Jane C. Tan

All Publications

• Validation of a Core Patient-Reported Outcome Measure for Life Participation in Kidney Transplant Recipients: the SONG Life Participation Instrument. Kidney international reports Jaure, A., Vastani, R. T., Teixeira-Pinto, A., Ju, A., Craig, J. C., Viecelli, A. K., Scholes-Robertson, N., Josephson, M. A., Ahn, C., Butt, Z., Caskey, F. J., Dobbels, F., Fowler, K., Jowsey-Gregoire, S., Jha, V., Tan, J. C., Sautenet, B., Howell, M. 2024; 9 (1): 87-95

  Abstract

  Life participation has been established as a critically important core for trials in kidney transplantation. We aimed to validate a patient-reported outcome measure for life participation in kidney transplant recipients.A psychometric evaluation of the Standardized Outcomes in Nephrology life participation (SONG-LP) measure was conducted in adult kidney transplant recipients. The measure includes 4 items of life participation (leisure, family, work, and social) each with a 5-point Likert scale. Each item is scored from 0 (never) to 4 (always) and the summary measure score the average of each item.A total of 249 adult kidney transplant recipients from 20 countries participated. The SONG-LP instrument demonstrated internal consistency (Cronbach's α = 0.87; 95% confidence intervals [CI]: 0.83-0.90, baseline) and test-retest reliability over 1 week (intraclass correlation coefficient of 0.62; 95% CI: 0.54-0.70). There was moderate to high correlation (0.65; 95% CI: 0.57-0.72) with the PROMIS Ability to Participate in Social Roles and Activities Short Form 8a that assessed a similar construct, and moderate correlation with measures that assessed related concepts (i.e., EQ5D 0.57; 95% CI: 0.49-0.65), PROMIS Cognitive Functional Abilities Subset Short Form 4a (0.40; 95% CI: 0.29-0.50).The SONG-LP instrument is a simple, internally consistent, reliable measure for kidney transplant recipients and correlates with similar measures. Routine incorporation in clinical trials will ensure consistent and appropriate assessment of life participation for informed patient-centered decision-making.

  View details for DOI 10.1016/j.ekir.2023.10.018

  View details for PubMedID 38312789

  View details for PubMedCentralID PMC10831350

• Estimating Life Years from Transplant in Older Candidates Stedman, M., Ahearn, P., Liu, C. K., Chertow, G. M., Tan, J. C. ELSEVIER SCIENCE INC. 2023: S681

  View details for Web of Science ID 001087126902166

• Deceased Donor Kidney Transplantation for Older Transplant Candidates: A New Microsimulation Model for Determining Risks and Benefits. Medical decision making : an international journal of the Society for Medical Decision Making Kaufmann, M. B., Tan, J. C., Chertow, G. M., Goldhaber-Fiebert, J. D. 2023: 272989X231172169

  Abstract

  Under the current US kidney allocation system, older candidates receive a disproportionately small share of deceased donor kidneys despite a reserve of potentially usable kidneys that could shorten their wait times. To consider potential health gains from increasing access to kidneys for these candidates, we developed and calibrated a microsimulation model of the transplantation process and long-term outcomes for older deceased donor kidney transplant candidates.We estimated risk equations for transplant outcomes using the Scientific Registry of Transplant Recipients (SRTR), which contains data on all US transplants (2010-2019). A microsimulation model combined these equations to account for competing events. We calibrated the model to key transplant outcomes and used acceptance sampling, retaining the best-fitting 100 parameter sets. We then examined life expectancy gains from allocating kidneys even of lower quality across patient subgroups defined by age and designated race/ethnicity.The best-fitting 100 parameter sets (among 4,000,000 sampled) enabled our model to closely match key transplant outcomes. The model demonstrated clear survival benefits for those who receive a deceased donor kidney, even a lower quality one, compared with remaining on the waitlist where there is a risk of removal. The expected gain in survival from receiving a lower quality donor kidney was consistent gains across age and race/ethnic subgroups.Limited available data on socioeconomic factors.Our microsimulation model accurately replicates a range of key kidney transplant outcomes among older candidates and demonstrates that older candidates may derive substantial benefits from transplantation with lower quality kidneys. This model can be used to evaluate policies that have been proposed to address concerns that the current system disincentivizes deceased donor transplants for older patients.The microsimulation model was consistent with the data after calibration and accurately simulated the transplantation process for older deceased donor kidney transplant candidates.There are clear survival benefits for older transplant candidates who receive deceased donor kidneys, even lower quality ones, compared with remaining on the waitlist.This model can be used to evaluate policies aimed at increasing transplantation among older candidates.

  View details for DOI 10.1177/0272989X231172169

  View details for PubMedID 37170943

• Association of Pretransplant Coronary Heart Disease Testing With Early Kidney Transplant Outcomes. JAMA internal medicine Cheng, X. S., Liu, S., Han, J., Stedman, M. R., Baiocchi, M., Tan, J. C., Chertow, G. M., Fearon, W. F. 2023

  Abstract

  Importance: Testing for coronary heart disease (CHD) in asymptomatic kidney transplant candidates before transplant is widespread and endorsed by various professional societies, but its association with perioperative outcomes is unclear.Objective: To estimate the association of pretransplant CHD testing with rates of death and myocardial infarction (MI).Design, Setting, and Participants: This retrospective cohort study included all adult, first-time kidney transplant recipients from January 2000 through December 2014 in the US Renal Data System with at least 1 year of Medicare enrollment before and after transplant. An instrumental variable (IV) analysis was used, with the program-level CHD testing rate in the year of the transplant as the IV. Analyses were stratified by study period, as the rate of CHD testing varied over time. A combination of US Renal Data System variables and Medicare claims was used to ascertain exposure, IV, covariates, and outcomes.Exposures: Receipt of nonurgent invasive or noninvasive CHD testing during the 12 months preceding kidney transplant.Main Outcomes and Measures: The primary outcome was a composite of death or acute MI within 30 days of after kidney transplant.Results: The cohort comprised 79 334 adult, first-time kidney transplant recipients (30 147 women [38%]; 25 387 [21%] Black and 48 394 [61%] White individuals; mean [SD] age of 56 [14] years during 2012 to 2014). The primary outcome occurred in 4604 patients (244 [5.3%]; 120 [2.6%] death, 134 [2.9%] acute MI). During the most recent study period (2012-2014), the CHD testing rate was 56% in patients in the most test-intensive transplant programs (fifth IV quintile) and 24% in patients at the least test-intensive transplant program (first IV quintile, P<.001); this pattern was similar across other study periods. In the main IV analysis, compared with no testing, CHD testing was not associated with a change in the rate of primary outcome (rate difference, 1.9%; 95% CI, 0%-3.5%). The results were similar across study periods, except for 2000 to 2003, during which CHD testing was associated with a higher event rate (rate difference, 6.8%; 95% CI, 1.8%-12.0%).Conclusions and Relevance: The results of this cohort study suggest that pretransplant CHD testing was not associated with a reduction in early posttransplant death or acute MI. The study findings potentially challenge the ubiquity of CHD testing before kidney transplant and should be confirmed in interventional studies.

  View details for DOI 10.1001/jamainternmed.2022.6069

  View details for PubMedID 36595271

• Infection, Rejection, and the Connection. Transplantation Higdon, L. E., Tan, J. C., Maltzman, J. S. 2022

  Abstract

  Solid organ transplantation is a life-saving treatment for people with end-stage organ disease. Immune-mediated transplant rejection is a common complication that decreases allograft survival. Although immunosuppression is required to prevent rejection, it also increases the risk of infection. Some infections, such as cytomegalovirus and BK virus, can promote inflammatory gene expression that can further tip the balance toward rejection. BK virus and other infections can induce damage that resembles the clinical pathology of rejection, and this complicates accurate diagnosis. Moreover, T cells specific for viral infection can lead to rejection through heterologous immunity to donor antigen directly mediated by antiviral cells. Thus, viral infections and allograft rejection interact in multiple ways that are important to maintain immunologic homeostasis in solid organ transplant recipients. Better insight into this dynamic interplay will help promote long-term transplant survival.

  View details for DOI 10.1097/TP.0000000000004297

  View details for PubMedID 36017937

• Trends in Coronary Artery Disease Screening before Kidney Transplantation. Kidney360 Cheng, X. S., Liu, S., Han, J., Stedman, M. R., Chertow, G. M., Tan, J. C., Fearon, W. F. 2022; 3 (3): 516-523

  Abstract

  Background: Coronary artery disease (CAD) screening in asymptomatic kidney transplant candidates is widespread but not well supported by contemporary cardiology literature. In this study we describe temporal trends in CAD screening before kidney transplant in the United States.Methods: Using the United States Renal Data System, we examined Medicare-insured adults who received a first kidney transplant from 2000 through 2015. We stratified analysis on the basis of whether the patient's comorbidity burden met guideline definitions of high risk for CAD. We examined temporal trends in nonurgent CAD tests within the year before transplant and the composite of death and nonfatal myocardial infarction in the 30 days after transplant.Results: Of 94,832 kidney transplant recipients, 37,139 (39%) underwent at least one nonurgent CAD test in the 1 year before transplant. From 2000 to 2015, the transplant program waitlist volume had increased as transplant volume stayed constant, whereas patients in the later eras had a slightly higher comorbidity burden (older, longer dialysis vintage, and a higher prevalence of diabetes mellitus and CAD). The likelihood of CAD test in the year before transplant increased from 2000 through 2003 and remained relatively stable thereafter. When stratified by CAD risk status, test rates decreased modestly in patients who were high risk but remained constant in patients who were low risk after 2008. Death or nonfatal myocardial infarction within 30 days after transplant decreased from 3% in 2000 to 2% in 2015. Nuclear perfusion scan was the most frequent modality of testing throughout the examined time periods.Conclusions: CAD testing rates before kidney transplantation have remained constant from 2000 through 2015, despite widespread changes in cardiology guidelines and practice.

  View details for DOI 10.34067/KID.0005282021

  View details for PubMedID 35582172

• Trends in Cost Attributable to Kidney Transplantation Evaluation and Waiting List Management in the United States, 2012-2017. JAMA network open Cheng, X. S., Han, J., Braggs-Gresham, J. L., Held, P. J., Busque, S., Roberts, J. P., Tan, J. C., Scandling, J. D., Chertow, G. M., Dor, A. 2022; 5 (3): e221847

  Abstract

  Importance: While recent policy reforms aim to improve access to kidney transplantation for patients with end-stage kidney disease, the cost implications of kidney waiting list expansion are not well understood. The Organ Acquisition Cost Center (OACC) is the mechanism by which Medicare reimburses kidney transplantation programs, at cost, for costs attributable to kidney transplantation evaluation and waiting list management, but these costs have not been well described to date.Objectives: To describe temporal trends in mean OACC costs per kidney transplantation and to identify factors most associated with cost.Design, Setting, and Participants: This economic evaluation included all kidney transplantation waiting list candidates and recipients in the United States from 2012 to 2017. A population-based study of cost center reports was conducted using data from all Center of Medicare & Medicaid-certified transplantation hospitals. Data analysis was conducted from June to August 2021.Exposures: Year, local price index, transplantation and waiting list volume of transplantation program, and comorbidity burden.Main Outcomes and Measures: Mean OACC costs per kidney transplantation.Results: In 1335 hospital-years from 2012 through 2017, Medicare's share of OACC costs increased from $0.95 billion in 2012 to $1.32 billion in 2017 (3.7% of total Medicare End-Stage Renal Disease program expenditure). Median (IQR) OACC costs per transplantation increased from $81 000 ($66 000 to $103 000) in 2012 to $100 000 ($82 000 to $125 000) in 2017. Kidney organ procurement costs contributed to 36% of mean OACC costs per transplantation throughout the study period. During the study period, transplantation hospitals experienced increases in kidney waiting list volume, kidney waiting list active volume, kidney transplantation volume, and comorbidity burden. For a median-sized transplantation program, mean OACC costs per transplantation decreased with more transplants (-$3500 [95% CI, -$4300 to -$2700] per 10 transplants; P<.001) and increased with year ($4400 [95% CI, $3500 to $5300] per year; P<.001), local price index ($1900 [95% CI, $200 to $3700] per 10-point increase; P=.03), patients listed active on the waiting list ($3100 [95% CI, $1700 to $4600] per 100 patients; P<.001), and patients on the waiting list with high comorbidities ($1500 [9% CI, $600 to $2500] per 1% increase in proportion of waitlisted patients with the highest comorbidity score; P=.002).Conclusions and Relevance: In this study, OACC costs increased at 4% per year from 2012 to 2017 and were not solely attributable to the cost of organ procurement. Expanding the waiting list will likely contribute to further increases in the mean OACC costs per transplantation and substantially increase Medicare liability.

  View details for DOI 10.1001/jamanetworkopen.2022.1847

  View details for PubMedID 35267033

• Racial Disparities in Pediatric Kidney Transplantation under the New Kidney Allocation System in the United States. Clinical journal of the American Society of Nephrology : CJASN Krissberg, J., Kaufmann, M., Gupta, A., Bendavid, E., Stedman, M., Cheng, X., Tan, J., Grimm, P., Chaudhuri, A. 2021

  Abstract

  Background and Objectives: In December 2014, the Kidney Allocation System (KAS) was implemented to improve equity in access to transplantation, but preliminary studies in children show mixed results. Thus, we aimed to assess how the 2014 KAS policy change affected racial/ethnic disparities in pediatric kidney transplantation access and related outcomes. Design, setting, participants, and measurements: A retrospective cohort study of children <18 years of age active on the kidney transplant list from 2008 to 2019 using the Scientific Registry of Transplant Recipients. Log-logistic accelerated failure time models were used to determine time from first activation on the transplant list and time on dialysis to deceased-donor transplant, each with KAS era or race/ethnicity as the exposure of interest. We used logistic regression to assess odds of delayed graft function. Log-rank tests assessed time to graft loss within racial/ethnic groups across KAS eras. Results: All children experienced longer wait times from activation to transplantation post-KAS. In univariable analysis, Black or Hispanic children or other children of color experienced longer times from activation to transplant compared to White children in the both eras; this finding was largely attenuated after multivariable analysis (time ratio 1.16, (95% CI 1.01-1.32); 1.13 (1.00-1.28); 1.17 (0.96-1.41) post-KAS, respectively). Multivariable analysis also showed that racial/ethnic disparities in time from dialysis initiation to transplantation in the pre-KAS era was mitigated in the post-KAS era. There were no disparities in odds of delayed graft function. Black or Hispanic children experienced longer times with a functioning graft in the post-KAS era. Conclusions: No racial/ethnic disparities from activation to deceased donor transplantation were seen before or after implementation of KAS in multivariable analysis, while time on dialysis to transplantation and odds of short-term graft loss improved in equity after KAS, without compromising disparities in delayed graft function.

  View details for DOI 10.2215/CJN.06740521

  View details for PubMedID 34670797

• Functional Consequences of Memory Inflation after Solid Organ Transplantation. Journal of immunology (Baltimore, Md. : 1950) Higdon, L. E., Schaffert, S., Cohen, R. H., Montez-Rath, M. E., Lucia, M., Saligrama, N., Margulies, K. B., Martinez, O. M., Tan, J. C., Davis, M. M., Khatri, P., Maltzman, J. S. 2021

  Abstract

  CMV is a major infectious complication following solid organ transplantation. Reactivation of CMV leads to memory inflation, a process in which CD8 T cells expand over time. Memory inflation is associated with specific changes in T cell function, including increased oligoclonality, decreased cytokine production, and terminal differentiation. To address whether memory inflation during the first year after transplantation in human subjects alters T cell differentiation and function, we employed single-cell-matched TCRalphabeta and targeted gene expression sequencing. Expanded T cell clones exhibited a terminally differentiated, immunosenescent, and polyfunctional phenotype whereas rare clones were less differentiated. Clonal expansion occurring between pre- and 3 mo posttransplant was accompanied by enhancement of polyfunctionality. In contrast, polyfunctionality and differentiation state were largely maintained between 3 and 12 mo posttransplant. Highly expanded clones had a higher degree of polyfunctionality than rare clones. Thus, CMV-responsive CD8 T cells differentiated during the pre- to posttransplant period then maintained their differentiation state and functional capacity despite posttransplant clonal expansion.

  View details for DOI 10.4049/jimmunol.2100405

  View details for PubMedID 34551963

• Karnofsky Performance Score-Failure to Thrive as a Frailty Proxy? Transplantation direct Stedman, M. R., Watford, D. J., Chertow, G. M., Tan, J. C. 2021; 7 (7): e708

  Abstract

  Among patients listed for kidney transplantation, the Karnofsky Performance Status (KPS) Scale has been used as a proxy for frailty and proposed as a predictor of long-term posttransplant outcomes. The KPS is required by the Organ Procurement and Transplantation Network for all transplants; however, the interrater reliability of KPS reporting in kidney transplant candidates has not been well investigated, and there is concern regarding limitations of using KPS that may influence transplant eligibility.Methods: We performed an observational study using existing Scientific Registry of Transplant Recipients data from 2006 to 2020 to examine the variability, reliability, and trends in the KPS among patients on the kidney transplant waitlist.Results: Our analysis included 8197 kidney transplant candidates with >1 KPS in a 3-mo period. We observed 2-7 scores per patient with an average score of 78.9 (SD = 12, 95% confidence interval, 78.8-79.1). We found substantial variability in KPS reporting, in which 27% of the patients had scores that varied widely with 20-80 points in difference. Interrater reliability in the 10-point scale was poor (30%). When using a condensed 4-category scale (disabled, requires assistance, capable of self-care, normal activity), 38% of patients experienced at least a 1-category shift in their score.Conclusions: The lack of reliability in KPS reporting raises concerns when applying the KPS as a proxy for frailty and a metric to be considered when evaluating candidacy for kidney transplantation.

  View details for DOI 10.1097/TXD.0000000000001164

  View details for PubMedID 34124344

• Immunosuppression Considerations for Older Kidney Transplant Recipients. Current transplantation reports Cheungpasitporn, W., Lentine, K. L., Tan, J. C., Kaufmann, M., Caliskan, Y., Bunnapradist, S., Lam, N. N., Schnitzler, M., Axelrod, D. A. 2021; 8 (2): 100-110

  Abstract

  While kidney transplantation improves the long-term survival of the majority of patients with end-stage kidney disease (ESKD), age-related immune dysfunction and associated comorbidities make older transplant recipients more susceptible to complications related to immunosuppression. In this review, we discuss appropriate management of immunosuppressive agents in older adults to minimize adverse events, avoid acute rejection, and maximize patient and graft survival.Physiological changes associated with senescence can impact drug metabolism and increase the risk of posttransplant infection and malignancy. Clinical trials assessing the safety and efficacy of immunosuppressive agents in older adults are lacking. Recent findings from U.S. transplant registry-based studies suggest that risk-adjusted death-censored graft failure is higher among older patients who received antimetabolite avoidance, mammalian target of rapamycin inhibitor (mTORi)-based, and cyclosporine-based regimens. Observational data suggest that risk-adjusted mortality may be increased in older patients who receive mTORi-based and cyclosporine-based regimens but lower in those managed with T-cell induction and maintenance steroid avoidance/withdrawal.Tailored immunosuppression management to improve patient and graft survival in older transplant recipients is an important goal of personalized medicine. Lower intensity immunosuppression, such as steroid-sparing regimens, appear beneficial whereas mTORi- and cyclosporine-based maintenance are associated with greater potential for adverse effects. Prospective clinical trials to assess the safety and efficacy of immunosuppression agents in older recipients are urgently needed.

  View details for DOI 10.1007/s40472-021-00321-6

  View details for PubMedID 34211822

  View details for PubMedCentralID PMC8244945

• Poor Reliability of Karnofsky Performance Score in Kidney Transplant Candidates Stedman, M. R., Watford, D. J., Chertow, G. M., Tan, J. C. WILEY. 2021: 662

  View details for Web of Science ID 000705310102383

• Performance versus Risk Factor-Based Approaches to Coronary Artery Disease Screening in Waitlisted Kidney Transplant Candidates. Cardiorenal medicine Cheng, X. S., Watford, D. J., Arashi, H., Stedman, M. R., Chertow, G. M., Tan, J. C., Fearon, W. F. 2021: 1-11

  Abstract

  INTRODUCTION: Current screening algorithms for coronary artery disease (CAD) before kidney transplantation result in many tests but few interventions.OBJECTIVE: The aim of this study was to study the utility of 6-minute walk test (6MWT), an office-based test of cardiorespiratory fitness, for risk stratification in this setting.METHODS: We enrolled 360 patients who are near the top of the kidney transplant waitlist at our institution. All patients underwent CAD evaluation irrespective of 6MWT results. We examined the association between 6MWT and time to CAD-related events (defined as cardiac death, revascularization, nonfatal myocardial infarction, and removal from the waitlist for CAD), treating noncardiac death and waitlist removal for non-CAD reasons as competing events.RESULTS: The 6MWT-based approach designated approximately 45% of patients as "low risk," whereas a risk factor- or symptom-based approach designated 14 and 81% of patients as "low risk," respectively. The 6MWT-based approach was not significantly associated with CAD-related events within 1 year (subproportional hazard ratio [sHR] 1.00 [0.90-1.11] per 50 m) but was significantly associated with competing events (sHR 0.70 [0.66-0.75] per 50 m). In a companion analysis, removing waitlist status from consideration, 6MWT result was associated with the development of CAD-related events (sHR 0.92 [0.84-1.00] per 50 m).CONCLUSIONS: The 6MWT designates fewer patients as high risk and in need of further testing (compared to risk factor-based approaches), but its utility as a pure CAD risk stratification tool is modulated by the background waitlist removal rate. CAD screening before kidney transplant should be tailored according to a patient's actual chance of receiving a transplant.

  View details for DOI 10.1159/000516158

  View details for PubMedID 34034263

• The Organ Procurement Costs of Expanding Deceased Donor Organ Acceptance Criteria: Evidence from a Cost Function Model. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Cheng, X. S., Held, P. J., Dor, A., Bragg-Gresham, J. L., Tan, J. C., Scandling, J. D., Chertow, G. M., Roberts, J. P. 2021

  Abstract

  A potential solution to the deceased donor organ shortage is to expand donor acceptability criteria. The procurement cost implications of using non-standard donors is unknown. Using five years of United States (US) organ procurement organization (OPO) data, we built a cost function model to make cost projections: the total cost was the dependent variable; production outputs, including the number of donors and organs procured, were the independent variables. In the model, procuring one kidney from a donor (single-organ donor) or procuring both kidneys from double/en bloc transplantation resulted in a marginal cost of $55k (95% confidence interval [CI] $28k-$99k) per kidney, and procuring only the liver from a donor results in a marginal cost of $41k (95% CI $12k-69k) per liver. Procuring two kidneys for two candidates from a donor lowered the marginal cost to $36k (95% CI $22k-$66k) per kidney, and procuring two kidneys and a liver lowers the marginal cost to $24k per organ (95% CI $17k-$45k). Economies of scale were observed, where high OPO volume correlated with lower costs. Despite higher cost per organ than for standard donors, kidney transplantation from non-standard donors remained cost effective based on contemporary US data.

  View details for DOI 10.1111/ajt.16617

  View details for PubMedID 33884757

• Immunosuppression Considerations for Older Kidney Transplant Recipients CURRENT TRANSPLANTATION REPORTS Cheungpasitporn, W., Lentine, K. L., Tan, J. C., Kaufmann, M., Caliskan, Y., Bunnapradist, S., Lam, N. N., Schnitzler, M., Axelrod, D. A. 2021

  View details for DOI 10.1007/s40472-021-00321-6

  View details for Web of Science ID 000645616200001

• Association of physical function and performance with peak VO2 in elderly patients with end stage kidney disease. Aging clinical and experimental research Myers, J., Chan, K. N., Chen, Y., Lit, Y., Massaband, P., Kiratli, B. J., Tan, J. C., Rabkin, R. 2021

  Abstract

  BACKGROUND: Physical function is impaired in end stage renal disease (ESRD). Various instruments have been used to assess the functional capabilities and health status of patients with ESRD, but it is not known which has the best association with peak VO2.AIMS: To assess the association between functional measures in ESRD.METHODS: Thirty nine elderly ESRD patients were evaluated with commonly used functional, health status, and quality of life measures, including maximal cardiopulmonary exercise testing (CPET), 6-min walk (6MWT), sit-to-stand test (STS), Veterans Specific Activity Questionnaire (VSAQ), upper and lower body strength, pulmonary function tests, and body composition determined by dual X-ray absorptiometry. The association between performance on these functional tools, clinical variables, and exercise test responses was assessed, and a non-exercise test multivariate model was developed to predict peak VO2.RESULTS: Peak VO2 was modestly related to VSAQ score (r=0.59, p<0.01), indices of upper and lower body strength (r=0.45, p<0.01 for both), and FEV1 (r=0.51, p<0.01). Functional and quality of life questionnaires were generally poorly related to one another and to peak VO2. In a multivariate model, 6MWT performance, forced expiratory volume in 1s (FEV1), and VSAQ score were the best predictors of peak VO2, yielding a multiple R=0.82, accounting for 67% of the variance in peak VO2.CONCLUSION: Exercise capacity can be reasonably estimated using non-exercise test variables in patients with ESRD, including a symptom questionnaire (VSAQ), 6MWT and FEV1.CLINICAL TRIAL INFORMATION: ClinicalTrials.gov identifier: NCT01990495. Registered Nov 21, 2013.

  View details for DOI 10.1007/s40520-021-01801-6

  View details for PubMedID 33686542

• And Then There Were Three: Effects of Pretransplant Dialysis on Multiorgan Transplantation. Transplantation direct Cheng, X. S., Han, J., Stedman, M. R., Chertow, G. M., Tan, J. C. 2021; 7 (2): e657

  Abstract

  Background: Simultaneous liver-kidney (SLK) and simultaneous heart-kidney (SHK) transplantation currently utilize 6% of deceased donor kidneys in the United States. To what extent residual kidney function accounts for apparent kidney allograft survival is unknown.Methods: We examined all adult SLK and SHK transplants in the United States during 1995-2014. We considered the duration of dialysis preceding SLK or SHK (≥90 d, 1-89 d, or none) as a proxy of residual kidney function. We used multinomial logistic regression to estimate the difference in the adjusted likelihood of 6- and 12-month apparent kidney allograft failure between the no dialysis versus ≥90 days dialysis groups.Results: Of 4875 SLK and 848 SHK recipients, 1775 (36%) SLK and 449 (53%) SHK recipients received no dialysis before transplant. The likelihood of apparent kidney allograft failure was 1%-3% lower at 12 months in SLK and SHK recipients who did not require pretransplant dialysis relative to recipients who required ≥90 days of pretransplant dialysis. Among 3978 SLK recipients who survived to 1 year, no pretransplant dialysis was associated with a lower risk of apparent kidney allograft failure over a median follow-up of 5.7 years (adjusted hazard ratio 0.73 [0.55-0.96]).Conclusions: Patients with residual kidney function at the time of multiorgan transplantation are less likely to have apparent failure of the kidney allograft. Whether residual kidney function facilitates function of the allograft or whether some SLK and SHK recipients have 3 functional kidneys is unknown. Sustained kidney function after SLK and SHK transplants does not necessarily indicate successful MOT.

  View details for DOI 10.1097/TXD.0000000000001112

  View details for PubMedID 33490382

• Sex Disparity in Deceased-Donor Kidney Transplant Access by Cause of Kidney Disease. Clinical journal of the American Society of Nephrology : CJASN Ahearn, P. n., Johansen, K. L., Tan, J. C., McCulloch, C. E., Grimes, B. A., Ku, E. n. 2021

  Abstract

  Women with kidney failure have lower access to kidney transplantation compared with men, but the magnitude of this disparity may not be uniform across all kidney diseases. We hypothesized that the attributed cause of kidney failure may modify the magnitude of the disparities in transplant access by sex.We performed a retrospective cohort study of adults who developed kidney failure between 2005 and 2017 according to the United States Renal Data System. We used adjusted Cox models to examine the association between sex and either access to waitlist registration or deceased-donor kidney transplantation, and tested for interaction between sex and the attributed cause of kidney failure using adjusted models.Among a total of 1,478,037 patients, 271,111 were registered on the waitlist and 89,574 underwent deceased-donor transplantation. The rate of waitlisting was 6.5 per 100 person-years in women and 8.3 per 100 person-years for men. In adjusted analysis, women had lower access to the waitlist (hazard ratio, 0.89; 95% confidence interval, 0.89 to 0.90) and to deceased-donor transplantation after waitlisting (hazard ratio, 0.96; 95% confidence interval, 0.94 to 0.98). However, there was an interaction between sex and attributed cause of kidney disease in adjusted models (P<0.001). Women with kidney failure due to type 2 diabetes had 27% lower access to the kidney transplant waitlist (hazard ratio, 0.73; 95% confidence interval, 0.72 to 0.74) and 11% lower access to deceased-donor transplantation after waitlisting compared with men (hazard ratio, 0.89; 95% confidence interval, 0.86 to 0.92). In contrast, sex disparities in access to either the waitlist or transplantation were not observed in kidney failure secondary to cystic disease.The disparity in transplant access by sex is not consistent across all causes of kidney failure. Lower deceased-donor transplantation rates in women compared with men are especially notable among patients with kidney failure attributed to diabetes.

  View details for DOI 10.2215/CJN.09140620

  View details for PubMedID 33500250

• An overview of frailty in kidney transplantation: measurement, management and future considerations. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Harhay, M. N., Rao, M. K., Woodside, K. J., Johansen, K. L., Lentine, K. L., Tullius, S. G., Parsons, R. F., Alhamad, T., Berger, J., Cheng, X. S., Lappin, J., Lynch, R., Parajuli, S., Tan, J. C., Segev, D. L., Kaplan, B., Kobashigawa, J., Dadhania, D. M., McAdams-DeMarco, M. A. 2020

  Abstract

  The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

  View details for DOI 10.1093/ndt/gfaa016

  View details for PubMedID 32191296

• Physical Performance Testing in Kidney Transplant Candidates at the Top of the Waitlist. American journal of kidney diseases : the official journal of the National Kidney Foundation Cheng, X. S., Myers, J. n., Han, J. n., Stedman, M. R., Watford, D. J., Lee, J. n., Discipulo, K. V., Chan, K. N., Chertow, G. M., Tan, J. C. 2020

  Abstract

  Frailty and poor physical function are associated with adverse kidney transplant outcomes, but how to incorporate this knowledge into clinical practice is uncertain. We studied the association between measured physical performance and clinical outcomes among patients on kidney transplant waitlists.Prospective observational cohort study.We studied consecutive patients evaluated in our Transplant Readiness Assessment Clinic, a top-of-the-waitlist management program, from May 2017 through December 2018 (N=305). We incorporated physical performance testing, including the 6-minute walk test (6MWT) and the sit-to-stand (STS) test, into routine clinical assessments.6MWT and STS test results.Primary - Time to adverse waitlist outcomes (removal from waitlist or death). Secondary - Time to transplantation, time to death.We used linear regression to examine the relationship between clinical characteristics and physical performance test results. We used subdistribution hazards models to examine the association between physical performance test results and outcomes.Median 6MWT and STS results were 393 meters (25th- 75th percentile range 305-455) and 17 repetitions (25th- 75th percentile range 12-21), respectively. Clinical characteristics and Estimated Post-Transplant Survival scores only accounted for 14-21% of the variance in 6MWT/STS results. 6MWT/STS results were associated with adverse waitlist outcomes (adjusted subdistribution hazard ratio [sHR] of 1.42 [95% confidence interval 1.30-1.56 per 50-meter lower in 6MWT and 1.53 [95% confidence interval 1.33-1.75] per 5-repetition lower in STS), and with transplantation (adjusted sHR of 0.80 [95% confidence interval 0.72-0.88] per 50-meter lower in 6MWT and 0.80 [95% confidence interval 0.71-0.89] per 5-repetition lower in STS). Addition of either STS or 6MWT to survival models containing clinical characteristics enhanced fit (likelihood ratio test p<0.001).Single-center observational study. Other measures of global health status (e.g., Fried frailty index or short physical performance battery) were not examined.Among waitlisted kidney transplant candidates with high Kidney Allocation Scores, standardized and easily performed physical performance test results are associated with waitlist outcomes and contain information beyond what is currently routinely collected in clinical practice.

  View details for DOI 10.1053/j.ajkd.2020.04.009

  View details for PubMedID 32512039

• To Kidney or Not to Kidney: Applying Lessons Learned from the Simultaneous Liver-Kidney Transplant Policy to Simultaneous Heart-Kidney Transplantation. Clinical transplantation Cheng, X. S., Khush, K. K., Wiseman, A. n., Teuteberg, J. n., Tan, J. C. 2020

  Abstract

  As the medical community is increasingly offering transplantation to patients with increasing comorbidity burdens, the number of simultaneous heart-kidney (SHK) transplants is rising in the United States. How to determine eligibility for SHK transplant versus heart transplant alone is an important unknown. In this review, we situate this problem in the broader picture of organ shortage. We critically appraise available literature on outcomes in SHK versus heart transplant alone. We posit staged kidney-after-heart transplantation as a plausible alternative to SHK transplantation and review the pros and cons. Drawing lessons from the field of simultaneous liver-kidney transplant, we argue for an analogous policy for SHK transplant with standardized minimal eligibility criteria and a modified Safety Net provision. The new policy will serve as a starting point for comparing simultaneous versus staged approaches and refining the medical eligibility criteria for SHK.

  View details for DOI 10.1111/ctr.13878

  View details for PubMedID 32279361

• Toward telemedicine-compatible physical functioning assessments in kidney transplant candidates. Clinical transplantation Watford, D. J., Cheng, X. S., Han, J. n., Stedman, M. R., Chertow, G. M., Tan, J. C. 2020: e14173

  Abstract

  Frailty is associated with adverse kidney transplant outcomes and can be assessed by subjective and objective metrics. There is increasing recognition of the value of metrics obtainable remotely. We compared the self-reported SF-36 physical functioning subscale score (SF-36 PF) with in-person physical performance tests (6-minute walk and sit-to-stand) in a prospective cohort of kidney transplant candidates. We assessed each metric's ability to predict time to the composite outcome of waitlist removal or death, censoring at transplant. We built time-dependent receiver operating characteristic curves and calculated the area under the curve [AUC(t)] at 1 year, using bootstrapping for internal validation. In 199 patients followed for a median of 346 days, 41 reached the composite endpoint. Lower SF-36 PF scores were associated with higher risk of waitlist removal/death, with every 10-point decrease corresponding to a 16% increase in risk. All models showed an AUC(t) of 0.83-0.84 that did not contract substantially after internal validation. Among kidney transplant candidates, SF-36 PF, obtainable remotely, can help to stratify the risk of waitlist removal or death, and may be used as a screening tool for poor physical functioning in ongoing candidate evaluation, particularly where travel, increasing patient volume, or other restrictions challenge in-person assessment.

  View details for DOI 10.1111/ctr.14173

  View details for PubMedID 33247983

• Impact of Functional Status on Outcomes of Simultaneous Pancreas-kidney Transplantation: Risks and Opportunities for Patient Benefit. Transplantation direct Lentine, K. L., Alhamad, T. n., Cheungpasitporn, W. n., Tan, J. C., Chang, S. H., Cooper, M. n., Dadhania, D. M., Axelrod, D. A., Schnitzler, M. A., Ouseph, R. n., Cabeza Rivera, F. H., Kasiske, B. L., Woodside, K. J., Parsons, R. F. 2020; 6 (9): e599

  Abstract

  The impact of functional status on survival among simultaneous pancreas-kidney transplant (SPKT) candidates and recipients is not well described.We examined national Scientific Registry of Transplant Recipients (SRTR) data for patients listed for SPKT in the United States (2006-2019). Functional status was categorized by center-reported Karnofsky Performance Score (KPS). We used Cox regression to quantify associations of KPS at listing and transplant with subsequent patient survival, adjusted for baseline patient and transplant factors (adjusted hazard ratio, 95% LCLaHR95%UCL). We also explored time-dependent associations of SPKT with survival risk after listing compared with continued waiting in each functional status group.KPS distributions among candidates (N = 16 822) and recipients (N = 10 316), respectively, were normal (KPS 80-100), 62.0% and 57.8%; capable of self-care (KPS 70), 23.5% and 24.7%; requires assistance (KPS 50-60), 12.4% and 14.2%; and disabled (KPS 10-40), 2.1% and 3.3%. There was a graded increase in mortality after listing and after transplant with lower functional levels. Compared with normal functioning, mortality after SPKT rose progressively for patients capable of self-care (aHR, 1.001.181.41), requiring assistance (aHR, 1.061.311.60), and disabled (aHR, 1.101.552.19). In time-dependent regression, compared with waiting, SPKT was associated with 2-fold mortality risk within 30 days of transplant. However, beyond 30 days, SPKT was associated with reduced mortality, from 52% for disabled patients (aHR, 0.260.480.88) to 70% for patients with normal functioning (aHR, 0.260.300.34).While lower functional status is associated with increased mortality risk among SPKT candidates and recipients, SPKT can provide long-term survival benefit across functional status levels in those selected for transplant.

  View details for DOI 10.1097/TXD.0000000000001043

  View details for PubMedID 32903964

  View details for PubMedCentralID PMC7447442

• Coronary Computed Tomography Angiography in Diagnosing Obstructive Coronary Artery Disease in Patients with Advanced Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Cardiorenal medicine Cheng, X. S., Mohanty, S. n., Turner, V. n., Mastrodicasa, D. n., Winther, S. n., Fleischmann, D. n., Tan, J. C., Fearon, W. F. 2020: 1–8

  Abstract

  Coronary computed tomography angiography (CCTA) is emerging as an important noninvasive testing modality for coronary angiography. The performance characteristic of CCTA in patients with advanced kidney disease is unknown.We performed a systematic review and meta-analysis of studies specifically investigating the sensitivity and specificity of CCTA compared to coronary angiogram as a reference standard in patients with advanced kidney disease, defined as dialysis dependence or nearing kidney transplantation. Two independent investigators assessed studies for inclusion/exclusion, quality, and characteristics, while a third investigator adjudicated.We identified 4 studies including a total of 217 patients, of whom 159 were dialysis dependent. Three of the 4 studies had a high risk of bias in patient selection and study flow, while 1 study rated low in all areas of bias. The studies were heterogeneous in their patient selection and CCTA protocol but consistent in their definition of obstructive coronary artery disease. The pooled sensitivity and specificity for CCTA were 0.96 (0.87-0.99) and 0.66 (0.57-0.74), respectively. When we restricted the analysis to dialysis-dependent patients, the pooled sensitivity and specificity for CCTA were 0.99 (0.74-1.00) and 0.67 (0.49-0.82), respectively.Based on limited data, CCTA appears to have comparable sensitivity but lower specificity relative to the non-kidney disease population.

  View details for DOI 10.1159/000510402

  View details for PubMedID 33321489

• Impact of Pretransplant Donor BK Viruria in Kidney Transplant Recipients JOURNAL OF INFECTIOUS DISEASES Tan, S. K., Huang, C., Sahoo, M. K., Weber, J., Kurzer, J., Stedman, M. R., Concepcion, W., Gallo, A. E., Alonso, D., Srinivas, T., Storch, G. A., Subramanian, A. K., Tan, J. C., Pinsky, B. A. 2019; 220 (3): 370–76

  View details for DOI 10.1093/infdis/jiz114

  View details for Web of Science ID 000477595700005

• Patient-reported outcome measures for life participation in kidney transplantation: A systematic review AMERICAN JOURNAL OF TRANSPLANTATION Ju, A., Chow, B., Ralph, A. F., Howell, M., Josephson, M. A., Ahn, C., Butt, Z., Dobbels, F., Fowler, K., Jowsey-Gregoire, S., Jha, V., Locke, J. E., Tan, J. C., Taylor, Q., Rutherford, C., Craig, J. C., Tong, A. 2019; 19 (8): 2306–17

  View details for DOI 10.1111/ajt.15267

  View details for Web of Science ID 000477056500021

• Establishing a Core Outcome Measure for Life Participation: A Standardized Outcomes in Nephrology-kidney Transplantation Consensus Workshop Report TRANSPLANTATION Ju, A., Josephson, M. A., Butt, Z., Jowsey-Gregoire, S., Tan, J., Taylor, Q., Fowler, K., Dobbels, F., Caskey, F., Jha, V., Locke, J., Knoll, G., Ahn, C., Hanson, C. S., Sautenet, B., Manera, K., Craig, J. C., Howell, M., Rutherford, C., Tong, A., SONG-Tx Life Participation Works 2019; 103 (6): 1199–1205

  View details for DOI 10.1097/TP.0000000000002476

  View details for Web of Science ID 000480682800030

• 6-Minute Walk Testing in Patients on the Kidney Transplant Waitlist. Cheng, X. S., Lee, J., Discipulo, K. V., Myers, J., Tan, J. C. WILEY. 2019: 455

  View details for Web of Science ID 000474897601323

• Impact of Pre-Transplant Donor BK Viruria in Kidney Transplant Recipients. The Journal of infectious diseases Tan, S. K., Huang, C., Sahoo, M. K., Weber, J., Kurzer, J., Stedman, M. R., Concepcion, W., Gallo, A. E., Alonso, D., Srinivas, T., Storch, G. A., Subramanian, A. K., Tan, J. C., Pinsky, B. A. 2019

  Abstract

  BACKGROUND: BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients.METHODS: We prospectively collected pre-transplant plasma and urine samples from living and deceased kidney donors and performed BKV PCR and IgG testing on pre-transplant and serially collected post-transplant samples in kidney transplant recipients.RESULTS: Among deceased donors, 8.1%(17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4%(6/39) of living donors and 8.5%(4/47) of deceased donors of recipients at our institution (p=0.50). BKV VP1 sequencing revealed identical virus between donor-recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6%vs.7.8%, p<0.001) and viremia (66.6%vs.8.9%, p<0.001) with a shorter time to onset (log-rank, p<0.001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pre-transplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (p=0.31,0.75,0.51,respectively).DISCUSSION: Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at-risk for BKV complications.

  View details for PubMedID 30869132

• Implications of Frailty for Peritransplant Outcomes in Kidney Transplant Recipients. Current transplantation reports Cheng, X. S., Lentine, K. L., Koraishy, F. M., Myers, J., Tan, J. C. 2019; 6 (1): 16–25

  Abstract

  Purpose of Review: Research over the past few decades points to the importance of frailty, or the lack of physiologic reserve, in the natural history of chronic diseases and in modifying the impact of potential interventions. End-stage kidney disease (ESKD) and the intervention of kidney transplantation are no exception. We review the recent epidemiologic and cohort-based evidence on the association between frailty and kidney transplant outcomes and provide a framework of questions with which to approach future research endeavors and clinical practice.Recent Findings: Frailty in kidney transplant candidates can be measured in numerous ways, including descriptive phenotype, description scores, functional testing, and surrogate measures. Regardless of the metric, the presence of frailty is strongly associated with inferior pre- and posttransplant outcomes compared to the absence of frailty. However, some frail patients with ESKD can benefit from transplant over chronic dialysis. Evidence-based approaches for identifying frail ESKD patients who can benefit from transplant over dialysis, with acceptable posttransplant outcomes, are lacking. Interventional trials to improve frailty and physical function before transplant (prehabilitation) and after transplant (rehabilitation) are also lacking.Conclusion: Frailty is increasingly recognized as highly relevant to peritransplant outcomes, but more work is needed to: 1) tailor management to the unique needs of frail patients, both pre- and posttransplant; 2) define phenotypes of frail patients who are expected to benefit from transplant over dialysis; and 3) develop interventions to reverse frailty, both pre- and post-transplant.

  View details for DOI 10.1007/s40472-019-0227-z

  View details for PubMedID 31131186

• Patient-reported outcome measures for life participation in kidney transplantation: A systematic review. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Ju, A., Chow, J., Ralph, A. F., Howell, M., Josephson, M., Ahn, C., Butt, Z., Dobbels, F., Fowler, K., Jowsey-Gregoire, S., Jha, V., Locke, J. E., Tan, J. C., Taylor, Q., Rutherford, C., Craig, J. C., Tong, A. 2019

  Abstract

  For many patients with end-stage kidney disease, transplantation improves survival and quality of life compared to dialysis. However, complications and side-effects in kidney transplant recipients can limit their ability to participate in activities of daily living including work, study and recreational activities. The aim of this study was to identify the characteristics, content and psychometric properties of the outcome measures used to assess life participation in kidney transplant recipients. We searched MEDLINE, Embase, PsycINFO, and CINAHL from inception to July 2018 for all studies that reported life participation in kidney transplant recipients. Two authors identified instruments measuring life participation and reviewed for characteristics. In total, 230 studies were included: 19 (8%) randomized trials, 17 (7%) non-randomized trials and 194 (85%) observational studies. Across these studies, we identified 29 different measures that were used to assess life participation. Twelve (41%) measures specifically assessed aspects of life participation (e.g. disability assessment, daily activities of living), while 17 (59%) assessed other constructs (e.g. quality of life) that included questions on life participation. Validation data to support the use of these measures in kidney transplant recipients were available for only seven measures. A wide range of measures have been used to assess life participation in kidney transplant recipients but validation data supporting the use of these measures in this population are sparse. A content relevant and validated measure to improve the consistency and accuracy of measuring life participation in research may inform strategies for transplant recipients to be better able to engage in their life activities. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30664327

• Perceptions and Practices Regarding Frailty in Kidney Transplantation: Results of A National Survey. Transplantation McAdams-DeMarco, M. A., Rasmussen, S. E., Chu, N. M., Agoons, D. n., Parsons, R. F., Alhamad, T. n., Johansen, K. L., Tullius, S. G., Lynch, R. n., Harhay, M. N., Rao, M. K., Berger, J. n., Cooper, M. n., Tan, J. C., Cheng, X. S., Woodside, K. J., Parajuli, S. n., Lentine, K. L., Kaplan, B. n., Segev, D. L., Kobashigawa, J. A., Dadhania, D. n. 2019

  Abstract

  Given the potential utility of frailty, a clinical phenotype of decreased physiologic reserve and resistance to stressors, to predict post-kidney transplant (KT) outcomes, we sought to understand the perceptions and practices regarding frailty measurement in US KT programs.Surveys were emailed to American Society of Transplantation Kidney/Pancreas Community of Practice members and 202 US transplant programs (11/2017-4/2018). Program characteristics were gleaned from SRTR.The 133 responding programs (response rate=66%) represented 77% of adult KTs and 79% of adult KT candidates in the US. Respondents considered frailty to be a useful concept in evaluating candidacy (99%) and endorsed a need to develop a frailty measurement specific to KT (92%). Frailty measurement was more common during candidacy evaluation (69%) than during KT admission (28%). Of the 202 programs, 38% performed frailty assessments in all candidates while 23% performed assessments only for older candidates. There was heterogeneity in the frailty assessment method; 18 different tools were utilized to measure frailty. The most common tool was a timed walk test (19%); 67% reported performing >1 tool. Among programs that measure frailty, 53% reported being less likely to list frail patients for KT.Among US KT programs, frailty is recognized as a clinically relevant construct and is commonly measured at evaluation. However, there is considerably heterogeneity in the tools used to measure frailty. Efforts to identify optimal measurement of frailty using either an existing or novel tool and subsequent standardization of its measurement and application across KT programs should be considered.

  View details for DOI 10.1097/TP.0000000000002779

  View details for PubMedID 31343576

• Defining a willingness-to-transplant threshold in an era of organ scarcity: Simultaneous liver-kidney transplant as a case example. Transplantation Cheng, X. S., Goldhaber-Fiebert, J. n., Tan, J. C., Chertow, G. M., Kim, W. R., Wall, A. E. 2019

  Abstract

  Organ scarcity continues in solid organ transplantation, such that the availability of organs limits the number of people able to benefit from transplantation. Medical advancements in managing end-stage organ disease have led to an increasing demand for multi-organ transplant, wherein a patient with multi-organ disease receives more than one organ from the same donor. Current allocation schemes give priority to multi-organ recipients over single-organ transplant recipients, which raises ethical questions regarding equity and utility.We use simultaneous liver-kidney (SLK) transplant, a type of multi-organ transplant, as a case study to examine the tension between equity and utility in multi-organ allocation. We adapt the health economics willingness-to-pay threshold to a solid organ transplant setting by coining a new metric: the willingness-to-transplant (WTT) threshold.We demonstrate how the WTT threshold can be used to evaluate different SLK allocation strategies by synthesizing utility and equity perspectives.We submit that this new framework enables us to distill the question of SLK allocation down to: what is the minimum amount of benefit we require from a deceased donor kidney to allocate it for a particular indication? Addressing the above question will prove helpful to devising a rational system of SLK allocation and is applicable to other transplant settings.

  View details for DOI 10.1097/TP.0000000000002788

  View details for PubMedID 31107820

• Establishing a Core Outcome Measure for Life Participation: a Standardized Outcomes in Nephrology - Kidney Transplantation (SONG-Tx) Consensus Workshop Report. Transplantation Ju, A., Josephson, M. A., Butt, Z., Jowsey-Gregoire, S., Tan, J., Taylor, Q., Fowler, K., Dobbels, F., Caskey, F., Jha, V., Locke, J., Knoll, G., Ahn, C., Hanson, C. S., Sautenet, B., Manera, K., Craig, J. C., Howell, M., Rutherford, C., Tong, A., SONG-Tx Life Participation Workshop Investigators* 2018

  Abstract

  BACKGROUND: Kidney transplantation confers substantial survival and quality of life benefits for many patients with end-stage kidney disease compared with dialysis, but complications and side-effects of immunosuppression can impair participation in daily life activities. Life participation is a critically important patient-reported outcome for kidney transplant recipients but is infrequently and inconsistently measured in trials. We convened a consensus workshop on establishing an outcome measure for life participation for use in all trials in kidney transplantation.METHODS: Twenty-five (43%) kidney transplant recipients/caregivers and 33 (57%) health professionals from 8 countries participated in 6 facilitated breakout group discussions. Transcripts were analyzed thematically.RESULTS: Four themes were identified. Returning to normality conveyed the patients' goals to fulfill their roles (ie, in their family, work, and community) and reestablish a normal lifestyle after transplant. Recognizing the diverse meaning and activities of 'life' explicitly acknowledged life participation as a subjective concept that could refer to different activities (eg, employment, recreation, family duties) for each individual patient. Capturing vulnerability and fluctuations posttransplant (eg, due to complications and side-effects) distinguished between experiences in the first year posttransplant and the long-term impact of transplantation. Having a scientifically rigorous, feasible and meaningful measure was expected to enable consistent and frequent assessment of life participation in trials in kidney transplantation.CONCLUSIONS: A feasible and validated core outcome measure for life participation is needed so that this critically important patient-reported outcome can be consistently and meaningfully assessed in trials in kidney transplantation to inform decision-making and care of recipients.

  View details for PubMedID 30300284

• Longitudinal Changes in Kidney Function Following Heart Transplantation: Stanford Experience. Clinical transplantation Taiwo, A., Khush, K., Stedman, M. R., Zheng, Y., Tan, J. C. 2018: e13414

  Abstract

  Many heart transplant recipients experience declining kidney function following transplantation. We aimed toquantify change in kidney function in heart transplant recipients stratified by pre-transplant kidney function. 230 adult heart transplant recipients between May 1, 2008 and December 31, 2014 were evaluated for up to 5 years post-transplant (median 1 year). Using 19,398 total eGFR assessments, we evaluated trends in estimated glomerular filtration rate (eGFR) in recipients with normal/near normal (eGFR >45 mL/min/1.73m2 ) versus impaired (eGFR <45 mL/min/1.73m2 ) kidney function and the likelihood of reaching an eGFR of 20 mL/min/1.73m2 after heart transplant. Baseline characteristics were similar. Immediately following heart transplant, the impaired pre-transplant kidney function group showed a mean eGFR gain of 9.5mL/min/1.73m2 (n=193) versus a mean decline of 4.9 mL/min/1.73m2 (n=37) in the normal/near normal group. Subsequent rates of eGFR decline were 2.2 mL/min/1.73m2 /yrversus2.9 mL/min/1.73m2 /yr, respectively. The probability of reaching an eGFR of 20 mL/min/1.73m2 or less at 1, 5, and 10 years following heart transplant was 1%, 4% and 30% in the impaired group, and <1%, <1%, and 10% in the normal/near normal group. Estimates of expected recovery in kidney function and its decline over time will help inform decision making about kidney care after heart transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13414

  View details for PubMedID 30240515

• A New Approach to Kidney Waitlist Management in the Kidney Allocation System Era: Pilot Implementation and Evaluation. Clinical transplantation Cheng, X. S., Busque, S., Lee, J., Discipulo, K., Hartley, C., Tulu, Z., Scandling, J. D., Tan, J. C. 2018: e13406

  Abstract

  Kidney transplant waitlist management is becoming increasingly complex. We introduced a novel waitlist management strategy at our center, the Transplant Readiness Assessment Clinic (TRAC), whereby patients whose Kidney Allocation Scores surpass a threshold are actively managed. From January 1, 2016 through June 30, 2017, we evaluated 195 patients through TRAC. Compared to pre-TRAC systems at our institution, TRAC resulted in a higher proportion of activation at 18-months (38% versus 22-26%, p<0.0001), despite being enriched in patients with long dialysis duration. TRAC also resulted in a higher proportion of waitlist removal (15% versus 8-9%, p<0.05) although combined waitlist removal and death on waitlist did not differ (18% versus 16-17%). Median time-to-activation was 356 days from TRAC evaluation. Of the transplant barriers, need for cardiovascular studies was the most common (31%), followed by other medical issues (23%), poor functional status (13%), and psychosocial issues (10%). By concentrating center resources on patients most likely to be transplanted after activation and performing active patient management close to the time of transplant, TRAC has the potential to significantly enhance kidney transplant success in regions with long wait-times. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30218580

• Native Kidney Cytomegalovirus Nephritis and Cytomegalovirus Prostatitis in a Kidney Transplant Recipient. Transplant infectious disease : an official journal of the Transplantation Society Tan, S. K., Cheng, X. S., Kao, C., Weber, J., Pinsky, B. A., Gill, H. S., Busque, S., Subramanian, A. K., Tan, J. C. 2018: e12998

  Abstract

  We present a case of cytomegalovirus (CMV) native kidney nephritis and prostatitis in a CMV D+/R- kidney transplant recipient who had completed six months of CMV prophylaxis four weeks prior to the diagnosis of genitourinary CMV disease. The patient had a history of benign prostatic hypertrophy and urinary retention that required self-catheterization to relieve high post-voiding residual volumes. At 7 months post-transplant, he was found to have a urinary tract infection, moderate hydronephrosis of the transplanted kidney, and severe hydroureteronephrosis of the native left kidney and ureter, and underwent native left nephrectomy and transurethral resection of the prostate. Histopathologic examination of kidney and prostate tissue revealed CMV inclusions consistent with invasive CMV disease. This case highlights that CMV may extend beyond the kidney allograft to involve other parts of the genitourinary tract, including the native kidneys and prostate. Furthermore, we highlight the tissue-specific risk factors that preceded CMV tissue invasion. In addition to concurrent diagnoses, health care providers should have a low threshold for considering late-onset CMV disease in high-risk solid organ transplant recipients presenting with signs and symptoms of genitourinary tract pathology. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30203504

• ESTABLISHING A CORE OUTCOME MEASURE FOR LIFE PARTICIPATION: A STANDARDISED OUTCOMES IN NEPHROLOGY - KIDNEY TRANSPLANTATION (SONG-TX) CONSENSUS WORKSHOP REPORT Ju, A., Josephson, M., Jowsey-Gregoire, S., Tan, J., Taylor, Q., Fowler, K., Dobbels, F., Caskey, F., Jha, V., Locke, J., Knoll, G., Ahn, C., Hanson, C., Manera, K., Sautenet, B., Craig, J., Tong, A. WILEY. 2018: 52–53

  View details for Web of Science ID 000443138700154

• Underutilization of Hepatitis C Virus Seropositive Donor Kidneys in the United States in the Current Opioid Epidemic and Direct-Acting Antiviral Era. Diseases (Basel, Switzerland) Li, A. A., Cholankeril, G., Cheng, X. S., Tan, J. C., Kim, D., Toll, A. E., Nair, S., Ahmed, A. 2018; 6 (3)

  Abstract

  In recent years, the opioid epidemic and new hepatitis C virus (HCV) treatments have changed the landscape of organ procurement and allocation. We studied national trends in solid organ transplantation (2000⁻2016), focusing on graft utilization from HCV seropositive deceased donors in the pre-2014 (2000⁻2013) versus current (2014⁻2016) eras with a retrospective analysis of the United Network for Organ Sharing database. During the study period, HCV seropositive donors increased from 181 to 661 donors/year. The rate of HCV seropositive donor transplants doubled from 2014 to 2016. Heart and lung transplantation data were too few to analyze. A higher number of HCV seropositive livers were transplanted into HCV seropositive recipients during the current era: 374 versus 124 liver transplants/year. Utilization rates for liver transplantation reached parity between HCV seropositive and non-HCV donors. While the number of HCV seropositive kidneys transplanted to HCV seropositive recipients increased from 165.4 to 334.7 kidneys/year from the pre-2014 era to the current era, utilization rates for kidneys remained lower in HCV seropositive than in non-HCV donors. In conclusion, relative underutilization of kidneys from HCV seropositive versus non-HCV donors has persisted, in contrast to trends in liver transplantation.

  View details for PubMedID 29996536

• Establishing a Core Outcome Measure for Life Participation: A Standardized Outcomes in Nephrology - Kidney Transplantation (SONG-Tx) Consensus Workshop Report. Ju, A., Josephson, M. A., Jowsey-Gregoire, S., Tan, J., Taylor, Q., Flower, K., Dobbels, F., Caskey, F., Jha, V., Locke, J., Knoll, G., Ahn, C., Hanson, C. S., Manera, K., Sautenet, B., Craig, J. C., Tong, A. LIPPINCOTT WILLIAMS & WILKINS. 2018: S562

  View details for Web of Science ID 000444541201148

• Antiviral Therapy for Donor-Derived Hepatitis C Virus Infection after Solid Organ Transplantation. Kwong, A., Wall, A., Melcher, M., Wang, U., Ahmed, A., Khush, K., Subramanian, A., Tan, J., Kwo, P. WILEY. 2018: 464

  View details for Web of Science ID 000431965401570

• Comparing Simultaneous Liver-Kidney Transplant Strategies: A Modified Cost-Effectiveness Analysis. Transplantation Cheng, X. S., Kim, W. R., Tan, J. C., Chertow, G. M., Goldhaber-Fiebert, J. 2018

  Abstract

  BACKGROUND: The proportion of patients with kidney failure at time of liver transplantation is at an historic high in the United States. The optimal timing of kidney transplantation with respect to the liver transplant is unknown.METHODS: We used a modified cost-effectiveness analysis to compare four strategies: the old system ("pre-OPTN"), the new Organ Procurement Transplant Network (OPTN) system since August 10, 2017 ("OPTN"), and two strategies which restrict simultaneous liver-kidney transplants ("safety net" and "stringent"). We measured "cost" by deployment of deceased donor kidneys (DDKs) to liver transplant recipients and effectiveness by life years (LYs) and quality-adjusted life years (QALYs) in liver transplant recipients. We validated our model against Scientific Registry for Transplant Recipients data.RESULTS: The OPTN, safety net and stringent strategies were on the efficient frontier. By rank order, OPTN > safety net > stringent strategy in terms of LY, QALY and DDK deployment. The pre-OPTN system was dominated, or outperformed, by all alternative strategies. The incremental LY per DDK between the strategies ranged from 1.30 to 1.85. The incremental QALY per DDK ranged from 1.11 to 2.03.CONCLUSION: These estimates quantify the "organ"-effectiveness of various kidney allocation strategies for liver transplant candidates. The OPTN system will likely deliver better liver transplant outcomes at the expense of more frequent deployment of DDKs to liver transplant recipients.

  View details for PubMedID 29554056

• Prehabilitation for Kidney Transplant Candidates: Is it Time? Clinical transplantation Cheng, X. S., Myers, J. N., Chertow, G. M., Rabkin, R., Chan, K. N., Chen, Y., Tan, J. C. 2017

  Abstract

  Many patients become frail with diminished cardiorespiratory fitness while awaiting kidney transplantation. Frailty and poor fitness powerfully predict mortality, transplant graft survival, and health care utilization after kidney transplantation. Efforts to intervene with post-transplant physical therapy have been met with limited success, in large part due to high study drop-out. We reviewed the literature on chronic kidney disease and exercise to propose a clinical framework for physical therapy interventions to improve fitness, scheduled for before the transplant. This framework may lead to better patient retention and compliance, and thus demonstrate better efficacy in mitigating the effects of frailty and poor fitness after kidney transplantation. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.13020

  View details for PubMedID 28564126

• Utility in Treating Kidney Failure in End-Stage Liver Disease With Simultaneous Liver-Kidney Transplantation TRANSPLANTATION Cheng, X. S., Stedman, M. R., Chertow, G. M., Kim, W. R., Tan, J. C. 2017; 101 (5): 1111-1119

  Abstract

  Simultaneous liver-kidney (SLK) transplantation plays an important role in treating kidney failure in patients with end-stage liver disease. It used 5% of deceased donor kidney transplanted in 2015. We evaluated the utility, defined as posttransplant kidney allograft lifespan, of this practice.Using data from the Scientific Registry of Transplant Recipients, we compared outcomes for all SLK transplants between January 1, 1995, and December 3, 2014, to their donor-matched kidney used in kidney-alone (Ki) or simultaneous pancreas kidney (SPK) transplants. Primary outcome was kidney allograft lifespan, defined as the time free from death or allograft failure. Secondary outcomes included death and death-censored allograft failure. We adjusted all analyses for donor, transplant, and recipient factors.The adjusted 10-year mean kidney allograft lifespan was higher in Ki/SPK compared with SLK transplants by 0.99 years in the Model for End-stage Liver Disease era and 1.71 years in the pre-Model for End-stage Liver Disease era. Death was higher in SLK recipients relative to Ki/SPK recipients: 10-year cumulative incidences 0.36 (95% confident interval 0.33-0.38) versus 0.19 (95% confident interval 0.17-0.21).SLK transplantation exemplifies the trade-off between the principles of utility and medical urgency. With each SLK transplantation, about 1 year of allograft lifespan is traded so that sicker patients, that is, SLK transplant recipients, are afforded access to the organ. These data provide a basis against which benefits derived from urgency-based allocation can be measured.

  View details for DOI 10.1097/TP.0000000000001491

  View details for PubMedID 28437790

• Long-term Patient and Graft Survival of Kidney Transplant Recipients with Hepatitis C Virus Infection in the United States. Transplantation Heo, N. Y., Mannalithara, A. n., Kim, D. n., Udompap, P. n., Tan, J. C., Kim, W. R. 2017

  Abstract

  Hepatitis C virus (HCV) infection is common among kidney transplant (KTx) recipients. However, the impact of HCV infection on long-term graft and recipient survival after KTx from the large-scale data remains to be determined.We used the Organ Procurement and Transplantation Network (OPTN) database to identify all adults undergoing KTx in 2004-2006 in the United States. A propensity score (PS) was created to match each HCV-positive recipient with a HCV-negative control for unbiased comparisons. Survival analysis was conducted to evaluate recipient and death-censored graft survival.Out of 33,357 adult primary KTx recipients, 1470 (4.4%) were HCV-positive. 1,364 HCV-positive and -negative pairs were selected based on PS-matching. Based on the multivariable regression models, HCV is associated with a higher risk of death (hazard ratio [HR]=1.50, 95% confidence interval [95% CI=1.28-1.75) and graft failure (HR=1.26, 95% CI=1.08-1.47). Infection was a more common cause of death in HCV-positive patients than in HCV-negative recipients (HR=1.64, 95% CI=1.12-2.42). The incidence of death due to liver failure was 0.23% per year among HCV-positive recipients, whereas no HCV-negative recipients died from liver failure. Graft failure due to recurrent disease was higher in HCV-positive than in HCV-negative recipients (HR=2.00; 95% CI=1.06-3.78).HCV infection is associated with decreased long-term recipient and graft survival. Future studies are needed to examine whether recently available, safe and effective antiviral therapy improves the long-term clinical outcome in these patients.

  View details for PubMedID 28976413

• Donation, Not Disease! A Multiple-Hit Hypothesis on Development of Post-Donation Kidney Disease. Current transplantation reports Cheng, X. S., Glassock, R. J., Lentine, K. L., Chertow, G. M., Tan, J. C. 2017; 4 (4): 320–26

  Abstract

  The risks following living kidney donation has been the subject of rigorous investigation in the past several decades. How to utilize the burgeoning new knowledge base to better the risk assessment, education, and health maintenance of donors is unclear. We review the physiologic and epidemiologic evidences on the post-donation state and submit a multiple-hit hypothesis to reconcile the finite elevation in risk of kidney disease after donation with the benign course of most kidney donors.The risk of end-stage kidney disease is higher in kidney donors compared to similarly healthy non-kidney donors. Nonetheless, post-donation kidney disease is uncommon and arises mostly in the setting of other "hits"-either a "first hit" present at birth or a "second hit" acquired later in life.The transplant community's focus should be directed toward (1) personalized risk assessment to inform consent before donation and (2) preventing and treating development of "second hits" following kidney donation.

  View details for PubMedID 29201600

• Management of Renal Failure in End-Stage Liver Disease: A Critical Appraisal LIVER TRANSPLANTATION Cheng, X. S., Tan, J. C., Kim, W. R. 2016; 22 (12): 1710-1719

  Abstract

  Renal failure is a late consequence of end-stage liver disease (ESLD). Even with liver transplantation, pretransplant renal impairment remains a strong predictor of posttransplant mortality. This review seeks to summarize and critically appraise common therapies used in this setting, including pharmacologic agents, procedures (transjugular intrahepatic portosystemic shunt, renal replacement therapy), and simultaneous liver-kidney transplantation. More experimental extracorporal modalities, eg, albumin dialysis or bioartificial livers, will not be discussed. A brief discussion on the definition and pathophysiologic underpinnings of renal failure in ESLD will be held at the beginning to lay the groundwork for the main section. Liver Transplantation 22 1710-1719 2016 AASLD.

  View details for DOI 10.1002/lt.24609

  View details for Web of Science ID 000389079500011

  View details for PubMedID 27875032

• Glomerular Function and Structure in Living Donors: Lessons from Single Nephron Studies. Current transplantation reports Lenihan, C. R., Myers, B. D., Tan, J. C. 2016; 3: 24-32

  Abstract

  One third of the kidney transplants performed in the USA come from living kidney donors. The long-term outcome of healthy individuals who donate kidneys is mostly excellent, although recent studies have suggested that living donation is associated with a small absolute increase in the risk of end stage renal failure. Much of our understanding about the progression of kidney disease comes from experimental models of nephron loss. For this reason, living kidney donation has long been of great interest to renal physiologists. This review will summarize the determinants of glomerular filtration and the physiology that underlies post-donation hyperfiltration. We describe the 'remnant kidney' model of kidney disease and the reasons why such progressive kidney disease very rarely ensues in healthy humans following uninephrectomy. We also review some of the methods used to determine glomerular number and size and outline their associations.

  View details for PubMedID 27004159

• Living Donor Kidney Transplantation: Facilitating Education about Live Kidney Donation-Recommendations from a Consensus Conference. Clinical journal of the American Society of Nephrology Tan, J. C., Gordon, E. J., Dew, M. A., Lapointe Rudow, D., Steiner, R. W., Woodle, E. S., Hays, R., Rodrigue, J. R., Segev, D. L. 2015; 10 (9): 1670-1677

  Abstract

  The Best Practice in Live Kidney Donation Consensus Conference held in June of 2014 included the Best Practices in Living Donor Education Workgroup, whose charge was to identify best practice strategies in education of living donors, community outreach initiatives, commercial media, solicitation, and state registries. The workgroup's goal was to identify critical content to include in living kidney donor education and best methods to deliver educational content. A detailed summary of considerations regarding educational content issues for potential living kidney donors is presented, including the consensus that was reached. Educational topics that may require updating on the basis of emerging studies on living kidney donor health outcomes are also presented. Enhancing the educational process is important for increasing living donor comprehension to optimize informed decision-making.

  View details for DOI 10.2215/CJN.01030115

  View details for PubMedID 25908792

  View details for PubMedCentralID PMC4559504

• The Association of Predonation Hypertension with Glomerular Function and Number in Older Living Kidney Donors JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lenihan, C. R., Busque, S., Derby, G., Blouch, K., Myers, B. D., Tan, J. C. 2015; 26 (6): 1261-1267

  Abstract

  The effect of preexisting hypertension on living donor nephron number has not been established. In this study, we determined the association between preexisting donor hypertension and glomerular number and volume and assessed the effect of predonation hypertension on postdonation BP, adaptive hyperfiltration, and compensatory glomerular hypertrophy. We enrolled 51 living donors to undergo physiologic, morphometric, and radiologic evaluations before and after kidney donation. To estimate the number of functioning glomeruli (NFG), we divided the whole-kidney ultrafiltration coefficient (Kf) by the single-nephron ultrafiltration coefficient (SNKf). Ten donors were hypertensive before donation. We found that, in donors ages >50 years old, preexisting hypertension was associated with a reduction in NFG. In a comparison of 10 age- and sex-matched hypertensive and normotensive donors, we observed more marked glomerulopenia in hypertensive donors (NFG per kidney, 359,499±128,929 versus 558,239±205,152; P=0.02). Glomerulopenia was associated with a nonsignificant reduction in GFR in the hypertensive group (89±12 versus 95±16 ml/min per 1.73 m(2)). We observed no difference in the corresponding magnitude of postdonation BP, hyperfiltration capacity, or compensatory renocortical hypertrophy between hypertensive and normotensive donors. Nevertheless, we propose that the greater magnitude of glomerulopenia in living kidney donors with preexisting hypertension justifies the need for long-term follow-up studies.

  View details for DOI 10.1681/ASN.2014030304

  View details for Web of Science ID 000355386100007

  View details for PubMedID 25525178

  View details for PubMedCentralID PMC4446872

• Consensus Conference on Best Practices in Live Kidney Donation: Recommendations to Optimize Education, Access, and Care AMERICAN JOURNAL OF TRANSPLANTATION Lapointe Rudow, D., Hays, R., Baliga, P., Cohen, D. J., Cooper, M., Danovitch, G. M., Dew, M. A., Gordon, E. J., Mandelbrot, D. A., McGuire, S., Milton, J., MOORE, D. R., Morgievich, M., Schold, J. D., Segev, D. L., Serur, D., Steiner, R. W., Tan, J. C., Waterman, A. D., Zavala, E. Y., Rodrigue, J. R. 2015; 15 (4): 914-922

  Abstract

  Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation.

  View details for DOI 10.1111/ajt.13173

  View details for Web of Science ID 000351675600011

  View details for PubMedID 25648884

• Longitudinal study of living kidney donor glomerular dynamics after nephrectomy JOURNAL OF CLINICAL INVESTIGATION Lenihan, C. R., Busque, S., Derby, G., Blouch, K., Myers, B. D., Tan, J. C. 2015; 125 (3): 1311-1318

  Abstract

  Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors.We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post- (median, 0.8 years), and late post- (median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects.Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (Kf), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, Kf) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the Kf. The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria.Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation.Not applicable. FUNDING. NIH (R01DK064697 and K23DK087937); Astellas Pharma US; the John M. Sobrato Foundation; the Satellite Extramural Grant Foundation; and the American Society of Nephrology.

  View details for DOI 10.1172/JCI78885

  View details for Web of Science ID 000350616500041

  View details for PubMedID 25689253

• The Consequences of Chronic Kidney Disease Mislabeling in Living Kidney Donors MAYO CLINIC PROCEEDINGS Lenihan, C. R., Tan, J. C. 2014; 89 (8): 1126-1129

  Abstract

  Despite numerous studies that substantiate its long-term safety, barriers to kidney donation persist. These include issues of insurability after donation and its consequent financial and emotional burdens. We present 2 cases in which mislabeling of kidney donors as having chronic kidney disease shortly after kidney donation adversely affected their insurability. A concerted effort should be made to affect public policy such that insurability and the psychosocial well-being of living donors are protected.

  View details for DOI 10.1016/j.mayocp.2014.04.002

  View details for Web of Science ID 000341411200015

  View details for PubMedCentralID PMC5096430

• The consequences of chronic kidney disease mislabeling in living kidney donors. Mayo Clinic proceedings Lenihan, C. R., Tan, J. C. 2014; 89 (8): 1126-9

  Abstract

  Despite numerous studies that substantiate its long-term safety, barriers to kidney donation persist. These include issues of insurability after donation and its consequent financial and emotional burdens. We present 2 cases in which mislabeling of kidney donors as having chronic kidney disease shortly after kidney donation adversely affected their insurability. A concerted effort should be made to affect public policy such that insurability and the psychosocial well-being of living donors are protected.

  View details for DOI 10.1016/j.mayocp.2014.04.002

  View details for PubMedID 24867395

  View details for PubMedCentralID PMC5096430

• A new clinical prediction tool for 5-year kidney transplant outcome. American journal of kidney diseases Lenihan, C. R., Lockridge, J. B., Tan, J. C. 2014; 63 (4): 549-551

  View details for DOI 10.1053/j.ajkd.2014.01.004

  View details for PubMedID 24670483

  View details for PubMedCentralID PMC4088343

• Acute transplant glomerulopathy with monocyte rich infiltrate. Transplant immunology Lenihan, C. R., Tan, J. C., Kambham, N. 2013; 29 (1-4): 114-117

  Abstract

  Acute transplant glomerulopathy refers to alloimmune mediated endothelial injury and glomerular inflammation that typically occurs early post-kidney transplantation. We report a case of a 48-year old woman with end stage renal disease from lupus nephritis who developed an unexplained rise in serum creatinine 2months after renal transplant. As immunosuppression, she received alemtuzumab induction followed by a tacrolimus, mycophenolate mofetil and prednisone maintenance regimen. Her biopsy revealed severe glomerular endothelial injury associated with monocyte/macrophage-rich infiltrate in addition to mild acute tubulointerstitial cellular rejection. We briefly discuss acute transplant glomerulitis, its pathology and association with chronic/overt transplant glomerulopathy, C4d negative antibody-mediated rejection and the significance of monocytes in rejection. We also postulate that alemtuzumab induction may have contributed to the unusual pattern of monocyte-rich transplant glomerulitis.

  View details for DOI 10.1016/j.trim.2013.09.004

  View details for PubMedID 24056179

• Evaluating Deceased Donor Registries: Identifying Predictive Factors of Donor Designation AMERICAN SURGEON Hajhosseini, B., Stewart, B., Tan, J. C., Busque, S., Melcher, M. L. 2013; 79 (3): 235-241

  Abstract

  The objectives of this study were to evaluate and compare the performance of the deceased donor registries of the 50 states and the District of Columbia and to identify possible predictive factors of donor designation. Data were collected retrospectively by Donate Life America using a questionnaire sent to Donor Designation Collaborative state teams between 2007 and 2010. By the end of 2010, there were 94,669,081 designated donors nationwide. This accounted for 39.8 per cent of the U.S. population aged 18 years and over. The number of designated organ donors and registry-authorized recovered donors increased each year; however, the total number of recovered donors in 2010 was the lowest since 2004. Donor designation rate was significantly higher when license applicants were verbally questioned at the Department of Motor Vehicles (DMV) regarding their willingness to register as a donor and when DMV applicants were not given an option on DMV application forms to contribute money to support organ donation, compared with not being questioned verbally, and being offered an option to contribute money. State registries continue to increase the total number of designated organ donors; however, the current availability of organs remains insufficient to meet the demand. These data suggest that DMV applicants who are approached verbally regarding their willingness to register as a donor and not given an option on DMV application forms to contribute money to support organ donation might be more likely to designate themselves to be a donor.

  View details for Web of Science ID 000315606500003

  View details for PubMedID 23461946

• Comorbidities and Kidney Transplant Evaluation in the Elderly AMERICAN JOURNAL OF NEPHROLOGY Lenihan, C. R., Hurley, M. P., Tan, J. C. 2013; 38 (3): 204-211

  Abstract

  The elderly are the fastest growing subpopulation with end-stage renal disease. The goal of our study was to define characteristics of elderly patients who were considered ineligible for transplantation compared to those who were listed.984 patients were referred for evaluation during a 2-year period. Records of patients ≥65 years of age (n = 123) were reviewed. Patients who were listed versus not listed were characterized. Factors associated with waitlisting were determined using standard statistical tools.Half of elderly transplant candidates were accepted for listing compared to 75.4% of those aged <65 years. In multivariable logistic regression, older age (OR 1.29 per year ≥65, 95% CI 1.14-1.45), coronary artery disease (OR 8.57, 95% CI 2.41-30.53), and poor mobility (OR 13.97, 95% CI 4.76-41.00) were independently associated with denial of listing. The receiver operating characteristic curve showed good discrimination for denial of listing (area under the receiver operating characteristic curve of 0.88).Elderly candidates carry a heavy burden of comorbidities and over half of those evaluated are deemed unsuitable for waitlisting. Better delineation of characteristics associated with suitability for transplant candidacy in the elderly is warranted to facilitate appropriate referrals by physicians and management of expectations in potential candidates.

  View details for DOI 10.1159/000354483

  View details for Web of Science ID 000325242000004

  View details for PubMedID 23988670

• Donor Recipient Sex Mismatch in Kidney Transplantation GENDER MEDICINE Tan, J. C., Kim, J. P., Chertow, G. M., Grumet, F. C., Desai, M. 2012; 9 (5): 335-347

  Abstract

  The lack of reliable human proxies for minor (ie, non-HLA) histocompatibility loci hampers the ability to leverage these factors toward improving transplant outcomes. Despite conflicting reports of the effect of donor-recipient sex mismatch on renal allografts, the association between acute rejection of renal allografts and the development of human alloantibodies to the male H-Y antigen suggested to us that donor-recipient sex mismatch deserved re-evaluation.To evaluate whether the relationships between donor sex and allograft failure differed by recipient sex.We studied recipients of deceased-donor (n = 125,369) and living-donor (n = 63,139) transplants in the United States Renal Data System. Using Cox proportional hazards models stratified by donor type, we estimated the association between donor-recipient sex mismatch and death-censored allograft failure with adjustment for known risk factors, with and without the use of multiple imputation methods to account for potential bias and/or loss of efficiency due to missing data.The advantage afforded by male donor kidneys was more pronounced among male than among female recipients (8% vs 2% relative risk reduction; interaction P < 0.01). This difference is of the order of magnitude of several other risk factors affecting donor selection decisions.Donor-recipient sex mismatch affects renal allograft survival in a direction consistent with immune responses to sexually determined minor histocompatibility antigens. Our study provides a paradigm for clinical detection of markers for minor histocompatibility loci.

  View details for DOI 10.1016/j.genm.2012.07.004

  View details for PubMedID 22906727

• Solid-Organ Transplantation in Older Adults: Current Status and Future Research AMERICAN JOURNAL OF TRANSPLANTATION Abecassis, M., Bridges, N. D., Clancy, C. J., Dew, M. A., Eldadah, B., Englesbe, M. J., Flessner, M. F., Frank, J. C., Friedewald, J., Gill, J., Gries, C., Halter, J. B., Hartmann, E. L., Hazzard, W. R., Horne, F. M., Hosenpud, J., Jacobson, P., Kasiske, B. L., Lake, J., Loomba, R., Malani, P. N., Moore, T. M., Murray, A., Nguyen, M., Powe, N. R., Reese, P. P., Reynolds, H., Samaniego, M. D., Schmader, K. E., Segev, D. L., Shah, A. S., Singer, L. G., Sosa, J. A., Stewart, Z. A., Tan, J. C., Williams, W. W., Zaas, D. W., High, K. P. 2012; 12 (10): 2608-2622

  Abstract

  An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

  View details for DOI 10.1111/j.1600-6143.2012.04245.x

  View details for Web of Science ID 000309180000009

  View details for PubMedID 22958872

  View details for PubMedCentralID PMC3459231

• Optimizing renal replacement therapy in older adults: a framework for making individualized decisions KIDNEY INTERNATIONAL Tamura, M. K., Tan, J. C., O'Hare, A. M. 2012; 82 (3): 261-269

  Abstract

  It is often difficult to synthesize information about the risks and benefits of recommended management strategies in older patients with end-stage renal disease since they may have more comorbidity and lower life expectancy than patients described in clinical trials or practice guidelines. In this review, we outline a framework for individualizing end-stage renal disease management decisions in older patients. The framework considers three factors: life expectancy, the risks and benefits of competing treatment strategies, and patient preferences. We illustrate the use of this framework by applying it to three key end-stage renal disease decisions in older patients with varying life expectancy: choice of dialysis modality, choice of vascular access for hemodialysis, and referral for kidney transplantation. In several instances, this approach might provide support for treatment decisions that directly contradict available practice guidelines, illustrating circumstances when strict application of guidelines may be inappropriate for certain patients. By combining quantitative estimates of benefits and harms with qualitative assessments of patient preferences, clinicians may be better able to tailor treatment recommendations to individual older patients, thereby improving the overall quality of end-stage renal disease care.

  View details for DOI 10.1038/ki.2011.384

  View details for Web of Science ID 000306370500005

  View details for PubMedID 22089945

  View details for PubMedCentralID PMC3396777

• Incidental kidney stones: a single center experience with kidney donor selection CLINICAL TRANSPLANTATION Kim, I. K., Tan, J. C., Lapasia, J., Elihu, A., Busque, S., Melcher, M. L. 2012; 26 (4): 558-563

  Abstract

  The presence of kidney stones has been a relative contraindication for living donation. With the widespread use of more sensitive imaging techniques as part of the routine living donor workup, kidney stones are more frequently detected, and their clinical significance in this setting is largely unknown. Records from 325 potential kidney donors who underwent MRA or CT-angiography were reviewed; 294 proceeded to donation. The prevalence of kidney stones found incidentally during donor evaluation was 7.4% (24 of 325). Sixteen donors with stones proceeded with kidney donation. All incidental calculi were nonobstructing and small (median 2 mm; range 1-9 mm). Eleven recipients were transplanted with allografts containing stones. One recipient developed symptomatic nephrolithasis after transplantation. This recipient was found to have newly formed stones secondary to hyperoxaluria, suggesting a recipient-driven propensity for stone formation. The remaining ten recipients have stable graft function, postoperative ultrasound negative for nephrolithiasis, and no sequelae from stones. No donor developed symptomatic nephrolithiasis following donation. Judicious use of allografts with small stones in donors with normal metabolic studies may be acceptable, and careful follow-up in recipients of such allografts is warranted.

  View details for DOI 10.1111/j.1399-0012.2011.01567.x

  View details for PubMedID 22168332

• Multiple renal arteries and non-contrast magnetic resonance angiography in transplant renal artery stenosis. Clinical kidney journal Munoz Mendoza, J., Melcher, M. L., Daniel, B., Tan, J. C. 2012; 5 (3): 272-275

  View details for DOI 10.1093/ckj/sfs027

  View details for PubMedID 26069784

• Validity of Surrogate Measures for Functional Nephron Mass TRANSPLANTATION Tan, J. C., Paik, J., Chertow, G. M., Grumet, F. C., Busque, S., Lapasia, J., Desai, M. 2011; 92 (12): 1335-1341

  Abstract

  Transplanted nephron mass is an important determinant of long-term allograft survival, but accurate assessment before organ retrieval is challenging. Newer radiologic imaging techniques allow for better determination of total kidney and cortical volumes.Using volume measurements reconstructed from magnetic resonance or computed tomography imaging from living donor candidates, we characterized total kidney (n=312) and cortical volumes (n=236) according to sex, age, weight, height, body mass index (BMI), and body surface area (BSA).The mean cortical volume was 204 mL (range 105-355 mL) with no significant differences between left and right cortical volumes. The degree to which existing anthropomorphic surrogates predict nephron mass was quantified, and a diligent attempt was made to derive a better surrogate model for nephron mass. Cortical volumes were strongly associated with sex and BSA, but not with weight, height, or BMI. Four prediction models for cortical volume constructed using combinations of age, sex, race, weight, and height were compared with models including either BSA or BMI.Among existing surrogate measures, BSA was superior to BMI in predicting renal cortical volume. We were able to construct a statistically superior proxy for cortical volume, but whether relevant improvements in predictive accuracy could be gained needs further evaluation in a larger population.

  View details for DOI 10.1097/TP.0b013e31823705ef

  View details for PubMedID 22011765

• Cytomegalovirus in the transplanted kidney: a report of two cases and review of prophylaxis. NDT plus Anand, S., Yabu, J. M., Melcher, M. L., Kambham, N., Laszik, Z., Tan, J. C. 2011; 4 (5): 342-345

  View details for DOI 10.1093/ndtplus/sfr074

  View details for PubMedID 25984184

• Living donor evaluation and exclusion: the Stanford experience CLINICAL TRANSPLANTATION Lapasia, J. B., Kong, S., Busque, S., Scandling, J. D., Chertow, G. M., Tan, J. C. 2011; 25 (5): 697-704

  Abstract

  The proportion of prospective living donors disqualified for medical reasons is unknown. The objective of this study is to delineate and quantify specific reasons for exclusion of prospective living donors from kidney donation.All adult prospective kidney donors who contacted our transplant program between October 1, 2007 and April 1, 2009 were included in our analysis (n = 484). Data were collected by review of an electronic transplant database.Of the 484 prospective donors, 39 (8%) successfully donated, 229 (47%) were excluded, 104 (22%) were actively undergoing evaluation, and 112 (23%) were withdrawn before evaluation was complete. Criteria for exclusion were medical (n = 150), psychosocial (n = 22), or histocompatibility (n = 57) reasons. Of the 150 prospective donors excluded for medical reasons, 79% were excluded because of obesity, hypertension, nephrolithiasis, and/or abnormal glucose tolerance. One hundred and forty-seven (61%) intended recipients had only one prospective living donor, of whom 63 (42%) were excluded.A significant proportion of prospective living kidney donors were excluded for medical reasons such as obesity (body mass index >30), hypertension, nephrolithiasis, and abnormal glucose tolerance. Longer-term studies are needed to characterize the risks to medically complex kidney donors and the potential risks and benefits afforded to recipients.

  View details for DOI 10.1111/j.1399-0012.2010.01336.x

  View details for PubMedID 21044160

• Donor-specific antibody against denatured HLA-A1: Clinically nonsignificant? HUMAN IMMUNOLOGY Pereira, S., Perkins, S., Lee, J., Shumway, W., LeFor, W., Lopez-Cepero, M., Wong, C., Connolly, A., Tan, J. C., Grumet, F. C. 2011; 72 (6): 492-498

  Abstract

  Pre-transplant screening of a woman with end-stage renal disease (ESRD) showed no anti-human leukocyte antigen (HLA) alloantibodies by anti-human globulin-complement-dependent cytotoxicity (AHG-CDC; class I) or enzyme-linked immunosorbent assay (class II). Following a negative AHG-CDC crossmatch, an HLA*01:01+ deceased donor (DD) kidney was transplanted in September 2005. Subsequent screening of pre-transplant serum by LABScreen Single Antigen (SA) array showed strong reactivity versus A*01:01. Despite that reactivity, at 5 years post-transplant, the patient has a serum creatinine of 1.6 mg/dl and has never experienced humoral or cellular rejection. Retrospective flow-cytometric crossmatch of pre- and post-transplant sera versus DD cells was negative. Rescreening of multiple pre- and post-transplant sera revealed anti-A1 reactivity persisting from the first through the last samples tested. The patient's anti-A1 was almost two fold more reactive with denatured A*01:01 FlowPRA SA beads after denaturation with acid treatment (pH 2.7) than with untreated beads. Parallel results were observed with pH 2.7 treated versus untreated A1+ T cells in FXM. These data highlight the difficulty in interpreting screening results obtained using bead arrays, because of antibodies that appear to recognize denatured but not native class I HLA antigens. We suggest that such bead-positive, flow cytometric crossmatch negative antibodies are not associated with humoral rejection, may not necessarily be detrimental to a graft, and deserve further evaluation before becoming a barrier to transplantation.

  View details for DOI 10.1016/j.humimm.2011.02.012

  View details for Web of Science ID 000291138900005

  View details for PubMedID 21396421

• Debate: PRO Position Formal Assessment of Donor Kidney Function Should Be Mandatory AMERICAN JOURNAL OF NEPHROLOGY Tan, J. C., Busque, S., Ho, B., Myers, B. D. 2011; 33 (3): 198-200

  View details for DOI 10.1159/000323230

  View details for Web of Science ID 000289236400002

  View details for PubMedID 21335961

• Donors with Kidney Stones: Should We Pass? Congress of the American-Society-of-Transplant-Surgeons Kim, I. K., Lapasia, J., Elihu, A., Tan, J., Scandling, J., Busque, S., Melcher, M. WILEY-BLACKWELL PUBLISHING, INC. 2011: 66–66

  View details for Web of Science ID 000286406500042

• Effects of aging on glomerular function and number in living kidney donors KIDNEY INTERNATIONAL Tan, J. C., Busque, S., Workeneh, B., Ho, B., Derby, G., Blouch, K. L., Sommer, F. G., Edwards, B., Myers, B. D. 2010; 78 (7): 686-692

  Abstract

  To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (≥ 55 years) compared to 33 younger (≤ 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.

  View details for DOI 10.1038/ki.2010.128

  View details for Web of Science ID 000281824200011

  View details for PubMedID 20463656

  View details for PubMedCentralID PMC3353650

• Renal allograft granulomas in the early post-transplant period. NDT plus Lapasia, J. B., Kambham, N., Busque, S., Tan, J. C. 2010; 3 (4): 397-401

  View details for DOI 10.1093/ndtplus/sfq081

  View details for PubMedID 25949441

  View details for PubMedCentralID PMC4421525

• Chronic Hepatitis C and Chronic Kidney Disease DIGESTIVE DISEASES AND SCIENCES Tan, J. C. 2010; 55 (5): 1197-1199

  View details for DOI 10.1007/s10620-010-1233-2

  View details for Web of Science ID 000277283500003

  View details for PubMedID 20376699

• Impact of Short Term Pre-Transplant Dialysis on Kidney Transplant Outcomes 10th American Transplant Congress Javaid, B., Kim, J., Yabu, J., Tan, J., Melcher, M., Busque, S., Scandling, J. WILEY-BLACKWELL. 2010: 525–525

  View details for Web of Science ID 000275921703406

• Risk of Graft Failure Due to Disease Recurrence in Patients with FSGS 10th American Transplant Congress Kim, J., Yabu, J., Tan, J., Scandling, J., Melcher, M., Busque, S., Javaid, B. WILEY-BLACKWELL. 2010: 196–197

  View details for Web of Science ID 000275921701535

• A Retrospective Analysis of Practices in Living Donor Evaluation and Exclusion. 10th American Transplant Congress Lapasia, J., Scandling, J. D., Javaid, B., Busque, S., Tan, J. C. WILEY-BLACKWELL. 2010: 541–541

  View details for Web of Science ID 000275921703464

• Imprecision of Creatinine-Based GFR Estimates in Uninephric Kidney Donors CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Tan, J. C., Ho, B., Busque, S., Blouch, K., Derby, G., Efron, B., Myers, B. D. 2010; 5 (3): 497-502

  Abstract

  To ensure long-term safety of living kidney donors, it is now recommended that they be followed for at least 2 years after donation and that serum creatinine levels be monitored. Such levels are often subjected by clinical laboratories to estimating equations and are reported as estimated GFR (eGFR). The accuracy of such equations in uninephric living donors has yet to be validated. This is especially important in older living donors, who often have senescence-related depression of GFR.We compared urinary creatinine clearance, four-variable Modification of Diet in Renal Disease estimating equation (eGFR), and the recently reported CKD-EPI GFR estimating equation with true GFR measured by the urinary iothalamate clearance (iGFR) in 64 subjects after kidney donation.Creatinine clearance overestimated iGFR. Both creatinine-based estimating equations were poorly correlated with and underestimated iGFR. More than half of kidney donors had eGFR <60 ml/min per 1.73 m(2) after donation, a level that categorized them as having stage 3 chronic kidney disease by our current laboratory reporting, whereas only 25% had iGFR <60 ml/min per 1.73 m(2). This misclassification disproportionately affected older donors age > or =55 years, of whom 80% had eGFR <60 ml/min per 1.73 m(2). Neither significant albuminuria nor hypertension was observed.The current practice of reporting eGFR after donation commonly leads to a misclassification of chronic kidney disease, particularly in older donors. To ensure long-term well-being of living kidney donors, more precise estimates of GFR are required, particularly among older potential donors.

  View details for DOI 10.2215/CJN.05280709

  View details for Web of Science ID 000275325000017

  View details for PubMedID 20110343

  View details for PubMedCentralID PMC2827575

• Cautious Optimism Concerning Long-Term Safety of Kidney Donation. NEW ENGLAND JOURNAL OF MEDICINE Tan, J. C., Chertow, G. M. 2009; 360 (5): 522-523

  View details for Web of Science ID 000262812400015

  View details for PubMedID 19179321

• Glomerular Function, Structure, and Number in Renal Allografts from Older Deceased Donors JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Tan, J. C., Workeneh, B., Busque, S., Blouch, K., Derby, G., Myers, B. D. 2009; 20 (1): 181-188

  Abstract

  The 5-yr survival rate of renal allografts is significantly lower for grafts from older deceased donors than from younger deceased donors. For evaluation of the potential contribution of renal senescence in this shortened graft survival, glomerular function and structure were analyzed in allografts from deceased donors older than 55 yr ("aging") or younger than 40 yr ("youthful"). Aging donors had a significantly higher prevalence of sclerotic glomeruli (P < 0.002), and their nonsclerotic glomeruli tended to be larger, had a larger filtration surface area (P = 0.02), and had a higher single-nephron ultrafiltration coefficient (K(f); P = 0.07), suggesting a compensatory response to functional loss of glomeruli. After serum creatinine reached a stable nadir in the transplant recipients, GFR and its hemodynamic determinants were evaluated and the whole allograft K(f) was computed. Compared with the allografts from youthful donors, allografts from aging donors exhibited a 32% lower GFR, which was exclusively attributable to a 45% reduction in allograft K(f) (both P < 0.001). In addition, the number of functioning glomeruli per allograft was profoundly lower in grafts from aging donors than from youthful donors (3.6 +/- 2.1 x 10(5) versus 8.5 +/- 3.4 x 10(5); P < 0.01), and this could not be explained by the relatively modest 17% prevalence of global glomerulosclerosis in the aging group. The marked reduction in overall glomerular number in many aging donors may lead to a "remnant kidney" phenomenon, potentially explaining the shorter mean survival of these allografts.

  View details for DOI 10.1681/ASN.2008030306

  View details for Web of Science ID 000262677200025

  View details for PubMedID 18815243

  View details for PubMedCentralID PMC2615719

• Estimated Number of Functioning Glomeruli in Older Living Kidney Donors. 9th Joint Meeting of the American-Society-of-Transplant-Surgeon/American-Society-of-Transplantation Tan, J. C., Busque, S., Myers, B. D. WILEY-BLACKWELL. 2009: 343–344

  View details for Web of Science ID 000265068800531

• H-Y antibody development associates with acute rejection in female patients with male kidney transplants TRANSPLANTATION Tan, J. C., Wadia, P. P., Coram, M., Grumet, F. C., Kambham, N., Miller, K., Pereira, S., Vayntrub, T., Miklos, D. B. 2008; 86 (1): 75-81

  Abstract

  Human minor histocompatibility antigens (mHA) and clinically relevant immune responses to them have not been well defined in organ transplantation. We hypothesized that women with male kidney transplants would develop antibodies against H-Y, the mHA encoded on the Y-chromosome, in association with graft rejection.We tested sera from 118 consecutive transplant recipients with kidney biopsies. Antibodies that specifically recognized the recombinant H-Y antigens RPS4Y1 or DDX3Y were detected by IgG enzyme-linked immunosorbent assay and western blotting. Immunogenic epitopes were further identified using overlapping H-Y antigen peptides for both the H-Y proteins.In the 26 female recipients of male kidneys, H-Y antibody development posttransplant (1) was more frequent (46%) than in other gender combinations (P<0.001), (2) showed strong correlation with acute rejection (P=0.00048), (3) correlated with plasma cell infiltrates in biopsied kidneys (P=0.04), and (4) did not correlate with C4d deposition or donor-specific anti-human leukocyte antigen (HLA) antibodies. Of the two H-Y antigens, RPS4Y1 was more frequently recognized (P=0.005).This first demonstration of a strong association between H-Y antibody development and acute rejection in kidney transplant recipients shows that in solid organ allografts, humoral immune responses against well defined mHA have clear clinical correlates, can be easily monitored, and warrant study for possible effects on long-term graft function.

  View details for DOI 10.1097/TP.0b013e31817352b9

  View details for Web of Science ID 000257790400014

  View details for PubMedID 18622281

  View details for PubMedCentralID PMC2943873

• Glomerular function and number in ECD transplants 8th American Transplant Congress Workeneh, B., Busque, S., Derby, G., Blouch, K., Myers, B., Tan, J. WILEY-BLACKWELL. 2008: 602–602

  View details for Web of Science ID 000255763202411

• Estimating equations for post-nephrectomy GFR in living kidney donors. 8th American Transplant Congress Tan, J. C., Ho, B., Busque, S., Myers, B. D. WILEY-BLACKWELL. 2008: 456–456

  View details for Web of Science ID 000255763201464

• The consequences of delayed graft function (DGF) after kidney transplantation Hwang, C. S., Tan, J. C., Scandling, J. D., Alfrey, E. J. WILEY-BLACKWELL. 2007: 233–234

  View details for Web of Science ID 000249954000926

• Adaptive hyperfiltration in the aging kidney after contralateral nephrectomy AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Saxena, A. B., Myers, B. D., Derby, G., Blouch, K. L., Yan, J., Ho, B., Tan, J. C. 2006; 291 (3): F629-F634

  Abstract

  We examined the magnitude of adaptive hyperfiltration in the remaining kidney of 16 aging (>57 yr) and 16 youthful (<55 yr) individuals who had undergone a contralateral nephrectomy. Healthy volunteers who were youthful (n = 143) or aging (n = 37) provided control values for the binephric condition. One-kidney glomerular filtration rate (GFR; +42%), renal plasma flow (+38%), plasma oncotic pressure (+2.8 mmHg), and mean arterial pressure (+7.0 mmHg) were all higher in youthful uninephric vs. binephric subjects. Corresponding excesses in aging uninephric vs. binephric subjects were by 38 and 36% and 1.4 and 14.0 mmHg, respectively. Modeling of these data revealed that an isolated increase in either the glomerular ultrafiltration coefficient (K(f)) by 110% or in the transcapillary hydraulic pressure gradient (DeltaP) by 7 mmHg, could account for the observed level of hyperfiltration in youthful uninephric subjects. Corresponding increases for aging uninephric subjects were 61% for K(f) and 5 mmHg for DeltaP. We conclude that the magnitude of adaptive hyperfiltration is similar in aging to that in youthful uninephric subjects, albeit at a lower absolute GFR level. Isolated increases in either K(f) or DeltaP or a combination of smaller increases in both can account for the hyperfiltration. Greater adaptive arterial hypertension in aging than youthful uninephric subjects raises the possibility of a disproportionate role for glomerular hypertension and DeltaP elevation in aging compared with youthful uninephric subjects. Glomerular hypertension could exacerbate the sclerosing glomerulopathy of senescence and lead to renal insufficiency. We recommend that living donors of a kidney transplantation in or beyond the seventh decade be used with caution.

  View details for DOI 10.1152/ajprenal.00329.2005.

  View details for Web of Science ID 000239658900014

  View details for PubMedID 16525160

• Circulating growth hormone binding protein levels and mononuclear cell growth hormone receptor expression in uremia 7th Symposium on Growth and Development in Children with Chronic Kidney Disease Greenstein, J., Guest, S., Tan, J. C., Tummala, P., Busque, S., Rabkin, R. W B SAUNDERS CO-ELSEVIER INC. 2006: 141–49

  Abstract

  Resistance to growth hormone (GH) in end-stage renal disease (ESRD) causes growth retardation and muscle wasting. In humans, circulating GH binding protein (GHBP), the extracellular domain of the GH receptor that is shed into the circulation and is believed to reflect tissue GH receptor levels, is reduced in uremia and suggests that cellular GH receptor levels are correspondingly reduced. If true, this could be a cause of GH resistance. We set out to establish whether serum GHBP levels reflect cellular GH receptor levels and whether changes in serum GHBP levels are related to nutritional or inflammatory status.GH receptor protein expression in peripheral blood mononuclear cells (PBMC) from 21 ESRD and 14 normal subjects were analyzed by fluorochrome flow cytometry.The GH receptor density and percent total PBMCs expressing the GH receptor were similar in the 2 groups, and there was no difference in percent GH receptor positive T or B cells or monocytes. In contrast, serum GHBP levels were 80% lower in ESRD. GHBP levels did not correlate with serum albumin, body mass index, or muscle mass but seemed to be partly related to the log serum C-reactive protein levels.Serum GHBP levels are markedly reduced in ESRD; this seems to occur independent of nutritional status and may in part be caused by inflammation. Because GH receptor expression on PBMC of ESRD and control subjects was similar, our findings argue against a reduction in GH receptor as a cause of GH resistance and the use of serum GHBP levels as a reliable marker of specific tissue GH receptor levels.

  View details for DOI 10.1053/j.jrn.2006.01.007

  View details for Web of Science ID 000236735600007

  View details for PubMedID 16567271

• Validation of a screening protocol for identifying low-risk candidates with type 1 diabetes mellitus for kidney with or without pancreas transplantation 35th Annual Meeting of the American-Society-of-Nephrology Ma, I. W., Valantine, H. A., Shibata, A., Waskerwitz, J., Dafoe, D. C., Alfrey, E. J., Tan, J. C., MILLAN, M., Busque, S., Scandling, J. D. WILEY-BLACKWELL PUBLISHING, INC. 2006: 139–46

  Abstract

  Certain clinical risk factors are associated with significant coronary artery disease in kidney transplant candidates with diabetes mellitus. We sought to validate the use of a clinical algorithm in predicting post-transplantation mortality in patients with type 1 diabetes. We also examined the prevalence of significant coronary lesions in high-risk transplant candidates.All patients with type 1 diabetes evaluated between 1991 and 2001 for kidney with/without pancreas transplantation were classified as high-risk based on the presence of any of the following risk factors: age >or=45 yr, smoking history >or=5 pack years, diabetes duration >or=25 yr or any ST-T segment abnormalities on electrocardiogram. Remaining patients were considered low risk. All high-risk candidates were advised to undergo coronary angiography. The primary outcome of interest was all-cause mortality post-transplantation.Eighty-four high-risk and 42 low-risk patients were identified. Significant coronary artery stenosis was detected in 31 high-risk candidates. Mean arterial pressure was a significant predictor of coronary stenosis (odds ratio 1.68; 95% confidence interval 1.14-2.46), adjusted for age, sex and duration of diabetes. In 75 candidates who underwent transplantation with median follow-up of 47 months, the use of clinical risk factors predicted all eight deaths. No deaths occurred in low-risk patients. A significant mortality difference was noted between the two risk groups (p = 0.03).This clinical algorithm can identify patients with type 1 diabetes at risk for mortality after kidney with/without pancreas transplant. Patients without clinical risk factors can safely undergo transplantation without further cardiac evaluation.

  View details for DOI 10.1111/j.1399-0012.2005.00461.x

  View details for Web of Science ID 000237095200001

  View details for PubMedID 16640517

• Donor renal cortical volumes and 6-month graft function in living donor transplantation. 6th American Transplant Congress Yan, J., Busque, S., Myers, B. D., Tan, J. C. WILEY-BLACKWELL. 2005: 262–262

  View details for Web of Science ID 000229231600418

• Suppressors of cytokine signaling in health and disease PEDIATRIC NEPHROLOGY Tan, J. C., Rabkin, R. 2005; 20 (5): 567-575

  Abstract

  Cytokines consist of a large family of secreted proteins, including pro-inflammatory agents, growth hormone and erythropoietin, that utilize the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signal transduction pathway to mediate many of their key physiologic and pathologic actions. These actions include cytokine-mediated inflammation, immunoregulation, hematopoiesis and growth. The JAK-STAT pathway is regulated by several processes, among which negative feedback regulation by the suppressors of cytokine signaling (SOCS), members of a family of eight proteins, is particularly important. Each cytokine induces one or more specific SOCS proteins that in turn down-regulate the signal initiated by the cytokine. Through their impact on the cytokine-activated JAK-STAT pathway, the SOCS proteins are involved in many diseases that come to the attention of the pediatric nephrologist. For example, an increase in the expression of SOCS-2 and -3 may be a cause of growth hormone resistance and thus may contribute to the growth retardation that affects children with chronic renal failure. Because of their obvious biologic importance, the SOCS proteins have been the subject of intense research that includes the development of strategies to utilize these proteins to control cytokine-induced JAK/STAT signal transduction for therapeutic purposes.

  View details for DOI 10.1007/s00467-004-1766-8

  View details for Web of Science ID 000228535900003

  View details for PubMedID 15723195

• Post kidney transplantation weight gain is not associated with steroid usage 6th American Transplant Congress Yan, J., Scandling, Y., Busque, S., Tan, J. C. WILEY-BLACKWELL. 2005: 534–534

  View details for Web of Science ID 000229231602300

• Growth hormone resistance in uremia, a role for impaired JAK/STAT signaling 7th Symposium on Growth and Development in Children with Chronic Kidney Disease Rabkin, R., Sun, D. F., Chen, Y., Tan, J., Schaefer, F. SPRINGER. 2005: 313–18

  Abstract

  Resistance to growth hormone (GH) is a significant complication of advanced chronic renal failure. Thus while the circulating GH levels are normal or even elevated in uremia, resistance to the hormone leads to stunting of body growth in children and contributes to muscle wasting in adults. Insensitivity to GH is the consequence of multiple defects in the GH/insulin-like growth factor-1 (IGF-1) system. Expression of the GH receptor may be reduced, although this is not a consistent finding, GH activation of the Janus kinase 2-signal transducer (JAK2) and activator of transcription (STAT) signal transduction pathway is depressed and this leads to reduced IGF-1 expression, and finally there is resistance to IGF-1, a major mediator of GH action. We review these various defects with an emphasis on the GH-activated JAK2-STAT5 pathway, since this pathway is essential for normal body growth and there has been recent progress in our understanding of the perturbations that occur in uremia.

  View details for DOI 10.1007/s00467-004-1713-8

  View details for Web of Science ID 000227713600011

  View details for PubMedID 15692835

• Preoperative renal volumes as a predictor of graft function in living donor transplantation AMERICAN JOURNAL OF KIDNEY DISEASES Saxena, A. B., Busque, S., Arjane, P., Myers, B. D., Tan, J. C. 2004; 44 (5): 877-885

  Abstract

  Nephron underdosing and donor kidney-recipient body size mismatch can lead to poor allograft function. The purpose of this study is to examine the relationship between donor kidney volume and posttransplantation graft function by using magnetic resonance imaging (MRI) to obtain renal volumes. Previous investigators used donor body surface area as a surrogate for kidney size or measured renal volume by using ultrasonography; both these techniques are inaccurate measures of renal volume. Intraoperative weights are more accurate, but provide information only after the transplantation is underway. More recently, MRI has been used preoperatively to screen living donors; these novel MRI techniques also provide information regarding renal size.We performed a retrospective analysis of 54 patients who underwent living donor transplantation at our institution from 2000 to 2002. All living donors underwent preoperative renovascular imaging using MRI, and renal volumes were obtained for each donor. A transplant kidney volume-recipient body weight (Vol/Wt) ratio was determined for each donor-recipient pair, and patients were divided into tertiles corresponding to 3 groups: high (>2.7), medium (2 to 2.7), and low (<2) "nephron dose" ratios.Glomerular filtration rate (GFR) correlated with Vol/Wt ratio at 6 and 12 months (r = 0.46; P = 0.0005 and r = 0.41; P = 0.003). At 6 months, mean GFRs in the low, medium, and high groups were 52.4 +/- 2.8 (SEM), 64.5 +/- 6.2, and 82.0 +/- 4.4 mL/min, respectively (P < 0.0005). At 12 months, GFRs in the low, medium, and high groups were 51.6 +/- 3.6, 63.3 +/- 3.8, and 83.9 +/- 5.4 mL/min, respectively (P < 0.0001).Transplantation of donor-recipient pairs with a Vol/Wt ratio less than 2 cm 3 /kg was associated with significantly worse graft function. Donor kidney volumes measured by means of preoperative MRI can be used to calculate Vol/Wt ratios before transplantation and identify patients at risk for a low GFR posttransplantation.

  View details for DOI 10.1053/j.ajkd.2004.07.012

  View details for Web of Science ID 000225044100015

  View details for PubMedID 15492954

• Dual-kidney transplantation with organs from expanded criteria donors: A long-term follow-up TRANSPLANTATION Tan, J. C., Alfrey, E. J., Dafoe, D. C., Millan, M. T., Scandling, J. D. 2004; 78 (5): 692-696

  Abstract

  Since 1995, dual-kidney transplantation using organs from marginal donors has been used at our center to expand the organ donor pool and decrease the waiting time for deceased donor kidney transplantation. This approach has allowed for a shorter waiting period without compromising outcome in the early posttransplant period. We now have 8-year follow-up in the first recipients. Older individuals were offered this option preferentially, because we reasoned that they would stand to benefit most from the shorter waiting period.Patients aged 55 years or more who underwent either dual-kidney transplantation with expanded criteria donors or single-kidney transplantation with standard donors were included in this study. All expanded criteria donor organs were those that were refused by all other local transplant centers. The primary endpoints were recipient death and graft failure.Waiting time for dual-kidney transplantation was 440 +/- 38 days versus 664 +/- 51 days for single-kidney transplantation (P<0.01). The 8-year actuarial patient survivals for the single- and dual-kidney transplants were 74.1% and 82.1%, respectively. The 8-year actuarial graft survivals for the single- and dual-kidney transplants were 59.4% and 69.7%, respectively.Eight-year actuarial patient and graft survivals in older individuals who underwent dual-kidney transplantation are equivalent to those who underwent standard single-kidney transplantation. With the continuing organ shortage and increasing waiting times for cadaver kidney transplantation, dual-kidney transplantation using organs that would otherwise be discarded offers a good option for older individuals who may not withstand a long waiting period.

  View details for DOI 10.1097/01.tp.0000130452.01521.b1

  View details for Web of Science ID 000223935400010

  View details for PubMedID 15371670

• Effect of steroid avoidance on early graft function after kidney transplantation 5th American Transplant Congress Roozrokh, H. C., Chen, L., Scandling, J. D., Momsen, A., Tan, J., Busque, S. WILEY-BLACKWELL. 2004: 354–354

  View details for Web of Science ID 000221322500721

• Adaptive renal hyperfiltration is preserved in older living kidney donors following uninephrectomy. 5th American Transplant Congress Bhatt, A., Myers, B. D., Derby, G. C., Blouch, K. L., Tan, J. C. WILEY-BLACKWELL. 2004: 595–595

  View details for Web of Science ID 000221322501588

• Pre-operative MRI kidney volumes as a predictor of graft function in living donor kidney transplantation. 36th Annual Meeting of the American-Society-of-Nephrology Bhatt, A., Arjane, P., Busque, S., Tan, J. C. AMER SOC NEPHROLOGY. 2003: 11A–11A

  View details for Web of Science ID 000186219100048

• Long-term graft survival of older donor kidneys is improved with dual kidney transplantation. 36th Annual Meeting of the American-Society-of-Nephrology Bhatt, A., Scandling, J. D., Myers, B. D., Tan, J. C. AMER SOC NEPHROLOGY. 2003: 666A–666A

  View details for Web of Science ID 000186219103084

• Growth hormone (GH) receptor expression in uremia. 36th Annual Meeting of the American-Society-of-Nephrology Greenstein, J., Guest, S., Tummala, P., Tan, J., Rabkin, R. AMER SOC NEPHROLOGY. 2003: 537A–538A

  View details for Web of Science ID 000186219102474

• Determinants of glomerular hypofiltration in aging humans KIDNEY INTERNATIONAL Hoang, K., Tan, J. C., Derby, G., Blouch, K. L., Masek, M., Ma, I., Lemley, K. V., Myers, B. D. 2003; 64 (4): 1417-1424

  Abstract

  The purpose of the present study was to confirm the extent to which glomerular filtration rate (GFR) is depressed in healthy, aging subjects and to elucidate the mechanism of such hypofiltration.Healthy volunteers aged 18 to 88 years (N = 159) underwent a determination of GFR, renal plasma flow (RPF), afferent oncotic pressure, and arterial pressure. Glomeruli in renal biopsies of healthy kidney transplant donors aged 23 to 69 years (N = 33) were subjected to a morphometric analysis, so as to determine glomerular hydraulic permeability and filtration surface area. The aforementioned GFR determinants were then subjected to mathematical modeling to compute the glomerular ultrafiltration coefficient (Kf) for two kidneys and individual glomeruli.GFR was significantly depressed (P < 0.0001) by 22% in aging (>or=55 years old) compared to youthful subjects (

  View details for Web of Science ID 000185226200031

  View details for PubMedID 12969161

• Growth hormone (GH) receptors in uremia. Western Regional Meeting of the American-Federation-for-Medical-Research Greenstein, J., Guest, S., Tummala, P., Rabkin, R., Tan, J. LIPPINCOTT WILLIAMS & WILKINS. 2003: S152–S152

  View details for Web of Science ID 000180569600354

• Validation of a screening protocol for coronary artery disease in kidney and/or pancreas transplant candidates with type I diabetes mellitus. Ma, I. W., Valantine, H. A., Shibata, A., Waskerwitz, J., Dafoe, D., Alfrey, E., Tan, J., MILLAN, M., Busque, S., Scandling, J. D. AMER SOC NEPHROLOGY. 2002: 191A–192A

  View details for Web of Science ID 000177757500943

• Current prevalence of coronary artery disease in kidney transplant candidates with type I diabetes mellitus. Ma, I. W., Valantine, H. A., Shibata, A., Waskerwitz, J., Dafoe, D., Alfrey, E., Tan, J., MILLAN, M., Busque, S., Scandling, J. D. AMER SOC NEPHROLOGY. 2002: 192A–192A

  View details for Web of Science ID 000177757500944

• Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation TRANSPLANTATION Millan, T. L., Shizuru, J. A., Hoffmann, P., Dejbakhsh-Jones, S., Scandling, J. D., GRUMET, F. C., Tan, J. C., Salvatierra, O., Hoppe, R. T., Strober, S. 2002; 73 (9): 1386-1391

  Abstract

  Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft.Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR).Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter.Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.

  View details for Web of Science ID 000175933100002

  View details for PubMedID 12023614

• A non-myeloablative conditioning regimen followed by progenitor cell (CD34+) infusion after kidney transplantation can achieve mixed chimerism and immunosuppressive drug withdrawal Millan, M. T., Shizuru, J. A., Hoffmann, P., Dejbakhsh-Jones, S., Scandling, J. D., GRUMET, F. C., Tan, J. C., Salvatierra, O., Strober, S. FEDERATION AMER SOC EXP BIOL. 2002: A1030–A1030

  View details for Web of Science ID 000174593901680

• Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: Cyclic AMP-AS intracellular intermediary NEUROSCIENCE CHEUN, J. E., Yeh, H. H. 1996; 74 (3): 835-844

  Abstract

  Norepinephrine and the beta-adrenergic receptor agonist, isoproterenol, have been shown to potentiate the amplitude of GABAA receptor-mediated whole-cell current responses in Purkinje cells acutely dissociated from the rat cerebellum. However, the steps leading from the activation of beta-adrenergic receptors to the modulation of GABAA receptor remain to be delineated. This study tested the hypothesis that a sequelae of intracellular intermediaries involving the cyclic AMP second messenger system serves as the subcellular link to promote this heteroreceptor interaction. Exposure to cholera toxin, but not to pertussis toxin, increased the amplitude of GABA-activated current responses in acutely dissociated Purkinje cells. Intracellular dialysis with guanosine 5'-O-(3-thiotriphosphate) also resulted in a time- and dose-dependent augmentation of the response to GABA. while guanosine 5'-O-(2-thiodiphosphate) blocked the norepinephrine-mediated facilitation. A positive modulation of the current response to GABA was observed following intracellular delivery of cyclic AMP or the catalytic subunit of the cyclic AMP-dependent protein kinase. Furthermore, the norepinephrine-induced potentiation of the GABA-activated current response was prevented in the presence of the Rp isomer of cyclic AMP, the regulatory subunit of cyclic AMP-dependent protein kinase and an inhibitor of cyclic AMP-dependent protein kinase. These findings led to the formulation of a working model in which activation of the beta-adrenergic receptor triggers a Gs-protein-mediated transduction cascade in cerebellar Purkinje cells which activates adenylate cyclase, resulting in a rise in intracellular levels of cyclic AMP, increased phosphorylating activity by cyclic AMP-dependent protein kinase and, ultimately, a potentiation of GABAA receptor function.

  View details for Web of Science ID A1996VH28200019

  View details for PubMedID 8884779

• MODULATION OF GABA-A RECEPTOR-ACTIVATED CURRENT BY NOREPINEPHRINE IN CEREBELLAR PURKINJE-CELLS NEUROSCIENCE CHEUN, J. E., Yeh, H. H. 1992; 51 (4): 951-960

  Abstract

  Previous studies employing extracellular single-unit recording in the intact cerebellum have demonstrated that norepinephrine can potentiate GABA-induced suppression of Purkinje cell spike activity. However, many issues related to the nature of this modulatory phenomenon remain to be resolved. Using whole-cell patch clamp recording, the present study investigated the effect of norepinephrine on GABA-activated membrane currents (IGABA) in solitary Purkinje cells isolated from neonatal rat cerebella following acute dissociation. Exposure of Purkinje cells to norepinephrine at a concentration which, by itself, had no obvious effect on Purkinje cell membrane conductance, consistently augmented IGABA. The catecholamine also potentiated GABA-gated chloride currents as well as muscimol-induced currents in Purkinje cells. Thus, the facilitating effect of norepinephrine on IGABA was attributed to an interaction between norepinephrine and the GABAA receptor-mediated chloride conductance. The effect of norepinephrine could be mimicked by isoproterenol as well as by 8-bromo cAMP, suggesting that a beta-receptor-mediated, cAMP-dependent cascade may underlie the observed heteroreceptor interaction. Our results establish the existence of a postsynaptic mechanism by which norepinephrine, through activation of the beta-adrenoceptor, may modulate GABAA receptor function in cerebellar Purkinje cells. This study provides the groundwork for a detailed investigation into the cascade of membrane and intracellular events underlying such a synergistic modulatory interaction at the cellular and subcellular levels.

  View details for Web of Science ID A1992KC90800020

  View details for PubMedID 1283212

• DIFFERENTIATION OF A STEM-CELL LINE TOWARD A NEURONAL PHENOTYPE INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE CHEUN, J. E., Yeh, H. H. 1991; 9 (4): 391-404

  Abstract

  This study examined the morphology and the development of inward currents in the course of differentiation of a stem cell toward a neuronal phenotype. Using the P19 embryonal cell line, whole-cell current profiles of P19 cells before, during and after retinoic acid-induced differentiation were matched with their morphology as well as with the expression of neuron-specific enolase-like immunoreactivity. Prior to and during the initial 48 hr of retinoic acid treatment, P19 cells either lacked detectable currents or expressed a voltage-dependent outward potassium current, did not display neuron-like morphology and did not express neuron-specific enolase-like immunoreactivity. Upon completion of retinoic acid treatment, the current profile of fully differentiated P19 cells was hallmarked by a large voltage-dependent inward current which consisted of a sodium current and a smaller cobalt-sensitive calcium component, in addition to the potassium current observed earlier. Such cells invariably emitted neurites and displayed neuron-specific enolase-like immunoreactivity. Interestingly, coupling was prevalent among P19 cells in the undifferentiated state but was absent in the fully differentiated cultures. In studying cells undergoing neuronal differentiation, these results underscore the importance of taking into account both electrical properties and morphological considerations in determining the degree of differentiation.

  View details for Web of Science ID A1991GC88400010

  View details for PubMedID 1950653

• MODULATORY ACTIONS OF NOREPINEPHRINE ON NEURAL CIRCUITS 3RD INTERNATIONAL SYMP ON NEUROTRANSMITTER RECEPTORS Woodward, D. J., Moises, H. C., Waterhouse, B. D., Yeh, H. H., CHEUN, J. E. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1991: 193–208

  Abstract

  A spectrum of studies has been conducted on a single aspect of NE function in which, through a beta-one receptor activation, NE appears to mediate a degree of physiological control over the gain of GABA mediated inhibition. It is significant that this single effect has been observed in numerous interrelated preparations ranging from single isolated Purkinje cells from young rats to adult Purkinje cells in awake locomoting rats. With respect to the functional conse-quences of these effects, our best current speculation as to "what NE does" is that NE acts to regulate the strength of these tuned gating mechanisms in both cerebral and cerebellar cortices. There are numerous unanswered questions raised by the past work. One pressing issue is - when and for what reason in normal function does the modulation take place? When does NE release normally occur (is it phasic or tonic), and which of the demonstrated actions appears and for how long in relation to period of receptor activation? Does NE release cause the circuit to "react" to conditions which need "improved neurocomputation" or does NE stabilize the circuit to react predictably in the face of stress? Finally, what is the molecular sequence of events between receptor activation and an alteration of GABA receptor channel opening? What additional molecular control mechanisms exist and how can the diverse inhibitory and modulatory phenomena be reconciled, both short and long term? Issues are defined which need to be clarified at all levels of the current skeleton of basic understanding. Our prediction is that pursuit of these issues will benefit from an exchange of insight gained from investigations at all levels.

  View details for Web of Science ID A1991BT51X00016

  View details for PubMedID 1759608

• THE CEREBELLAR NOREPINEPHRINE SYSTEM - INHIBITION, MODULATION, AND GATING PROGRESS IN BRAIN RESEARCH Woodward, D. J., Moises, H. C., Waterhouse, B. D., Yeh, H. H., CHEUN, J. E. 1991; 88: 331-341

  Abstract

  A series of studies has been conducted to determine the mode of action on the cerebellar cortical circuitry of the norepinephrine (NE)-containing afferents from the locus coeruleus. NE has been known to exert an "inhibitory" action on the background firing observed in Purkinje cells, due presumably to a shift in conductances favoring hyperpolarization. An additional independent action at low threshold appears to be an enhancement of GABA, the inhibitory transmitter of cerebellar interneurons. Recent whole-cell patch-clamp studies on isolated Purkinje cells indicate that exposure to NE increases the chloride current caused by transient pulses of GABA applied iontophoretically. NE applied to Purkinje cells in the parafloccular lobule during stimulation by moving visual patterns revealed the capacity either to "gate" signals initially not expressed, or to amplify the gain of phasic excitations. The control of emergent circuit functions may be the functional consequence of the multiple modulatory functions of NE.

  View details for Web of Science ID A1991GX16500025

  View details for PubMedID 1687621

• PROPERTIES OF GABA-ACTIVATED WHOLE-CELL CURRENTS IN BIPOLAR CELLS OF THE RAT RETINA VISUAL NEUROSCIENCE Yeh, H. H., Lee, M. B., CHEUN, J. E. 1990; 4 (4): 349-357

  Abstract

  This paper describes experiments on GABA-activated whole-cell membrane currents in bipolar cells freshly isolated from the adult rat retina. The main goal was to determine whether bipolar cell responses to GABA could be resolved in terms of mediation by the GABAA receptor, the GABAB receptor, or both. Bipolar cells were isolated by gentle enzymatic dissociation and identified by their distinct morphology. GABA agonists and antagonists were applied focally by pressure and the resultant currents were recorded under whole-cell voltage clamp. In all bipolar cells tested, GABA (0.1-100 microM) induced a monophasic response associated with a conductance increase (IGABA). The shift in reversal potential for IGABA as a function of pipet [Cl-] paralleled that predicted based on the Nernst equation for Cl-. IGABA was mimicked by muscimol (5-20 microM) and antagonized by bicuculline (20-100 microM). Baclofen (0.1-1.0 mM) produced no apparent conductance change. "Hot spots" of sensitivity to GABA which might be associated with regions of synaptic contact were not found; both the soma and processes of all bipolar cells were responsive to focally applied GABA. Furthermore, all bipolar cells tested responded to glycine. In conclusion, we have established the presence of GABAA receptors on rat retinal bipolar cells. Our data suggest further that these cells lack GABAB receptors. Finally, our observation that bipolar cells in the rat retina are relatively homogeneous in terms of their sensitivity to GABA and glycine lead us to postulate that the functional significance of the presence of receptors and their distribution on a neuron may be dictated more by the topography of the presynaptic inputs than by its inherent chemosensitivity.

  View details for Web of Science ID A1990DE84300004

  View details for PubMedID 2176813