604 CRIC participants (91% of the full CRIC cohort) with both a baseline UCr and FFM measurement were included; of these, 232 had contemporaneous dual-energy x-ray absorptiometry measurements. Participants were recruited between July 2003 and March 2007. UCr and FFM were modestly correlated (rho=0.50; P<0.001), while FFM and appendicular lean mass were highly correlated (rho=0.91; P<0.001). Higher urinary urea nitrogen, black race, younger age, and lower serum cystatin C level were all significantly associated with higher UCr. Over a median (interquartile range) of 4.2 (3.1-5.0) years of follow-up, 336 (9.3%) participants died and 510 (14.2%) reached ESRD. Lower UCr was associated with death and ESRD even after adjustment for FFM (adjusted hazard ratio for death per 1 SD higher level of UCr, 0.63 [95% confidence interval, 0.56 to 0.72]; adjusted hazard ratio for ESRD per 1 SD higher level of UCr, 0.70 [95% confidence interval, 0.63 to 0.75]).Among a cohort of individuals with CKD, lower UCr is associated with death and ESRD independent of FFM as assessed by bioelectrical impedance analysis.

  View details for DOI 10.2215/CJN.03790414

  View details for Web of Science ID 000345947800013

  View details for PubMedID 25381342

• Lean mass deficits, vitamin D status and exercise capacity in children and young adults after Fontan palliation HEART Avitabile, C. M., Leonard, M. B., Zemel, B. S., Brodsky, J. L., Lee, D., Dodds, K., Hayden-Rush, C., Whitehead, K. K., Goldmuntz, E., Paridon, S. M., Rychik, J., Goldberg, D. J. 2014; 100 (21): 1702-1707

  Abstract

  We sought to evaluate body composition in children and young adults with Fontan physiology. Leg lean mass (LM) deficits correlate with diminished exercise capacity in other populations and may contribute to exercise limitations in this cohort.This cross-sectional study included whole body dual energy X-ray absorptiometry scans in 50 Fontan participants ≥5 years, and measures of peak oxygen consumption (VO2) in 28. Whole body and leg LM (a measure of skeletal muscle) were converted to sex- and race-specific Z-scores, relative to age and stature, based on 992 healthy reference participants.Median age was 11.5 (range 5.1-33.5) years at 9.3 (1.1-26.7) years from Fontan. Height Z-scores were lower in Fontan compared with reference participants (-0.47±1.08 vs 0.25±0.93, p<0.0001). Body mass index Z-scores were similar (0.15±0.98 vs 0.35±1.02, p=0.18). LM Z-scores were lower in Fontan compared with reference participants (whole body LM -0.33±0.77 vs 0.00±0.74, p=0.003; leg LM -0.89±0.91 vs 0.00±0.89, p<0.0001). LM Z-scores were not associated with age or Fontan characteristics. Leg LM Z-scores were lower in vitamin D deficient versus sufficient Fontan participants (-1.47±0.63 vs -0.71±0.92, p=0.01). Median per cent predicted peak VO2 was 81% (range 13%-113%) and was associated with leg LM Z-scores (r=0.54, p=0.003).Following Fontan, children and young adults are shorter than their peers and have significant LM deficits. Skeletal muscle deficits were associated with vitamin D deficiency and reduced exercise capacity. Future studies should examine the progression of these deficits to further understand the contribution of peripheral musculature to Fontan exercise capacity.

  View details for DOI 10.1136/heartjnl-2014-305723

  View details for Web of Science ID 000345027300013

  View details for PubMedID 24973081

• Deficits in Muscle Mass, Muscle Density, and Modified Associations With Fat in Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Baker, J. F., Von Feldt, J., Mostoufi-Moab, S., Noaiseh, G., Taratuta, E., Kim, W., Leonard, M. B. 2014; 66 (11): 1612-1618

  Abstract

  To quantify muscle outcomes, independent of fat mass, in rheumatoid arthritis (RA) patients compared to healthy controls.Quantitative computed tomography scans measured calf muscle and fat cross-sectional area (CSA) and muscle density (an index of intramuscular adipose tissue), and isometric dynamometry was used to measure ankle muscle strength in 50 participants with RA ages 18-70 years and 500 healthy controls. Multivariable linear regression models assessed muscle deficits in RA after adjusting for group differences in adiposity and assessing for an altered muscle-fat association. Associations between RA disease characteristics and fat-adjusted muscle outcomes were also assessed.Compared to controls, RA subjects had significantly greater body mass index (BMI) and fat area, and lower muscle area, muscle density, and muscle strength (P < 0.001 for all). Strength deficits were eliminated with adjustment for the smaller muscle area. The magnitude of muscle deficits, relative to controls, was significantly greater (P < 0.03 for interaction) in participants with lower fat area and BMI. Among those in the lower tertiles of adiposity, RA subjects demonstrated more significant deficits compared to controls with similar adiposity. In contrast, among those in the highest tertile for adiposity, RA was not associated with muscle deficits. Among RA, greater Sharp/van der Heijde scores were associated with lower muscle CSA and muscle density. Greater disease activity and disability were associated with low muscle density.Deficits in muscle area and muscle density are present in RA patients compared to controls and are most pronounced in subjects with low fat mass. Greater joint destruction is associated with greater muscle deficits.

  View details for DOI 10.1002/acr.22328

  View details for Web of Science ID 000344334200003

  View details for PubMedID 24664868

• A Comparison of Fat and Lean Body Mass Index to BMI for the Identification of Metabolic Syndrome in Children and Adolescents JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Weber, D. R., Leonard, M. B., Shults, J., Zemel, B. S. 2014; 99 (9): 3208-3216

  Abstract

  The use of body mass index (BMI) to assess risk for cardiometabolic disease in the pediatric population may be limited by a failure to differentiate between fat and lean body mass.The objectives of the study were to identify biologically based criteria for the definition of obesity using fat (FMI) and lean body mass index (LBMI) and to compare the ability of FMI and LBMI to BMI to identify the presence of metabolic syndrome (MetSyn).This was a cross-sectional study using National Health and Nutrition Examination Survey 1999-2006 data.A total of 3004 participants aged 12-20 years with dual-energy X-ray absorptiometry body composition and fasting laboratory data participated in the study.Adjusted odds ratios for MetSyn according to FMI and LBMI status and area under the curve for the identification of MetSyn were measured.Receiver-operating characteristic curve analyses identified the 80th percentile for FMI and the 74th percentile for LBMI as the optimal cut points for the identification of MetSyn. There was no difference in the area under the curve for FMI [0.867; 95% confidence interval (CI) 0.838-0.891] vs BMI (0.868; 95% CI 0.837-0.894) Z-scores for MetSyn discrimination. Separate multivariate regression models identified odds ratios for the identification of MetSyn of 6.2 (95% CI 3.3-11.5) for BMI-Z, 6.4 (95% CI 3.7-11.1) for FMI-Z, and 4.6 (95% CI 3.0-7.1) for LBMI-Z. Models containing both FMI-Z and LBMI-Z revealed that greater LBMI-Z was associated with greater odds of low high-density lipoprotein (1.5; 95% CI 1.2-1.9), high blood pressure (1.8; 95% CI 1.1-2.9), and insulin resistance (1.8; 95% CI 1.4-2.5), independent of FMI-Z.The use of FMI and LBMI does not improve upon BMI for the identification of MetSyn in the pediatric population. Unexpectedly, higher LBMI was associated with greater odds of multiple cardiometabolic risk factors independent of FMI. The use of FMI and LBMI allow for the independent evaluation of relationships between body compartments and disease and warrants future research.

  View details for DOI 10.1210/jc.2014-1684

  View details for Web of Science ID 000342341400058

  View details for PubMedID 24926951

• Risk of hip fracture associated with untreated and treated chronic hepatitis B virus infection JOURNAL OF HEPATOLOGY Byrne, D. D., Newcomb, C. W., Carbonari, D. M., Nezamzadeh, M. S., Leidl, K. B., Herlim, M., Yang, Y., Hennessy, S., Kostman, J. R., Leonard, M. B., Localio, A. R., Lo Re, V. 2014; 61 (2): 210-218

  Abstract

  Chronic hepatitis B (CHB) infection is associated with reduced bone mineral density, but its association with fractures is unknown. Our objectives were to determine whether untreated or treated CHB-infected persons are at increased risk for hip fracture compared to uninfected persons.We conducted a cohort study among 18,796 untreated CHB-infected, 7777 treated CHB-infected, and 979,751 randomly sampled uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999-2007). CHB infection was defined by two CHB diagnoses recorded >6 months apart and was classified as treated if a diagnosis was recorded and antiviral therapy was dispensed. After propensity score matching of CHB-infected and uninfected persons, Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident hip fracture in: (1) untreated CHB-infected vs. uninfected, and (2) treated CHB-infected vs. uninfected patients.Untreated CHB-infected patients of black race had a higher rate of hip fracture than uninfected black persons (HR, 2.55 [95% CI, 1.42-4.58]). Compared to uninfected persons, relative hazards of hip fracture were increased for untreated white (HR, 1.26 [95% CI, 0.98-1.62]) and Hispanic (HR, 1.36 [95% CI, 0.77-2.40]) CHB-infected patients, and treated black (HR, 3.09 [95% CI, 0.59-16.22]) and white (HR, 1.90 [95% CI, 0.81-4.47]) CHB-infected patients, but these associations were not statistically significant.Among U.S. Medicaid enrollees, untreated CHB-infected patients of black race had a higher risk of hip fracture than uninfected black persons.

  View details for DOI 10.1016/j.jhep.2014.04.001

  View details for Web of Science ID 000339775700008

  View details for PubMedID 24713185

• Changes in trabecular bone density in incident pediatric Crohn's disease: a comparison of imaging methods OSTEOPOROSIS INTERNATIONAL Tsampalieros, A., Berkenstock, M. K., Zemel, B. S., Griffin, L., Shults, J., Burnham, J. M., Baldassano, R. N., Leonard, M. B. 2014; 25 (7): 1875-1883

  Abstract

  This study of changes in dual energy x-ray absorptiometry (DXA) spine BMD following diagnosis and treatment for childhood Crohn's disease demonstrated that changes in conventional posteroanterior BMD results were confounded by impaired growth, and suggested that lateral spine measurements and strategies to estimate volumetric BMD were more sensitive to disease and treatment effects.We previously reported significant increases in peripheral quantitative CT (pQCT) measures of trabecular volumetric bone mineral density (vBMD) following diagnosis and treatment of pediatric Crohn's disease (CD). The objective of this study was to compare pQCT trabecular vBMD and three DXA measures of spine BMD in this cohort: (1) conventional posteroanterior BMD (PA-BMD), (2) PA-BMD adjusted for height Z (PA-BMDHtZ), and (3) width-adjusted volumetric BMD (WA-BMD) estimated from PA and lateral scans.Spine DXA [lumbar (L1-4) for posteroanterior and L3 for lateral] and tibia pQCT scans were obtained in 65 CD subjects (ages 7-18 years) at diagnosis and 12 months later. BMD results were converted to sex, race, and age-specific Z-scores based on reference data in >650 children (ages 5-21 years). Multivariable linear regression models identified factors associated with BMD Z-scores.At CD diagnosis, all BMD Z-scores were lower compared with the reference children (all p values <0.01). The pQCT vBMD Z-scores (-1.46 ± 1.30) were lower compared with DXA PA-BMD (-0.75 ± 0.98), PA-BMDHtZ (-0.53 ± 0.87), and WA-BMD (-0.61 ± 1.10) among CD participants. Only PA-BMD Z-scores were correlated with height Z-scores at baseline (R = 0.47, p < 0.0001). pQCT and WA-BMD Z-scores increased significantly over 12 months to -1.04 ± 1.26 and -0.20 ± 1.14, respectively. Changes in all four BMD Z-scores were positively associated with changes in height Z-scores (p < 0.05). Glucocorticoid doses were inversely associated with changes in WA-BMD (p < 0.01) only.Conventional and height Z-score-adjusted PA DXA methods did not demonstrate the significant increases in trabecular vBMD noted on pQCT and WA-BMD scans. WA-BMD captured glucocorticoid effects, potentially due to isolation of the vertebral body on the lateral projection. Future studies are needed to identify the BMD measure that provides greatest fracture discrimination in CD.

  View details for DOI 10.1007/s00198-014-2701-x

  View details for Web of Science ID 000337034600007

  View details for PubMedID 24760243

• Serum Aldosterone and Death, End-Stage Renal Disease, and Cardiovascular Events in Blacks and Whites Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study HYPERTENSION Deo, R., Yang, W., Khan, A. M., Bansal, N., Zhang, X., Leonard, M. B., Keane, M. G., Soliman, E. Z., Steigerwalt, S., Townsend, R. R., Shlipak, M. G., Feldman, H. I. 2014; 64 (1): 103-110

  Abstract

  Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin-angiotensin-aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93-1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85-1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with chronic kidney disease because elevated cortisol levels may activate the mineralocorticoid receptor.

  View details for DOI 10.1161/HYPERTENSIONAHA.114.03311

  View details for Web of Science ID 000337700400018

  View details for PubMedID 24752431

• Changes in Vitamin D-Related Mineral Metabolism After Induction With Anti-Tumor Necrosis Factor-alpha Therapy in Crohn's Disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Augustine, M. V., Leonard, M. B., Thayu, M., Baldassano, R. N., de Boer, I. H., Shults, J., Denson, L. A., DeBoer, M. D., Herskovitz, R., Denburg, M. R. 2014; 99 (6): E991-E998

  Abstract

  Preclinical studies suggest that TNF-α suppresses PTH synthesis, inhibits renal 1α-hydroxylase activity, and impairs fibroblast growth factor 23 (FGF23) degradation. The impact of inflammation on vitamin D and mineral metabolism has not been well-characterized in Crohn's disease (CD).The objective of the study was to assess short-term changes in vitamin D-related mineral metabolism in CD after anti-TNF-α induction therapy.Eighty-seven CD participants, aged 5-39 years, were assessed at the initiation of anti-TNF-α therapy and 10 weeks later.Indices of clinical disease activity and serum concentrations of vitamin D metabolites, vitamin D-binding protein (DBP), calcium, PTH, FGF23, IL-6, and TNF-α were measured at each visit. A multivariable generalized estimating equation (GEE) regression analysis was used to examine the correlates of PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations at each visit.After anti-TNF-α therapy, cytokines and inflammatory markers [IL-6, TNF-α, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)] concentrations decreased (all P < .0001), and PTH and 1,25(OH)2D concentrations increased (median 21 vs 30 pg/mL, P < .0001, and median 41.7 vs 48.1 pg/mL, P = .014, respectively). Levels of 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D, DBP, and FGF23 did not change. In GEE analyses, higher IL-6, TNF-α, ESR, and CRP were associated with lower PTH concentrations (all P < .001), adjusted for corrected calcium and 25(OH)D levels. Higher PTH was associated with higher 1,25(OH)2D concentrations (P < .001) at each visit, independent of 25(OH)D concentrations. Higher levels of all inflammatory markers were associated with lower 1,25(OH)2D concentrations (all P < .05). However, when PTH was added to these models, the inflammatory markers (with the exception of CRP) were no longer significantly associated with 1,25(OH)2D.Greater inflammation was associated with lower PTH and 1,25(OH)2D concentrations. After anti-TNF-α induction, PTH and 1,25(OH)2D concentrations increased without concomitant changes in 25(OH)D and FGF23, consistent with effects of inflammation on PTH and thereby renal conversion of 25(OH)D to 1,25(OH)2D.

  View details for DOI 10.1210/jc.2013-3846

  View details for Web of Science ID 000342340500007

  View details for PubMedID 24617709

• Prevalence of diagnosed chronic hepatitis B infection among US Medicaid enrollees, 2000-2007 29th International Conference on Pharmacoepidemiology and Therapeutic Risk Management Byrne, D. D., Newcomb, C. W., Carbonari, D. M., Nezamzadeh, M. S., Leidl, K. B., Herlim, M., Yang, Y., Hennessy, S., Kostman, J. R., Leonard, M. B., Localio, R., Lo Re, V. ELSEVIER SCIENCE INC. 2014: 418–23

  Abstract

  Few population-based studies have estimated the number of persons diagnosed with chronic hepatitis B (CHB) infection in the United States. Our objective was to estimate the prevalence of diagnosed CHB infection among persons enrolled in the U.S. Medicaid programs of California, Florida, New York, Ohio, and Pennsylvania between 2000 and 2007. As part of our analyses, we confirmed the accuracy of CHB diagnoses within the Medicaid database.CHB infection was defined by the presence of two outpatients CHB diagnoses recorded more than 6 months apart. Two clinicians reviewed the medical records of a random sample of patients who met this definition to confirm the diagnosis, which enabled calculation of the positive predictive value (PPV). The period prevalence of diagnosed CHB infection among Medicaid enrollees with at least 6 months of membership from 2000 to 2007 was then estimated, adjusting for both the PPV and estimated sensitivity of our definition of CHB infection.The definition of CHB infection accurately identified clinician-confirmed cases (PPV, 96.3%; 95% confidence interval [CI], 87.3-99.5). Using this definition, 31,046 cases of CHB were diagnosed among 31,358,010 eligible Medicaid members from the five states (prevalence, 9.9 [95% CI, 9.8-10.0] per 10,000). Adjusting for the PPV and estimated sensitivity of our CHB definition, the prevalence of diagnosed CHB infection was 15.6 (95% CI, 15.4-15.7) per 10,000.Two outpatient CHB diagnoses recorded more than 6 months apart validly identified clinician-confirmed CHB. The prevalence of diagnosed CHB infection among U.S. Medicaid enrollees was 15.6 per 10,000.

  View details for DOI 10.1016/j.annepidem.2014.02.013

  View details for Web of Science ID 000336638300002

  View details for PubMedID 24703196

• Increasing Use of Vitamin D Supplementation in the Chronic Renal Insufficiency Cohort Study JOURNAL OF RENAL NUTRITION Mariani, L. H., White, M. T., Shults, J., Anderson, C. A., Feldman, H. I., Wolf, M., Reese, P. P., Denburg, M. R., Townsend, R. R., Lo, J. C., Cappola, A. R., Carlow, D., Gadegbeku, C. A., Steigerwalt, S., Leonard, M. B. 2014; 24 (3): 186-193

  Abstract

  This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown.CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry.The proportion of participants reporting supplement use increased (P < .0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (<20 ng/mL), whereas 22.7% of non-Black and 62.4% of black participants not reporting supplement use were deficient.Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices.

  View details for DOI 10.1053/j.jrn.2014.01.015

  View details for Web of Science ID 000335313500009

  View details for PubMedID 24613295

• 2013 Pediatric Position Development Conference: Executive Summary and Reflections JOURNAL OF CLINICAL DENSITOMETRY Gordon, C. M., Leonard, M. B., Zemel, B. S. 2014; 17 (2): 219-224

  Abstract

  The International Society for Clinical Densitometry (ISCD) convened its second Pediatric Position Development Conference (PDC) on October 2-3, 2013 in Baltimore, MD. The conference was co-sponsored by the American Society for Bone and Mineral Research (ASBMR) and was held immediately before their annual meeting. The aim of a PDC is to make recommendations for standards in the field of bone densitometry. The recommendations address issues such as quality control, data acquisition and analysis, and the interpretation and reporting of bone densitometric results. In 2007, ISCD convened its first Pediatric PDC to address issues specific to skeletal health assessments in children and adolescents. The 2013 Pediatric PDC focused on advances in the field since that initial conference that would lead to revisions of the original positions. Topics for consideration were developed by the ISCD and its Scientific Advisory Committee. Clinically relevant questions related to each topic were assigned to task forces for a comprehensive review of the medical literature and subsequent presentation of reports to an international panel of experts. Expert panelists included representatives from both the ISCD and ASBMR. The recommendations of the PDC Expert Panel were subsequently reviewed by the ISCD Board of Directors and positions accepted by majority vote. The approved recommendations became the Official Positions of the ISCD. The positions are to be submitted to the ASBMR for its consideration for endorsement. Topics considered at the Pediatric PDC included fracture prediction and definition of osteoporosis, dual-energy X-ray absorptiometry assessment in chronic diseases that may affect the skeleton, dual-energy X-ray absorptiometry interpretation and reporting, quantitative computed tomography measurements, and densitometry in infants and young children. We discuss potential implications of the new recommendations and factors leading to a change in the wording of these positions, considering the science that has evolved over the past 6yr.

  View details for DOI 10.1016/j.jocd.2014.01.007

  View details for Web of Science ID 000335933500001

  View details for PubMedID 24657108

• Bone Health in Children and Adolescents With Chronic Diseases That May Affect the Skeleton: The 2013 ISCD Pediatric Official Positions JOURNAL OF CLINICAL DENSITOMETRY Bianchi, M. L., Leonard, M. B., Bechtold, S., Hoegler, W., Mughal, M. Z., Schoenau, E., Sylvester, F. A., Vogiatzi, M., van den Heuvel-Eibrink, M. M., Ward, L. 2014; 17 (2): 281-294

  View details for DOI 10.1016/j.jocd.2014.01.005

  View details for Web of Science ID 000335933500006

• Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions. Journal of clinical densitometry Bianchi, M. L., Leonard, M. B., Bechtold, S., Högler, W., Mughal, M. Z., Schönau, E., Sylvester, F. A., Vogiatzi, M., van den Heuvel-Eibrink, M. M., Ward, L. 2014; 17 (2): 281-294

  Abstract

  The aim of this Task Force was to review the use of dual-energy X-ray absorptiometry (DXA) in children and adolescents with underlying chronic diseases that pose risk factors for compromised bone health, such as inflammation, glucocorticoid therapy, or decreased mobility. The Task Force systematically analyzed more than 270 studies, with an emphasis on those published in the interval since the original 2007 Position Statements. Important developments over this period included prospective cohort studies demonstrating that DXA measures of areal bone mineral density (aBMD) predicted incident fractures and the development of robust reference data and strategies to adjust for bone size in children with growth impairment. In this report, we summarize the current literature on the relationship between DXA-based aBMD and both fracture (vertebral and non-vertebral) outcomes and non-fracture risk factors (e.g., disease characteristics, ambulatory status, and glucocorticoid exposure) in children with chronic illnesses. Most publications described the aBMD profile of children with underlying diseases, as well as the cross-sectional or longitudinal relationship between aBMD and clinically relevant non-fracture outcomes. Studies that addressed the relationship between aBMD and prevalent or incident fractures in children with chronic illnesses are now emerging. In view of these updated data, this report provides guidelines for the use of DXA-based aBMD in this setting. The initial recommendation that DXA is part of a comprehensive skeletal healthy assessment in patients with increased risk of fracture is unchanged. Although the prior guidelines recommended DXA assessment in children with chronic diseases at the time of clinical presentation with ongoing monitoring, this revised Position Statement focuses on the performance of DXA when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture and when the DXA results will influence that management.

  View details for DOI 10.1016/j.jocd.2014.01.005

  View details for PubMedID 24656723

• Changes in DXA and Quantitative CT Measures of Musculoskeletal Outcomes Following Pediatric Renal Transplantation AMERICAN JOURNAL OF TRANSPLANTATION Tsampalieros, A., Griffin, L., Terpstra, A. M., Kalkwarf, H. J., Shults, J., Foster, B. J., Zemel, B. S., Foerster, D. L., Leonard, M. B. 2014; 14 (1): 124-132

  Abstract

  This prospective study evaluated changes in dual energy X-ray absorptiometry (DXA) whole body bone mineral content (WB-BMC) and spine areal bone mineral density (spine-BMD), and tibia quantitative computed tomography (QCT) trabecular and cortical volumetric BMD and cortical area in 56 children over 12 months following renal transplantation. At transplant, spine-BMD Z-scores were greater in younger recipients (<13 years), versus 898 reference participants (p < 0.001). In multivariate models, greater decreases in spine-BMD Z-scores were associated with greater glucocorticoid dose (p < 0.001) and declines in parathyroid hormone levels (p = 0.008). Changes in DXA spine-BMD and QCT trabecular BMD were correlated (r = 0.47, p < 0.01). At 12 months, spine-BMD Z-scores remained elevated in younger recipients, but did not differ in older recipients (≥ 13) and reference participants. Baseline WB-BMC Z-scores were significantly lower than reference participants (p = 0.02). Greater glucocorticoid doses were associated with declines in WB-BMC Z-scores (p < 0.001) while greater linear growth was associated with gains in WB-BMC Z-scores (p = 0.01). Changes in WB-BMC Z-scores were associated with changes in tibia cortical area Z-scores (r = 0.52, p < 0.001), but not changes in cortical BMD Z-scores. Despite resolution of muscle deficits, WB-BMC Z-scores at 12 months remained significantly reduced. These data suggest that spine and WB DXA provides insight into trabecular and cortical outcomes following pediatric renal transplantation.

  View details for DOI 10.1111/ajt.12524

  View details for Web of Science ID 000328597900017

  View details for PubMedID 24298998

• Childhood Cancer Survivors Exposed to Total Body Irradiation Are At Significant Risk For Slipped Capital Femoral Epiphysis During Recombinant Growth Hormone Therapy PEDIATRIC BLOOD & CANCER Mostoufi-Moab, S., Isaacoff, E. J., Spiegel, D., Gruccio, D., Ginsberg, J. P., Hobbie, W., Shults, J., Leonard, M. B. 2013; 60 (11): 1766-1771

  Abstract

  Childhood cancer survivors treated with cranial or total body irradiation (TBI) are at risk for growth hormone deficiency (GHD). Recombinant growth hormone (rhGH) therapy is associated with slipped capital femoral epiphysis (SCFE). We compared the incidence of SCFE after TBI versus cranial irradiation (CI) in childhood cancer survivors treated with rhGH.Retrospective cohort study (1980-2010) of 119 survivors treated with rhGH for irradiation-induced GHD (56 TBI; 63 CI). SCFE incidence rates were compared in CI and TBI recipients, and compared with national registry SCFE rates in children treated with rhGH for idiopathic GHD.Median survivor follow-up since rhGH initiation was 4.8 (range 0.2-18.3) years. SCFE was diagnosed in 10 subjects post-TBI and none after CI (P < 0.001). All 10 subjects had atypical valgus SCFE, and 7 were bilateral at presentation. Within TBI recipients, age at cancer diagnosis, sex, race, underlying malignancy, age at radiation, and age at initiation of rhGH did not differ significantly between those with versus without SCFE. The mean (SD) age at SCFE diagnosis was 12.3 (2.7) years and median duration of rhGH therapy to SCFE was 1.8 years. The SCFE incidence rate after TBI exposure was 35.9 per 1,000 person years, representing a 211-fold greater rate than reported in children treated with rhGH for idiopathic GH deficiency.The markedly greater SCFE incidence rate in childhood cancer survivors with TBI-associated GHD, compared with rates in children with idiopathic GHD, suggests that cancer treatment effects to the proximal femoral physis may contribute to SCFE. Pediatr Blood Cancer. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/pbc.24667

  View details for Web of Science ID 000324299800014

  View details for PubMedID 23818448

• Reply to RF Burton. American journal of clinical nutrition Weber, D. R., Moore, R. H., Leonard, M. B., Zemel, B. S. 2013; 98 (5): 1368-1369

  View details for DOI 10.3945/ajcn.113.068379

  View details for PubMedID 24142240

• Vitamin D bioavailability and catabolism in pediatric chronic kidney disease PEDIATRIC NEPHROLOGY Denburg, M. R., Kalkwarf, H. J., de Boer, I. H., Hewison, M., Shults, J., Zemel, B. S., Stokes, D., Foerster, D., Laskin, B., Ramirez, A., Leonard, M. B. 2013; 28 (9): 1843-1853

  Abstract

  Vitamin D-binding protein (DBP) and catabolism have not been examined in the clinical setting of childhood chronic kidney disease (CKD).The concentrations of serum vitamin D {25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], 24,25-dihydroxyvitamin D [24,25(OH)(2)D]}, DBP, intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF23) were measured in 148 participants with CKD stages 2-5D secondary to congenital anomalies of the kidney/urinary tract (CAKUT), glomerulonephritis (GN), or focal segmental glomerulosclerosis (FSGS). Free and bioavailable 25(OH)D concentrations were calculated using total 25(OH)D, albumin, and DBP concentrations.The concentrations of all vitamin D metabolites were lower with more advanced CKD (p < 0.001) and glomerular diagnoses (p ≤ 0.002). Among non-dialysis participants, DBP was lower in FSGS versus other diagnoses (FSGS-dialysis interaction p = 0.02). Winter season, older age, FSGS and GN, and higher FGF23 concentrations were independently associated with lower concentrations of free and bioavailable 25(OH)D. Black race was associated with lower total 25(OH)D and DBP, but not free or bioavailable 25(OH)D. 24,25(OH)(2)D was the vitamin D metabolite most strongly associated with iPTH. Lower 25(OH)D and higher iPTH concentrations, black race, and greater CKD severity were independently associated with lower levels of 24,25(OH)(2)D, while higher FGF23 concentrations and GN were associated with higher levels of 24,25(OH)(2)D.Children with CKD exhibit altered catabolism and concentrations of DBP and free and bioavailable 25(OH)D, and there is an important impact of their underlying disease.

  View details for DOI 10.1007/s00467-013-2493-9

  View details for Web of Science ID 000322323700017

  View details for PubMedID 23728936

• Long-Term Inflammation and Glucocorticoid Therapy Impair Skeletal Modeling During Growth in Childhood Crohn Disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Tsampalieros, A., Lam, C. K., Spencer, J. C., Thayu, M., Shults, J., Zemel, B. S., Herskovitz, R. M., Baldassano, R. N., Leonard, M. B. 2013; 98 (8): 3438-3445

  Abstract

  Glucocorticoids and inflammation inhibit bone formation; however, the impact on skeletal modeling is unknown.The objectives of the study were to examine changes in bone mineral density (BMD) and cortical structure after Crohn disease (CD) diagnosis and identify associations with growth, glucocorticoids, and disease activity.This was a prospective cohort study among 76 CD participants, aged 5-21 years. Tibia quantitative computed tomography trabecular BMD and cortical dimensions were obtained at diagnosis and 6 and 12 and a median of 42 months later; 51 completed the final visit.Sex, race, and age-specific Z-scores were generated for outcomes based on more than 650 reference participants, and cortical dimension Z-scores were further adjusted for tibia length. Generalized estimating equations were used to model changes in Z-scores.Disease activity improved over the study interval (P < .001). Trabecular BMD Z-scores improved over the first 6 months; increases were associated with improved disease activity (P < .001), younger age (P = .005), and increases in vitamin D levels (P = .02). Greater increases in tibia length were associated with greater increases in cortical area Z-scores (P < .001). Greater glucocorticoid doses and disease activity were significantly associated with failure to accrue cortical area and were more pronounced with greater linear growth (interaction P < .05). Mean (±SD) trabecular BMD (-1.0 ± 1.21) and cortical area (-0.57 ± 1.10) Z-scores at the final visit were significantly reduced.CD was associated with persistent deficits in trabecular BMD, although younger participants demonstrated a greater potential for recovery. In addition, greater linear growth was associated with a greater recovery of cortical dimensions, especially among participants with less glucocorticoid exposure and inflammation. These data suggest that younger age and concurrent growth provide a window of opportunity for skeletal recovery.

  View details for DOI 10.1210/jc.2013-1631

  View details for Web of Science ID 000322781300063

  View details for PubMedID 23690309

• Fat and lean BMI reference curves in children and adolescents and their utility in identifying excess adiposity compared with BMI and percentage body fat AMERICAN JOURNAL OF CLINICAL NUTRITION Weber, D. R., Moore, R. H., Leonard, M. B., Zemel, B. S. 2013; 98 (1): 49-56

  Abstract

  Body mass index (BMI) and percentage body fat (%BF) are widely used to assess adiposity. These indexes fail to account for independent contributions of fat mass (FM) and lean body mass (LBM) to body weight, which vary according to age, sex, pubertal status, and population ancestry in the pediatric population.The objective was to develop pediatric reference curves for fat mass index (FMI) and lean body mass index (LBMI) and evaluate the effects of population ancestry and LBM on measures of excess adiposity (BMI, %BF, and FMI).Sex-specific FMI and LBMI reference curves relative to age for children and adolescents aged 8-20 y were generated from cross-sectional body-composition data measured by dual-energy X-ray absorptiometry from NHANES.The mean LBMI z score was higher in blacks (males: 0.26; females: 0.45) than in whites (males: -0.07; females: -0.09) and Mexican Americans (males: 0.05; females: -0.09). The positive predictive value of overweight by BMI to identify excess adiposity defined by FMI was lower in blacks (males: 35.9%; females: 30.3%) than in whites (males: 65.4%; females: 52.2%) and Mexican Americans (males: 73.3%; females: 68.3%). Participants classified as having excess adiposity by FMI but normal adiposity by %BF had significantly higher BMI, LBMI, and height z scores than did those classified as having excess adiposity by %BF but normal adiposity by FMI.Relative to FMI, the prevalence of excess adiposity is overestimated by BMI in blacks and underestimated by %BF in individuals with high LBM. The use of FMI and LBMI improves on the use of %BF and BMI by allowing for the independent assessment of FM and LBM.

  View details for DOI 10.3945/ajcn.112.053611

  View details for Web of Science ID 000320909200008

  View details for PubMedID 23697708

• FGF23 Modifies the Relationship Between Vitamin D and Cardiac Remodeling CIRCULATION-HEART FAILURE Ky, B., Shults, J., Keane, M. G., Sutton, M. S., Wolf, M., Feldman, H. I., Reese, P. P., Anderson, C. A., Townsend, R. R., Deo, R., Lo, J., Gadegbeku, C., Carlow, D., Sulik, M. J., Leonard, M. B. 2013; 6 (4): 817-824

  Abstract

  There is growing evidence to support an important role for vitamin D and related hormones, parathyroid hormone and fibroblast growth factor 23 (FGF23), on cardiac remodeling in chronic kidney disease. Our objective was to determine the relationships between vitamin D and cardiac remodeling in chronic kidney disease and the effects of parathyroid hormone and FGF23 on these associations.In 1431 participants from the Chronic Renal Insufficiency Cohort study, we measured 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), FGF23, and parathyroid hormone and performed quantitative echocardiography. Using linear regression methods, we determined significant negative interactions between 25(OH)D and FGF23 on left ventricular (LV) mass (P=0.016), end-diastolic volume (P=0.029), and end-systolic volumes (P=0.021). In participants with an FGF23 level greater than the median of 123.5 RU/mL, each doubling of 25(OH)D was associated with a 2.5% (95% confidence interval, -4.8, -0.2) lower LV mass. This association was less pronounced with FGF23 levels less than the median (0.4%; 95% confidence interval, -1.9, 2.7). Conversely, in participants with deficient 25(OH)D levels <20 ng/mL, each doubling of FGF23 was associated with a 3.4% (95% confidence interval, 1.2, 5.6) greater LV mass compared with only a 1.6% (95% confidence interval, -0.2, 3.5) difference in participants with sufficient 25(OH)D. Similar findings were observed with 25(OH)D and volumes (P<0.05), and 1,25(OH)2D and LV mass and volumes (P<0.005). There was no effect modification by parathyroid hormone.We identified significant interactions among 25(OH)D, 1,25(OH)2D, and FGF23 on cardiac remodeling. Increased LV mass and cavity dilatation were observed with low 25(OH)D and high FGF23. Our findings suggest that consideration of both hormones is crucial to understanding the role of either in cardiac remodeling, and may have important therapeutic implications.

  View details for DOI 10.1161/CIRCHEARTFAILURE.112.000105

  View details for Web of Science ID 000335157800032

  View details for PubMedID 23748358

• Mineral Metabolism and Cortical Volumetric Bone Mineral Density in Childhood Chronic Kidney Disease JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Denburg, M. R., Tsampalieros, A. K., de Boer, I. H., Shults, J., Kalkwarf, H. J., Zemel, B. S., Foerster, D., Stokes, D., Leonard, M. B. 2013; 98 (5): 1930-1938

  Abstract

  The relationships among cortical volumetric bone mineral density (CortBMD) and comprehensive measures of mineral metabolism have not been addressed in chronic kidney disease (CKD).The aim of the study was to identify the determinants of CortBMD in childhood CKD. A secondary objective was to assess whether CortBMD was associated with subsequent fracture.This prospective cohort study included 171 children, adolescents, and young adults (aged 5-21 years) with CKD stages 2-5D at enrollment and 89 1 year later.Serum measures included vitamin D [25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25(OH)₂D), 24,25-dihydroxyvitamin D], vitamin D-binding protein, intact PTH, fibroblast growth factor 23, calcium, and phosphorus. Tibia quantitative computed tomography measures of CortBMD were expressed as sex-, race-, and age-specific Z-scores based on 675 controls. Multivariable linear regression identified the independent correlates of CortBMD Z-scores and the change in CortBMD Z-scores.Lower calcium (β = .31/1 mg/dL, P = .01) and 25(OH)D (β = .18/10 ng/mL, P = .04) and higher PTH (β = -.02/10%, P = .002) and 1,25(OH)₂D (β = -.07/10%, P < .001) were independently associated with lower CortBMD Z-scores at baseline. The correlations of total, free, and bioavailable 25(OH)D with CortBMD did not differ. Higher baseline 1,25(OH)₂D (P < .05) and greater increases in PTH (P < .001) were associated with greater declines in CortBMD Z-scores. Greater increases in calcium concentrations were associated with greater increases in CortBMD Z-scores in growing children (interaction P = .009). The hazard ratio for fracture was 1.75 (95% confidence interval 1.15-2.67; P = .009) per SD lower baseline CortBMD.Greater PTH and 1,25(OH)₂D and lower calcium concentrations were independently associated with baseline and progressive cortical deficits in childhood CKD. Lower CortBMD Z-score was associated with increased fracture risk.

  View details for DOI 10.1210/jc.2012-4188

  View details for Web of Science ID 000318688200053

  View details for PubMedID 23547048

• Changes in bone structure and the muscle-bone unit in children with chronic kidney disease KIDNEY INTERNATIONAL Tsampalieros, A., Kalkwarf, H. J., Wetzsteon, R. J., Shults, J., Zemel, B. S., Foster, B. J., Foerster, D. L., Leonard, M. B. 2013; 83 (3): 495-502

  Abstract

  The impact of pediatric chronic kidney disease (CKD) on acquisition of volumetric bone mineral density (BMD) and cortical dimensions is lacking. To address this issue, we obtained tibia quantitative computed tomography scans from 103 patients aged 5-21 years with CKD (26 on dialysis) at baseline and 12 months later. Gender, ethnicity, tibia length, and/or age-specific Z-scores were generated for trabecular and cortical BMD, cortical area, periosteal and endosteal circumference, and muscle area based on over 700 reference subjects. Muscle area, cortical area, and periosteal and endosteal Z-scores were significantly lower at baseline compared with the reference cohort. Cortical BMD, cortical area, and periosteal Z-scores all exhibited a significant further decrease over 12 months. Higher parathyroid hormone levels were associated with significantly greater increases in trabecular BMD and decreases in cortical BMD in the younger patients (significant interaction terms for trabecular BMD and cortical BMD). The estimated glomerular filtration rate was not associated with changes in BMD Z-scores independent of parathyroid hormone. Changes in muscle and cortical area were significantly and positively associated in control subjects but not in CKD patients. Thus, children and adolescents with CKD have progressive cortical bone deficits related to secondary hyperparathyroidism and potential impairment of the functional muscle-bone unit. Interventions are needed to enhance bone accrual in childhood-onset CKD.

  View details for DOI 10.1038/ki.2012.347

  View details for Web of Science ID 000316156100022

  View details for PubMedID 23032560

• Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome JOURNAL OF BONE AND MINERAL RESEARCH Tsampalieros, A., Gupta, P., Denburg, M. R., Shults, J., Zemel, B. S., Mostoufi-Moab, S., Wetzsteon, R. J., Herskovitz, R. M., Whitehead, K. M., Leonard, M. B. 2013; 28 (3): 480-488

  Abstract

  The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty-six NS participants, aged 5 to 21 years, were enrolled a median of 4.3 (0.5 to 8.1) years after diagnosis. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race, and age-specific Z-scores were generated for trabecular vBMD (TrabBMD-Z), cortical vBMD (CortBMD-Z), and cortical area (CortArea-Z) based on >650 reference participants. CortArea-Z was further adjusted for tibia length-for-age Z-score. Quasi-least squares regression was used to identify determinants of changes in pQCT Z-scores. At enrollment, mean TrabBMD-Z (-0.54 ± 1.32) was significantly lower (p = 0.0001) and CortBMD-Z (0.73 ± 1.16, p < 0.0001) and CortArea-Z (0.27 ± 0.91, p = 0.03) significantly greater in NS versus reference participants, as previously described. Forty-eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD-Z and CortBMD-Z did not change significantly over the study interval; however, CortArea-Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea-Z (p = 0.003) were independently associated with greater increases in CortBMD-Z. Greater increases in tibia length were associated with greater declines in CortArea-Z (p < 0.01); this association was absent in reference participants (interaction p < 0.02). In conclusion, GC therapy was associated with increases in CortBMD-Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea-Z (ie, new bone formation) were associated with declines in CortBMD-Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings.

  View details for DOI 10.1002/jbmr.1785

  View details for Web of Science ID 000315106300008

  View details for PubMedID 23044926

• Associations between body composition and bone density and structure in men and women across the adult age spectrum BONE Baker, J. F., Davis, M., Alexander, R., Zemel, B. S., Mostoufi-Moab, S., Shults, J., Sulik, M., Schiferl, D. J., Leonard, M. B. 2013; 53 (1): 34-41

  Abstract

  The objective of this study was to identify independent associations between body composition and bone outcomes, including cortical structure and cortical and trabecular volumetric bone mineral density (vBMD) across the adult age spectrum.This cross-sectional study evaluated over 400 healthy adults (48% male, 44% black race), ages 21-78years. Multivariable linear regression models evaluated associations between whole-body DXA measures of lean body mass index (LBMI) and fat mass index (FMI) and tibia peripheral quantitative CT (pQCT) measures of cortical section modulus, cortical and trabecular vBMD and muscle density (as a measure of intramuscular fat), adjusted for age, sex, and race. All associations reported below were statistically significant (p<0.05).Older age and female sex were associated with lower LBMI and muscle strength. Black race was associated with greater LBMI but lower muscle density. Greater FMI was associated with lower muscle density. Cortical section modulus was positively associated with LBMI and muscle strength and negatively associated with FMI. Adjustment for body composition eliminated the greater section modulus observed in black participants and attenuated the lower section modulus in females. Greater LBMI was associated with lower cortical BMD and greater trabecular BMD. FMI was not associated with either BMD outcome. Greater muscle density was associated with greater trabecular and cortical BMD. Associations between body composition and bone outcomes did not vary by sex (no significant tests for interaction).These data highlight age-, sex- and race-specific differences in body composition, muscle strength and muscle density, and demonstrate discrete associations with bone density and structure. These data also show that age-, sex- and race-related patterns of bone density and strength are independent of differences in body composition. Longitudinal studies are needed to examine the temporal relations between changes in bone and body composition.

  View details for DOI 10.1016/j.bone.2012.11.035

  View details for Web of Science ID 000314257100007

  View details for PubMedID 23238122

  View details for PubMedCentralID PMC3552077

• Nutritional vitamin D use in chronic kidney disease: a survey of pediatric nephrologists PEDIATRIC NEPHROLOGY Griffin, L. M., Denburg, M. R., Shults, J., Furth, S. L., Salusky, I. B., Hwang, W., Leonard, M. B. 2013; 28 (2): 265-275

  Abstract

  Vitamin D deficiency may contribute to risk of cardiovascular disease, diabetes, and infections, in addition to known effects on mineral metabolism. Controversy remains regarding the use of nutritional vitamin D supplementation in chronic kidney disease (CKD), and the supplementation practices of pediatric nephrologists are unknown.An electronic survey containing eight vignettes was sent to physician members of the International Pediatric Nephrology Association in 2011 to identify physician and patient characteristics that influence nephrologists to supplement CKD patients with nutritional vitamin D. Vignettes contained patient characteristics including light vs dark skin, CKD stage, cause of renal disease, parathyroid hormone (PTH), and 25(OH) vitamin D levels. Multivariate logistic generalized estimating equation regression was used to identify predictors of supplementation.Of 1,084 eligible physicians, 504 (46%) completed the survey. Supplementation was recommended in 73% of cases overall (ranging from 91% of those with vitamin D levels <10 ng/mL to 35% with levels >30). Greater CKD severity was associated with greater recommendation of supplementation, especially for patients with higher vitamin D levels (test for interaction p < 0.0001). PTH level above target for CKD stage was associated with greater recommendation to supplement in pre-dialysis CKD, but did not have an impact on recommendations in dialysis patients (test for interaction p < 0.0001). Skin color, cause of CKD, and albumin levels were not associated with supplementation recommendation.Recommending nutritional vitamin D is common worldwide, driven by CKD stage and vitamin D and PTH levels. Future studies are needed to establish the risks and benefits of supplementation.

  View details for DOI 10.1007/s00467-012-2307-5

  View details for Web of Science ID 000313431600012

  View details for PubMedID 23086591

• Changes in Vitamin D and Parathyroid Hormone Metabolism in Incident Pediatric Crohn's Disease INFLAMMATORY BOWEL DISEASES Prosnitz, A. R., Leonard, M. B., Shults, J., Zemel, B. S., Hollis, B. W., Denson, L. A., Baldassano, R. N., Cohen, A. B., Thayu, M. 2013; 19 (1): 45-53

  Abstract

  Prior studies of vitamin D metabolism in Crohn's disease (CD) did not include controls or examine changes following diagnosis. This study examined associations among 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and parathyroid hormone (PTH) levels in incident pediatric CD, compared with controls, and following diagnosis.Serum vitamin D and PTH were measured at diagnosis (n = 78), 6, 12, and a median of 43 months (n = 52) later in CD participants, and once in 221 controls. Multivariate regression was used to examine baseline associations and quasi-least squares regression to assess subsequent changes.At diagnosis, 42% of CD participants were 25(OH)D-deficient (<20 ng/mL). The odds ratio for deficiency was 2.1 (95% confidence interval [CI]: 1.1, 3.9; P < 0.05) vs. controls, adjusted for age, race, and season. 1,25(OH)(2)D was lower in CD vs. controls (P < 0.05), adjusted for 25(OH)D, tumor necrosis factor alpha (TNF-α), and PTH. TNF-α was associated with lower 1,25(OH)(2)D (P < 0.05), and the positive association between PTH and 1,25(OH)(2)D in controls was absent in CD (interaction P = 0.02). Among participants with 25(OH)D <30 ng/mL, CD was associated with lower PTH (P < 0.05) vs. controls. Following diagnosis, 25(OH)D and 1,25(OH)(2)D improved (P < 0.001). At the final visit, 3% were 25(OH)D-deficient, PTH was no longer low relative to 25(OH)D, and 1,25(OH)(2)D was significantly elevated (P < 0.001) compared with controls.Incident CD was associated with 25(OH)D and 1,25(OH)2D deficiency and a relative hypoparathyroidism that resolved following diagnosis. Inflammatory cytokine suppression of PTH and renal 1-α-hyroxylase may contribute to these alterations.

  View details for DOI 10.1002/ibd.22969

  View details for Web of Science ID 000316397200014

  View details for PubMedID 22488969

• Physical Performance and Frailty in Chronic Kidney Disease AMERICAN JOURNAL OF NEPHROLOGY Reese, P. P., Cappola, A. R., Shults, J., Townsend, R. R., Gadegbeku, C. A., Anderson, C., Baker, J. F., Carlow, D., Sulik, M. J., Lo, J. C., Go, A. S., Ky, B., Mariani, L., Feldman, H. I., Leonard, M. B. 2013; 38 (4): 307-315

  Abstract

  Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established.We measured the Short Physical Performance Battery (SPPB; a summary test of gait speed, chair raises and balance; range 0-12) and the five elements of frailty among 1,111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status.Median (interquartile range, IQR) age was 65 (57-71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36-62) ml/min/1.73 m(2), and median SPPB score was 9 (7-10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73 m(2), the SPPB was 0.51 points lower for eGFR 30-59; 0.61 points lower for eGFR 15-29, and 1.75 points lower for eGFR <15 (p < 0.01 for all comparisons). eGFR 30-59 (odds ratio, OR 1.45; p = 0.024), eGFR 15-29 (OR 2.02; p = 0.002) and eGFR <15 (OR 4.83; p < 0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73 m(2).CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions.

  View details for DOI 10.1159/000355568

  View details for Web of Science ID 000326134100006

  View details for PubMedID 24107579

  View details for PubMedCentralID PMC4019506

• Body composition analysis in the pediatric population. Pediatric endocrinology reviews : PER Weber, D. R., Leonard, M. B., Zemel, B. S. 2012; 10 (1): 130-139

  Abstract

  Body composition analysis has become a useful tool in both clinical and research settings. Its use in the pediatric population is complicated by the rapid periods of growth and physical development that are characteristic of infancy, childhood, and adolescence. A thorough understanding of the changing nature of body composition during this time is essential for choosing the most appropriate measurement technique for a given individual, population, or clinical question. Growing evidence suggests that tissues such as fat, muscle, and bone are intimately involved in the regulation of whole body energy metabolism. This knowledge, when coupled with advancements in imaging techniques such as MRI and PET-CT, offers the possibility of developing new models of "functional" body composition. These models may prove to be especially important when assessing malnutrition and metabolic risk in patients with chronic disease.

  View details for PubMedID 23469390

• Risk of hip fracture associated with hepatitis c virus infection and hepatitis C/human immunodeficiency virus coinfection HEPATOLOGY Lo Re, V., Volk, J., Newcomb, C. W., Yang, Y., Freeman, C. P., Hennessy, S., Kostman, J. R., Tebas, P., Leonard, M. B., Localio, A. R. 2012; 56 (5): 1688-1698

  Abstract

  Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our aims were to determine whether persons with HCV infection alone are at increased risk for hip fracture, compared to uninfected individuals, and to examine whether the risk of hip fracture is higher among HCV/HIV-coinfected persons, compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV-coinfected, 276,901 HCV-monoinfected, 95,827 HIV-monoinfected, and 3,110,904 HCV/HIV-uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999-2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1,000 person-years), increased with the presence of either HIV infection (1.95 events/1,000 person-years) or HCV infection (2.69 events/1,000 person-years), and were highest among HCV/HIV-coinfected individuals (3.06 events/1,000 person-years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [HR] [95% confidence interval; CI]) of hip fracture, compared to HCV-monoinfected (HR, 1.38; 95% CI: 1.25-1.53), HIV-monoinfected (females: HR, 1.76; 95% CI: 1.44-2.16; males: HR, 1.36; 95% CI: 1.20-1.55), and HCV/HIV-uninfected persons (females: HR, 2.65; 95% CI: 2.21-3.17; males: HR, 2.20; 95% CI: 1.97-2.47). HCV monoinfection was associated with an increased risk of hip fracture, compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18-39 years: HR, 3.56; 95% CI: 2.93-4.32; males, 18-39 years: HR, 2.40; 95% CI: 2.02-2.84).Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture, compared to HCV-monoinfected, HIV-monoinfected, and HCV/HIV-uninfected persons. HCV-monoinfected patients had an increased risk of hip fracture, compared to uninfected individuals.

  View details for DOI 10.1002/hep.25866

  View details for Web of Science ID 000310543100014

  View details for PubMedID 22619086

• Longitudinal Assessment of Bone Density and Structure in Childhood Survivors of Acute Lymphoblastic Leukemia without Cranial Radiation JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Mostoufi-Moab, S., Brodsky, J., Isaacoff, E. J., Tsampalieros, A., Ginsberg, J. P., Zemel, B., Shults, J., Leonard, M. B. 2012; 97 (10): 3584-3592

  Abstract

  Children with acute lymphoblastic leukemia (ALL) are at risk for impaired bone accrual. This peripheral quantitative computed tomography study assessed changes in bone mineral density (BMD) and structure after completion of ALL treatment.Fifty ALL participants, ages 5-22 yr, were enrolled within 2 yr (median 0.8 yr) after completing ALL therapy. Tibia peripheral quantitative computed tomography scans were performed at enrollment and 12 months later. Age-, sex-, and race-specific Z-scores for trabecular BMD (TrabBMD), cortical BMD (CortBMD), and cortical area (CortArea) were generated based on more than 650 reference participants. Multivariable linear regression models examined determinants of changes in Z-scores.At enrollment, mean TrabBMD (-1.03±1.34) and CortBMD (-0.84±1.05) Z-scores were low (both P<0.001) compared with reference participants. TrabBMD and CortBMD Z-scores increased to -0.58±1.41 and -0.51±0.91 over 1 yr, respectively (both P<0.001). Changes in cortical outcomes varied according to the interval since completion of therapy. Among those enrolled less than 6 months after therapy, CortArea Z-scores increased and CortBMD Z-scores decreased (both P<0.01). Among those enrolled 6 months or more after therapy, CortArea Z-scores did not change and CortBMD Z-scores increased (P<0.01). Changes in CortArea and CortBMD Z-scores were inversely associated (r=-0.32, P<0.001). Cumulative glucocorticoid exposure, leukemia risk status, and antimetabolite chemotherapy were not associated with outcomes.TrabBMD was low after completion of ALL therapy and improved significantly. Early increases in cortical dimensions were associated with declines in CortBMD; however, participants further from ALL therapy demonstrated stable cortical dimensions and increases in CortBMD, potentially reflecting the time necessary to mineralize newly formed bone.

  View details for DOI 10.1210/jc.2012-2393

  View details for Web of Science ID 000309664400054

  View details for PubMedID 22865901

• Vitamin D, Metabolic Dyslipidemia, and Metabolic Syndrome in Rheumatoid Arthritis AMERICAN JOURNAL OF MEDICINE Baker, J. F., Mehta, N. N., Baker, D. G., Toedter, G., Shults, J., Von Feldt, J. M., Leonard, M. B. 2012; 125 (10)

  Abstract

  Vitamin D deficiency is a potential risk factor for cardiometabolic disease. We investigated the associations between vitamin D and dyslipidemia and the metabolic syndrome in patients with rheumatoid arthritis, a group at high risk for cardiovascular disease.Serum 25(OH)vitamin D and lipoprotein levels were measured at baseline in a random sample of 499 participants, ages 18-85 years, enrolled in a randomized trial of golimumab (GOlimumab Before Employing methotrexate as the First-line Option in the treatment of Rheumatoid arthritis of Early onset or GO-BEFORE Trial). Participants had rheumatoid arthritis with active disease, and were naïve to methotrexate and biologic therapies. Multivariable linear regression was performed to assess associations between vitamin D levels and lipoprotein fractions. Multivariable logistic regression was performed to determine the odds of hyperlipidemia and the metabolic syndrome in participants with vitamin D deficiency (<20 ng/mL).In multivariable linear regression, vitamin D levels (per 10 ng/mL) were associated inversely with low-density lipoprotein (β: -0.029 [-0.049, -0.0091], P=.004) and triglyceride (β: -0.094 [-0.15, -0.039] P=.001) levels, adjusted for demographic, cardiovascular, and disease-specific variables. Vitamin D and high-density lipoprotein levels were not associated in univariate or multivariate analyses. Vitamin D deficiency was associated independently with an increased odds of hyperlipidemia (odds ratio 1.72; 95% confidence interval, 1.10-2.45; P=.014) and metabolic syndrome (odds ratio 3.45; 95% confidence interval, 1.75-6.80; P <.001) in adjusted models.In conclusion, vitamin D deficiency was associated with the metabolic syndrome and dyslipidemia in rheumatoid arthritis, suggesting a potential role in cardiovascular disease risk. Large-scale, prospective studies are needed to determine if vitamin D supplementation improves lipoprotein levels and reduces cardiovascular risk in rheumatoid arthritis.

  View details for DOI 10.1016/j.amjmed.2012.01.025

  View details for Web of Science ID 000309120400036

  View details for PubMedID 22800875

• Associations between vitamin D, disease activity, and clinical response to therapy in rheumatoid arthritis CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Baker, J. F., Baker, D. G., TOEDTER, G., Shults, J., Von Feldt, J. M., Leonard, M. B. 2012; 30 (5): 658-664

  Abstract

  Vitamin D deficiency is a potential risk factor for autoimmunity. Prior studies of the association between vitamin D levels and rheumatoid arthritis (RA) disease activity have yielded conflicting results.Serum 25(OH)vitamin D levels were measured at baseline in 499 participants with active RA, ages 18-85 years, enrolled in a randomised clinical trial of golimumab (Go-Before Trial). Subjects were methotrexate and biologic therapy naïve. Multivariable linear regression was used to assess associations between vitamin D levels and disease activity scores (DAS28), van der Heijde-Sharp (vdHS) erosion scores, and serum inflammatory markers. Generalised estimating equations were used to evaluate the associations between vitamin D status and the response to therapy over 52 weeks, using the DAS28 and ACR response.Forty-eight percent of participants were vitamin D deficient, defined as serum 25(OH)vitamin D <20 ng/mL. Deficiency was not associated with greater DAS28 (β-0.021 [95% CI -0.22, 0.18]), adjusted for age, race, sex, BMI, disease duration and glomerular filtration rate. Vitamin D deficiency was not associated with baseline vdHS scores or inflammatory markers in adjusted or unadjusted models. There was no association between baseline vitamin D deficiency and change in DAS28 (β = -0.024 [-0.30, 0.25]), proportion meeting ACR response (OR 0.82 [0.56, 1.20]), or radiographic progression at 52 weeks (OR 0.91 [0.59-1.40]).Vitamin D levels were not associated with RA disease activity, inflammatory markers, or vdHS scores at baseline. Furthermore, there was no association between baseline vitamin D level and response to therapy or radiographic progression.

  View details for Web of Science ID 000310828600003

  View details for PubMedID 22776409

• Estimating GFR Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study AMERICAN JOURNAL OF KIDNEY DISEASES Anderson, A. H., Yang, W., Hsu, C., Joffe, M. M., Leonard, M. B., Xie, D., Chen, J., Greene, T., Jaar, B. G., Kao, P., Kusek, J. W., Landis, J. R., Lash, J. P., Townsend, R. R., Weir, M. R., Feldman, H. I. 2012; 60 (2): 250-261

  Abstract

  Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies.Cross-sectional study of 1,433 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (ie, the GFR subcohort) to derive an internal GFR estimating equation using a split-sample approach.Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black.CRIC GFR estimating equation.Urinary (125)I-iothalamate clearance testing (measured GFR [mGFR]).Laboratory measures, including serum creatinine and cystatin C, and anthropometrics.In the validation data set, the model that included serum creatinine level, serum cystatin C level, age, sex, and race was the most parsimonious and similarly predictive of mGFR compared with a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, root mean square errors for the separate models were 0.207 versus 0.202, respectively. Performance of the CRIC GFR estimating equation was most accurate for the subgroups of younger participants, men, nonblacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m(2), those with higher 24-hour urine creatinine excretion, those with lower high-sensitivity C-reactive protein levels, and those with higher mGFRs.Urinary clearance of (125)I-iothalamate is an imperfect measure of true GFR; cystatin C level is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors.The CRIC GFR estimating equation predicts mGFR accurately in the CRIC cohort using serum creatinine and cystatin C levels, age, sex, and race. Its performance was best in younger and healthier participants.

  View details for DOI 10.1053/j.ajkd.2012.04.012

  View details for Web of Science ID 000306477200013

  View details for PubMedID 22658574

• Assessment of dual-energy x-ray absorptiometry measures of bone health in pediatric chronic kidney disease PEDIATRIC NEPHROLOGY Griffin, L. M., Kalkwarf, H. J., Zemel, B. S., Shults, J., Wetzsteon, R. J., Strife, C. F., Leonard, M. B. 2012; 27 (7): 1139-1148

  Abstract

  Dual-energy X-ray absorptiometry (DXA) techniques are limited in childhood chronic kidney disease (CKD) by the confounding effect of short stature and opposing parathyroid hormone effects on trabecular and cortical bone. Peripheral quantitative computed tomography (pQCT) is not subject to these limitations.Lumbar spine (LS) and whole-body (WB) DXA and tibia pQCT scans were obtained in 88 stage 4-5 CKD and >650 healthy participants, ages 5-21 years. Sex- and race-specific Z-scores were generated for bone mineral density (BMD) and bone mineral content (BMC) by DXA, relative to age and adjusted for height Z-score (LS-BMD-Z and WB-BMC-Z), and compared to pQCT Z-scores for trabecular BMD (TrabBMD-Z) for age and cortical BMC (CortBMC-Z) for age and tibia length.LS-BMD-Z [0.50 (95% C.I. 0.28, 0.73), p<0.0001] and TrabBMD-Z [0.53 (0.27, 0.79), p<0.0001] were greater in CKD, and WB-BMC-Z [-0.36 (-0.53, -0.19), p<0.0001] and CortBMC-Z [-0.48 (-0.70, -0.27), p<0.0001] were lower, compared to reference participants. Z-scores were correlated at trabecular (LS-BMD-Z and TrabBMD-Z: R=0.36) and cortical (WB-BMC-Z and CortBMC-Z: R=0.64) sites in CKD; similar to correlations in reference participants.Lumbar spine and whole-body DXA suggested greater trabecular BMD and lower cortical BMC in CKD, consistent with pQCT results; however, correlations were modest. Studies are needed to identify methods that predict fracture in childhood CKD.

  View details for DOI 10.1007/s00467-012-2116-x

  View details for Web of Science ID 000304626700014

  View details for PubMedID 22350304

• Factors Associated With Depressive Symptoms and Use of Antidepressant Medications Among Participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies AMERICAN JOURNAL OF KIDNEY DISEASES Fischer, M. J., Xie, D., Jordan, N., Kop, W. J., Krousel-Wood, M., Tamura, M. K., Kusek, J. W., Ford, V., Rosen, L. K., Strauss, L., Teal, V. L., Yaffe, K., Powe, N. R., Lash, J. P. 2012; 60 (1): 27-38

  Abstract

  Depressive symptoms are correlated with poor health outcomes in adults with chronic kidney disease (CKD). The prevalence, severity, and treatment of depressive symptoms and potential risk factors, including level of kidney function, in diverse populations with CKD have not been well studied.Cross-sectional analysis.Participants at enrollment into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies. CRIC enrolled Hispanics and non-Hispanics at 7 centers in 2003-2007, and H-CRIC enrolled Hispanics at the University of Illinois in 2005-2008.Depressive symptoms measured by Beck Depression Inventory (BDI).Demographic and clinical factors.Elevated depressive symptoms (BDI score ≥11) and antidepressant medication use.Of 3,853 participants, 27.4% had evidence of elevated depressive symptoms and 18.2% were using antidepressant medications; 31.0% of persons with elevated depressive symptoms were using antidepressants. The prevalence of elevated depressive symptoms varied by level of kidney function: 23.6% for participants with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) and 33.8% of those with eGFR <30 mL/min/1.73 m(2). Lower eGFR (OR per 10-mL/min/1.73 m(2) decrease, 1.10; 95% CI, 1.04-1.17), and non-Hispanic black race (OR, 1.42; 95% CI, 1.16-1.74) were each associated with increased odds of elevated depressive symptoms after controlling for other factors. In regression analyses incorporating BDI score, whereas female sex was associated with greater odds of antidepressant use, Hispanic ethnicity, non-Hispanic black race, and higher urine albumin levels were associated with decreased odds of antidepressant use (P < 0.05 for each).Absence of clinical diagnosis of depression and use of nonpharmacologic treatments.Although elevated depressive symptoms were common in individuals with CKD, use of antidepressant medications is low. Individuals of racial and ethnic minority background and with more advanced CKD had a greater burden of elevated depressive symptoms and lower use of antidepressant medications.

  View details for DOI 10.1053/j.ajkd.2011.12.033

  View details for Web of Science ID 000305406200007

  View details for PubMedID 22497791

• Fibroblast Growth Factor 23 and Inflammation in CKD CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Mendoza, F. A., Lsakova, T., Ricardo, A. C., Xie, H., Navaneethan, S. D., Anderson, A. H., Bazzano, L. A., Xie, D., Kretzler, M., Nesse, L., Hamm, L. L., Negrea, L., Leonard, M. B., Raj, D., Wolf, M. 2012; 7 (7): 1155-1162

  Abstract

  Levels of fibroblast growth factor 23 (FGF23) and inflammatory markers are commonly elevated in CKD, and each is associated with adverse clinical outcomes. This study tested the hypothesis that FGF23 is independently associated with inflammation in CKD.The association between levels of FGF23 and the inflammatory markers IL-6, C-reactive protein (CRP), TNF-α, and fibrinogen was assessed in a cross-sectional analysis of 3879 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study between June 2003 and September 2008.FGF23 correlated directly with IL-6 (r=0.4), CRP (r=0.2), TNF-α (r=0.4), and fibrinogen (r=0.3; P<0.001 for each). In univariate and multivariable-adjusted linear regression analyses, natural log (ln) transformed FGF23 was significantly associated with lnIL-6, lnCRP, lnTNF-α, and fibrinogen (P<0.001 for each). Each unit higher lnFGF23 was associated with severe inflammation, defined as levels of all inflammatory markers in the highest 25th percentile, in univariate (odds ratio [OR], 2.4 [95% confidence interval (CI), 2.0-2.9]) and multivariable-adjusted (OR, 2.0 [95% CI, 1.6-2.5]) logistic regression analyses. Ascending FGF23 quartiles were independently associated with severe inflammation (OR, 5.6 for the highest versus lowest FGF23 quartile [95% CI, 2.3-13.9]; P for trend < 0.001).Higher FGF23 levels are independently associated with higher levels of inflammatory markers in patients with CKD and with significantly greater odds of severe inflammation. Future studies should evaluate whether inflammation modifies the association between FGF23 and adverse outcomes in CKD.

  View details for DOI 10.2215/CJN.13281211

  View details for Web of Science ID 000306148500015

  View details for PubMedID 22554719

• Earlier Onset and Greater Severity of Disordered Mineral Metabolism in Diabetic Patients With Chronic Kidney Disease DIABETES CARE Wahl, P., Xie, H., Scialla, J., Anderson, C. A., Bellovich, K., Brecklin, C., Chen, J., Feldman, H., Gutierrez, O. M., Lash, J., Leonard, M. B., Negrea, L., Rosas, S. E., Anderson, A. H., Townsend, R. R., Wolf, M., Isakova, T. 2012; 35 (5): 994-1001

  Abstract

  Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status.Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30-39 vs. 20-29, P < 0.001; FGF23: eGFR 50-59 vs. 40-49, P < 0.001).Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.

  View details for DOI 10.2337/dc11-2235

  View details for Web of Science ID 000303218900012

  View details for PubMedID 22446176

• Vitamin D deficiency is common in children and adolescents with chronic kidney disease KIDNEY INTERNATIONAL Kalkwarf, H. J., Denburg, M. R., Strife, C. F., Zemel, B. S., Foerster, D. L., Wetzsteon, R. J., Leonard, M. B. 2012; 81 (7): 690-697

  Abstract

  Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease.

  View details for DOI 10.1038/ki.2011.431

  View details for Web of Science ID 000301847900011

  View details for PubMedID 22205356

• Interpretation of Body Mass Index in Children with CKD CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Gao, T., Leonard, M. B., Zemel, B., Kalkwarf, H. J., Foster, B. J. 2012; 7 (4): 558-564

  Abstract

  Clinical practice guidelines recommend that body mass index (BMI) in children with CKD be expressed relative to height-age (BMI-height-age-z) rather than chronologic age (BMI-age-z) to account for delayed growth and sexual maturation. This approach has not been validated. This study sought to (1) compare children who have CKD with healthy children regarding the relationships between BMI-age-z and each of relative lean mass (LM) and adiposity and (2) determine whether BMI-height-age-z reflects relative LM and adiposity in CKD in the same way that BMI-age-z does in healthy children.In a cross-sectional study, dual-energy x-ray absorptiometry was used to assess whole-body fat mass (FM) and LM in 143 participants with CKD and 958 healthy participants (age, 5-21 years); FM and LM were expressed as sex-specific Z-scores relative to height (LM-height-z, FM-height-z), with healthy participants as the reference. BMI-age-z and BMI-height-age-z were determined using the 2000 Centers for Disease Control and Prevention reference data.Compared with healthy children of the same sex, age, race, and BMI-age-z, LM-height-z was significantly higher in males with all CKD stages (by 0.41-0.43 SDs) and in females with mild to moderate CKD (by 0.38 SD); FM-height-z was significantly higher in both males (by 0.26 SD) and females (by 0.52 SD) with severe CKD. Underestimation of relative LM and adiposity was improved by expressing BMI relative to height-age.In children with CKD, BMI-height-age-z reflects relative LM and adiposity in the same way that BMI-age-z does in healthy children.

  View details for DOI 10.2215/CJN.09710911

  View details for Web of Science ID 000302281900007

  View details for PubMedID 22300738

• Bone Density and Structure in Long-Term Survivors of Pediatric Allogeneic Hematopoietic Stem Cell Transplantation JOURNAL OF BONE AND MINERAL RESEARCH Mostoufi-Moab, S., Ginsberg, J. P., Bunin, N., Zemel, B., Shults, J., Leonard, M. B. 2012; 27 (4): 760-769

  Abstract

  Children requiring allogeneic hematopoietic stem cell transplantation (alloHSCT) have multiple risk factors for impaired bone accrual. The impact of alloHSCT on volumetric bone mineral density (vBMD) and cortical structure has not been addressed. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained in 55 alloHSCT recipients, ages 5 to 26 years, a median of 7 (range, 3-16) years after alloHSCT. pQCT outcomes were converted to sex- and race- specific Z-scores relative to age based on reference data in >700 concurrent healthy participants. Cortical section modulus (Zp; a summary measure of cortical bone structure and strength), and muscle and fat area Z-scores were further adjusted for tibia length for age Z-scores. AlloHSCT survivors had lower height Z-scores (-1.21 ± 1.25 versus 0.23 ± 0.92; p < 0.001), versus reference participants; BMI Z-scores did not differ. AlloHSCT survivors had lower trabecular vBMD (-1.05; 95% confidence interval [CI], -1.33 to -0.78; p < 0.001), cortical Zp (-0.63; 95% CI, -0.91 to -0.35; p < 0.001), and muscle (-1.01; 95% CI, -1.30 to -0.72; p < 0.001) Z-scores and greater fat (0.82; 95% CI, 0.54-1.11; p < 0.001) Z-scores, versus reference participants. Adjustment for muscle deficits eliminated Zp deficits in alloHSCT. Total body irradiation (TBI) was associated with lower trabecular vBMD (-1.30 ± 1.40 versus -0.49 ± 0.88; p = 0.01) and muscle (-1.34 ± 1.42 versus -0.34 ± 0.87; p < 0.01) Z-scores. Growth hormone deficiency (GHD) was associated with lower Zp Z-scores (-1.64 ± 2.47 versus -0.28 ± 1.24; p = 0.05); however, muscle differences were not significant (-1.69 ± 1.84 versus -0.78 ± 1.01; p = 0.09). History of graft versus host disease was not associated with pQCT outcomes. In summary, alloHSCT was associated with significant deficits in trabecular vBMD, cortical geometry, and muscle area years after transplantation. TBI and GHD were significant risk factors for musculoskeletal deficits. Future studies are needed to determine the metabolic and fracture implications of these deficits, and to identify therapies to improve bone accrual following alloHSCT during childhood.

  View details for DOI 10.1002/jbmr.1499

  View details for Web of Science ID 000301708100005

  View details for PubMedID 22189761

• Bone Density and Cortical Structure after Pediatric Renal Transplantation JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Terpstra, A. M., Kalkwarf, H. J., Shults, J., Zemel, B. S., Wetzsteon, R. J., Foster, B. J., Strife, C. F., Foerster, D. L., Leonard, M. B. 2012; 23 (4): 715-726

  Abstract

  The impact of renal transplantation on trabecular and cortical bone mineral density (BMD) and cortical structure is unknown. We obtained quantitative computed tomography scans of the tibia in pediatric renal transplant recipients at transplantation and 3, 6, and 12 months; 58 recipients completed at least two visits. We used more than 700 reference participants to generate Z-scores for trabecular BMD, cortical BMD, section modulus (a summary measure of cortical dimensions and strength), and muscle and fat area. At baseline, compared with reference participants, renal transplant recipients had significantly lower mean section modulus and muscle area; trabecular BMD was significantly greater than reference participants only in transplant recipients younger than 13 years. After transplantation, trabecular BMD decreased significantly in association with greater glucocorticoid exposure. Cortical BMD increased significantly in association with greater glucocorticoid exposure and greater decreases in parathyroid hormone levels. Muscle and fat area both increased significantly, but section modulus did not improve. At 12 months, transplantation associated with significantly lower section modulus and greater fat area compared with reference participants. Muscle area and cortical BMD did not differ significantly between transplant recipients and reference participants. Trabecular BMD was no longer significantly elevated in younger recipients and was low in older recipients. Pediatric renal transplant associated with persistent deficits in section modulus, despite recovery of muscle, and low trabecular BMD in older recipients. Future studies should determine the implications of these data on fracture risk and identify strategies to improve bone density and structure.

  View details for DOI 10.1681/ASN.2011050480

  View details for Web of Science ID 000302333300019

  View details for PubMedID 22282589

• Micro-MR Imaging-based Computational Biomechanics Demonstrates Reduction in Cortical and Trabecular Bone Strength after Renal Transplantation RADIOLOGY Rajapakse, C. S., Leonard, M. B., Bhagat, Y. A., Sun, W., Magland, J. F., Wehrli, F. W. 2012; 262 (3): 912-920

  Abstract

  To examine the ability of three-dimensional micro-magnetic resonance (MR) imaging-based computational biomechanics to detect mechanical alterations in trabecular bone and cortical bone in the distal tibia of incident renal transplant recipients 6 months after renal transplantation and compare them with bone mineral density (BMD) outcomes.The study was approved by the institutional review board and complied with HIPAA guidelines. Written informed consent was obtained from all subjects. Micro-MR imaging of distal tibial metaphysis was performed within 2 weeks after renal transplantation (baseline) and 6 months later in 49 participants (24 female; median age, 44 years; range, 19-61 years) with a clinical 1.5-T whole-body imager using a modified three-dimensional fast large-angle spin-echo pulse sequence. Micro-finite-element models for cortical bone, trabecular bone, and whole-bone section were generated from each image by delineating the endosteal and periosteal boundaries. Mechanical parameters (stiffness and failure load) were estimated with simulated uniaxial compression tests on the micro-finite-element models. Structural parameters (trabecular bone volume fraction [BV/TV, bone volume to total volume ratio], trabecular thickness [TbTh], and cortical thickness [CtTh]) were computed from micro-MR images. Total hip and spine areal BMD were determined with dual-energy x-ray absorptiometry (DXA). Parameters obtained at the follow-up were compared with the baseline values by using parametric or nonparametric tests depending on the normality of data.All mechanical parameters were significantly lower at 6 months compared with baseline. Decreases in cortical bone, trabecular bone, and whole-bone stiffness were 3.7% (P = .03), 4.9% (P = .03), and 4.3% (P = .003), respectively. Decreases in cortical bone, trabecular bone, and whole-bone failure strength were 7.6% (P = .0003), 6.0% (P = .004), and 5.6% (P = .0004), respectively. Conventional structural measures, BV/TV, TbTh, and CtTh, did not change significantly. Spine BMD decreased by 2.9% (P < .0001), while hip BMD did not change significantly at DXA.MR imaging-based micro-finite-element analysis suggests that stiffness and failure strength of the distal tibia decrease over a 6-month interval after renal transplantation.

  View details for DOI 10.1148/radiol.11111044

  View details for Web of Science ID 000302121400020

  View details for PubMedID 22357891

• Reduced Fracture Risk With Early Corticosteroid Withdrawal After Kidney Transplant AMERICAN JOURNAL OF TRANSPLANTATION Nikkel, L. E., Mohan, S., Zhang, A., McMahon, D. J., Boutroy, S., Dube, G., Tanriover, B., Cohen, D., Ratner, L., Hollenbeak, C. S., Leonard, M. B., Shane, E., Nickolas, T. L. 2012; 12 (3): 649-659

  Abstract

  Corticosteroid use after kidney transplantation results in severe bone loss and high fracture risk. Although corticosteroid withdrawal in the early posttransplant period has been associated with bone mass preservation, there are no published data regarding corticosteroid withdrawal and risk of fracture. We hypothesized lower fracture incidence in patients discharged from the hospital without than with corticosteroids after transplantation. From the United States Renal Data System (USRDS), 77, 430 patients were identified who received their first kidney transplant from 2000 to 2006. Fracture incidence leading to hospitalization was determined from 2000 to 2007; discharge immunosuppression was determined from United Networks for Organ Sharing forms. Time-to-event analyses were used to evaluate fracture risk. Median (interquartile range) follow-up was 1448 (808-2061) days. There were 2395 fractures during follow-up; fracture incidence rates were 0.008 and 0.0058 per patient-year for recipients discharged with and without corticosteroid, respectively. Corticosteroid withdrawal was associated with a 31% fracture risk reduction (HR 0.69; 95% CI 0.59-0.81). Fractures associated with hospitalization are significantly lower with regimens that withdraw corticosteroid. As this study likely underestimates overall fracture incidence, prospective studies are needed to determine differences in overall fracture risk in patients managed with and without corticosteroids after kidney transplantation.

  View details for DOI 10.1111/j.1600-6143.2011.03872.x

  View details for Web of Science ID 000300832500022

  View details for PubMedID 22151430

• Changes in vitamin D binding protein and vitamin D concentrations associated with liver transplantation LIVER INTERNATIONAL Reese, P. P., Bloom, R. D., Feldman, H. I., Huverserian, A., Thomasson, A., Shults, J., Hamano, T., Goral, S., Shaked, A., Olthoff, K., Rickels, M. R., Bleicher, M., Leonard, M. B. 2012; 32 (2): 287-296

  Abstract

  Vitamin D deficiency is associated with fractures, infections and death. Liver disease impairs vitamin D and vitamin D binding protein (DBP) metabolism.We aimed to determine the impact of liver transplantation on vitamin D, particularly on DBP and free vitamin D concentrations.Serum 25(OH)D, 1,25(OH)(2) D and DBP concentrations were measured in 202 adults before liver transplantation and 3 months later in 155. Free vitamin D concentrations were estimated from these values. Risk factors for 25(OH)D deficiency (<20 ng/ml) and low 1,25(OH)(2) D (<20 pg/ml) were examined with logistic regression, and changes in concentrations following transplantation with linear regression.Pretransplant, 84% were 25(OH)D deficient, 13% had 25(OH)D concentrations <2.5 ng/ml, and 77% had low 1,25(OH)(2) D. Model for end-stage liver disease score ≥ 20 (P < 0.005) and hypoalbuminemia (P < 0.005) were associated with low 25(OH)D and 1,25(OH)(2) D concentrations. Following transplantation, 25(OH)D concentrations increased a median of 17.8 ng/ml (P < 0.001). Albumin increased from a median of 2.7 to 3.8 g/dl (P < 0.001) and DBP from 8.6 to 23.8 mg/dl (P < 0.001). Changes in total 25(OH)D were positively and independently associated with changes in DBP (P < 0.05) and albumin (P < 0.001). Free 25(OH)D concentrations rose from 6.0 to 9.7 pg/ml (P < 0.001). In contrast, total 1,25(OH)(2)D concentrations rose only by 4.3 pg/ml (P < 0.001) and free 1,25(OH)(2D concentrations declined (P < 0.001).Serum total and free 25(OH)D and DBP concentrations rose substantially following transplantation, while 1,25(OH)(2) D concentrations showed modest changes and free 1,25(OH)(2) D decreased. Studies of the effects of vitamin D status on diverse transplant complications are needed.

  View details for DOI 10.1111/j.1478-3231.2011.02638.x

  View details for Web of Science ID 000298919500014

  View details for PubMedID 22098635

• Associations Between Psychiatric Comorbidities and Sleep Disturbances in Children With Attention-Deficit/Hyperactivity Disorder JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS Accardo, J. A., Marcus, C. L., Leonard, M. B., Shults, J., Meltzer, L. J., Elia, J. 2012; 33 (2): 97-105

  Abstract

  Children with attention-deficit/hyperactivity disorder (ADHD) often have sleep complaints and also higher rates of psychiatric comorbidities such as mood and anxiety disorders that may affect sleep. The authors hypothesized that children with ADHD and psychiatric comorbidities would have higher overall sleep disturbance scores as measured by a sleep questionnaire than children with ADHD without comorbidities.This cross-sectional analysis in an academic center studied 317 children with ADHD; 195 subjects had no comorbid conditions, 60 were anxious and 62 were depressed. Participants completed the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present State, 4th Revised Edition and the Children's Sleep Habits Questionnaire.Median age (range) was 8.9 (6-18.7) years; 78% were male. Median (interquartile range) Total Sleep Disturbance Score (TSDS) on Children's Sleep Habits Questionnaire for subjects with no comorbidities was 44 (40-49); anxiety, 48 (43-54); and depression, 46 (41-52). Compared with subjects without comorbidities, TSDS in anxious subjects was greater (p = .008). TSDS in depressed subjects was not significantly different. Compared with subjects without comorbidities, anxious subjects had higher Bedtime Resistance, Sleep Onset Delay, and Night Wakings subscales (p = .03, .007, and .007, respectively); depressed subjects had higher Sleep Onset Delay and Sleep Duration subscales (p = .003 and .01, respectively).Anxiety in children with ADHD contributed to higher overall sleep disturbance scores, compared with children with ADHD alone. Both comorbidities were associated with higher Sleep Onset Latency subscale scores. Further study of the impact of psychiatric comorbidities on sleep in children with ADHD is warranted.

  View details for DOI 10.1097/DBP.0b013e31823f6853

  View details for Web of Science ID 000300399700001

  View details for PubMedID 22261833

• Body Composition Abnormalities in Long-Term Survivors of Pediatric Hematopoietic Stem Cell Transplantation JOURNAL OF PEDIATRICS Mostoufi-Moab, S., Ginsberg, J. P., Bunin, N., Zemel, B. S., Shults, J., Thayu, M., Leonard, M. B. 2012; 160 (1): 122-128

  Abstract

  To quantify lean mass (LM) and fat mass (FM) in survivors of childhood allogeneic hematopoietic stem-cell transplantation (alloHSCT) compared with healthy reference participants and identify risk factors for body composition abnormalities.Whole body LM and FM were measured with dual energy x-ray absorptiometry in 54 survivors (ages 5-25 years) and 894 healthy reference participants in a cross-sectional study. Multivariate regression models were used to compare sex- and race-specific Z-scores for LM for height (LM-Ht) and FM for height (FM-Ht) in survivors and reference participants and to identify correlates of LM-Ht and FM-Ht Z-scores in alloHSCT.Height Z-scores were significantly lower in alloHSCT survivors (P < .001) compared with reference participants; body mass index Z-scores did not differ (P = .13). Survivors had significantly lower mean LM-Ht Z-scores (-0.72; 95% CI, -1.02--0.42; P < .001) and greater FM-Ht Z-scores (1.10; 95% CI, 0.84-1.39; P < .001) compared with reference participants. LM-Ht Z-score deficits in alloHSCT survivors were larger (-1.26; 95% CI, -1.53--0.99; P < .001) after adjustment for FM-Ht Z-scores. Endocrinopathies and alloHSCT characteristics were not associated with LM-Ht or FM-Ht Z-scores.Survivors of childhood alloHSCT have significant LM deficits and FM excess. Future studies should identify the mechanism and consequences of these abnormalities.

  View details for DOI 10.1016/j.jpeds.2011.06.041

  View details for Web of Science ID 000298143000029

  View details for PubMedID 21839468

• Correlates of Osteoprotegerin and Association with Aortic Pulse Wave Velocity in Patients with Chronic Kidney Disease CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Scialla, J. J., Leonard, M. B., Townsend, R. R., Appel, L., Wolf, M., Budoff, M. J., Chen, J., Lustigova, E., Gadegbeku, C. A., Glenn, M., Hanish, A., Raj, D., Rosas, S. E., Seliger, S. L., Weir, M. R., Parekh, R. S. 2011; 6 (11): 2612-2619

  Abstract

  Osteoprotegerin (OPG), a cytokine that regulates bone resorption, has been implicated in the process of vascular calcification and stiffness.Serum OPG was measured in 351 participants with chronic kidney disease (CKD) from one site of the Chronic Renal Insufficiency Cohort Study. Cortical bone mineral content (BMC) was measured by quantitative computed tomography in the tibia. Multivariable linear regression was used to test the association between serum OPG and traditional cardiovascular risk factors, measures of abnormal bone and mineral metabolism, and pulse wave velocity.Higher serum OPG levels were associated with older age, female gender, greater systolic BP, lower estimated GFR, and lower serum albumin. OPG was not associated with measures of abnormal bone or mineral metabolism including serum phosphorus, albumin-corrected serum calcium, intact parathyroid hormone, bone-specific alkaline phosphatase, or cortical BMC. Among 226 participants with concurrent aortic pulse wave velocity measurements, increasing tertiles of serum OPG were associated with higher aortic pulse wave velocity after adjustment for demographics, traditional vascular risk factors, and nontraditional risk factors such as estimated GFR, albuminuria, serum phosphate, corrected serum calcium, presence of secondary hyperparathyroidism, serum albumin, and C-reactive protein or after additional adjustment for cortical BMC in a subset (n = 161).These data support a strong relationship between serum OPG and arterial stiffness independent of many potential confounders including traditional cardiovascular risk factors, abnormal bone and mineral metabolism, and inflammation.

  View details for DOI 10.2215/CJN.03910411

  View details for Web of Science ID 000296821300011

  View details for PubMedID 21940840

• Validation of The Health Improvement Network (THIN) database for epidemiologic studies of chronic kidney disease PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Denburg, M. R., Haynes, K., Shults, J., Lewis, J. D., Leonard, M. B. 2011; 20 (11): 1138-1149

  Abstract

  Chronic kidney disease (CKD) is a prevalent and important outcome and covariate in pharmacoepidemiology. The Health Improvement Network (THIN) in the UK represents a unique resource for population-based studies of CKD. We compiled a valid list of Read codes to identify subjects with moderate to advanced CKD.A cross-sectional validation study was performed to identify codes that best define CKD Stages 3-5. All subjects with at least one non-zero measure of serum creatinine after 1 January 2002 were included. Estimated glomerular filtration rate (eGFR) was calculated according to the Schwartz formula for subjects aged < 18 years and the Modification of Diet in Renal Disease formula for subjects aged ≥ 18 years. CKD was defined as an eGFR <60 mL/minute/1.73 m² on at least two occasions, more than 90 days apart.The laboratory definition identified 230,426 subjects with CKD, for a period prevalence in 2008 of 4.56% (95%CI, 4.54-4.58). A list of 45 Read codes was compiled, which yielded a positive predictive value of 88.9% (95%CI, 88.7-89.1), sensitivity of 48.8%, negative predictive value of 86.5%, and specificity of 98.2%. Of the 11.1% of subjects with a code who did not meet the laboratory definition, 83.6% had at least one eGFR <60. The most commonly used code was for CKD Stage 3.The proposed list of codes can be used to accurately identify CKD when serum creatinine data are limited. The most sensitive approach for the detection of CKD is to use this list to supplement creatinine measures.

  View details for DOI 10.1002/pds.2203

  View details for Web of Science ID 000296974300003

  View details for PubMedID 22020900

• Associations between body mass, radiographic joint damage, adipokines and risk factors for bone loss in rheumatoid arthritis RHEUMATOLOGY Baker, J. F., George, M., Baker, D. G., Toedter, G., Von Feldt, J. M., Leonard, M. B. 2011; 50 (11): 2100-2107

  Abstract

  To evaluate the association between BMI and radiographic joint damage (RJD) in RA.van der Heijde-Sharp (vdHS) erosion scores were determined in 499 participants with RA, ages 18-85 years, while enrolled in a clinical trial of golimumab (GO-BEFORE trial). Subjects were MTX and biologic therapy naïve. Multivariable logistic regressions determined the odds of prevalent RJD (defined as vdHS score >10) according to BMI category. Longitudinal analyses evaluated the association between BMI category and progression of vdHS score over 52 weeks. Analyses in a subset of 100 participants examined the association between adipokines and vdHS scores.At enrolment and 52 weeks, 37.6 and 43.6% of participants had RJD. Compared with normal weight, obese subjects had lower odds of RJD [0.40 (95% CI 0.22, 0.74); P = 0.003], and underweight subjects had greater odds [3.86 (95% CI 1.66, 9.00); P = 0.002] at baseline, adjusted for demographic and disease characteristics. The baseline associations between BMI category and RJD were greater among participants with multiple risk factors for bone loss (female >50 years, smoking, glucocorticoid exposure and vitamin D deficiency); test for interaction P = 0.05. Adjustment for adiponectin levels did not attenuate the association between BMI and vdHS scores. Baseline BMI and change in weight did not independently predict radiographic progression (P > 0.1).Higher BMI was independently associated with less RJD and was greatest in participants with risk factors for bone loss. Future studies are needed to examine the associations between RJD, obesity, weight loss and osteoporosis.

  View details for DOI 10.1093/rheumatology/ker294

  View details for Web of Science ID 000296295800025

  View details for PubMedID 21890621

• On the Significance of Motion Degradation in High-resolution 3D mu MRI of Trabecular Bone ACADEMIC RADIOLOGY Bhagat, Y. A., Rajapakse, C. S., Magland, J. F., Wald, M. J., Song, H. K., Leonard, M. B., Wehrli, F. W. 2011; 18 (10): 1205-1216

  Abstract

  Subtle subject movement during high-resolution three-dimensional micro-magnetic resonance imaging of trabecular bone (TB) causes blurring, thereby rendering the data unreliable for quantitative analysis. In this work, the effects of translational and rotational motion displacements were evaluated qualitatively and quantitatively.In experiment 1, motion was induced by applying various simulated and previously observed in vivo trajectories as phase shifts to k-space or rotation angles to k-space segments of a virtually motion-free data set. In experiment 2, images that were visually free of motion artifacts from two groups of 10 healthy individuals, differing in age, were selected to probe the effects of motion on TB parameters. In both experiments, images were rated for motion severity, and the scores were compared to a focus criterion, the normalized gradient squared.Strong correlations were observed between the motion quality scores and the corresponding normalized gradient squared values (R(2) = 0.52-0.64, P < .01). The results from experiment 1 demonstrated consistently lower image quality and alterations in structural parameters of 9% to 45% with increased amplitude of displacements. In experiment 2, the significant differences in structural parameter group means of the motion-free images were lost upon motion degradation. Autofocusing, a postprocessing correction method, partially recovered the sharpness of the original motion-free images in 13 of 20 subjects.Quantitative TB structural measures are highly sensitive to subtle motion-induced degradation, which adversely affects precision and statistical power. The results underscore the influence of subject movement in high-resolution three-dimensional micro-magnetic resonance imaging and its correction for TB structure analysis.

  View details for DOI 10.1016/j.acra.2011.06.006

  View details for Web of Science ID 000295344500002

  View details for PubMedID 21816638

• Volumetric Bone Mineral Density and Bone Structure in Childhood Chronic Kidney Disease JOURNAL OF BONE AND MINERAL RESEARCH Wetzsteon, R. J., Kalkwarf, H. J., Shults, J., Zemel, B. S., Foster, B. J., Griffin, L., Strife, C. F., Foerster, D. L., Jean-Pierre, D. K., Leonard, M. B. 2011; 26 (9): 2235-2244

  Abstract

  Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (vBMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomographic scans were obtained in 156 children with CKD [69 stages 2 to 3, 51 stages 4 to 5, and 36 stage 5D (dialysis)] and 831 healthy participants aged 5 to 21 years. Sex-, race-, and age- or tibia length-specific Z-scores were generated for trabecular BMD (TrabBMD), cortical BMD (CortBMD), cortical area (CortArea) and endosteal circumference (EndoC). Greater CKD severity was associated with a higher TrabBMD Z-score in younger participants (p < .001) compared with healthy children; this association was attenuated in older participants (interaction p < .001). Mean CortArea Z-score was lower (p < .01) in CKD 4-5 [-0.49, 95% confidence interval (CI) -0.80, -0.18)] and CKD 5D (-0.49, 95% CI -0.83, -0.15) compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD Z-score (p < .01), and this association was significantly attenuated in older participants (interaction p < .05). Higher levels of PTH and biomarkers of bone formation (bone-specific alkaline phosphatase) and resorption (serum C-terminal telopeptide of type 1 collagen) were associated with lower CortBMD and CortArea Z-scores and greater EndoC Z-score (r = 0.18-0.36, all p ≤ .02). CortBMD Z-score was significantly lower in CKD participants with PTH levels above versus below the upper limit of the Kidney Disease Outcome Quality Initiative (KDOQI) CKD stage-specific target range: -0.46 ± 1.29 versus 0.12 ± 1.14 (p < .01). In summary, childhood CKD and secondary hyperparathyroidism were associated with significant reductions in cortical area and CortBMD and greater TrabBMD in younger children. Future studies are needed to establish the fracture implications of these alterations and to determine if cortical and trabecular abnormalities are reversible.

  View details for DOI 10.1002/jbmr.427

  View details for Web of Science ID 000294444300024

  View details for PubMedID 21590737

• Discriminants of Prevalent Fractures in Chronic Kidney Disease JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Nickolas, T. L., Cremers, S., Zhang, A., Thomas, V., Stein, E., Cohen, A., Chauncey, R., Nikkel, L., Yin, M. T., Liu, X. S., Boutroy, S., Staron, R. B., Leonard, M. B., McMahon, D. J., Dworakowski, E., Shane, E. 2011; 22 (8): 1560-1572

  Abstract

  Patients with chronic kidney disease (CKD) have higher rates of fracture than the general population. Increased bone remodeling, leading to microarchitectural deterioration and increased fragility, may accompany declining kidney function, but there are no reliable methods to identify patients at increased risk for fracture. In this cross-sectional study of 82 patients with predialysis CKD, high-resolution imaging revealed that the 23 patients with current fractures had significantly lower areal density at the femoral neck; total, cortical, and trabecular volumetric bone density; cortical area and thickness; and trabecular thickness. Compared with levels in the lowest tertile, higher levels of osteocalcin, procollagen type-1 N-terminal propeptide, and tartrate-resistant acid phosphatase 5b were associated with higher odds of fracture, even after adjustment for femoral neck T-score. Discrimination of fracture prevalence was best with a femoral neck T-score of -2.0 or less and a value in the upper two tertiles for osteocalcin, procollagen type-1 N-terminal propeptide, or tartrate-resistant acid phosphatase 5b; these values corresponded to the upper half of the normal premenopausal reference range. In summary, these cross-sectional data suggest that measurement of bone turnover markers may increase the diagnostic accuracy of densitometry to identify patients with CKD at high risk for fracture.

  View details for DOI 10.1681/ASN.2010121275

  View details for Web of Science ID 000294083300023

  View details for PubMedID 21784896

• Skeletal Health of Children and Adolescents With Inflammatory Bowel Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Pappa, H., Thayu, M., Sylvester, F., Leonard, M., Zemel, B., Gordon, C. 2011; 53 (1): 11-25

  Abstract

  Current evidence points to suboptimal bone health in children and adolescents with inflammatory bowel disease (IBD) when compared with their healthy peers. This compromise is evident from diagnosis. The clinical consequences and long-term outcome of this finding are still unknown. The mechanism of suboptimal bone health in children and adolescents with IBD lays mainly in reduced bone formation, but also reduced bone resorption, processes necessary for bone growth. Factors contributing to this derangement are inflammation, delayed growth and puberty, lean mass deficits, and use of glucocorticoids. We recognize that evidence is sparse on the topic of bone health in children and adolescents with IBD. In this clinical guideline, based on current evidence, we provide recommendations on screening and monitoring bone health in children and adolescents with IBD, including modalities to achieve this and their limitations; monitoring of parameters of growth, pubertal development, and reasons for concern; evaluation of vitamin D status and vitamin D and calcium intake; exercise; and nutritional support. We also report on the current evidence of the effect of biologics on bone health in children and adolescents with IBD, as well as the role of bone active medications such as bisphosphonates. Finally, we summarize the existing numerous gaps in knowledge and potential subjects for future research endeavors.

  View details for DOI 10.1097/MPG.0b013e31821988a3

  View details for Web of Science ID 000291925500003

  View details for PubMedID 21694532

• Circulating MicroRNA Is a Biomarker of Pediatric Crohn Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Zahm, A. M., Thayu, M., Hand, N. J., Horner, A., Leonard, M. B., Friedman, J. R. 2011; 53 (1): 26-33

  Abstract

  The gold standard for the diagnosis and evaluation of Crohn disease (CD) is endoscopy/colonoscopy, although this is invasive, costly, and associated with risks to the patient. Recently, circulating microRNAs (miRNAs) have emerged as promising noninvasive biomarkers. Here, we examined the utility of serum miRNAs as biomarkers of CD in children.Studies were conducted using sera samples from patients with pediatric CD, healthy controls, and a comparison group of patients with pediatric celiac disease. Serum miRNA levels were explored initially using a microfluidic quantitative reverse transcription-polymerase chain reaction array platform. Findings were subsequently validated using quantitative reverse transcription-polymerase chain reaction in larger validation sample sets. The diagnostic utility of CD-associated serum miRNA was examined using receiver operating characteristic analysis.A survey of miRNA levels in the sera of control and patients with CD detected significant elevation of 24 miRNAs, 11 of which were chosen for further validation. All of the candidate biomarker miRNAs were confirmed in an independent CD sample set (n = 46). To explore the specificity of the CD-associated miRNAs, they were measured in the sera of patients with celiac disease (n = 12); none were changed compared with healthy controls. Receiver operating characteristic analyses revealed that serum miRNAs have promising diagnostic utility, with sensitivities for CD above 80%. Significant decreases in serum miRNAs were observed in 24 incident patients with pediatric CD after 6 months of treatment.The present study identifies 11 CD-associated serum miRNA with encouraging diagnostic potential. Our findings suggest serum miRNAs may prove useful as noninvasive biomarkers in CD.

  View details for DOI 10.1097/MPG.0b013e31822200cc

  View details for Web of Science ID 000291925500004

  View details for PubMedID 21546856

• Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal Disease in Patients With Chronic Kidney Disease JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Isakova, T., Xie, H., Yang, W., Xie, D., Anderson, A. H., Scialla, J., Wahl, P., Gutierrez, O. M., Steigerwalt, S., He, J., Schwartz, S., Lo, J., Ojo, A., Sondheimer, J., Hsu, C., Lash, J., Leonard, M., Kusek, J. W., Feldman, H. I., Wolf, M. 2011; 305 (23): 2432-2439

  Abstract

  A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease.To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease.A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008.All-cause mortality and end-stage renal disease.At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2).Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

  View details for DOI 10.1001/jama.2011.826

  View details for Web of Science ID 000291597300023

  View details for PubMedID 21673295

• Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease KIDNEY INTERNATIONAL Isakova, T., Wahl, P., Vargas, G. S., Gutierrez, O. M., Scialla, J., Xie, H., Appleby, D., Nessel, L., Bellovich, K., Chen, J., Hamm, L., Gadegbeku, C., Horwitz, E., Townsend, R. R., Anderson, C. A., Lash, J. P., Hsu, C., Leonard, M. B., Wolf, M. 2011; 79 (12): 1370-1378

  Abstract

  Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.

  View details for DOI 10.1038/ki.2011.47

  View details for Web of Science ID 000291093300013

  View details for PubMedID 21389978

• Exposure to CYP3A4-inducing and CYP3A4-non-inducing antiepileptic agents and the risk of fractures PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Schelleman, H., Pollard, J. R., Newcomb, C., Markowitz, C. E., Bilker, W. B., Leonard, M. B., Hennessy, S. 2011; 20 (6): 619-625

  Abstract

  To evaluate whether exposure to Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)-inducing antiepileptics increases fracture risk compared to CYP3A4-non-inducing antiepileptics.We performed a retrospective cohort study of initiators of antiepileptic agents using a UK medical record database (The Health Improvement Network) from 1995 to 2007. We considered an antiepileptic user an initiator if he or she had not received a prescription for an antiepileptic agent within the first year after entry in the database. Proportional hazards regression was used to calculate hazard ratios for fracture during long-term (≥ 6 months) exposure to CYP3A4 inducing versus CYP3A4 non-inducing antiepileptics.We identified 4077 initiators of CYP3A4-inducing antiepileptics and 6433 initiators of CYP3A4-non-inducing antiepileptics with at least 6 months of antiepileptic exposure. During 6006 person-years exposed to CYP3A4-inducing antiepileptics, 118 fractures were identified for an incidence rate of 1.96 (95% confidence interval (CI): 1.63-2.35) fractures per 100 person-years. During 7184 person-years exposed to CYP3A4-non-inducing antiepileptics, 127 fractures were identified, for an incidence rate of 1.77 (95% CI: 1.47-2.10) fractures per 100 person-years. The adjusted hazard ratio for CYP3A4-inducing antiepileptic versus CYP3A4-non-inducing antiepileptic was 1.21 (95% CI: 0.93-1.56). No duration-response relationship was evident.Our results do not support the hypothesis that CYP3A4 induction by antiepileptic agents increases the fracture risk. Further research will be needed to evaluate whether mechanisms other than CYP3A4 induction might explain some of the elevated risk of fractures associated with long-term use of antiepileptic agents.

  View details for DOI 10.1002/pds.2141

  View details for Web of Science ID 000292601300008

  View details for PubMedID 21538673

• Mechanical loads and cortical bone geometry in healthy children and young adults BONE Wetzsteon, R. J., Zemel, B. S., Shults, J., Howard, K. M., Kibe, L. W., Leonard, M. B. 2011; 48 (5): 1103-1108

  Abstract

  Muscle and bone form a functional unit. While muscle size is a useful surrogate of mechanical load on bone, the independent contributions to bone strength of muscle force, muscle size, gravitational load (body weight), and physical activity have not been assessed. Three hundred twenty-one healthy participants (32% black, 47% male), aged 5-35 years were assessed. Peak dorsiflexion muscle torque (ft-lbs) of the ankle was assessed using isometric dynamometry. Tibia peripheral quantitative computed tomography measures included polar section modulus (Zp; mm(3)), periosteal and endosteal circumference (mm), cortical area (mm(2)), and volumetric bone mineral density (vBMD; mg/cm(3)) at the 38% site, and muscle cross-sectional area (CSA; mm(2)), at the 66% site. Physical activity (average hours per week) was assessed by questionnaire. Log linear regression was used to assess determinants of muscle specific force (MSF; torque relative to muscle CSA) and Zp adjusted for age and tibia length. MSF was greater in blacks than whites (p<0.05) and lower in females than males (p<0.001). Zp was greater in blacks than whites (p=0.002) in Tanner stages 1-4, but the difference was attenuated in Tanner 5 (interaction, p=0.02); R(2)=0.87. Muscle CSA, muscle torque, body weight, and physical activity were added to the model and each load covariate was independently and significantly (all, p<0.02) associated with Zp (R(2)=0.92), periosteal circumference, and cortical area. Inclusion of these measures attenuated but did not eliminate the significant race differences. Only muscle CSA was positively associated with endosteal circumference, while none of the load covariates were associated with vBMD. In conclusion, bone geometry is associated with several factors that define the mechanical load on bone, independent of age, tibia length, maturation, race, and sex. Race differences in Zp were not explained by these measures of mechanical load. Given that inclusion of muscle torque, body weight, and physical activity resulted in a nominal increase in the R(2), muscle size is an adequate surrogate for the mechanical load on bone in healthy participants.

  View details for DOI 10.1016/j.bone.2011.01.005

  View details for Web of Science ID 000289879900019

  View details for PubMedID 21241839

• Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort (CRIC) NEPHROLOGY DIALYSIS TRANSPLANTATION Isakova, T., Anderson, C. A., Leonard, M. B., Xie, D., Gutierrez, O. M., Rosen, L. K., Theurer, J., Bellovich, K., Steigerwalt, S. P., Tang, I., Anderson, A. H., Townsend, R. R., He, J., Feldman, H. I., Wolf, M. 2011; 26 (4): 1258-1265

  Abstract

  Secondary hyperparathyroidism is a common complication of chronic kidney disease (CKD) that is associated with bone disease, cardiovascular disease and death. Pathophysiological factors that maintain secondary hyperparathyroidism in advanced CKD are well-known, but early mechanisms of the disease that can be targeted for its primary prevention are poorly understood. Diuretics are widely used to control volume status and blood pressure in CKD patients but are also known to have important effects on renal calcium handling, which we hypothesized could alter the risk of secondary hyperparathyroidism.We examined the relationship of diuretic treatment with urinary calcium excretion, parathyroid hormone (PTH) levels and prevalence of secondary hyperparathyroidism (PTH ≥ 65 pg/mL) in a cross-sectional study of 3616 CKD patients in the Chronic Renal Insufficiency Cohort.Compared with no diuretics, treatment with loop diuretics was independently associated with higher adjusted urinary calcium (55.0 versus 39.6 mg/day; P < 0.001), higher adjusted PTH [67.9, 95% confidence interval (CI) 65.2-70.7 pg/mL, versus 52.8, 95% CI 51.1-54.6 pg/mL, P < 0.001] and greater odds of secondary hyperparathyroidism (odds ratio 2.1; 95% CI 1.7-2.6). Thiazide monotherapy was associated with lower calciuria (25.5 versus 39.6 mg/day; P < 0.001) but only modestly lower PTH levels (50.0, 95% CI 47.8-52.3, versus 520.8, 95% CI 51.1-54.6 pg/mL, P = 0.04) compared with no diuretics. However, coadministration of thiazide and loop diuretics was associated with blunted urinary calcium (30.3 versus 55.0 mg/day; P <0.001) and odds of hyperparathyroidism (odds ratio 1.3 versus 2.1; P for interaction = 0.05) compared with loop diuretics alone.Loop diuretic use was associated with greater calciuria, PTH levels and odds of secondary hyperparathyroidism compared to no treatment. These associations were attenuated in patients who were coadministered thiazides. Diuretic choice is a potentially modifiable determinant of secondary hyperparathyroidism in CKD.

  View details for DOI 10.1093/ndt/gfr026

  View details for Web of Science ID 000289309400023

  View details for PubMedID 21382989

• Association of Chronic Kidney Disease with Muscle Deficits in Children JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Foster, B. J., Kalkwarf, H. J., Shults, J., Zemel, B. S., Wetzsteon, R. J., Thayu, M., Foerster, D. L., Leonard, M. B. 2011; 22 (2): 377-386

  Abstract

  The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.

  View details for DOI 10.1681/ASN.2010060603

  View details for Web of Science ID 000287673600024

  View details for PubMedID 21115614

• Vitamin D deficiency and parathyroid hormone levels following renal transplantation in children PEDIATRIC NEPHROLOGY Tuchman, S., Kalkwarf, H. J., Zemel, B. S., Shults, J., Wetzsteon, R. J., Foerster, D., Strife, C. F., Leonard, M. B. 2010; 25 (12): 2509-2516

  Abstract

  The objectives were to determine the prevalence of vitamin D deficiency [25(OH)D < 10 ng/ml] in pediatric renal transplant (RTx) recipients, compared with controls and identify correlates of changes in 25(OH)D and intact parathyroid hormone (iPTH) levels following transplantation. Serum 25(OH)D, 1,25(OH)(2)D, and iPTH were measured once in 275 healthy controls and at transplantation, and 3 and 12 months posttransplantation in 58 RTx recipients. Multivariate logistic regression models determined the odds ratio (OR) of vitamin D deficiency in RTx recipients vs. controls adjusted for age, sex, race, and season. Generalized estimating equations were used to assess changes following transplantation. At transplantation, 22% of nonblack and 27% of black RTx recipients were vitamin D deficient. The adjusted OR of vitamin D deficiency was greater in RTx recipients (p < 0.001) compared with controls; however, the transplant association was greater in nonblack vs. black individuals (interaction p = 0.02). Overall, 25(OH)D levels did not change significantly following transplantation. Younger age (p < 0.01), nonblack race (p < 0.001), visits in nonwinter months (p < 0.001), and supplementation with ≥400 IU/day ergo/cholecalciferol (p < 0.001) were associated with increases (or lesser declines) in 25(OH)D following transplantation. Increases in 25(OH)D levels (p < 0.001) and vitamin D supplementation (p < 0.01) were associated with greater reductions in iPTH levels following transplantation, independent of 1,25(OH)(2)D levels.

  View details for DOI 10.1007/s00467-010-1612-0

  View details for Web of Science ID 000283366600015

  View details for PubMedID 20872272

• Longitudinal relations between obesity and hypertension following pediatric renal transplantation PEDIATRIC NEPHROLOGY Denburg, M. R., Pradhan, M., Shults, J., Jones, A., Palmer, J. A., Baluarte, H. J., Leonard, M. B. 2010; 25 (10): 2129-2139

  Abstract

  Obesity and hypertension frequently complicate renal transplantation (RTxp). The objective was to assess relations among obesity, hypertension, and glucocorticoids in pediatric RTxp recipients. A retrospective cohort study was carried out in 141 RTxp recipients, 2-21 years of age, with >or=12 months of follow-up. Body mass index Z-score (BMI-Z), systolic and diastolic blood pressure Z-scores (SBP-Z and DBP-Z), and medications at 1, 3, 6, and 12 months and annually thereafter were recorded. Quasi-least squares regression analysis was used. The prevalence of obesity (BMI>or=95th percentile) increased from 13% at baseline to >30% from 3 months onward. Greater glucocorticoid exposure (mg/kg/day) was associated with greater increases in BMI-Z (p<0.001). This association was greater in males, younger recipients, and those with lower baseline BMI-Z (all interactions p<0.02). The prevalence of systolic hypertension (SBP>or=95th percentile) was 73% at 1 month and >or=40% at all follow-up visits. Greater glucocorticoid exposure (p<0.001) and increases in BMI-Z (p=0.005) were independent determinants of SBP-Z over time. Cyclosporine (versus tacrolimus) was independently associated with greater SBP-Z and DBP-Z (p=0.001). Sustained obesity and hypertension frequently complicated pediatric RTxp. Obesity was an independent determinant of systolic hypertension. Strategies are needed to prevent obesity and its impact on hypertension, cardiovascular disease, and allograft survival.

  View details for DOI 10.1007/s00467-010-1572-4

  View details for Web of Science ID 000281110700015

  View details for PubMedID 20567855

• Changing Indications for Upper Endoscopy in Children During a 20-year Period JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Franciosi, J. P., Fiorino, K., Ruchelli, E., Shults, J., Spergel, J., Liacouras, C. A., Leonard, M. 2010; 51 (4): 443-447

  Abstract

  In parallel with the increase in pediatric esophagogastroduodenoscopy (EGD) procedures since the 1970s, the incidence of disorders that require EGD for diagnosis in children has increased. The aim of this study was to identify changes in subject characteristics and endoscopic procedures during a 20-year interval in children undergoing EGD at a single center.All of the children undergoing first EGD with biopsy in 1985, 1995, or 2005 were identified. Details of the clinical presentation and EGD were abstracted from medical records in a random sample of subjects within each time point.The number of first-time EGDs rose dramatically from 107 in 1985 to 1294 in 2005. The proportion of subjects that were younger than 1 year of age varied significantly from 13% in 1985 to 23% in 1995 and 8% in 2005 (P < 0.001). The proportion of subjects with gastrointestinal (GI) bleeding declined from 34% to 5% during the 20-year interval (P < 0.001), whereas the proportion with abdominal pain increased from 23% to 43% (P < 0.01). During the same interval, the proportion of subjects with complete EGD (biopsies from the esophagus, stomach, and duodenum) increased from 18% of EGDs in 1985 to 95% in 2005 (P < 0.001).This study of children undergoing first-time EGDs with biopsy during a 20-year interval demonstrated significant differences in subject characteristics and endoscopy practices. The inclusion of children with less severe clinical presentation and the collection of greater numbers of biopsies per procedure may contribute to the rising incidence rates of pediatric GI disorders.

  View details for DOI 10.1097/MPG.0b013e3181d67bee

  View details for Web of Science ID 000282123600011

  View details for PubMedID 20562722

• Differences in Overnight Polysomnography Scores Using the Adult and Pediatric Criteria for Respiratory Events in Adolescents SLEEP Accardo, J. A., Shults, J., Leonard, M. B., Traylor, J., Marcus, C. L. 2010; 33 (10): 1333-1339

  Abstract

  There was no consensus in the 2007 American Academy of Sleep Medicine scoring manual on whether pediatric or adult respiratory criteria should be used in adolescents due to lack of data. Our objective was to compare pediatric and adult criteria in adolescents referred for obstructive sleep apnea (OSA). We hypothesized that pediatric criteria would capture more respiratory events than adult criteria.Retrospective cross-sectional analysis.Clinical sleep laboratory.101 subjects aged 13-18 years clinically referred for OSA.Overnight polysomnogram. Data were scored using both adult and pediatric AASM criteria. For adult criteria, data were scored using both AASM hypopnea rule A, defined by > or = 4% desaturation, and B, defined by > or = 3% desaturation or arousal.Median (range) apnea hypopnea index (AHI) by pediatric criteria was 1.7 events/hour (0-42.9). AHI using rule A was 0.4 (0-35.6); rule B, 1.4 (0-38.4). A higher pediatric AHI was associated with greater differences between pediatric and adult AHI using either rule A or B. There was no significant discordance in OSA classification comparing pediatric and adult criteria rule B (P = 0.3), but there was a significant rate of discordance classification comparing pediatric and adult criteria rule A(P < 0.001).Either pediatric or adult criteria rule B can be used in adolescents as few subjects change diagnostic category between these 2 criteria. Use of adult rule A results in fewer children meeting criteria for OSA. Further research into the clinical relevance of the scoring metric in adolescents is warranted.

  View details for Web of Science ID 000282249700010

  View details for PubMedID 21061855

• Determinants of Changes in Linear Growth and Body Composition in Incident Pediatric Crohn's Disease GASTROENTEROLOGY Thayu, M., Denson, L. A., Shults, J., Zemel, B. S., Burnham, J. M., Baldassano, R. N., Howard, K. M., Ryan, A., Leonard, M. B. 2010; 139 (2): 430-438

  Abstract

  Pediatric Crohn's disease (CD) is associated with growth, lean mass (LM), and fat mass (FM) deficits. This study assessed and identified determinants of changes in height and body composition in children with CD following.Whole-body LM and FM were assessed using dual-energy x-ray absorptiometry in 78 CD subjects at diagnosis, 6, 12, and a median of 43 months (range, 24-63) later. Race- and sex-specific Z scores for lean mass (LM-ht-Z) and fat mass (FM-ht-Z) relative to height were derived using reference data in >900 controls. Serum cytokines and growth factors were measured, and quasi-least squares regression was used to identify determinants of changes in height and body composition.LM-ht-Z and FM-ht-Z (both P<.005) improved significantly after diagnosis; however, female patients had persistent LM deficits vs controls (-0.50+/-1.02, P<.05). Serum interleukin-6, tumor necrosis factor-alpha, and lipopolysaccharide binding protein decreased significantly (all P<.001). Greater increases in LM-ht-Z were associated with infliximab therapy (P<.05), increases in albumin (P<.001) and decreases in erythrocyte sedimentation rate (P<.05), interleukin-6 (P<.005), and lipopolysaccharide binding protein (P<.05). Greater increases in FM-ht-Z were associated with glucocorticoid, methotrexate, and infliximab therapy, and increases in albumin (P<.05) and growth hormone binding protein (P<.05). Overall, height-Z did not improve; however, greater increases in insulin-like growth factor-1 (P<.05) and decreases in tumor necrosis factor-alpha (P<.05), interleukin-6 (P<.05), and lipopolysaccharide binding protein (P<.05) levels were associated with increases in height-Z.Immune-mediated mechanisms contribute to growth and body composition deficits in CD. Therapies should target these deficits.

  View details for DOI 10.1053/j.gastro.2010.04.044

  View details for Web of Science ID 000280479100014

  View details for PubMedID 20417635

• Bone Mass and Microarchitecture in CKD Patients with Fracture JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Nickolas, T. L., Stein, E., Cohen, A., Thomas, V., Staron, R. B., McMahon, D. J., Leonard, M. B., Shane, E. 2010; 21 (8): 1371-1380

  Abstract

  Patients with predialysis chronic kidney disease (CKD) have increased risk for fracture, but the structural mechanisms underlying this increased skeletal fragility are unknown. We measured areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry at the spine, hip, and radius, and we measured volumetric BMD (vBMD), geometry, and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius and tibia in patients with CKD: 32 with fracture and 59 without fracture. Patients with fracture had lower aBMD at the spine, total hip, femoral neck, and the ultradistal radius, the last having the strongest association with fracture. By HR-pQCT of the radius, patients with fracture had lower cortical area and thickness, total and trabecular vBMD, and trabecular number and greater trabecular separation and network heterogeneity. At the tibia, patients with fracture had significantly lower cortical area, thickness, and total and cortical density. Total vBMD at both radius and tibia most strongly associated with fracture. By receiver operator characteristic curve analysis, patients with longer duration of CKD had area under the curve of >0.75 for aBMD at both hip sites and the ultradistal radius, vBMD and geometry at the radius and tibia, and microarchitecture at the tibia. In summary, patients with predialysis CKD and fractures have lower aBMD by dual-energy x-ray absorptiometry and lower vBMD, thinner cortices, and trabecular loss by HR-pQCT. These density and structural differences may underlie the increased susceptibility to fracture among patients with CKD.

  View details for DOI 10.1681/ASN.2009121208

  View details for Web of Science ID 000280746200023

  View details for PubMedID 20395370

• Pathologic Lower Extremity Fractures in Children With Alagille Syndrome JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Bales, C. B., Kamath, B. M., Munoz, P. S., Nguyen, A., Piccoli, D. A., Spinner, N. B., Horn, D., Shults, J., Leonard, M. B., Grimberg, A., Loomes, K. M. 2010; 51 (1): 66-70

  Abstract

  : In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, 1 of the leading inherited causes of pediatric cholestatic liver disease.: Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance of the Children's Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to 1 question, and details characterizing each patient's medical, growth, and fracture history were obtained through chart review and telephone contact.: Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures per 10,000 person-years (95% confidence interval 206.5, 698.0) and 127.6 femur fractures per 10,000 person-years (95% confidence interval 42.4, 297.7). There were no differences in sex, age distribution, or organ system involvement between the fracture and no-fracture groups.: Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. Although this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and explore factors contributing to bone fragility in these children.

  View details for DOI 10.1097/MPG.0b013e3181cb9629

  View details for Web of Science ID 000279160100013

  View details for PubMedID 20453673

• Effects of Sex, Race, and Puberty on Cortical Bone and the Functional Muscle Bone Unit in Children, Adolescents, and Young Adults JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Leonard, M. B., Elmi, A., Mostoufi-Moab, S., Shults, J., Burnham, J. M., Thayu, M., Kibe, L., Wetzsteon, R. J., Zemel, B. S. 2010; 95 (4): 1681-1689

  Abstract

  Sex and race differences in bone development are associated with differences in growth, maturation, and body composition.The aim of the study was to determine the independent effects of sex, race, and puberty on cortical bone development and muscle-bone relations in children and young adults.We conducted a cross-sectional study of 665 healthy participants (310 male, 306 black) ages 5-35 yr.Tibia peripheral quantitative computed tomography measures were made of cortical bone mineral content (BMC) and bone mineral density (BMD), periosteal (Peri) and endosteal circumferences, section modulus (Zp), and muscle area. Regression models were adjusted for tibia length, age, race, sex, and Tanner stage.All cortical measures were greater in blacks than whites (all P < or = 0.001) in Tanner stages 1-4; however, differences in BMC, Peri, and Zp were negligible in Tanner stage 5 (all interactions, P < 0.01). Cortical BMC, Peri, and Zp were lower in females than males in all Tanner stages (all P < 0.001), and the sex differences in Peri and Zp were greater in Tanner stage 5 (interaction, P < 0.02). Cortical BMD was greater (P < 0.0001) and endosteal circumference was lower (P < 0.01) in Tanner 3-5 females, compared with males. Adjustment for muscle area attenuated but did not eliminate sex and race differences in cortical dimensions. Associations between muscle and bone outcomes did not differ according to sex or race.Sex and race were associated with maturation-specific differences in cortical BMD and dimensions that were not fully explained by differences in bone length or muscle. No race or sex differences in the functional muscle bone unit were identified.

  View details for DOI 10.1210/jc.2009-1913

  View details for Web of Science ID 000276402300025

  View details for PubMedID 20157194

• Height Adjustment in Assessing Dual Energy X-Ray Absorptiometry Measurements of Bone Mass and Density in Children JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Zemel, B. S., Leonard, M. B., Kelly, A., Lappe, J. M., Gilsanz, V., Oberfield, S., Mahboubi, S., Shepherd, J. A., Hangartner, T. N., Frederick, M. M., Winer, K. K., Kalkwarf, H. J. 2010; 95 (3): 1265-1273

  Abstract

  In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature.The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children.Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP).We conducted the study in five clinical centers in the United States.We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female).No interventions were used.We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age (BMC/BMD(height age)), height (BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)).Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P < 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz).Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores.

  View details for DOI 10.1210/jc.2009-2057

  View details for Web of Science ID 000275197500034

  View details for PubMedID 20103654

• Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort Cognitive Study JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Yaffe, K., Ackerson, L., Tamura, M. K., Le Blanc, P., Kusek, J. W., Sehgal, A. R., Cohen, D., Anderson, C., Appel, L., DeSalvo, K., Ojo, A., Seliger, S., Robinson, N., Makos, G., Go, A. S. 2010; 58 (2): 338-345

  Abstract

  To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors.Cross-sectional.Chronic Renal Insufficiency Cohort Study.Eight hundred twenty-five adults aged 55 and older with CKD.Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m(2)) was estimated using the four-variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score < or =1 standard deviations from the mean).Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1-3.9), naming (AOR=1.9, 95% CI=1.0-3.3), attention (AOR=2.4, 95% CI=1.3-4.5), executive function (AOR=2.5, 95% CI=1.9-4.4), and delayed memory (AOR=1.5, 95% CI=0.9-2.6) but not on category fluency (AOR=1.1, 95% CI=0.6-2.0) than those with mild to moderate CKD (eGFR 45-59).In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.

  View details for DOI 10.1111/j.1532-5415.2009.02670.x

  View details for Web of Science ID 000274183800017

  View details for PubMedID 20374407

  View details for PubMedCentralID PMC2852884

• Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents PEDIATRIC NEPHROLOGY Bianchi, M. L., Baim, S., Bishop, N. J., Gordon, C. M., Hans, D. B., Langman, C. B., Leonard, M. B., Kalkwarf, H. J. 2010; 25 (1): 37-47

  Abstract

  Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.

  View details for DOI 10.1007/s00467-009-1249-z

  View details for Web of Science ID 000271961000005

  View details for PubMedID 19603190

• Variation in Inpatient Therapy and Diagnostic Evaluation of Children with Henoch Schonlein Purpura JOURNAL OF PEDIATRICS Weiss, P. F., Klink, A. J., Hexem, K., Burnham, J. M., Leonard, M. B., Keren, R., Localio, R., Feudtner, C. 2009; 155 (6): 812-U272

  View details for DOI 10.1016/j.jpeds.2009.05.030

  View details for Web of Science ID 000209321900012

• Variation in inpatient therapy and diagnostic evaluation of children with Henoch Schönlein purpura. journal of pediatrics Weiss, P. F., Klink, A. J., Hexem, K., Burnham, J. M., Leonard, M. B., Keren, R., Localio, R., Feudtner, C. 2009; 155 (6): 812-818 e1

  Abstract

  To describe variation regarding inpatient therapy and evaluation of children with Henoch Schönlein purpura (HSP) admitted to children's hospitals across the United States.We conducted a retrospective cohort study of children discharged with a diagnosis of HSP between 2000 and 2007 by use of inpatient administrative data from 36 children's hospitals. We examined variation among hospitals in the use of medications, diagnostic tests, and intensive care services with multivariate mixed effects logistic regression models.During the initial HSP hospitalization (n = 1988), corticosteroids were the most common medication (56% of cases), followed by opioids (36%), nonsteroidal antiinflammatory drugs (35%), and antihypertensive drugs (11%). After adjustment for patient characteristics, hospitals varied significantly in their use of corticosteroids, opioids, and nonsteroidal antiinflammatory drugs; the use of diagnostic abdominal imaging, endoscopy, laboratory testing, and renal biopsy; and the use of intensive care services. By contrast, hospitals did not differ significantly regarding administration of antihypertensive drugs or performance of skin biopsy.The significant variation identified may contribute to varying HSP clinical outcomes between hospitals, warrants further investigation, and represents a potentially important opportunity to improve quality of care.

  View details for DOI 10.1016/j.jpeds.2009.05.030

  View details for PubMedID 19643437

• Serum Adiponectin Levels and Ambulatory Blood Pressure Monitoring in Pediatric Renal Transplant Recipients TRANSPLANTATION Sethna, C. B., Leonard, M. B., Gallagher, P. R., Meyers, K. E. 2009; 88 (8): 1030-1037

  Abstract

  BACKGROUND.: Reduced levels of serum adiponectin, an adipokine, are associated with cardiovascular and obesity-related diseases; however, relations between adiponectin and hypertension are unclear. METHODS.: This cross-sectional study examined adiponectin and ambulatory blood pressure monitoring (ABPM) in 33 pediatric renal transplant recipients (TXP), aged 8 to 19 years, median of 1.9 years after transplant. Serum total adiponectin (microg/mL) and high molecular weight-to-total adiponectin ratio (HMWr), 24-hr ABPM, and dual x-ray absorptiometry measures of fat mass were obtained. RESULTS.: The 12 TXP with hypertension (defined as BP index >1.0 and BP load >25%) had lower total adiponectin levels (7.4+/-3.2 vs. 10.9+/-5.2 microg/mL, P=0.045) compared with nonhypertensive TXP. Hypertensive TXP trended toward lower HMWr compared with nonhypertensive TXP (0.40+/-0.09 vs. 0.47+/-0.11, P=0.064). Levels did not differ according to sex, obesity or dipper status. In univariate analyses, total adiponectin and HMWr were negatively and significantly correlated with indexed BP in the daytime, nighttime, and 24-hr periods (R=-0.35 to -0.57). After adjustment for estimated glomerular filtration rate, fat mass, anti-hypertensive medication and fasting glucose, (1) lower total adiponectin was significantly and independently associated with greater elevations in all ABPM indexes except for nighttime systolic indexed BP, and (2) HMWr was inversely associated with all ABPM indexes. Lower adiponectin levels (P=0.049) and HMWr (P=0.042) were associated with greater odds of hypertension. CONCLUSION.: These data indicate that lower total adiponectin and HMWr were significantly and independently associated with greater ambulatory blood pressure.

  View details for DOI 10.1097/TP.0b013e3181b9e1ec

  View details for Web of Science ID 000271169700014

  View details for PubMedID 19855250

• Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men 16th Conference on Retroviruses and Opportunistic Infections (CROI) Lo Re, V., Guaraldi, G., Leonard, M. B., Localio, A. R., Lin, J., Orlando, G., Zirilli, L., Rochira, V., Kostman, J. R., Tebas, P. LIPPINCOTT WILLIAMS & WILKINS. 2009: 2191–98

  Abstract

  Few studies have examined the impact of viral hepatitis on bone mineral density (BMD), and none have done so among HIV-infected patients. Our objective was to determine whether viral hepatitis was associated with low BMD in HIV.: A cross-sectional study among 1237 HIV-infected patients (625 with viral hepatitis).Dual-energy X-ray absorptiometry scans of the lumbar spine and femoral neck were obtained. Clinical data, hepatitis B and C status, and markers of bone metabolism were determined at dual-energy X-ray absorptiometry scanning. Multivariable logistic regression examined the association between hepatitis and low BMD (Z-score < or =-2.0 at the lumbar spine, femoral neck, or both).Mean BMD Z-scores were lower among hepatitis-coinfected women at the lumbar spine {-0.15 versus +0.29; difference = -0.44 [95% confidence Interval (CI) -0.65 to -0.23]; P < 0.001} and femoral neck [-0.64 versus -0.39; difference = -0.25 (95% CI -0.44 to -0.06); P = 0.009] compared with HIV-monoinfected women. No differences in mean BMD Z-scores were observed between coinfected and monoinfected men. After adjustment for age, BMI, duration of HIV, antiretroviral use, physical activity, and smoking, viral hepatitis was associated with low BMD among women (adjusted odds ratio 2.87, 95% CI 1.31-6.29) but not men (adjusted odds ratio 1.19, 95% CI 0.74-1.91). Coinfected women had lower mean parathyroid hormone (60.1 versus 68.1 pg/ml; P = 0.02) but similar mean 25-hydroxyvitamin D (19.1 versus 19.6 ng/ml; P = 0.6) and osteocalcin (3.0 versus 3.2 ng/ml; P = 0.8) concentrations than HIV-monoinfected women.Viral hepatitis was associated with a higher risk of low BMD among HIV-infected women but not men.

  View details for DOI 10.1097/QAD.0b013e32832ec258

  View details for Web of Science ID 000271599200015

  View details for PubMedID 19779322

• Cardiorespiratory Fitness in Pediatric Renal Transplant Recipients TRANSPLANTATION Sethna, C. B., Salerno, A. E., McBride, M. G., Shults, J., Paridon, S. M., Sharma, N., Meyers, K. E., Leonard, M. B. 2009; 88 (3): 395-401

  Abstract

  The impact of body size, fat-free mass (FFM), and fat mass (FM) on cardiorespiratory fitness in pediatric renal transplant recipients (TX) has not been established. Study objectives were to assess maximal oxygen consumption (VO2max) in TX and controls, adjusted for body composition, and to identify risk factors for reduced fitness in TX.Cycle ergometry and dual-energy X-ray absorptiometry were obtained in 50 TX and 70 controls, ages 8 to 21 years. Control recruitment was targeted to include obese subjects with body mass index Z-scores comparable with TX. Allometric regression models were used.TX had significantly lower height Z-scores (P<0.001) and comparable body mass index Z-scores. VO2max per body weight (mL/kg/min) and per FFM (mL/kgFFM/min) did not differ between groups. However, VO2max was 13% lower (95% CI 18, 8; P<0.001) in TX, compared with controls, adjusted for FM, FFM, sex, and race. Greater FFM, lower FM, non-black race, and male sex were independently associated with greater VO2max. Within TX, hemoglobin levels were positively associated with VO2max (P=0.04) and sirolimus use was associated with lower VO2max (P<0.01).TX had significant VO2max deficits that were not captured by conventional measures (mL/kg/min). Greater FM was an independent risk factor for low VO2max. Lower fitness in TX may be related to sirolimus effects on skeletal muscle.

  View details for DOI 10.1097/TP.0b013e3181aed7d1

  View details for Web of Science ID 000268940000018

  View details for PubMedID 19667944

• Hypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus JOURNAL OF PEDIATRICS Wright, T. B., Shults, J., Leonard, M. B., Zemel, B. S., Burnham, J. M. 2009; 155 (2): 260-265

  Abstract

  To determine whether pediatric systemic lupus erythematosus (SLE) is associated with alterations in the vitamin D-parathyroid hormone (PTH) axis and to assess the relation between vitamin D deficiency and SLE activity.25-hydroxy vitamin D [25(OH)D], 1,25-dihydroxy vitamin D [1,25(OH)2D], and intact PTH were measured in subjects with SLE (n = 38) and healthy controls (n = 207), ages 5 to 21 years. Vitamin D status and its relation with disease activity were assessed using multivariable logistic and linear regression.Severe vitamin D deficiency (25(OH)D <10 ng/ml) was observed in a significantly higher proportion of subjects with SLE (36.8% vs 9.2%, P < .001). In SLE, the odds ratio (OR) for severe deficiency was 2.37 (P = .09), adjusting for age, sex, race, and season. However, for each 1 SD greater body mass index (BMI) z-score, 25(OH)D levels were 4.2 ng/mL lower (P = .01) in SLE, compared with controls. Adjusting for 25(OH)D levels, SLE was associated with significantly lower 1,25(OH)2D (P < .001) and intact PTH levels (P = .03). Greater SLE disease activity index scores were observed in those with 25(OH)D <20 ng/mL (P = .01).SLE was associated with vitamin D deficiency, particularly among those subjects with SLE who were overweight. Future studies should assess the effect of vitamin D supplementation on skeletal and nonskeletal outcomes in SLE.

  View details for DOI 10.1016/j.jpeds.2009.02.033

  View details for Web of Science ID 000268781200026

  View details for PubMedID 19446841

• Revised Pediatric Reference Data for the Lateral Distal Femur Measured by Hologic Discovery/Delphi Dual-Energy X-Ray Absorptiometry JOURNAL OF CLINICAL DENSITOMETRY Zemel, B. S., Stallings, V. A., Leonard, M. B., Paulhamus, D. R., Kecskemethy, H. H., Harcke, H. T., Henderson, R. C. 2009; 12 (2): 207-218

  Abstract

  Lateral distal femur (LDF) scans by dual-energy X-ray absorptiometry (DXA) are often feasible in children for whom other sites are not measurable. Pediatric reference data for LDF are not available for more recent DXA technology. The objective of this study was to assess older pediatric LDF reference data, construct new reference curves for LDF bone mineral density (BMD), and demonstrate the comparability of LDF BMD to other measures of BMD and strength assessed by DXA and by peripheral quantitative computed tomography (pQCT). LDF, spine and whole body scans of 821 healthy children, 5-18 yr of age, recruited at a single center were obtained using a Hologic Discovery/Delphi system (Hologic, Inc., Bedford, MA). Tibia trabecular and total BMD (3% site), cortical geometry (38% site) (cortical thickness, section modulus, and strain-strength index) were assessed by pQCT. Sex- and race-specific reference curves were generated using LMS Chartmaker (LMS Chartmaker Pro, version 2.3. Tim Cole and Huiqi Pan. Copyright 1997-2006, Medical Research Council, UK) and Z-scores calculated and compared by correlation analysis. Z-scores for LDF BMD based on published findings demonstrated overestimation or underestimation of the prevalence of low BMD-for-age depending on the region of interest considered. Revised LDF reference curves were generated. The new LDF Z-scores were strongly and significantly associated with weight, body mass index, spine and whole body BMD Z-scores, and all pQCT Z-scores. These findings demonstrate the comparability of LDF measurements to other clinical and research bone density assessment modes, and enable assessment of BMD in children with disabilities, who are particularly prone to low trauma fractures of long bones, and for whom traditional DXA measurement sites are not feasible.

  View details for DOI 10.1016/j.jocd.2009.01.005

  View details for Web of Science ID 000266251100009

  View details for PubMedID 19321369

• Divergent Effects of Glucocorticoids on Cortical and Trabecular Compartment BMD in Childhood Nephrotic Syndrome JOURNAL OF BONE AND MINERAL RESEARCH Wetzsteon, R. J., Shults, J., Zemel, B. S., Gupta, P. U., Burnham, J. M., Herskovitz, R. M., Howard, K. M., Leonard, M. B. 2009; 24 (3): 503-513

  Abstract

  Glucocorticoid (GC) effects on skeletal development have not been established. The objective of this pQCT study was to assess volumetric BMD (vBMD) and cortical dimensions in childhood steroid-sensitive nephrotic syndrome (SSNS), a disorder with minimal independent deleterious skeletal effects. Tibia pQCT was used to assess trabecular and cortical vBMD, cortical dimensions, and muscle area in 55 SSNS (age, 5-19 yr) and >650 control participants. Race-, sex-, and age-, or tibia length-specific Z-scores were generated for pQCT outcomes. Bone biomarkers included bone-specific alkaline phosphatase and urinary deoxypyridinoline. SSNS participants had lower height Z-scores (p < 0.0001) compared with controls. In SSNS, Z-scores for cortical area were greater (+0.37; 95% CI = 0.09, 0.66; p = 0.01), for cortical vBMD were greater (+1.17; 95% CI = 0.89, 1.45; p < 0.0001), and for trabecular vBMD were lower (-0.60; 95% CI, = -0.89, -0.31; p < 0.0001) compared with controls. Muscle area (+0.34; 95% CI = 0.08, 0.61; p = 0.01) and fat area (+0.56; 95% CI = 0.27, 0.84; p < 0.001) Z-scores were greater in SSNS, and adjustment for muscle area eliminated the greater cortical area in SSNS. Bone formation and resorption biomarkers were significantly and inversely associated with cortical vBMD in SSNS and controls and were significantly lower in the 34 SSNS participants taking GCs at the time of the study compared with controls. In conclusion, GCs in SSNS were associated with significantly greater cortical vBMD and cortical area and lower trabecular vBMD, with evidence of low bone turnover. Lower bone biomarkers were associated with greater cortical vBMD. Studies are needed to determine the fracture implications of these varied effects.

  View details for DOI 10.1359/JBMR.081101

  View details for Web of Science ID 000263572100014

  View details for PubMedID 19016583

• A Structural Approach to Skeletal Fragility in Chronic Kidney Disease SEMINARS IN NEPHROLOGY Leonard, M. B. 2009; 29 (2): 133-143

  Abstract

  Renal osteodystrophy is a multifactorial disorder of bone metabolism in chronic kidney disease (CKD). As CKD progresses, ensuing abnormalities in mineral metabolism result in distortions in trabecular microarchitecture, thinning of the cortical shell, and increased cortical porosity. Recent studies have shown significantly increased hip fracture rates in CKD stages 3 and 4, in dialysis patients, and in transplant recipients. The majority of studies of bone loss in CKD relied on dual-energy x-ray absorptiometry (DXA) measures of bone mineral density. However, DXA summarizes the total bone mass within the projected bone area, concealing distinct structural alterations in trabecular and cortical bone. Recent data have confirmed that peripheral quantitative computed tomography (pQCT) measures of cortical density and thickness provide substantially better fracture discrimination in dialysis patients, compared with hip or spine DXA. This review summarizes the growing evidence for bone fragility in CKD stages 3 through 5, considers the effects of CKD on trabecular and cortical bone structure as it relates to fracture risk, and details the potential advantages and disadvantages of DXA and alternative measures of bone density, geometry, and microarchitecture, including pQCT, high-resolution pQCT, and micro-magnetic resonance imaging for fracture risk assessment in CKD.

  View details for DOI 10.1016/j.semnephrol.2009.01.006

  View details for Web of Science ID 000265459400006

  View details for PubMedID 19371804

• A Note on the Use of Unbiased Estimating Equations to Estimate Correlation in Analysis of Longitudinal Trials BIOMETRICAL JOURNAL Sun, W., Shults, J., Leonard, M. 2009; 51 (1): 5-18

  Abstract

  Longitudinal trials can yield outcomes that are continuous, binary (yes/no), or are realizations of counts. In this setting we compare three approaches that have been proposed for estimation of the correlation in the framework of generalized estimating equations (GEE): quasi-least squares (QLS), pseudo-likelihood (PL), and an approach we refer to as Wang-Carey (WC). We prove that WC and QLS are identical for the first-order autoregressive AR(1) correlation structure. Using simulations, we then develop guidelines for selection of an appropriate method for analysis of data from a longitudinal trial. In particular, we argue that no method is uniformly superior for analysis of unbalanced and unequally spaced data with a Markov correlation structure. Choice of the best approach will depend on the degree of imbalance and variability in the temporal spacing of measurements, value of the correlation, and type of outcome, e.g. binary or continuous. Finally, we contrast the methods in analysis of a longitudinal study of obesity following renal transplantation in children.

  View details for DOI 10.1002/bimj.200710493

  View details for Web of Science ID 000264082000001

  View details for PubMedID 19197953

• Serum Alkaline Phosphatase Reflects Post-Fontan Hemodynamics in Children PEDIATRIC CARDIOLOGY Chin, A. J., Stephens, P., Goldmuntz, E., Leonard, M. B. 2009; 30 (2): 138-145

  Abstract

  Although survivors of Fontan palliation for a single ventricle are known to have lower cardiac index than patients with two-ventricle surgical reconstructions, it is unclear whether two frequently observed sequelae, short stature and protein-losing enteropathy (PLE), have hemodynamic origins. A serum marker that reflects hemodynamic status would be a tremendous asset in the long-term management of children with these sequelae. The authors recently noted severely reduced total alkaline phosphatase (TALP) levels in two children with early-onset PLE after Fontan operations, both of whom had low cardiac output at cardiac catheterization. Catheter-based or surgical interventions that rapidly increased cardiac output in these two patients resulted not only in relief of PLE but also in a prompt TALP rise. To examine whether the apparent correlation of low TALP with impaired cardiac output also is seen in Fontan patients without PLE, this study retrospectively examined the TALP data from two other Fontan patients who underwent cardiac catheterization specifically to assess the potential benefit of vasodilator therapy. The TALP levels were abnormally low in both cases but increased after up-titration of angiotensin-converting enzyme inhibition. Serum TALP activity, an indicator of osteoblastic function particularly in pre-adolescence, may be a marker of low cardiac output after a Fontan operation.

  View details for DOI 10.1007/s00246-008-9292-2

  View details for Web of Science ID 000263097500008

  View details for PubMedID 18685798

• Retrospective 3D Registration of Trabecular Bone MR Images for Longitudinal Studies JOURNAL OF MAGNETIC RESONANCE IMAGING Magland, J. F., Jones, C. E., Leonard, M. B., Wehrli, F. W. 2009; 29 (1): 118-126

  Abstract

  To evaluate an automatic 3D registration algorithm for serial high-resolution images of trabecular bone (TB) in studies designed to evaluate the response of the trabecular architecture to intervention or disease progression.An efficient algorithm for registering high-resolution 3D images of TB is presented. The procedure identifies the six parameters of rigid displacement between two scans performed at different timepoints. By assuming a relatively small through-plane rotation, considerable time is saved by combining the results of a collection of regional 2D registrations throughout the TB region of interest (ROI). The algorithm was applied to 26 pairs of MR images acquired 6 months apart. Reproducibility of local TB structural parameters (plate, rod, and junction density) computed in manually selected regions were compared between baseline and registered follow-up images.All 26 registrations were completed successfully in less than 30 seconds per image pair. The resampled follow-up images agreed with baseline to around one pixel throughout the volume at 137 x 137 x 410 microm(3) image resolution. Structural parameters in each region correlated well from baseline to follow-up with intraclass correlation coefficients ranging between 85%-97% for TB plate density. Interregional variations in the parameters were large as compared with intraregion reproducibility.The proposed algorithm was successful in automatically registering baseline and follow-up TB images in a translational study, and may be useful in regional analyses in longitudinal MR studies of TB architecture.

  View details for DOI 10.1002/jmri.21551

  View details for Web of Science ID 000262168200015

  View details for PubMedID 19097098

• Bone Health in a Nonjaundiced Population of Children with Biliary Atresia GASTROENTEROLOGY RESEARCH AND PRACTICE Kramer, R. A., Zemel, B. S., Arvay-Nezu, J. L., Stallings, V. A., Leonard, M. B., Haber, B. A. 2009

  Abstract

  To assess bone health in a cohort of nonjaundiced children with biliary atresia (BA) and the effect of growth and development on bone outcomes.Children ages one to eighteen years receiving care from Children's Hospital of Philadelphia were recruited. Each child was seen once and assessed for growth, pubertal development, concurrent medications, bilirubin, ALT, albumin, vitamin D status, bone mineral density (BMD), and bone mineral content (BMC) of the lumbar spine and whole body.BMD declined significantly with age, and upon further analysis with a well-phenotyped control cohort, it was found that BMC was significantly decreased for both lumbar spine and whole body, even after adjustment for confounding variables. An age interaction was identified, with older subjects having a significantly greater impairment in BMC.These preliminary results demonstrate that children with BA, including those without jaundice, are likely to have compromised bone health even when accounting for height and puberty, which are common confounding factors in chronic disease. Further investigation is needed to identify the determinants of poor bone mineral status and to develop strategies to prevent osteoporosis later in life.

  View details for DOI 10.1155/2009/387029

  View details for Web of Science ID 000284907400001

  View details for PubMedID 19606216

• Longitudinal Assessment of Bone Density and Structure in an Incident Cohort of Children With Crohn's Disease GASTROENTEROLOGY Dubner, S. E., Shults, J., Baldassano, R. N., Zemel, B. S., Thayu, M., Burnham, J. M., Herskovitz, R. M., Howard, K. M., Leonarda, M. B. 2009; 136 (1): 123-130

  Abstract

  The impact of childhood Crohn's disease (CD) on volumetric bone mineral density (vBMD), bone structure, and muscle mass have not been established. The objective of this longitudinal study was to assess musculoskeletal outcomes in an incident cohort of children with CD using peripheral quantitative computed tomography (pQCT).Tibia pQCT was performed in 78 CD subjects (ages, 5-18 years) at diagnosis and in 67 over the subsequent year. pQCT outcomes were converted to sex- and race-specific z scores based on reference data in over 650 controls. Multivariable linear regression models identified factors associated with changes in bone outcomes.At diagnosis, CD subjects had significant deficits in trabecular vBMD (z score, -1.32+/-1.32; P< .001), cortical section modulus (a measure of bone geometry and strength) (z score, -0.44+/-1.11; P< .01), and muscle (z score, -0.96+/-1.02; P< .001) compared with controls. Over the first 6 months, trabecular vBMD and muscle z scores improved significantly (both, P< .001); however, section modulus worsened (P= .0001), and all 3 parameters remained low after 1 year. Increases in muscle z scores were associated with less severe declines in cortical section modulus z scores. Improvements in trabecular vBMD z scores were greater in prepubertal subjects. Glucocorticoids were associated with increases in cortical vBMD.Substantial deficits in trabecular vBMD, cortical bone geometry, and muscle were observed at CD diagnosis. Trabecular vBMD improved incompletely; however, cortical deficits progressed despite improvements in muscle. Glucocorticoids were not associated with bone loss. Therapies to improve bone accrual in childhood CD are needed.

  View details for DOI 10.1053/j.gastro.2008.09.072

  View details for Web of Science ID 000262028500020

  View details for PubMedID 19026647

  View details for PubMedCentralID PMC2705767

• Association of Serum Intact Parathyroid Hormone with Lower Estimated Glomerular Filtration Rate CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Muntner, P., Jones, T. M., Hyre, A. D., Melamed, M. L., Alper, A., Raggi, P., Leonard, M. B. 2009; 4 (1): 186-194

  Abstract

  The prevalence of mineral metabolism abnormalities is almost universal in stage 5 chronic kidney disease (CKD), but the presence of abnormalities in milder CKD is not well characterized.Data on adults > or =20 yr of age from the National Health and Nutrition Examination Survey 2003-2004 (N = 3949) were analyzed to determine the association between moderate declines in estimated GFR (eGFR), calculated using the Modfication of Diet in Renal Disease formula, and serum intact parathyroid hormone (iPTH) > or = 70 pg/ml.The geometric mean iPTH level was 39.3 pg/ml. The age-standardized prevalence of elevated iPTH was 8.2%, 19.3%, and 38.3% for participants with eGFR > or = 60, 45 to 59, and 30 to 44 ml/min/1.73 m(2), respectively (P-trend < 0.001). After adjustment for age; race/ethnicity; sex; menopausal status; education; income; cigarette smoking; alcohol consumption; body mass index; hypertension; diabetes mellitus; vitamin D supplement use; total calorie and calcium intake; and serum calcium, phosphorus, and 25-hydroxyvitamin D levels-and compared with their counterparts with an eGFR > or = 60 ml/min/1.73 m(2)-the prevalence ratios of elevated iPTH were 2.30 and 4.69 for participants with an eGFR of 45 to 59 and 30 to 44 ml/min/1.73 m(2), respectively (P-trend < 0.001). Serum phosphorus > or = 4.2 mg/dl and 25-hydroxyvitamin D < 17.6 ng/ml were more common at lower eGFR levels. No association was present between lower eGFR and serum calcium < 9.4 mg/dl.This study indicates that elevated iPTH levels are common among patients with moderate CKD.

  View details for DOI 10.2215/CJN.03050608

  View details for Web of Science ID 000262681200028

  View details for PubMedID 19019998

• Improvement in Biomarkers of Bone Formation During Infliximab Therapy in Pediatric Crohn's Disease: Results of the REACH Study CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Thayu, M., Leonard, M. B., Hyams, J. S., Crandall, W. V., Kugathasan, S., Otley, A. R., Olson, A., Johanns, J., Marano, C. W., Heuschkel, R. B., Veereman-Wauters, G., Griffiths, A. M., Baldassano, R. N. 2008; 6 (12): 1378-1384

  Abstract

  Crohn's disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy.One hundred twelve subjects ages 6-17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy. Serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), urine C-telopeptide of collagen cross-links (CTX-1), and deoxypyrodinoline (DPD) were collected at baseline and 10 weeks. PCDAI and height z-scores were assessed at baseline and at 10 and 54 weeks.Models were adjusted for bone age, gender, height, and steroid use. Baseline BSAP and P1NP levels were negatively associated with PCDAI (both P = .01). BSAP and P1NP increased during induction (both P < .001) and were associated with 54-week increases in height z-score (P < .05 and P < .001, respectively). Improvements in P1NP were associated with 54-week decreases in PCDAI (P = .01). CTX-1 and DPD also increased during induction (P < .001 and P = .01, respectively) but were not associated with changes in PCDAI. Changes in CTX-1 were associated with improvements in height z-score (P < .002).Infliximab therapy is associated with dramatic increases in BSAP and P1NP, consistent with inhibition of tumor necrosis factor-alpha effects on osteoblasts. The increases in CTX-1 and DPD likely reflect coupling of bone formation and resorption and increases in linear growth.

  View details for DOI 10.1016/j.cgh.2008.07.010

  View details for Web of Science ID 000261724300015

  View details for PubMedID 19081527

• International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions BONE Lewiecki, E. M., Gordon, C. M., Baim, S., Leonard, M. B., Bishop, N. J., Bianchi, M., Kalkwarf, H. J., Langman, C. B., Plotkin, H., Rauch, F., Zemel, B. S., Binkley, N., Bilezikian, J. P., Kendler, D. L., Hans, D. B., Silverman, S. 2008; 43 (6): 1115-1121

  Abstract

  The International Society for Clinical Densitometry (ISCD) periodically convenes Position Development Conferences (PDCs) in order to establish standards and guidelines for the assessment of skeletal health. The most recent Adult PDC was held July 20-22, 2007, in Lansdowne, Virginia, USA; the first Pediatric PDC was June 20-21, 2007 in Montreal, Quebec, Canada. PDC topics were selected according to clinical relevancy, perceived need for standardization, and likelihood of achieving agreement. Each topic area was assigned to a task force for a comprehensive review of the scientific literature. The findings of the review and recommendations were presented to adult and pediatric international panels of experts. The panels voted on the appropriateness, necessity, quality of the evidence, strength, and applicability (worldwide or variable according to local requirements) of each recommendation. Those recommendations that were approved by the ISCD Board of Directors become Official Positions. This is a review of the methodology of the PDCs and selected ISCD Official Positions.

  View details for DOI 10.1016/j.bone.2008.08.106

  View details for Web of Science ID 000261825900020

  View details for PubMedID 18793764

• Interpretation of Biomarkers of Bone Metabolism in Children: Impact of Growth Velocity and Body Size in Healthy Children and Chronic Disease JOURNAL OF PEDIATRICS Tuchman, S., Thayu, M., Shults, J., Zemel, B. S., Burnham, J. M., Leonard, M. B. 2008; 153 (4): 484-490

  Abstract

  To determine the effects of growth, maturation, and whole body bone mineral content (WB-BMC) accrual on biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP]) and resorption (urine deoxypyridinoline/creatinine [DPD]) in healthy children and children with Crohn's disease.BSAP and DPD were measured at baseline, with growth and dual energy x-ray absorptiometry (DXA) WB-BMC measured at baseline and 6 months in 202 control subjects and 110 subjects with Crohn's disease, ages 5 to 21 years. Multivariable linear regression identified determinants of biomarkers in control subjects and subjects with Crohn's disease.In control subjects, BSAP and DPD were significantly and independently associated with sex, Tanner stage, WB-BMC, height velocity, and WB-BMC accrual rates; these covariates explained 77% to 80% of the variability in the bone biomarkers, respectively. Subjects with Crohn's disease had lower height-for-age (P < .001) and WB-BMC-for-height (P <.05) than control subjects. Crohn's disease was associated with lower BSAP (P < .001) and greater DPD (P < .001), independent of growth, maturation, baseline WB-BMC, and WB-BMC accrual, compared with control subjects.These data illustrate the potential confounding effects of growth and WB-BMC on bone metabolism biomarkers in children. After adjustment for these effects, Crohn's disease was associated with lower biomarkers of bone formation and greater bone resorption.

  View details for DOI 10.1016/j.jpeds.2008.04.028

  View details for Web of Science ID 000260101600011

  View details for PubMedID 18555484

• Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry OSTEOPOROSIS INTERNATIONAL Lewiecki, E. M., Gordon, C. M., Baim, S., Binkley, N., Bilezikian, J. P., Kendler, D. L., Hans, D. B., Silverman, S., Bishop, N. J., Leonard, M. B., Bianchi, M., Kalkwarf, H. J., Langman, C. B., Plotkin, H., Rauch, F., Zemel, B. S. 2008; 19 (10): 1369-1378

  Abstract

  The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

  View details for DOI 10.1007/s00198-008-0689-9

  View details for Web of Science ID 000259820100002

  View details for PubMedID 18633664

• Chronic kidney disease and bone fracture: a growing concern KIDNEY INTERNATIONAL Nickolas, T. L., Leonard, M. B., Shane, E. 2008; 74 (6): 721-731

  Abstract

  Susceptibility to fracture is increased across the spectrum of chronic kidney disease (CKD). Moreover, fracture in patients with end-stage kidney disease (ESKD) results in significant excess mortality. The incidence and prevalence of CKD and ESKD are predicted to increase markedly over the coming decades in conjunction with the aging of the population. Given the high prevalence of both osteoporosis and CKD in older adults, it is of the utmost public health relevance to be able to assess fracture risk in this population. Dual-energy X-ray absorptiometry (DXA), which provides an areal measurement of bone mineral density (aBMD), is the clinical standard to predict fracture in individuals with postmenopausal or age-related osteoporosis. Unfortunately, DXA does not discriminate fracture status in patients with ESKD. This may be, in part, because excess parathyroid hormone (PTH) secretion may accompany declining kidney function. Chronic exposure to high PTH levels preferentially causes cortical bone loss, which may be partially offset by periosteal expansion. DXA can neither reliably detect changes in bone volume nor distinguish between trabecular and cortical bone. In addition, DXA measurements may be low, normal, or high in each of the major forms of renal osteodystrophy (ROD). Moreover, postmenopausal or age-related osteoporosis may also affect patients with CKD and ESKD. Currently, transiliac crest bone biopsy is the gold standard to diagnose ROD and osteoporosis in patients with significant kidney dysfunction. However, bone biopsy is an invasive procedure that requires time-consuming analyses. Therefore, there is great interest in developing non-invasive high-resolution imaging techniques that can improve fracture risk prediction for patients with CKD. In this paper, we review studies of fracture risk in the setting of ESKD and CKD, the pathophysiology of increased fracture risk in patients with kidney dysfunction, the utility of various imaging modalities in predicting fracture across the spectrum of CKD, and studies evaluating the use of bisphosphonates in patients with CKD.

  View details for DOI 10.1038/ki.2008.264

  View details for Web of Science ID 000258874600008

  View details for PubMedID 18563052

• Status of bone mineral density in patients selected for cardiac transplantation. Endocrine practice Iqbal, N., Ducharme, J., Desai, S., Chambers, S., Terembula, K., Chan, G. W., Shults, J., Leonard, M. B., Kumanyika, S. 2008; 14 (6): 704-712

  Abstract

  To determine the prevalence and correlates of low bone mineral density (BMD) in ambulatory outpatients with end-stage heart failure who were awaiting cardiac transplantation.Fifty-five cardiac transplant candidates with end-stage heart failure were enrolled in this study. Bone mineral density at the lumbar spine and proximal femur was determined by dual-energy x-ray absorptiometry. Laboratory studies included serum alkaline phosphatase, calcium, intact parathyroid hormone, and 25-hydroxyvitamin D.The mean proximal femur and lumbar spine Z scores were 0.3 +/- 1.1 and 0.3 +/- 1.5, respectively. The mean BMD was not lower than that of the age-and sex-matched reference population. Z scores were less than -1 in 23% at the lumbar spine and 15% at the proximal femoral neck. On the basis of T scores, osteopenia (T scores between -1 and -2.5) was present in 24% (confidence interval, 13% to 35%) of patients at the lumbar spine and in 20% (confidence interval, 10% to 30%) at the proximal femur; osteoporosis (T scores of less than -2.5) was present in 4% of the study population. Half of the patients in this study sample had elevated intact parathyroid hormone levels, and a third of the patients had low 25-hydroxyvitamin D levels.Lumbar spine and hip BMD measurements were not significantly low relative to age and sex in ambulatory patients with heart failure awaiting cardiac transplantation.

  View details for PubMedID 18996789

• Cortical bone water: In vivo quantification with ultrashort echo-time MR imaging RADIOLOGY Techawiboonwong, A., Song, H. K., Leonard, M. B., Wehrli, F. W. 2008; 248 (3): 824-833

  Abstract

  To develop and evaluate a method based on ultrashort echo-time radial magnetic resonance (MR) imaging to quantify bone water (BW) concentration as a new metric of bone quality in human cortical bone in vivo.Human subject studies were institutional review board approved and HIPAA compliant; informed consent was obtained. Cortical BW concentration was determined with custom-designed MR imaging sequences at 3.0 T and was validated in sheep and human cortical bone by using exchange of native water with deuterium oxide (D(2)O). The submillisecond T2* of BW requires correction for relaxation losses during the radiofrequency pulse. BW was measured at the tibial midshaft in healthy pre- and postmenopausal women (mean age, 34.6 and 69.4 years, respectively; n = 5 in each group) and in patients receiving maintenance hemodialysis (mean age, 51.8 years; n = 6) and was compared with bone mineral density (BMD) at the same site at peripheral quantitative computed tomography, as well as with BMD of the lumbar spine and hip at dual x-ray absorptiometry. Data were analyzed by using the Pearson correlation coefficient and two-sided t tests as appropriate.Excellent agreement was obtained ex vivo between the water displaced by using D(2)O exchange and water measured with respect to a reference sample (r(2) = 0.99, P < .001). In vivo, BW in the postmenopausal group was greater by 65% (28.7% +/- 1.3 [standard deviation] vs 17.4% +/- 2.2, P < .001) than in the premenopausal group, and patients with renal osteodystrophy had higher BW (41.4% +/- 9.6) than the premenopausal group by 135% (P < .001) and the postmenopausal group by 43% (P = .02). BMD showed an opposite behavior, with much smaller group differences. Because the majority of BW is in the pore system of cortical bone, this parameter provides a surrogate measure for cortical porosity.A new MR imaging-based method for quantifying BW noninvasively has been demonstrated.

  View details for DOI 10.1148/radiol.2482071995

  View details for Web of Science ID 000258541500018

  View details for PubMedID 18632530

• Bone density, structure, and strength in juvenile idiopathic arthritis ARTHRITIS AND RHEUMATISM Burnham, J. M., Shults, J., Dubner, S. E., Sembhi, H., Zemel, B. S., Leonard, M. B. 2008; 58 (8): 2518-2527

  Abstract

  To identify determinants of musculoskeletal deficits (muscle cross-sectional area [mCSA], trabecular volumetric bone mineral density [vBMD], and cortical bone strength [section modulus]) in patients with juvenile idiopathic arthritis (JIA) and to determine if cortical bone strength is appropriately adapted to muscle forces.Peripheral quantitative computed tomography (pQCT) of the tibia was performed in 101 patients with JIA (79% female; 24 with oligoarticular JIA, 40 with polyarticular JIA, 18 with systemic JIA, and 19 with spondylarthritis [SpA]) and 830 healthy control subjects; all were ages 5-22 years. Outcomes of pQCT were expressed as sex- and race-specific Z scores. Multivariable linear regression models assessed mCSA and bone status in JIA patients compared with controls and identified factors associated with musculoskeletal deficits in JIA.The median duration of JIA was 40 months; 29% of the JIA patients had active arthritis, and 28% had received glucocorticoid therapy during the previous year. Compared with the controls, the mCSA and section modulus Z scores were significantly lower in patients with polyarticular JIA and those with SpA. Trabecular vBMD Z scores were significantly lower in patients with polyarticular JIA, those with systemic JIA, and those with SpA. Significant predictors of musculoskeletal deficits included active arthritis in the previous 6 months (mCSA), temporomandibular joint disease (mCSA and section modulus), functional disability (mCSA and vBMD), short stature (vBMD), infliximab exposure (vBMD), and JIA duration (section modulus). The section modulus was significantly reduced relative to mCSA in patients with JIA after adjustment for age and limb length.Marked deficits in vBMD and bone strength occur in JIA in association with severe and longstanding disease. Contrary to the findings of previous studies, bone deficits were greater than expected relative to the mCSA, which illustrates the importance of adjusting for age and bone length.

  View details for DOI 10.1002/art.23683

  View details for Web of Science ID 000259055400037

  View details for PubMedID 18668565

  View details for PubMedCentralID PMC2705769

• Special report on the 2007 pediatric Position Development Conference of the International Society for Clinical Densitometry SOUTHERN MEDICAL JOURNAL Gordon, C. M., Baim, S., Bianchi, M., Bishop, N. J., Hans, D. B., Kalkwarf, H., Langman, C., Leonard, M. B., Plotkin, H., Rauch, F., Zemel, B. S. 2008; 101 (7): 740-743

  Abstract

  The International Society for Clinical Densitometry periodically holds Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines for the assessment of skeletal health, including nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests. Topics are selected for consideration according to criteria that include clinical relevancy, uncertainty in the application of medical evidence to clinical practice, and the likelihood of the expert panel to reach a consensus agreement. The first Pediatric PDC was June 20 to 21, 2007 in Montreal, Quebec, Canada. Topics included fracture prediction and definition of osteoporosis in children; dual-energy x-ray absorptiometry (DXA) assessment in children with chronic disease that may affect the skeleton; DXA interpretation and reporting in children and adolescents; and the use of peripheral quantitative computed tomography in children and adolescents. This report describes the methodology and presents the results of this recent PDC.

  View details for Web of Science ID 000257477600018

  View details for PubMedID 18580718

• Assessment of spine bone mineral density in juvenile idiopathic arthritis: Impact of scan projection JOURNAL OF CLINICAL DENSITOMETRY Dubner, S. E., Shults, J., Leonard, M. B., Zemell, B. S., Sembhi, H., Burnham, J. M. 2008; 11 (2): 302-308

  Abstract

  Although children with juvenile idiopathic arthritis (JIA) are at risk for vertebral fractures, recent conventional posterior-anterior (PA) spine dual-energy X-ray absorptiometry studies reported minimal areal bone mineral density (aBMD, g/cm2) deficits. Width-adjusted BMD (WA-BMD, g/cm3) represents the bone mineral content (BMC) from the lateral projection, excluding the dense cortical spinous processes, divided by the estimated vertebral body volume based on paired PA-lateral bone dimensions. Therefore, WA-BMD may be more sensitive to JIA effects on the predominantly trabecular vertebral body. Age- and sex-specific Z-scores for spine aBMD and WA-BMD were generated in 84 JIA subjects compared with healthy controls, aged 5-21 yr. JIA was associated with lower mean WA-BMD Z-scores (-0.78, 95% CI: -1.03, -0.53; p<0.001) and aBMD Z-scores (-0.26, 95% CI: -0.49, -0.02; p<0.05), compared with controls. WA-BMD Z-scores were significantly lower than aBMD Z-scores in JIA (p<0.001). A significant JIA by age interaction (p<0.001) indicated that the magnitude of the difference between WA-BMD and aBMD Z-scores was greater in younger subjects. In conclusion, WA-BMD may be more sensitive to disease effects in children because it selectively measures the trabecular-rich vertebral body and is independent of growth-related changes in BMC of the dense spinous processes.

  View details for DOI 10.1016/j.jocd.2007.10.005

  View details for Web of Science ID 000256640900012

  View details for PubMedID 18164636

• Observational study of bone accretion during successful weight loss in obese adolescents OBESITY Stettler, N., Berkowtiz, R. I., Cronquist, J. L., Shults, J., Wadden, T. A., Zemel, B. S., Leonard, M. B. 2008; 16 (1): 96-101

  Abstract

  To assess bone mineral content (BMC) among obese adolescents who lose weight during a critical period for bone accretion.Whole body, lumbar spine, lower, and upper limb BMC were measured in 62 obese adolescents who completed an intensive 12-month weight loss trial. BMC was adjusted for height (z -scores) using data from a reference group of 66 adolescents (who were 18% overweight).At baseline, the BMC of the obese group was higher than the reference group. During the 12-month weight loss program, unadjusted BMC increased among the obese adolescents, despite successful weight loss. After adjustment for height, whole body BMC did not change significantly from baseline to 12 months (mean +/- s.d.: 1.08 +/- 0.67 to 1.06 +/- 0.67, P = 0.7). Region-specific BMC-for-height however decreased for the lower (1.07 +/- 0.57 to 0.95 +/- 0.59, P < 0.001) and upper (1.29 +/- 0.56 to 1.18 +/- 0.57, P = 0.01) limbs, but lumbar spine BMC-for-height increased (0.14 +/- 1.06 to 0.40 +/- 0.94, P < 0.001). These changes were largely and independently explained by changes in lean and fat mass.This study confirms that obese adolescents have high BMC for height and suggests that, unlike adults, their BMC continues to increase during weight loss and remains higher than the BMC of a reference group. After adjustment for growth-related changes, lower and upper limb BMC appears to decrease, while lumbar spine BMC appears to increase. These results suggest that to optimize the health benefits of weight loss among obese adolescents, their bone health should be better understood and addressed.

  View details for DOI 10.1038/oby.2007.17

  View details for Web of Science ID 000252554300017

  View details for PubMedID 18223619

• Official positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Pediatric Position Development Conference JOURNAL OF CLINICAL DENSITOMETRY Baim, S., Leonard, M. B., Bianchi, M., Hans, D. B., Kalkwarf, H. J., Langman, C. B., Rauch, F. 2008; 11 (1): 6-21

  Abstract

  The International Society for Clinical Densitometry (ISCD) convenes a Position Development Conference (PDC) every 2 yr to make recommendations for standards in the field of bone densitometry. The recommendations are based on clinically relevant issues in bone densitometry such as quality control, acquisition, analysis, interpretation, and reporting. In 2007, ISCD convened its first Pediatric Position Development Conference to address issues specific to the assessment of skeletal health in children and adolescents. Topics for consideration are developed by the ISCD Board of Directors and its Scientific Advisory Committee. Clinically relevant questions related to each topic area are assigned to task forces for a comprehensive review of the medical literature and subsequent presentation of the reports to an international panel of experts. For this PDC, the Expert Panel included representatives of the American Society for Bone and Mineral Research and International Bone and Mineral Society. The recommendations of the PDC Expert Panel are then reviewed by the ISCD Board of Directors. Recommendations that are approved become Official Positions of the ISCD. The Pediatric PDC was held June 20-21, 2007, in Montreal, Quebec, Canada. Topics considered were restricted to children and adolescents, and included DXA prediction of fracture and definition of osteoporosis; DXA assessment in diseases that may affect the skeleton; DXA interpretation and reporting; and peripheral quantitative computed tomography measurement. This report describes the methodology and results of the 2007 Pediatric PDC, and a summary of all ISCD Official Positions, including the ones recently adopted by this 2007 Pediatric PDC and the 2007 Lansdowne, Virginia, USA Adult PDC.

  View details for DOI 10.1016/j.jocd.2007.12.002

  View details for Web of Science ID 000255568300002

  View details for PubMedID 18442749

• Volumetric bladder ultrasound performed by trained nurses increases catheterization success in pediatric patients Annual Meeting of the Society-of-Academic-Emergency-Medicine Baumann, B. M., McCans, K., Stahmer, S. A., Leonard, M. B., Shults, J., Holmes, W. C. W B SAUNDERS CO-ELSEVIER INC. 2008: 18–23

  Abstract

  The objective of the study was to determine whether the use of volumetric ultrasound by trained pediatric emergency department (ED) nurses improves first-attempt urine collection success rates.This randomized controlled trial was conducted in children aged < or = 36 months requiring diagnostic urine samples. Children were randomized to either the conventional (nonimaged) or the ultrasound arm. Demographics, number of catheterizations required for success, postponements, and collection times were recorded.Forty-five children were assigned to the conventional and 48 to the ultrasound arm (n = 93). First-attempt success rates were higher in the ultrasound arm: 67% (conventional) vs 92% (ultrasound) (P = .003). Both urinalysis and culture were less likely to be completed on conventional group specimens (91% vs 100%; P = .04). However, mean conventional group urine collection time was less than the ultrasound group's collection time (12 vs 28 minutes; P < .001).Although there is a time delay, urine collection in the ultrasound arm generated a significant improvement over conventional catheterization in obtaining an adequate urine sample.

  View details for DOI 10.1016/j.ajem.2007.03.020

  View details for Web of Science ID 000252161800004

  View details for PubMedID 18082776

• Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation AMERICAN JOURNAL OF CLINICAL NUTRITION Rovner, A. J., Stallings, V. A., Schall, J. I., Leonard, M. B., Zemel, B. S. 2007; 86 (6): 1694-1699

  Abstract

  Cystic fibrosis (CF) with pancreatic insufficiency is associated with poor absorption of fat and fat-soluble vitamins, including vitamin D. Pancreatic enzyme supplementation does not completely correct fat malabsorption in CF patients.The objective of the study was to compare the vitamin D status of children, adolescents, and young adults with CF who were treated with routine vitamin D and pancreatic enzyme supplements with the vitamin D status of a healthy reference group from a similar geographic area.Growth, dietary intake, and serum concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and parathyroid hormone (PTH) were measured in 101 white subjects with CF and a reference group of 177 white subjects.The median daily vitamin D supplementation in the CF group was 800 IU. The mean +/- SD serum concentrations of 25(OH)D were 20.7 +/- 6.5 ng/mL in the CF group and 26.2 +/- 8.6 ng/mL in the reference group (P < 0.001). Vitamin D deficiency and insufficiency were defined as 25(OH)D concentrations < 11 ng/mL and < 30 ng/mL, respectively. Seven percent of the CF group and 2% of the healthy reference group were vitamin D deficient (P < 0.03). Ninety percent of the CF group and 74% of the healthy reference group were vitamin D insufficient (P < 0.01). Twenty-five percent of the CF group and 9% of the healthy reference group had elevated PTH (P < 0.006). The odds of vitamin D insufficiency in the CF group, compared with the healthy reference group, were 1.2 (95% CI: 1.1, 1.3) after adjustment for season and age.Despite daily vitamin D supplementation, serum 25(OH)D concentrations remain low in children, adolescents, and young adults with CF.

  View details for Web of Science ID 000251575500018

  View details for PubMedID 18065588

• A structural approach to the assessment of fracture risk in children and adolescents with chronic kidney disease PEDIATRIC NEPHROLOGY Leonard, M. B. 2007; 22 (11): 1815-1824

  Abstract

  Children with chronic kidney disease (CKD) have multiple risk factors for impaired accretion of trabecular and cortical bone. CKD during childhood poses an immediate fracture risk and compromises adult bone mass, resulting in significantly greater skeletal fragility throughout life. High-turnover disease initially results in thickened trabeculae, with greater bone volume. As disease progresses, resorption cavities dissect trabeculae, connectivity degrades, and bone volume decreases. Increased bone turnover also results in increased cortical porosity and decreased cortical thickness. Dual-energy X-ray absorptiometry (DXA)-based measures of bone mineral density (BMD) are derived from the total bone mass within the projected bone area (g/cm(2)), concealing distinct disease effects in trabecular and cortical bone. In contrast, peripheral quantitative computed tomography (pQCT) estimates volumetric BMD (vBMD, g/cm(3)), distinguishes between cortical and trabecular bone, and provides accurate estimates of cortical dimensions. Recent data have confirmed that pQCT measures of cortical vBMD and thickness provide substantially greater fracture discrimination in adult dialysis patients compared with hip or spine DXA. The following review considers the structural effects of renal osteodystrophy as it relates to fracture risk and the potential advantages and disadvantages of DXA and alternative measures of bone density, geometry, and microarchitecture, such as pQCT, micro-CT (microCT), and micro magnetic resonance imaging (microMRI) for fracture risk assessment.

  View details for DOI 10.1007/s00467-007-0490-6

  View details for Web of Science ID 000249820000002

  View details for PubMedID 17622566

• Caregiver and health care provider satisfaction with volumetric bladder ultrasound ACADEMIC EMERGENCY MEDICINE Baumann, B. M., McCans, K., Stahmer, S. A., Leonard, M. B., Shults, J., Holmes, W. C. 2007; 14 (10): 903-907

  Abstract

  Conventional (nonimaged) bladder catheterization has lower first-attempt success rates (67%-72%) when compared with catheterization aided by volumetric bladder ultrasonography (US) (92%-100%), yet the total time to urine sample collection with US can be quite lengthy. Given the advantage and disadvantages, the authors assessed caregiver and health care provider satisfaction with these two methods.Caregivers and health care providers of children enrolled in a prospective, randomized, controlled trial examining the first-attempt urine collection success rates with these two methods completed standardized questionnaires. Each child's caregiver, nurse, and physician noted their perceptions, satisfaction, and future preferences using Likert-scale assessments.Of 93 caregivers, 45 had children randomized to the conventional arm and 48 to the US arm. Nine physicians and three nurses participated. Both caregiver groups had similar previous catheterization experience; none had children undergo volumetric bladder sonography. Caregivers in the conventional group rated their children's discomfort higher (4.4 vs. 3.4; p = 0.02) and were less satisfied (4.5 vs. 6.4; p < 0.0001) than those in the US group. Nurses' satisfaction with catheterization in the conventional group was lower than in the US group (3.0 vs. 5.5), as was physicians' satisfaction (4.3 vs. 5.7; p < 0.0001). Both nurses and physicians indicated that they would be less likely to use conventional catheterization in future attempts.Caregivers in the conventional group rated their children's discomfort higher than did caregivers in the US group. Both caregivers and health care providers expressed greater satisfaction with US and were more likely to prefer this imaging modality with future catheterization attempts.

  View details for DOI 10.1197/j.aem.2007.06.041

  View details for Web of Science ID 000250020700012

  View details for PubMedID 17898252

• Gender differences in body composition deficits at diagnosis in children and adolescents with Crohn's disease INFLAMMATORY BOWEL DISEASES Thoyu, M., Shults, J., Burnham, J. M., Zemel, B. S., Baldassano, R. N., Leonard, M. B. 2007; 13 (9): 1121-1128

  Abstract

  Childhood Crohn's disease (CD) is associated with poor growth and decreased body mass index (BMI); however, lean mass (LM) and fat mass (FM) deficits prior to therapy have not been characterized.To quantify LM and FM in incident pediatric CD subjects and controls, and to identify determinants of LM and FM deficits.Whole body LM and FM were assessed using DXA in 78 CD subjects and 669 healthy controls, ages 5-21 yr. Gender specific z-scores for LM (LM-Ht) and FM (FM-Ht) relative to height were derived using log linear regression models in the controls. Multivariate linear regression models adjusted for potential confounders.CD was associated with significantly lower height and BMI for age. Within CD subjects, FM-Ht and LM-Ht were significantly lower in females compared with males (FM-Ht z: -0.66+/-0.83 vs. -0.08+/-0.95, p<0.01; LM-Ht z: -1.12+/-1.12 vs. -0.57+/-0.99, p<0.05). In females, CD was associated with significantly lower LM-Ht (p<0.001) and FM-Ht (p=0.001), adjusted for age, race and Tanner stage, compared with controls. LM and FM deficits were significantly greater in older females with CD; 47% of adolescent females had LM-Ht

  View details for DOI 10.1002/ibd.20149

  View details for Web of Science ID 000249109500009

  View details for PubMedID 17427245

• Risk factors for low serum 25-hydroxyvitamin D concentrations in otherwise healthy children and adolescents AMERICAN JOURNAL OF CLINICAL NUTRITION Weng, F. L., Shults, J., Leonard, M. B., Stallings, V. A., Zemel, B. S. 2007; 86 (1): 150-158

  Abstract

  Serum 25-hydroxyvitamin D [25(OH)D] concentrations serve as a biomarker for vitamin D stores. Prior studies have not examined the risk factors for low vitamin D concentrations in a multiethnic sample of US youth across a broad age range.The objective was to determine the prevalence of and factors associated with low concentrations of 25(OH)D in children and adolescents.Serum 25(OH)D concentrations were measured in 382 healthy children aged 6-21 y living in the northeastern United States. Dietary and supplemental vitamin D intake was assessed by interview. Fat and lean mass were assessed by dual-energy X-ray absorptiometry. Multivariable ordinal logistic regression was used to determine factors associated with decreased concentrations of 25(OH)D.The median concentration of 25(OH)D was 28 ng/mL (interquartile range: 19-35 ng/mL), and 55% of subjects had 25(OH)D concentrations <30 ng/mL. 25(OH)D concentrations were inversely correlated with parathyroid hormone concentrations (Spearman's r=-0.31, P<0.001) but were not significantly correlated with 1,25-dihydroxyvitamin D concentrations. In the multivariable model, older age (P<0.001), black race [odds ratio (OR): 14.2; 95% CI: 8.53, 23.5], wintertime study visit (OR: 3.55; 95% CI: 2.29, 5.50), and total daily vitamin D intake <200 IU (OR: 1.58; 95% CI: 1.02, 2.46) were associated with low vitamin D concentrations. Fat and lean mass were not independently associated with vitamin D status in this healthy-weight sample.Low serum 25(OH)D concentrations are prevalent in otherwise healthy children and adolescents in the northeastern United States and are related to low vitamin D intake, race, and season.

  View details for Web of Science ID 000247981900022

  View details for PubMedID 17616775

• Alterations in proximal femur geometry in children treated with glucocorticoids for Crohn disease or nephrotic syndrome: Impact of the underlying disease JOURNAL OF BONE AND MINERAL RESEARCH Burnham, J. M., Shults, J., Petit, M. A., Semeao, E., Beck, T. J., Zemel, B. S., Leonard, M. B. 2007; 22 (4): 551-559

  Abstract

  Proximal femur geometry was assessed in children and young adults treated with chronic GCs for CD or SSNS. Subperiosteal width and section modulus were significantly lower in CD and greater in SSNS compared with controls, highlighting the importance of the underlying disease, persistent inflammation, and alterations in lean mass.The impact of glucocorticoid (GC) therapy on bone structure during growth is unknown. Our objective was to characterize proximal femur geometry in children and young adults with Crohn disease (CD) or steroid-sensitive nephrotic syndrome (SSNS) compared with controls and to evaluate the influence of lean mass and GC therapy on bone parameters.DXA scans of the hip and whole body were obtained in 88 subjects with CD, 65 subjects with SSNS, and 128 controls (4-26 years of age). Hip structural analysis parameters (subperiosteal width, cross-sectional area [CSA], and section modulus in the narrow neck [NN], intertrochanteric region [IT], and femoral shaft [FS]), areal BMD, and whole body lean mass were expressed as Z scores compared with controls. Multivariable linear regression was used to adjust outcomes for group differences in age, sex, race, and height.Mean lean mass Z scores were lower in CD (-0.63, p < 0.001) and greater in SSNS (0.36, p = 0.03) compared with controls. Hip areal BMD Z scores were lower in CD (-0.73, p < 0.001) but not SSNS (-0.02, p > 0.2) compared with controls. In CD, Z scores for subperiosteal width (NN: -1.66, p < 0.001; FS: -0.86, p < 0.001) and section modulus (NN: -0.60, p = 0.003; FS: -0.36, p = 0.03) were significantly lower than controls. In contrast, in SSNS, Z scores were greater for IT subperiosteal width (0.39, p = 0.02), FS CSA (0.47, p = 0.005), and FS section modulus (0.49, p = 0.004). Alterations in section modulus in CD and SSNS were eliminated after adjustment for lean mass. Cumulative GC dose was inversely associated with FS subperiosteal width and section modulus only in CD.These data show that the effects of GC on proximal femur geometry during growth are influenced by the underlying disease, persistent inflammation, and alterations in lean mass. These data also provide insight into the structural basis of hip fragility in CD.

  View details for DOI 10.1359/JBMR.070110

  View details for Web of Science ID 000245234000009

  View details for PubMedID 17243860

• Glucocorticoid-induced osteoporosis in children: Impact of the underlying disease Workshop on Skeletal Effects of Pharmacologic Agents in Children Leonard, M. B. AMER ACAD PEDIATRICS. 2007: S166–S174

  Abstract

  Glucocorticoids inhibit osteoblasts through multiple mechanisms, which results in significant reductions in bone formation. The growing skeleton may be especially vulnerable to adverse glucocorticoid effects on bone formation, which could possibly compromise trabecular and cortical bone accretion. Although decreased bone mineral density has been described in various pediatric disorders that require glucocorticoids, and a population-based study reported increased fracture risk in children who require >4 courses of glucocorticoids, some of the detrimental bone effects attributed to glucocorticoids may be caused by the underlying inflammatory disease. For example, inflammatory cytokines that are elevated in chronic disease, such as tumor necrosis factor alpha, suppress bone formation and promote bone resorption through mechanisms similar to glucocorticoid-induced osteoporosis. Summarized in this review are changes in bone density and dimensions during growth, the effects of glucocorticoids and cytokines on bone cells, the potential confounding effects of the underlying inflammatory-disease process, and the challenges in interpreting dual-energy x-ray absorptiometry results in children with altered growth and development in the setting of glucocorticoid therapy. Two recent studies of children treated with chronic glucocorticoids highlight the differences in the effect of underlying disease, as well as the importance of associated alterations in growth and development.

  View details for DOI 10.1542/peds.2006-2023J

  View details for Web of Science ID 000247759900008

  View details for PubMedID 17332238

• Quantitative microcomputed tomography assessment of intratrabecular, intertrabecular, and cortical bone architecture in a rat model of severe renal osteodystrophy JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Hopper, T. A., Wehrli, F. W., Saha, P. K., Andre, J. B., Wright, A. C., Sanchez, C. P., Leonard, M. B. 2007; 31 (2): 320-328

  Abstract

  To determine the effects of renal osteodystrophy (ROD) on bone microarchitecture in growing rats.A total of 24 rats underwent 5/6 nephrectomy (NX) and were fed a high-phosphorus diet to induce ROD; another 6 underwent sham NX. In vitro microcomputed tomography images (GEMS, London, Ontario, Canada) were obtained in the femoral metaphysis and midshaft.Trabecular and cortical bone volume/total volume (BV/TV) were significantly lower in NX specimens because of pores within the trabeculae and along the endosteal surface. Topological analysis using component labeling in 3-dimensions verified that trabecular pores connected to the marrow space. After the trabecular pores were filled using a morphological filter, trabecular thickness was significantly increased in NX. In contrast, cortical thickness was significantly decreased in NX compared with controls; however, after filling the endocortical pores, thickness did not differ.The ROD resulted in decreased cortical and trabecular BV/TV, increased porosity, and increased trabecular thickness. Advanced image processing algorithms demonstrated the effects of cortical and trabecular porosity on BV/TV and structure in ROD.

  View details for Web of Science ID 000245456700027

  View details for PubMedID 17414773

• Improved generalized estimating equation analysis via xtqls for quasi-least squares in Stata STATA JOURNAL Shults, J., Ratcliffe, S. J., Leonard, M. 2007; 7 (2): 147-166

  View details for Web of Science ID 000248072200001

• The dysfunctional muscle-bone unit in juvenile idiopathic arthritis. Journal of musculoskeletal & neuronal interactions Burnham, J. M., Shults, J., Sembhi, H., Zemel, B. S., Leonard, M. B. 2006; 6 (4): 351-352

  View details for PubMedID 17185819

• Childhood onset arthritis is associated with an increased risk of fracture: a population based study using the General Practice Research Database ANNALS OF THE RHEUMATIC DISEASES Burnham, J. M., Shults, J., Weinstein, R., Lewis, J. D., Leonard, M. B. 2006; 65 (8): 1074-1079

  Abstract

  Childhood onset arthritis is associated with low bone mass and strength.To determine whether childhood onset arthritis is associated with greater fracture risk.In a retrospective cohort study all subjects with onset of arthritis between 1 and 19 years of age in the United Kingdom General Practice Research Database were identified. As controls, all sex and age matched subjects from a practice that included a subject with arthritis were included. Incidence rate ratios (IRRs) for first fracture were generated using Mantel-Haenszel methods and Poisson regression.1939 subjects with arthritis (51% female) and 207 072 controls (53% female) were identified. The median age at arthritis diagnosis was 10.9 years. A total of 129 (6.7%) first fractures were noted in subjects with arthritis compared with 6910 (3.3%) in controls over a median follow up of 3.90 and 3.95 years in the subjects with arthritis and controls, respectively. The IRR (95% confidence interval) for first fracture among subjects with arthritis, compared with controls, according to the age at the start of follow up were 1.49 (0.91 to 2.31) for age <10 years, 3.13 (2.21 to 4.33) at 10-15 years, 1.75 (1.18 to 2.51) at 15-20 years, 1.40 (0.91 to 2.08) at 20-45 years, and 3.97 (2.23 to 6.59) at >45 years.Childhood onset arthritis is associated with a clinically significant increased risk of fracture in children, adolescents and, possibly, adults. Studies are urgently needed to characterise the determinants of structural bone abnormalities in childhood arthritis and devise prevention and treatment strategies.

  View details for DOI 10.1136/ard.2005.048835

  View details for Web of Science ID 000239006000016

  View details for PubMedID 16627541

• Risk factors for glucocorticoid-induced obesity in children with steroid-sensitive nephrotic syndrome PEDIATRIC NEPHROLOGY Foster, B. J., Shults, J., Zemel, B. S., Leonard, M. B. 2006; 21 (7): 973-980

  Abstract

  The objective of this work was to determine the prevalence of obesity, defined as BMI >95th percentile, in children treated with glucocorticoids for steroid-sensitive nephrotic syndrome (SSNS), and to identify risk factors for the development for glucocorticoid-induced obesity. The experimental design involved a cross-sectional study of 96 individuals (4 to 21 yrs) treated with glucocorticoids for SSNS and 186 healthy reference subjects. Logistic regression was used to generate odds ratios for obesity. Glucocorticoid exposure was classified as recent in the 54 subjects treated with glucocorticoids in the prior six months, and remote in the remaining 42 subjects. Recent exposure was associated with significantly increased odds of obesity [odds ratio (95% CI): 26.14 (7.54, 90.66)] in non-blacks only. Each one-unit increase in maternal BMI was associated with a 35% increase in the odds of obesity in recent SSNS subjects (p=0.003). The effect of maternal BMI on the odds of obesity was significantly greater in recent SSNS subjects than in reference subjects (test for interaction p=0.038). The odds of obesity were also significantly increased [odds ratio 5.22 (1.77, 15.41), p=0.003] in all subjects with remote glucocorticoid exposure (black and non-black). These results indicate that non-black race and increased maternal BMI are risk factors for glucocorticoid-induced obesity in subjects with recent exposure.

  View details for DOI 10.1007/s00467-006-0100-z

  View details for Web of Science ID 000238293200014

  View details for PubMedID 16773410

• DXA estimates of vertebral volumetric bone mineral density in children: Potential advantages of paired posteroanterior and lateral scans JOURNAL OF CLINICAL DENSITOMETRY Leonard, M. B., Shults, J., Zemel, B. S. 2006; 9 (3): 265-273

  Abstract

  Dual-energy X-ray absorptiometry (DXA) estimates of areal bone mineral density (BMD) are confounded by bone size in children. Two strategies have been proposed to estimate vertebral volumetric BMD: (1) bone mineral apparent density (BMAD) is based on the posteroanterior (PA) spine scan; (2) width-adjusted bone mineral density (WABMD) is based on paired PA lateral scans. The objective of this study was to compare DXA estimates of vertebral bone mineral content (BMC), volume and volumetric BMD obtained from Hologic PA scans (Hologic, Inc., Bedford, MA) alone, and paired PA lateral scans in 124 healthy children, ages 4 to 20 yr. The PA scans were used to estimate bone volume (PA Volume) as (PA Area)1.5 and BMAD as [(PA BMC)/(PA Volume)]. Paired PA lateral scans were used to estimate width-adjusted bone volume (WA Volume) as [(pi/4)(PA width)(lateral depth)(vertebral height)] and WABMD as [(lateral BMC)/(WA Volume)]. Generalized estimating equations were used to compare the relationship between scan type (PA vs. paired PA lateral) and bone outcomes, and the effects of height and maturation on this relationship. The estimates of BMC and volume derived from PA scans and paired PA lateral scans were highly correlated (r>0.97); WABMD and BMAD were less correlated (r=0.81). The increases in BMC, volume, and volumetric BMD with greater height and maturation were significantly larger (all p<0.001) when estimated from paired PA lateral scans, compared with PA scans alone. The proportion of spine BMC contained within the vertebral body, versus the cortical spinous processes, increased significantly with age (p<0.001) from 28% to 69%. The smaller increases in bone measures on PA scans may have been due to magnification error by the fan beam as posterior tissue thickness increased in taller, more mature subjects, and the distance of the vertebrae from the X-ray source increased. In conclusion, paired Hologic PA lateral scans may increase sensitivity to growth-related increases in trabecular BMC and density in the spine, with less bias due to magnification error.

  View details for DOI 10.1016/j.jocd.2006.05.008

  View details for Web of Science ID 000240321200003

  View details for PubMedID 16931343

• Predictors of immunomodulator use as early therapy in pediatric Crohn's disease JOURNAL OF CLINICAL GASTROENTEROLOGY Jacobstein, D. A., Mamula, P., Markowitz, J. E., Leonard, M., Baldassano, R. N. 2006; 40 (2): 145-148

  Abstract

  The goals of this study were to identify markers in a patient's presentation and disease progression that predict the need for the use of immunomodulators in a pediatric population.Although immunomodulator safety and efficacy have been documented in Crohn's disease, models for predicting outcome and the need for immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) early in the disease course have not been investigated in children or adults.Data on newly diagnosed Crohn's disease patients were prospectively collected within 3 weeks of diagnosis, 6 months after diagnosis, and 1 year after diagnosis. Information collected at each visit included medication use and disease activity assessment.A total of 57 patients who were followed for > or = 6 months were evaluated. Overall, 34 of 57 (59.6%) were started on immunomodulators within 1 year of diagnosis. Mean serum albumin (3.35 g/dL vs. 3.7 g/dL, P = 0.013) and hematocrit (33.3% vs. 35.9%, P = 0.023) at diagnosis were lower, and erythrocyte sedimentation rate (32 vs. 12, P = 0.011) at diagnosis was higher in patients who required immunomodulators. The total Pediatric Crohn's Disease Activity Index score as well as the physical examination score and patient recall score within the PCDAI at diagnosis were not different among those who received immunomodulators and those that did not.Immunomodulators are frequently used within 1 year of diagnosis in pediatric Crohn's disease. Lower serum albumin levels and hematocrit, and elevated erythrocyte sedimentation rate at diagnosis may predict the need for immunomodulators earlier in the disease course.

  View details for Web of Science ID 000234966200011

  View details for PubMedID 16394876

• The state of pediatric bone: Summary of the ASBMR pediatric bone initiative JOURNAL OF BONE AND MINERAL RESEARCH Klein, G. L., Fitzpatrick, L. A., Langman, C. B., Beck, T. J., Carpenter, T. O., Gilsanz, V., Holm, I. A., Leonard, M. B., Specker, B. L. 2005; 20 (12): 2075-2081

  View details for DOI 10.1359/JBMR.050901

  View details for Web of Science ID 000233517700001

  View details for PubMedID 16294260

• Bone area and bone mineral content deficits in children with sickle cell disease PEDIATRICS Buison, A. M., Kawchak, D. A., Schall, J. I., Ohene-Frempong, K., Stallings, V. A., Leonard, M. B., Zemel, B. S. 2005; 116 (4): 943-949

  Abstract

  Children with sickle cell disease (SCD) experience poor growth, altered body composition, and delayed maturation. Deficits in bone mineral content (BMC) and bone area (BA) have not been well characterized. The objectives of this study were to assess whole-body BMC (WBBMC) and WBBA in children with SCD, type SS (SCD-SS), compared with healthy control subjects, adjusted for growth and body composition, and to determine the relationships of WBBMC and WBBA to bone age and hematologic parameters in children with SCD-SS.WBBMC, WBBA, and lean mass were measured by dual-energy x-ray absorptiometry in children who were aged 4 to 19 years. Growth, sexual development, and bone age were assessed. Gender-specific z scores for WBBMC relative to age and height were generated from control data.Ninety children with SCD-SS and 198 healthy control subjects were evaluated. SCD-SS was associated with poor growth. WBBMC was significantly decreased in SCD-SS compared with control subjects, adjusted for age, height, pubertal status, and lean mass. WBBMC relative to age and WBBMC relative to height z scores were -0.95 +/- 0.99 and -0.54 +/- 0.97, respectively, and were associated with hemoglobin and hematocrit levels and history of delayed bone age.Children with SCD-SS have significant deficits in WBBMC that persist despite adjustment for poor growth and decreased lean mass. These children may be at increased risk for fragility fractures and suboptimal peak bone mass.

  View details for DOI 10.1542/peds.2005-2582

  View details for Web of Science ID 000232289700019

  View details for PubMedID 16199706

• Mild to moderate cystic fibrosis is not associated with increased fracture risk in children and adolescents JOURNAL OF PEDIATRICS Rovner, A. J., Zemel, B. S., Leonard, M. B., Schall, J. I., Stallings, V. A. 2005; 147 (3): 327-331

  Abstract

  To determine whether children and adolescents with cystic fibrosis (CF), pancreatic insufficiency (PI), and mild-to-moderate lung disease have an increased risk of fracture compared with concurrent healthy control subjects.A lifetime fracture history questionnaire was administered to 186 subjects (ages 6 to 25 years) with CF, PI and mild-to-moderate lung disease and 427 healthy white control subjects (ages 4 to 25 years).A fracture was reported by 24% of subjects with CF and 23% of healthy control subjects. Average age of first fracture was similar between the groups (8.3 years for subjects and 8.8 years for controls). The radius/ulna was the most common fracture site in both groups. Risk of fracture, adjusted for sex and age, was not greater in the CF group compared with the control group (hazard ratio: 0.96, 95% CI: 0.68, 1.30, P = .82).Children and adolescents with CF, PI, and mild-to-moderate lung disease were not at an increased risk of fracture.

  View details for DOI 10.1016/j.jpeds.2005.04.015

  View details for Web of Science ID 000232412100014

  View details for PubMedID 16182670

• Body-corn position alterations consistent with cachexia in children and young adults with Crohn disease AMERICAN JOURNAL OF CLINICAL NUTRITION Burnham, J. M., Shults, J., Semeao, E., Foster, B. J., Zemel, B. S., Stallings, V. A., Leonard, M. B. 2005; 82 (2): 413-420

  Abstract

  Crohn disease (CD) in children is associated with low body mass index (BMI), poor growth, and delayed maturation; alterations in lean and fat mass, however, are poorly characterized.The objective was to quantify lean and fat mass in children and young adults with CD and in healthy control subjects, relative to height and pubertal maturation.This cross-sectional study assessed whole-body lean and fat mass by using dual-energy X-ray absorptiometry in 104 subjects with CD and in 233 healthy control subjects aged 4-25 y. Linear regression was used to determine the effect of CD on body composition and to generate sex-specific SD scores (z scores) for lean and fat mass relative to height.Subjects with CD had lower height-for-age and BMI-for-age z scores (P < 0.001 for both) than did control subjects. CD was associated with significant deficits in lean mass after adjustment for height, age, race, and Tanner stage (P = 0.003); deficits in fat mass were not observed. The mean (+/-SD) lean mass-for-height and fat mass-for-height z scores in the subjects with CD were -0.61 +/- 0.92 and -0.04 +/- 0.86, respectively. Within the control group, fat mass-for-height was positively correlated with lean mass-for height (r = 0.41, P < 0.0001); this association was absent in the subjects with CD.Children and young adults with CD had significant deficits in lean mass but preserved fat mass, which is consistent with cachexia. Further research is needed to identify physical activity, nutritional, and antiinflammatory interventions to improve body composition in persons with CD.

  View details for Web of Science ID 000231293100021

  View details for PubMedID 16087987

• First NIH/office of rare diseases conference on cystinosis: Past, present, and future PEDIATRIC NEPHROLOGY Kleta, R., Kaskel, F., Dohil, R., Goodyer, P., Guay-Woodford, L. M., Harms, E., Ingelfinger, J. R., Koch, V. H., Langman, C. B., Leonard, M. B., Mannon, R. B., Sarwal, M., Schneider, J. A., Skovby, F., Sonies, B. C., Thoene, J. G., Trauner, D. A., Gahl, W. A. 2005; 20 (4): 452-454

  View details for DOI 10.1007/s00467-004-1777-5

  View details for Web of Science ID 000227442100003

  View details for PubMedID 15747161

• Proximal femur bone geometry is appropriately adapted to lean mass in overweight children and adolescents BONE Petit, M. A., Beck, T. J., Shults, J., Zemel, B. S., Foster, B. J., Leonard, M. B. 2005; 36 (3): 568-576

  Abstract

  It is unclear if the bones of overweight children are appropriately adapted to increased loads. The objective of this study was to compare bone geometry in 40 overweight (body mass index [BMI] > 85th percentile) and 94 healthy weight (BMI < or = 85th percentile) subjects, ages 4-20 years. Dual energy X-ray absorptiometry (Hologic QDR 2000) scans were analyzed at the femoral shaft (FS) and narrow neck (NN) by the Hip Structure Analysis program. Subperiosteal width, cortical thickness and indices of bone axial and bending strength (bone cross-sectional area [CSA] and section modulus [Z]) were measured from bone mass profiles. Multivariate regression models were used to compare overweight and healthy weight subjects. Z was 11 (95% CI 5, 19) and 13 (7, 20) percent higher at the FS and NN, respectively, in overweight subjects (P < 0.001), adjusted for height, maturation and gender. At the NN, higher Z was due to greater subperiosteal width [4% (2, 7)] and bone CSA [10% (5, 16]) and at the FS, to higher bone CSA [10% (5, 16)] and thicker cortices [9% (3, 15)]. When lean mass was added to the models, bone variables did not differ between overweight and healthy weight subjects (P > 0.22), with the exception of NN subperiosteal width [3% (0, 6), P = 0.04]. Fat mass did not contribute significantly to any model. In summary, proximal femur bone geometric strength in overweight children was appropriately adapted to lean mass and height but greater weight in the form of fat mass did not have an independent effect on bone bending strength. These geometric adaptations are consistent with the mechanostat hypothesis that bone strength adapts primarily to muscle forces, not to static loads represented by body weight.

  View details for DOI 10.1016/j.bone.2004.12.003

  View details for Web of Science ID 000228196900022

  View details for PubMedID 15777684

• Assessment of bone mass following renal transplantation in children 7th Symposium on Growth and Development in Children with Chronic Kidney Disease Leonard, M. B. SPRINGER. 2005: 360–67

  Abstract

  Throughout childhood and adolescence, skeletal growth results in site-specific increases in trabecular and cortical dimensions and density. Childhood osteoporosis can be defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Pediatric renal transplant recipients have multiple risk factors for impaired bone density and bone strength, including pre-existing renal osteodystrophy, delayed growth and development, malnutrition, decreased weight-bearing activity, inflammation, and immunosuppressive therapies. Dual energy X-ray absorptiometry (DXA) is the most-common method for the assessment of skeletal status in children and adults. However, DXA has many important limitations that are unique to the assessment of bone health in children. Furthermore, DXA is limited in its ability to distinguish between the distinct, and sometimes opposing, effects of renal disease on cortical and trabecular bone. This review summarizes these limitations and the difficulties in assessing and interpreting bone measures in pediatric transplantation are highlighted in a review of select studies. Alternative strategies are presented for clinical and research applications.

  View details for DOI 10.1007/s00467-004-1747-y

  View details for Web of Science ID 000227713600020

  View details for PubMedID 15692834

• Nutrition in children with kidney disease: Pitfalls of popular assessment methods 1st Joint Congress of the International-Society-for-Peritoneal-Dialysis/European Peritoneal Dialysis Meeting Foster, B. J., Leonard, M. B. MULTIMED INC. 2005: S143–S146

  Abstract

  Children with chronic kidney disease (CKD) are considered at high risk for protein-energy malnutrition. Clinical practice guidelines generally recommend an evaluation of numerous nutritional parameters to give a complete and accurate picture of nutritional status. This review summarizes the potential limitations of commonly used methods of nutritional assessmentin the setting of CKD. Unrecognized fluid overload and inappropriate normalization of body composition measures are the most important factors leading to misinterpretation of the nutritional assessment in CKD. The importance of expressing body composition measures relative to height or height-age in a population in whom short stature and pubertal delay are highly prevalent is emphasized. The limitations of growth as a marker for nutritional status are also addressed. In addition, the prevailing belief that children with CKD are at high risk for malnutrition is challenged.

  View details for Web of Science ID 000230035800038

  View details for PubMedID 16048282

• Impact of simultaneous kidney-pancreas transplant and timing of transplant on kidney allograft survival AMERICAN JOURNAL OF TRANSPLANTATION Israni, A. K., Feldman, H. I., PROPERT, K. J., Leonard, M., Mange, K. C. 2005; 5 (2): 374-382

  Abstract

  Since 1988 over 10 000 simultaneous cadaveric pancreas-kidney transplants (SPK) have been performed in the United States among patients with end-stage renal disease due to Type 1 diabetes (T1DM). The two aims of this study were to assess the impact on kidney allograft survival of (i) SPK versus transplantation of a kidney alone (KA), and (ii) SPK prior to versus after initiation of chronic dialysis. This retrospective, non-concurrent cohort study examined registry data collected from 8323 patients waitlisted in the United States for an SPK and transplanted with either an SPK or a KA during January 1, 1990 - October 31, 2002. SPK recipients had an adjusted hazard ratio for kidney allograft loss of 0.63 (95% CI: 0.51-0.77, p < 0.001) compared to transplantation without pancreas allograft. SPK recipients who received their allografts prior to beginning chronic dialysis had a lower rate of kidney allograft loss than SPK recipients who received their transplant after initiation of chronic dialysis (adjusted hazard rates (HR) = 0.83, 95% CI: 0.69-0.99, p = 0.042). Simultaneous transplantation of pancreas-kidney compared to kidney transplantation alone and SPK prior to the initiation of chronic dialysis compared to SPK after initiation of dialysis were both associated with longer kidney allograft survival.

  View details for DOI 10.1111/j.1600-6143.2004.00688.x

  View details for Web of Science ID 000226332700023

  View details for PubMedID 15643998

• Vitamin D insufficiency in steroid-sensitive nephrotic syndrome in remission PEDIATRIC NEPHROLOGY Weng, F. L., Shults, J., Herskovitz, R. M., Zemel, B. S., Leonard, M. B. 2005; 20 (1): 56-63

  Abstract

  Serum 25-hydroxyvitamin D [25(OH)D] concentrations are the best indicator of vitamin D nutritional status. We measured serum 25(OH)D concentrations in 94 healthy controls and in 41 subjects (aged 4-22 years) with steroid-sensitive nephrotic syndrome (SSNS) in remission. Children with remitted SSNS had significantly lower 25(OH)D concentrations than healthy controls (median 16.4 ng/ml versus 23.9 ng/ml, P<0.001). In a multivariable logistic regression model, the odds ratios (OR) of vitamin D insufficiency [25(OH)D <20 ng/ml] were independently increased in SSNS subjects [OR 11.2 (95% confidence interval 3.5-36.2)], non-whites [OR 12.9 (4.6-36.2)], older children [OR 1.20 per year (1.06-1.36)], and winter months [OR 6.7 (2.5-18.4)]. Within the SSNS subjects, multiple linear regression determined that serum 25(OH)D concentrations were not associated with SSNS disease characteristics measured in this study, such as duration of disease, number of relapses, cumulative glucocorticoids, and interval since last relapse. In conclusion, children with remitted SSNS have lower serum 25(OH)D concentrations than healthy controls. This difference persisted after adjusting for the potential confounding effects of age, race, season, and milk intake. Children with remitted SSNS may benefit from routine measurement of 25(OH)D, but the clinical significance of low 25(OH)D in this population remains unclear.

  View details for DOI 10.1007/s00467-004-1694-7

  View details for Web of Science ID 000225758100011

  View details for PubMedID 15602667

• Deficits in size-adjusted bone mass in children with Alagille syndrome JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Olsen, I. E., Ittenbach, R. F., Rovner, A. J., Leonard, M. B., Mulberg, A. E., Stallings, V. A., Piccoli, D. A., Zemel, B. S. 2005; 40 (1): 76-82

  Abstract

  To describe bone status in children with Alagille syndrome (AGS) and healthy control children adjusted for age, gender and height (HT), and to identify dietary intake and AGS-related factors associated with bone status.Prepubertal children with AGS and healthy controls comparable in age and ethnicity were evaluated. Subjects were > or =4 years of age, prepubertal and had whole body (WB) and/or lumbar spine (LS) dual energy X-ray absorptiometry (DXA) scans of acceptable quality. Anthropometric (weight, HT), diet and AGS-specific data (e.g., coefficient of fat absorption, labs, liver transplantation) were also collected. Bone area (BA), bone mineral content (BMC) and HT were log transformed for best fit. Bone data were analyzed unadjusted, adjusted for gender, age and HT, and as HT-specific z-scores.AGS and control groups were similar in age, pubertal status and ethnicity. Children with AGS were small-for-age, had decreased BA and BMC-for-age, and decreased WB BA and BMC-for-HT z-scores compared to healthy controls. Prevalence of low BMC-for-HT z-scores (< -2) among AGS subjects was 20% for the WB and 39% for the LS. Bone mineralization was positively related to fat absorption but not dietary intake.Children with AGS have deficits in bone size and bone mass relative to body size. Modifiable factors, such as treatment of malabsorption should be explored as an early focus of AGS care to prevent bone fragility.

  View details for Web of Science ID 000226148300014

  View details for PubMedID 15625431

• Whole body BMC in pediatric Crohn disease: Independent effects of altered growth, maturation, and body composition JOURNAL OF BONE AND MINERAL RESEARCH Burnham, J. M., Shults, J., Semeao, E., Foster, B., Zemel, B. S., Stallings, V. A., Leonard, M. B. 2004; 19 (12): 1961-1968

  Abstract

  Whole body BMC was assessed in 104 children and young adults with CD and 233 healthy controls. CD was associated with significant deficits in BMC and lean mass, relative to height. Adjustment for lean mass eliminated the bone deficit in CD. Steroid exposure was associated with short stature but not bone deficits relative to height.Children with Crohn disease (CD) have multiple risk factors for impaired bone accrual. The confounding effects of poor growth and delayed maturation limit the interpretation of prior studies of bone health in CD. The objective of this study was to assess BMC relative to growth, body composition, and maturation in CD compared with controls.Whole body BMC and lean mass were assessed by DXA in 104 CD subjects and 233 healthy controls, 4-26 years of age. Multivariable linear regression models were developed to sequentially adjust for differences in skeletal size, pubertal maturation, and muscle mass. BMC-for-height z scores were derived to determine CD-specific covariates associated with bone deficits.Subjects with CD had significantly lower height z score, body mass index z score, and lean mass relative to height compared with controls (all p < 0.0001). After adjustment for group differences in age, height, and race, the ratio of BMC in CD relative to controls was significantly reduced in males (0.86; 95% CI, 0.83, 0.94) and females (0.91; 95% CI, 0.85, 0.98) with CD. Adjustment for pubertal maturation did not alter the estimate; however, addition of lean mass to the model eliminated the bone deficit. Steroid exposure was associated with short stature but not bone deficits.This study shows the importance of considering differences in body size and composition when interpreting DXA data in children with chronic inflammatory conditions and shows an association between deficits in muscle mass and bone in pediatric CD.

  View details for DOI 10.1359/JBMR.040908

  View details for Web of Science ID 000225341700005

  View details for PubMedID 15537438

• Interactions between growth and body composition in children treated with high-dose chronic glucocorticoids(1-3) AMERICAN JOURNAL OF CLINICAL NUTRITION Foster, B. J., Shults, J., Zemel, B. S., Leonard, M. B. 2004; 80 (5): 1334-1341

  Abstract

  Glucocorticoid therapy retards growth during childhood and is believed to lead to a Cushingoid body habitus. However, despite prolonged, repeated courses of glucocorticoid, children with steroid-sensitive nephrotic syndrome (SSNS) have almost normal adult height. Little information exists on body composition.We sought to assess the effect of glucocorticoids on height and body composition by comparing children with SSNS with concurrent healthy reference children. We hypothesized that chronic glucocorticoid therapy leads to obesity, decreased lean mass, and distorted distributions of fat and lean.We performed a cross-sectional study of 52 subjects with SSNS (4-21 y) and 259 reference subjects. The evaluation included height, weight, and pubertal status. Fat and lean masses were assessed by dual-energy X-ray absorptiometry in all subjects. Lifetime glucocorticoid exposure was recorded for subjects with SSNS. Outcomes were expressed as SD scores (SDS).Forty-one percent of subjects with SSNS were obese [body mass index (BMI) > 95th percentile], but regional fat distribution was normal. Mean total lean mass-for-height was 0.43 SD (95% CI: 0.15, 0.72) higher and mean appendicular lean mass-for-total-lean-mass was lower (-0.39 SD; 95% CI: -0.64, -0.14) in SSNS compared with reference children. The mean height-SDS in SSNS was -0.08 SD (95% CI: -0.37, 0.21) relative to national reference data, but height-SDS was significantly decreased given the degree of obesity. Height-SDS was positively associated with BMI-SDS among subjects with SSNS.Glucocorticoid therapy for SSNS is complicated by obesity and relatively low appendicular lean mass. Overall height-SDS is normal because of a mitigating effect of elevated BMI on glucocorticoid-induced growth retardation.

  View details for Web of Science ID 000225036000032

  View details for PubMedID 15531684

• Racial and center differences in hemodialysis adequacy in children treated at pediatric centers: A North American pediatric renal transplant cooperative study (NAPRTCS) report 36th Annual Meeting of the American-Society-of-Nephrology Leonard, M. B., Stablein, D. M., Ho, M., Jabs, K., Feldman, H. I. AMER SOC NEPHROLOGY. 2004: 2923–32

  Abstract

  This study assessed hemodialysis adequacy in pediatric centers. Monthly adequacy data were requested in NAPRTCS enrollees on hemodialysis for at least 6 mo. Data forms were returned for 147 children from 32 centers. Data are presented for the 138 children (57% boys, 45% black) that were dialyzed 3 times/wk, representing 2282 patient-months of follow-up. Pre- and postdialysis BUN levels were reported in all children. Kt/V values were reported in 76 children; however, sufficient data were obtained to calculate Kt/V in 129 children. On average, 14.9 Kt/V and 15.2 urea reduction ratio (URR) values were calculated per child. Aggregate dialysis dose was defined as adequate if Kt/V was >1.2 in at least 75% of calculated Kt/V measures within a subject. Mean +/- SD age was 11.3 +/- 3.7 yr (median, 12.0 yr). Hemodialysis dose was variable within subjects (median CV%: URR 8.2, Kt/V 16.9). Aggregate dialysis dose was adequate in 70% of subjects. Multivariate logistic regression showed male gender (OR, 0.41; 95% CI, 0.16 to 0.98), black race (OR, 0.28; 95% CI, 0.11 to 0.67), larger body surface area (fourth versus first quartile: OR, 0.22; 95% CI, 0.05 to 0.80), and absence of reported Kt/V at the treating center (OR, 0.26; 95% CI, 0.10 to 0.62) were significant predictors of inadequate dialysis dose. Age, renal diagnosis, and center size were not associated with adequacy. Racial and gender disparities in hemodialysis dose existed among children at specialized academic pediatric centers and a substantial proportion received inadequate hemodialysis.

  View details for DOI 10.1097/01.ASN.0000143475.39388.DE

  View details for Web of Science ID 000224684200018

  View details for PubMedID 15504946

• Measuring nutritional status in children with chronic kidney disease AMERICAN JOURNAL OF CLINICAL NUTRITION Foster, B. J., Leonard, M. B. 2004; 80 (4): 801-814

  Abstract

  Children with chronic kidney disease (CKD) are at risk of protein-energy malnutrition. Existing clinical practice guidelines recognize this and recommend specific methods to assess nutritional status in patients with CKD. This review summarizes the methods for nutritional assessment currently recommended in the United States for children with CKD and details the strengths and limitations of these techniques in the clinical setting. Dietary assessment, serum albumin, height, estimated dry weight, weight/height index, upper arm anthropometry, head circumference, and the protein equivalent of nitrogen appearance are reviewed. We also describe methods for body-composition assessment, such as dual-energy X-ray absorptiometry, bioelectrical impedance analysis (BIA), total body potassium, densitometry, and in vivo neutron activation analysis, pointing out some advantages and disadvantages of each. In CKD, fluid overload is the most important factor leading to misinterpretation of nutritional assessment measures. Abnormalities in the distribution of fat and lean tissue may also compromise the interpretation of some anthropometric measures. In addition, metabolic abnormalities may influence the results obtained by some techniques. Issues specific to evaluating nutritional status in the pediatric population are also discussed, including normalization of nutritional measures to body size and sexual maturity. We stress the importance of expressing body-composition measures relative to height in a population in whom short stature is highly prevalent.

  View details for Web of Science ID 000224073000003

  View details for PubMedID 15447884

• Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome NEW ENGLAND JOURNAL OF MEDICINE Leonard, M. B., Feldman, H. I., Shults, J., Zemel, B. S., Foster, B. J., Stallings, V. A. 2004; 351 (9): 868-875

  Abstract

  Glucocorticoids suppress bone formation, impair growth, and induce obesity. We determined the effects of long-term treatment with glucocorticoids on bone mineral content in children with glucocorticoid-sensitive nephrotic syndrome, a disorder with minimal known independent effects on bone.We performed dual-energy x-ray absorptiometry of the whole body and spine in 60 children and adolescents with the nephrotic syndrome and 195 control subjects. We used linear regression analysis of log-transformed values to compare the bone mineral content in patients with that in controls.Patients had received an average of 23,000 mg of glucocorticoids and were shorter (P=0.008) and had a greater body-mass index (P<0.001) than controls. The bone mineral content of the spine, adjusted for bone area, age, sex, degree of maturation (Tanner stage), and race, did not differ significantly between patients and controls (ratio, 0.99; 95 percent confidence interval, 0.96 to 1.02; P=0.51). After adjustment for the z score for body-mass index, the bone mineral content of the spine was significantly lower in patients than in controls (0.96; 95 percent confidence interval, 0.92 to 0.99; P=0.01). Whole-body bone mineral content, adjusted for height, age, sex, degree of maturation, and race, was significantly higher in patients than in controls (ratio, 1.11; 95 percent confidence interval, 1.05 to 1.18; P<0.001); however, the addition of the z score for body-mass index to the model eliminated the association with the nephrotic syndrome (ratio, 0.99; 95 percent confidence interval, 0.94 to 1.03; P=0.55).Intermittent treatment with high-dose glucocorticoids during growth does not appear to be associated with deficits in the bone mineral content of the spine or whole body relative to age, bone size, sex, and degree of maturation. Glucocorticoid-induced increases in body-mass index were associated with increased whole-body bone mineral content and maintenance of the bone mineral content of the spine.

  View details for Web of Science ID 000223512500008

  View details for PubMedID 15329424

• Obesity during childhood and adolescence augments bone mass and bone dimensions AMERICAN JOURNAL OF CLINICAL NUTRITION Leonard, M. B., Shults, J., Wilson, B. A., Tershakovec, A. M., Zemel, B. S. 2004; 80 (2): 514-523

  Abstract

  Studies of the effect of childhood obesity on bone accrual during growth have yielded conflicting results, largely related to the failure to adequately characterize the confounding effects of growth, maturation, and body composition.The objective of this study was to determine the effect of childhood obesity on skeletal mass and dimensions relative to height, body composition, and maturation in males and females.In 132 nonobese (body mass index < 85th percentile) and 103 obese (body mass index > or = 95th percentile) subjects aged 4-20 y, whole-body and vertebral bone mineral content (BMC) was determined by using dual-energy X-ray absorptiometry, and bone area, areal bone mineral density (BMD), and fat and lean masses were measured. Vertebral volumetric BMD was estimated as BMC/area(1.5).Obesity was associated with greater height-for-age, advanced maturation for age, and greater lean mass for height (all P < 0.001). Sex-specific multivariate regressions with adjustment for maturation showed that obesity was associated with greater vertebral areal BMD for height, greater volumetric BMD, and greater vertebral BMC for bone area (all P < 0.05). After adjustment for maturation and lean mass, obesity was associated with significantly greater whole-body bone area and BMC for age and for height (all P < 0.001).In contrast with the results of prior studies, obesity during childhood and adolescence was associated with increased vertebral bone density and increased whole-body bone dimensions and mass. These differences persisted after adjustment for obesity-related increases in height, maturation, and lean mass. Future studies are needed to determine the effect of these differences on fracture risk.

  View details for Web of Science ID 000222912800039

  View details for PubMedID 15277178

• Quantitative high-resolution magnetic resonance imaging reveals structural implications of renal osteodystrophy on trabecular and cortical bone JOURNAL OF MAGNETIC RESONANCE IMAGING Wehrli, F. W., Leonard, M. B., Saha, P. K., Gomberg, B. R. 2004; 20 (1): 83-89

  Abstract

  To explore the potential role of micro-magnetic resonance imaging (micro-MRI) for quantifying trabecular and cortical bone structural parameters in renal osteodystrophy (ROD), a multifactorial disorder of bone metabolism, traditionally evaluated by bone biopsy.Seventeen hemodialysis patients (average PTH level = 502 +/- 415 microg/liter) were compared with 17 age-, gender-, and body mass index (BMI)-matched control subjects. The average dialysis duration for the patients was 5.5 years (range = 0.96-18.2 years). Three-dimensional (3D) fast large-angle spin-echo (FLASE) MR images of the distal tibia (voxel size = 137 x 137 x 410 microm(3)) were processed to yield bone volume fraction (BV/TV). From a skeletonized representation of the trabecular bone network, the topology of each bone voxel was determined providing surface and curve voxel densities (SURF and CURV) and the topological erosion index (EI). Further, high-resolution two-dimensional (2D) spin-echo images were collected at the tibial midshaft for measurement of cortical bone cross-sectional area (CCA), relative CCA expressed as a percentage of total bone area (RCA), and mean cortical thickness (MCT).The data show both RCA and MCT to be lower in the patients (61.2 vs. 69.1%, P = 0.008, and 4.53 vs. 5.19 mm, P = 0.01). BV/TV and SURF were lower, while EI was increased in the patients, although these differences were not quite significant (P = 0.06-0.09). All of the cortical and trabecular findings are consistent with increased bone fragility.The data suggest that micro-MRI may have potential to characterize the structural implications of metabolic bone disease, potentially providing a noninvasive tool for the evaluation of therapies for ROD.

  View details for DOI 10.1002/jmri.20085

  View details for Web of Science ID 000222411900011

  View details for PubMedID 15221812

• Interpretation of whole body dual energy X-ray absorptiometry measures in children: comparison with peripheral quantitative computed tomography BONE Leonard, M. B., Shults, J., Elliott, D. M., Stallings, V. A., Zemel, B. S. 2004; 34 (6): 1044-1052

  Abstract

  The assessment of bone health in children requires strategies to minimize the confounding effects of bone size on dual energy X-ray absorptiometry (DXA) areal bone mineral density (BMD) results. Cortical bone composes 80% of the total skeletal bone mass. The objective of this study was to develop analytic strategies for the assessment of whole body DXA that describe the biomechanical characteristics of cortical bone across a wide range of body sizes using peripheral quantitative computed tomography (pQCT) measures of cortical geometry, density (mg/mm(3)), and strength as the gold standard. Whole body DXA (Hologic QDR 4500) and pQCT (Stratec XCT-2000) of the tibia diaphysis were completed in 150 healthy children 6-21 years of age. To assess DXA and pQCT measures relative to age, body size, and bone size, gender-specific regression models were used to establish z scores for DXA bone mineral content (BMC) for age, areal BMD for age, bone area for height, bone area for lean mass, BMC for height, BMC for lean mass, and BMC for bone area; and for pQCT, bone cross-sectional area (CSA) for tibia length and bone strength (stress-strain index, SSI) for tibia length. DXA bone area for height and BMC for height were both strongly and positively associated with pQCT CSA for length and with SSI for length (all P < 0.0001), suggesting that decreases in DXA bone area for height or DXA BMC for height represent narrower bones with less resistance to bending. DXA BMC for age (P < 0.01) and areal BMD (P < 0.05) for age were moderately correlated with strength. Neither DXA bone area for lean mass nor BMC for lean mass correlated with pQCT CSA for length or SSI for length. DXA BMC for bone area was weakly associated with pQCT SSI for length, in females only. Therefore, normalizing whole body DXA bone area for height and BMC for height provided the best measures of bone dimensions and strength. DXA BMC normalized for bone area and lean mass were poor indicators of bone strength.

  View details for DOI 10.1016/j.bone.2003.12.003

  View details for Web of Science ID 000222219600015

  View details for PubMedID 15193552

• Osteoporosis in chronic kidney disease AMERICAN JOURNAL OF KIDNEY DISEASES Cunningham, J., Sprague, S. M., Cannata-Andia, J., Coco, M., Cohen-Solal, M., Fitzpatrick, L., Goltzmann, D., Lafage-Proust, M. H., Leonard, M., Ott, S., Rodriguez, M., Stehman-Breen, C., Stern, P., Weisinger, J. 2004; 43 (3): 566-571

  View details for DOI 10.1053/j.ajkd.2003.12.004

  View details for Web of Science ID 000220538800020

  View details for PubMedID 14981616

• Bone disease in pediatric rheumatologic disorders. Current rheumatology reports Burnham, J. M., Leonard, M. B. 2004; 6 (1): 70-78

  Abstract

  Children with rheumatic disorders have multiple risk factors for impaired bone health, including delayed growth and development, malnutrition, decreased weight-bearing activity, inflammation, and glucocorticoid therapy. The impact of rheumatic disease during childhood may be immediate, resulting in fragility fractures, or delayed, because of suboptimal peak bone mass accrual. Recent years have seen increased interest in the effects of pediatric rheumatic disorders on bone mineralization, such as juvenile rheumatoid arthritis, systemic lupus erythematosus, and juvenile dermatomyositis. This review outlines the expected gains in bone size and mass during childhood and adolescence, and summarizes the advantages and disadvantages of available technologies for the assessment of skeletal growth and fragility in children. The varied threats to bone health in pediatric rheumatic disorders are reviewed, with emphasis on recent insights into the molecular mechanisms of inflammation-induced bone resorption. The literature assessing bone deficits and risk factors for impaired bone health in pediatric rheumatic disorders is reviewed, with consideration of the strengths and limitations of prior studies. Finally, future research directions are proposed.

  View details for PubMedID 14713405

• Assessment of bone health in children and adolescents with cancer: Promises and pitfalls of current techniques 7th International Conference on the Long-Term Complications of Treatment of Children and Adolescents for Cancer Leonard, M. B. WILEY-LISS. 2003: 198–207

  Abstract

  During childhood and adolescence, skeletal development is characterized by gender-, face-, and maturation-specific increases in cortical dimensions and trabecular density. Children with cancer have multiple risk factors for impuired bone mineralization, including delayed growth and maturation, sex hormone deficiencies, decreasal physical activity and biomechanical loading of the skeleton, glucocorticoid and other immunosuppressive therapies, growth hormone deficiency, and malnutrition. This review outlines the expected gains in bone dimensions, mineral content and strength during childhood and adolescence. Varied threats to bone health in the child with cancer are summarized, with special attention to potential effects on bone formation and resorption in the growing skeleton. The strengths and limitations of dual energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) techniques in the assessment of the different disease-related effects on bone strength are discussed, and alternative analytic approaches explored.

  View details for DOI 10.1002/mpo.10337

  View details for Web of Science ID 000184414500005

  View details for PubMedID 12868119

• Calcium-free hemodialysis for hypercalcemia of malignancy in a newborn PEDIATRIC NEPHROLOGY Pradhan, M., Leonard, M. B. 2003; 18 (5): 474-476

  Abstract

  Hypercalcemia associated with malignancy is very rare in the newborn period. Severe hypercalcemia causes neurological and cardiological disturbances and can be life threatening. Calcium-free hemodialysis has not been reported for the treatment of malignancy associated hypercalcemia in neonates. We report a 5-day-old infant with severe hypercalcemia (serum calcium 22 mg/dl) secondary to a solid tumor in the pelvis. Aggressive pharmacological treatment with furosemide, pamidronate, and calcitonin failed to reduce the serum calcium adequately. Implementation of calcium-free hemodialysis resulted in a rapid reduction of the serum calcium from 22.6 mg/dl to 11.6 mg/dl. Hemodialysis was well tolerated with no hemodynamic complications. Continuous veno-venous hemodialysis was used to maintain normocalcemia.

  View details for DOI 10.1007/s00467-003-1138-9

  View details for Web of Science ID 000183186600017

  View details for PubMedID 12687453

• Long versus standard initial steroid therapy for children with the nephrotic syndrome - A report from the Southwest Pediatric Nephrology Study Group PEDIATRIC NEPHROLOGY Lande, M. B., Gullion, C., Hogg, R. J., Gauthier, B., Shah, B., Leonard, M. B., Bonilla-Felix, M., Nash, M., Roy, S., Strife, C. F., Arbus, G. 2003; 18 (4): 342-346

  Abstract

  A retrospective cohort study was conducted by the Southwest Pediatric Nephrology Study Group (SPNSG) to address whether a longer initial course of corticosteroids in patients with idiopathic nephrotic syndrome (INS) provides superior protection against relapse without increased adverse effects. In order to be included in the evaluation, patients with INS must have responded to an initial steroid course, either standard or long regimen as defined here, and completed at least 1 year of follow-up. The standard regimen consisted of prednisone 2.0+/-0.3 mg/kg per day or 60+/-10 mg/m(2) per day for 28+/-4 days, followed by alternate-day prednisone for 4-12 weeks. The long regimen consisted of daily prednisone 2.0+/-0.3 mg/kg per day or 60+/-10 mg/m(2) per day for 42+/-6 days, followed by alternate-day prednisone for 6-14 weeks. The primary outcome measure was relapse of NS within 12 months of discontinuing the initial course of prednisone. There were 151 children who met the criteria for the study; 82 received the standard regimen and 69 the long regimen. The two groups did not differ in age, race, blood pressure, serum albumin, or serum cholesterol prior to the initial steroid course. The cumulative prednisone dose was 49% higher in the long regimen group than in the standard regimen group. Relapse within 12 months was reported in 72.5% of patients who received the long regimen versus 84.1% of those who received the standard regimen. The odds ratio for relapse within 12 months was 0.496 (95% confidence interval 0.22, 1.088), long versus standard regimen. This did not reach statistical significance ( chi(2)=3.058, P=0.08). The odds ratio of experiencing at least one side effect was 3.76, long relative to standard regimen ( n=133, P<0.001). Our data suggest that prolongation of the steroid treatment for the initial episode of steroid-sensitive NS may have a beneficial effect, but at the cost of increased side effects. However, definitive conclusions are limited by the retrospective design of the study and the number of patients. This may have caused failure to achieve statistical significance on the basis of a type II error.

  View details for DOI 10.1007/s00467-002-1052-6

  View details for Web of Science ID 000182761800005

  View details for PubMedID 12700959

• A prospective cohort study of incident maintenance dialysis in children: An NAPRTC study KIDNEY INTERNATIONAL Leonard, M. B., Donaldson, L. A., Ho, M., Geary, D. F. 2003; 63 (2): 744-755

  Abstract

  Prior studies of dialysis practices and outcomes have included children with varied duration of end-stage renal disease (ESRD). This study evaluated dialysis characteristics, complications, practices, and outcomes in an incident pediatric cohort.The cohort was limited to 1992 subjects enrolled in the North American Pediatric Renal Transplant Cooperative Study registry, starting hemodialysis (HD) or peritoneal dialysis (PD) between 1992 and 1998, without prior dialysis or transplantation.At dialysis initiation, the median glomerular filtration rate (GFR; Schwartz formula) was 6 to 11 mL/min/1.73 m2, and 90th percentile was 14 to 25 mL/min/1.73 m2. GFR was not associated with age or race. PD was used in 97% of infants, 70 to 80% of children and 59% of adolescents. Blacks were significantly less likely to be started on PD than whites. Twenty percent of patients switched dialysis modality, largely due to infection, inadequate access or family choice. Younger children received HD almost exclusively through percutaneous catheters, while 57% of children more than six years old were dialyzed with fistula or graft after six months on HD. The prevalence of anemia (Hct <33%) still exceeded 40% after six months of dialysis. The median interval to transplantation was 1.4 years, and was significantly greater in non-white, young, and female patients. Mortality rates (deaths/1000 patient-years) varied with age, from 13.6 in infants to 2.2 in adolescents.These data demonstrate considerable variability in patient management across pediatric centers. Prospective studies are needed to determine the optimum adequacy of care among children on dialysis and to identify populations at risk.

  View details for Web of Science ID 000180419300038

  View details for PubMedID 12631143

• Decline in renal function following thoracic organ transplantation in children AMERICAN JOURNAL OF TRANSPLANTATION Pradhan, M., Leonard, M. B., Bridges, N. D., Jabs, K. L. 2002; 2 (7): 652-657

  Abstract

  Heart and/or lung transplantation are life-saving treatments for end-stage cardiopulmonary disease; however, chronic renal failure may develop. The impact of thoracic organ transplant on renal function in infants and children is not well characterized. This retrospective cohort study evaluated renal function following thoracic organ transplantation in 46 children (32 heart, 9 lung, 5 heart-lung; median age 4.1 years) with at least 12 months of follow-up. Glomerular filtration rate (GFR, ml/min/1.73 m2) was estimated by the Schwartz formula throughout and each GFR estimate was converted to per cent normal for age (GFR%). Changes in renal function following transplantation were analyzed using longitudinal mixed-effects linear regression models. GFR% decreased following thoracic organ transplantation (p <0.001). Younger age at transplant was associated with a greater decline in GFR% (p <0.01). The decline in GFR% persisted after adjustment for nutritional status with body mass index or weight-for-length z-scores. The prevalence of renal insufficiency (GFR% <75) increased from 22% at transplant to 55% and 85% at 1 and 5 years post transplant, respectively, while 15% had a GFR% <50 at 5 years post transplantation. Higher tacrolimus trough levels over the first 6 months correlated with a lower GFR% (p <0.01). Renal function declined significantly following thoracic organ transplantation.

  View details for Web of Science ID 000177118200011

  View details for PubMedID 12201367

• Current concepts in pediatric bone disease PEDIATRIC CLINICS OF NORTH AMERICA Leonard, M. B., Zemel, B. S. 2002; 49 (1): 143-?

  Abstract

  It is widely believed that osteoporosis prevention may be best accomplished during childhood and adolescence, when bones are growing rapidly and are most sensitive to environmental influences, such as diet and physical activity. For children with chronic diseases, a variety of factors may influence normal bone mineralization, including altered growth, delayed maturation, inflammation, malabsorption, reduced physical activity, glucocorticoid exposure, and poor dietary intake. In healthy children, maintaining adequate levels of calcium intake, serum vitamin D, and weightbearing physical activity may be sufficient to prevent osteoporosis later in life. Far less is known about effective prevention and treatment of poor bone mineralization in children with chronic illness, such as CF or CD. Osteoporosis prevention and intervention measures during childhood are limited by the paucity of reference data on bone mineralization. Although it is widely recognized that puberty, skeletal maturation, and body size influence BMC and bone density, no reference data for bone mineralization are scaled to these important measures. In children with chronic disease with delayed growth and maturation, the creation of such reference data is of paramount importance. In addition, the dynamic changes that occur during growth and maturation in the structural characteristics of trabecular and cortical bone and the development of the bone-muscle unit may influence current and future fracture risk. Further research is needed to characterize these changes and their use in the assessment of bone health and fracture risk in children. Only then can the impact of treatment strategies be appreciated fully.

  View details for Web of Science ID 000173506600009

  View details for PubMedID 11826803

• Adverse neurologic events associated with rebound hypertension nifedipine in childhood after using short-acting in hypertension PEDIATRIC EMERGENCY CARE Leonard, M. B., Kasner, S. E., Feldman, H. I., Schulman, S. L. 2001; 17 (6): 435-437

  Abstract

  Short-acting nifedipine (SA-NIF) is widely prescribed for acute hypertension (HTN) in children despite reports of ischemic complications in adults. We describe two children with neurologic events caused by rebound hypertension following SA-NIF use.Patient 1 is a 7-year-old with acute nephritis and blood pressure (BP) of 185/130. She received SA-NIF which decreased BP to 114/79. When BP rebounded to 160/103, she developed severe cortical visual impairment. Head CT demonstrated edema and petechial hemorrhages in the watershed region. Patient 2 is a 10-year-old renal transplant recipient who received SA-NIF for a BP of 155/98, which resulted in a prompt decrease to 114/74. Two hours later he developed aphasia and right-sided neglect. His BP increased to 168/88 and he developed partial complex seizures. Brain MRI showed high signal intensity in the watershed areas with early gadolinium enhancement.The temporal association of the neurologic events with the rebound increase in BP suggests a possible role for the SA-NIF, consistent with its pharmacokinetic profile. Although the adult literature has focused on the unpredictable decline in BP after SA-NIF treatment, these cases suggest that rapid increases in BP following the maximal SA-NIF effect may be associated with impaired cerebral autoregulation and encephalopathy in children. These cases underscore the need for frequent blood pressure determinations and therapy to prevent rebound hypertension.

  View details for Web of Science ID 000173001500008

  View details for PubMedID 11753188

• Early risk factors for increased adiposity: a cohort study of African American subjects followed from birth to young adulthood AMERICAN JOURNAL OF CLINICAL NUTRITION Stettler, N., Tershakovec, A. M., Zemel, B. S., Leonard, M. B., Boston, R. C., Katz, S. H., Stallings, V. A. 2000; 72 (2): 378-383

  Abstract

  Obesity is an increasing concern in the United States. Effective prevention of obesity requires the risk factors to be well defined. African Americans have a high risk of obesity.The objective of this study was to identify risk factors, present at birth, for increased adiposity in adulthood in an African American population.In this retrospective analysis of a prospective cohort study, anthropometric and socioeconomic variables were collected at birth. A representative sample of 447 African American subjects was followed up until young adulthood, when skinfold thickness was measured. Associations between the independent variables and increased adiposity (skinfold thickness above the 85th percentile) were explored by using unadjusted and adjusted analyses.Three variables measured at birth were independently associated with adiposity in young adulthood, explaining 12% of the variance. The odds ratios (with 95% CIs) of these variables for increased adiposity were 2.7 (1.2, 6.2) for female sex, 4.0 (1.4, 11. 2) for first-born status, and 1.15 (1.06, 1.25) for each unit increment in maternal prepregnancy body mass index (BMI; in kg/m(2)). After adjustment for these variables, birth weight for gestational age and socioeconomic variables were not associated with adiposity.This cohort study of African American subjects was the first to identify first-born status as an independent risk factor for increased adiposity in adulthood in a US population. The results of the study strengthen previous reports of the effect of female sex and maternal BMI on adulthood obesity. Identification of risk factors early in life may help target prevention toward high-risk children and allow healthy lifestyles to be established before the onset of obesity.

  View details for Web of Science ID 000088565100011

  View details for PubMedID 10919930

• Increased urinary transforming growth factor-beta(1) excretion in children with posterior urethral valves UROLOGY Dell, K. M., Hoffman, B. B., Leonard, M. B., ZIYADEH, F. N., Schulman, S. L. 2000; 56 (2): 311-314

  Abstract

  Patients with posterior urethral valves (PUV) are at significant risk for progression to end-stage renal disease, despite early correction of the obstruction. Experimental models of urinary obstruction demonstrate increased renal expression of the profibrotic inflammatory mediator, transforming growth factor-beta(1) (TGF-beta(1)). Urinary TGF-beta(1) excretion is elevated in certain glomerular diseases, but has not been well studied in patients with obstructive lesions. The objective of this study was to examine urinary TGF-beta(1) excretion in children with PUV.Fourteen patients with PUV, aged 3.2 to 14.5 years, with estimated glomerular filtration rates (GFRs) of 12.8 to 139 mL/min/1.73 m(2) were enrolled. Sixteen normal subjects (9 male, 7 female), aged 4.3 to 20.5 years, served as controls. Total urinary TGF-beta(1) concentration was assayed by enzyme-linked immunoabsorbent assay, and expressed as a ratio to urinary creatinine concentration.Urinary TGF-beta(1) excretion was significantly greater in patients with PUV (range 0 to 0.063, median 0.019 ng/mg urine creatinine) compared with that of healthy controls (range 0 to 0.022, median 0.005 ng/mg urine creatinine) (P <0.01). There was no correlation between urinary TGF-beta(1) excretion and estimated GFR, past urinary diversion surgery, or bladder wall thickening. Among healthy controls, urinary TGF-beta(1) was not correlated with age or gender.Results from this study suggest that TGF-beta(1) may contribute to progressive renal insufficiency in patients with PUV. Further studies are indicated to determine if agents that affect TGF-beta(1) expression, such as angiotensin-converting enzyme inhibitors, can slow the progression of renal disease in PUV.

  View details for Web of Science ID 000088574000026

  View details for PubMedID 10925100

• Variability among pediatric nephrologists in the initial therapy of nephrotic syndrome PEDIATRIC NEPHROLOGY Lande, M. B., Leonard, M. B. 2000; 14 (8-9): 766-769

  Abstract

  The objective of this study was to describe the practices of North American pediatric nephrologists in treating new-onset steroid-sensitive nephrotic syndrome and impressions regarding the effect of therapy duration on the risk of relapse. A questionnaire was mailed to 130 pediatric nephrologists in the United States and Canada. One hundred and five (81%) replied. Of the respondents, 39% believed a longer steroid regimen results in more-sustained remissions; 19% did not; 18% believed perhaps, but not enough to risk the increased side-effects of the longer steroid regimen; and 24% did not know. Half of the respondents prescribed an 8-week regimen and 21% prescribed a 12-week regimen; however, in 70% of both regimens, respondents appended an additional taper. The remaining respondents either tapered at urinary remission (14%) or used another regimen (15%). Physicians using the 12-week regimen expected 44% of patients to be relapse free at 1 year, compared with 31% of patients of respondents using other regimens (P=0.005). Over the previous 5 years, 38% of respondents changed their approach; of these, 70% lengthened the treatment course. Physician perceptions and strategies did not vary according to years of clinical experience. In conclusion, there is significant variability in practice and perceptions among pediatric nephrologists; however, most have extended therapy beyond the traditional 8-week course.

  View details for PubMedID 10955923

• Discrepancies in pediatric bone mineral density reference data: Potential for misdiagnosis of osteopenia JOURNAL OF PEDIATRICS Leonard, M. B., PROPERT, K. J., Zemel, B. S., Stallings, V. A., Feldman, H. I. 1999; 135 (2): 182-188

  Abstract

  To evaluate published pediatric dual-energy x-ray absorptiometry bone mineral density (BMD) reference data by comparing the diagnostic classification of measured BMD in children at risk for osteopenia as healthy or osteopenic according to reference source.Spine BMD was measured in 95 children, ages 9 to 15 years, at risk for osteopenia because of childhood disease. The BMD results were converted to age-specific z scores for each of the 5 reference data sets, and the z -score distributions were compared.Between 11% and 30% of children were classified as osteopenic (z score < -2.0) depending on the reference data set. The 2 sex-specific reference data sets yielded similar diagnostic classification of boys and girls: 10% of boys and 11% to 16% of girls were osteopenic (P =.4). The 3 sex-nonspecific reference data sets classified 9% to 13% of girls and 24% to 44% of boys as osteopenic; the diagnosis of osteopenia was significantly greater in boys (P <.01).The use of different published reference data for the assessment of children at risk for osteopenia results in inconsistent diagnostic classification of BMD results. These inconsistencies can be partially attributed to sex-nonspecific reference data that result in misclassification of boys as osteopenic.

  View details for Web of Science ID 000081885900011

  View details for PubMedID 10431112

• Evaluation of low density spine software for the assessment of bone mineral density in Children 19th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research Leonard, M. B., Feldman, H. I., Zemel, B. S., Berlin, J. A., Barden, E. M., Stallings, V. A. WILEY-BLACKWELL. 1998: 1687–90

  Abstract

  Pediatric dual-energy X-ray absorptiometry spine scans often cannot be analyzed with standard software due to a failure to identify the bone edges of low density vertebrae. Low density spine (LDS) software improves bone detection compared with standard software. The objective of this study was to compare bone mineral density (BMD) measurements obtained with the standard and LDS software in 27 healthy nonobese, 32 obese, and 41 chronically ill children, ages 2-18 years. Lumbar spine (L1-L4) BMD, measured by standard analysis, ranged from 0.531-1.244 gm/cm2. Reanalysis with the LDS software resulted in a systematic increase (mean +/- SD) in estimated bone area of 17.0+/-5.0%, an increase in bone mineral content of 6.1+/-6.3%, and a mean decrease in BMD of 8.7+/-1.7% (all p < 0.001). This resulted in a mean decrease in BMD Z score of 0.7+/-0.2. Linear regression models, predicting standard BMD from LDS BMD, were fit for the three subject groups (R2 = 0.993-0.995). Small differences in slopes were detected across groups (p = 0.07); LDS BMD predicted higher standard BMD in obese subjects. In conclusion, LDS analysis resulted in a clinically significant decrease in measured BMD. The association between analysis methods was exceptionally high (R2 > 0.99), indicating that LDS BMD accurately predicts standard BMD. Although LDS BMD in obese subjects predicts higher standard BMD results than in nonobese subjects, the small difference is of questionable clinical significance. LDS software is a useful tool for the assessment of BMD in children.

  View details for Web of Science ID 000076526500007

  View details for PubMedID 9797476

• Interaction between tacrolimus and chloramphenicol in a renal transplant recipient TRANSPLANTATION Schulman, S. L., Shaw, L. M., Jabs, K., Leonard, M. B., Brayman, K. L. 1998; 65 (10): 1397-1398

  Abstract

  The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient.An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation.Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicolChloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

  View details for Web of Science ID 000073990700020

  View details for PubMedID 9625026

• Plasma zinc status, growth, and maturation in children with sickle cell disease JOURNAL OF PEDIATRICS Leonard, M. B., Zemel, B. S., Kawchak, D. A., Ohene-Frempong, K., Stallings, V. A. 1998; 132 (3): 467-471

  Abstract

  The objective of this study was to determine the relation of plasma zinc (Zn) status to growth and maturation in children with SS genotype sickle cell disease.A cross-sectional study of 104 subjects who were 50% female and ranged in age from 0.4 to 18 years was performed. Measures included plasma Zn concentration (Znp), height, weight, skinfold thicknesses, elbow breadth, upper arm muscle area, and fat-free mass and fat mass by total body electrical conductivity. Skeletal maturation was assessed by hand-wrist x-ray evaluation and sexual maturation by Tanner stage.A total of 44% of the patients had low Znp (<10.7 micromol/L [70 microg/dl]); those with low Znp had significantly lower SD scores for height (p = 0.003), weight (p = 0.003), upper arm muscle area (p = 0.045), fat-free mass (p = 0.025), and elbow breadth (p = 0.017) and greater skeletal maturation delay (p = 0.04). In older children (>9 years) low Znp was associated with decreased Tanner scores for pubic hair (p = 0.001) and breast and genital maturation (p = 0.009). No significant differences were seen in age, sex, or fat stores according to Zn status.Decreased plasma Zn is common in children with SS genotype sickle cell disease and is associated with decreased linear growth, skeletal growth, muscle mass, and sexual and skeletal maturation.

  View details for Web of Science ID 000072877800022

  View details for PubMedID 9544903

• CONTINUOUS PARENTERAL INFUSION OF VITAMIN-E PHARMACOKINETICS AND BILIRUBIN PRODUCTION IN PREMATURE NEONATES ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Stevenson, D. K., Vreman, H. J., Ferguson, J. E., Lenert, L. A., Leonard, M. B., Gale, R. 1989; 570: 352-357

  Abstract

  We conclude that 5 mg/kg of vitamin E, administered intra-arterially as an 8-hour continuous infusion, significantly and predictably raises serum vitamin E levels into the supraphysiologic range with no apparent side effects. In a group of premature infants whose initial serum vitamin E levels were generally greater than or equal to 0.5 mg/dL, no decrease in bilirubin production was observed. Thus, vitamin E deficiency probably does not play a prominent role in jaundice of prematurity.

  View details for Web of Science ID A1989CV07100032

  View details for PubMedID 2629604

• VANCOMYCIN PHARMACOKINETICS IN VERY LOW BIRTH-WEIGHT NEONATES PEDIATRIC INFECTIOUS DISEASE JOURNAL Leonard, M. B., Koren, G., Stevenson, D. K., Prober, C. G. 1989; 8 (5): 282-286

  Abstract

  The pharmacokinetics of vancomycin hydrochloride was studied in 12 very low birth weight infants. The gestational age (mean +/- SD) was 25.9 +/- 1.3 weeks and body weight was 769.2 +/- 151.5 g at the time of initiation of the study. Vancomycin was infused over a period of 60 minutes in a dosage of 14.2 +/- 3.2 mg/kg once daily in 10 patients, twice daily in 1 patient and every 36 hours in 1 patient for a mean of 10.5 +/- 4.9 days. Serial blood samples were obtained and the concentration time data were fitted to a one-compartment open model using the ADAPT computer program. A significant positive correlation was found between postconceptional age and vancomycin clearance (P less than 0.005) and between vancomycin elimination half-life and plasma creatinine (P less than 0.01). A negative correlation existed between plasma creatinine and vancomycin clearance (P less than 0.005), between postconceptional age and plasma creatinine (P less than 0.005) and between vancomycin half-life and postconceptional age (P less than 0.01). On the basis of these findings a vancomycin dosage of 15 mg/kg every 24 hours for infants less than 1000 g should yield concentrations within the accepted therapeutic range. This susceptible population requires frequent monitoring of vancomycin concentrations because of the high degree of interpatient variability and the continuous maturation of renal function.

  View details for Web of Science ID A1989U613900006

  View details for PubMedID 2657617

• INTERPRETING THE CARBOXYHEMOGLOBIN CONCENTRATION IN FETAL CORD BLOOD JOURNAL OF DEVELOPMENTAL PHYSIOLOGY Leonard, M. B., Vreman, H. J., Ferguson, J. E., Smith, D. W., Stevenson, D. K. 1989; 11 (2): 73-76

  Abstract

  We calculated the fetal-to-maternal carboxyhaemoglobin concentration ratio in 19 mother-infant pairs at the time of term delivery. Mothers, who had a less than 10% drop in their carboxyhaemoglobin concentration during labour, had an average ratio of 1.40 +/- 0.19. For mothers whose carboxyhaemoglobin concentrations dropped by 10% or more during labour, the average fetal-to-maternal carboxyhaemoglobin concentration ratio was 1.83 +/- 0.48. There was a strong correlation (r = 0.82) between the percent change in maternal carboxyhaemoglobin concentration during labour and the fetal-to-maternal carboxyhaemoglobin concentration ratio at the time of delivery. We conclude that increased CO elimination during labour may be accompanied by rapid changes in the maternal carboxyhaemoglobin concentration, leading to a spuriously high fetal-to-maternal carboxyhemoglobin concentration ratio at the time of delivery.

  View details for Web of Science ID A1989AJ93800003

  View details for PubMedID 2778293

• CONTINUOUS PARENTERAL INFUSION OF VITAMIN-E PHARMACOKINETICS AND BILIRUBIN PRODUCTION IN PREMATURE NEONATES CONF ON VITAMIN E : BIOCHEMISTRY AND HEALTH IMPLICATIONS Stevenson, D. K., Vreman, H. J., Ferguson, J. E., Lenert, L. A., Leonard, M. B., Gale, R. NEW YORK ACAD SCIENCES. 1989: 352–357

  View details for Web of Science ID A1989BQ32R00032

• THE FETAL TO MATERNAL CARBOXYHEMOGLOBIN (HBCO) RATIO AS A PREDICTOR OF NEONATAL JAUNDICE Leonard, M. B., Vreman, H. J., Ferguson, J. E., Stevenson, D. K. SLACK INC. 1987: A235–A235

  View details for Web of Science ID A1987F528501362