Clinical Focus


  • Nephrology (Kidney)
  • Glomerular Disease
  • Amyloidosis
  • Kidney and Pancreas Transplantation
  • Nephrology

Academic Appointments


Administrative Appointments


  • Associate Chair, Stanford University School of Medicine - Medicine (2002 - 2007)
  • Clinical Chief, Nephrology, Stanford University (1999 - 2012)
  • Director, Stanford Glomerular DIsease Center (2010 - Present)

Honors & Awards


  • America's Top Doctors, Best Doctors (2004-2018)
  • America's Top Doctors Award, Castle Connolly Medical Ltd. ((2015-2018))
  • America's Top Doctors Award, Castle Connolly Medical Ltd. ((2014))

Boards, Advisory Committees, Professional Organizations


  • Editorial Board, Kidney News, American Society of Nephrology (2010 - 2021)
  • Member, Glomerular Disease Advisory Committee, American Society of Nephrology (2013 - 2017)
  • Member (ex-oficio), Communications Committee, American Society of Nephrology (2015 - Present)

Professional Education


  • Fellowship: Stanford University School of Medicine (1992) CA
  • Medical Education: New York Medical College Registrar (1985) NY
  • Residency: Long Island Jewish Medical Center (1988) NY
  • Board Certification: American Board of Internal Medicine, Nephrology (1990)
  • Board Certification: American Board of Internal Medicine, Internal Medicine (1988)
  • Internship: Long Island Jewish Medical Center (1986) NY

Current Research and Scholarly Interests


We are continuing to grow a glomerulonephritis cohort study, including immunologic characterization. We have completed interventional studies of preeclampsia exploring the nitric oxide, endothelin system and effects on glomerular function and morphometry. We continue to recruit patients for treatment and observational studies of glomerular disease, including FSGS, membranous and particularly IgA nephropathy. We also are actively studying renal disease in systemic amyloidosis.

Clinical Trials


  • A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Refractory Lupus Nephritis Recruiting

    A Study of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Subjects With Refractory Lupus Nephritis

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  • A Study of Felzartamab in Participants With Lupus Nephritis Recruiting

    The goal of this clinical trial is to evaluate the safety and tolerability of felzartamab plus standard of care in participants with refractory Lupus Nephritis (LN).

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  • A Study to Evaluate the Safety and Efficacy of Zanubrutinib in Participants With Primary Membranous Nephropathy Recruiting

    The primary objectives of this study are: In Part 1 to evaluate the efficacy of zanubrutinib as measured by proteinuria reduction, and in Part 2 to evaluate the efficacy of zanubrutinib compared with tacrolimus as measured by complete remission rate, in participants with primary membranous nephropathy who are on optimal supportive care.

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  • Atacicept in Subjects With IgA Nephropathy Recruiting

    A Phase 3 Study with Atacicept in Subjects With IgA Nephropathy (ORIGIN 3)

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  • FIH Study of NRTX-1001 Neural Cell Therapy in Drug-Resistant Unilateral Mesial Temporal Lobe Epilepsy Recruiting

    This clinical trial is designed to test whether a single stereotactic intracerebral administration of inhibitory nerve cells into subjects with drug-resistant mesial temporal lobe epilepsy is safe (frequency of adverse events) and effective (seizure frequency).

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  • Nephrotic Syndrome Study Network Recruiting

    Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and Membranous nephropathy (MN), generate an enormous individual and societal financial burden, accounting for approximately 12% of prevalent end stage renal disease (ESRD) cases (2005) at an annual cost in the US of more than $3 billion. However, the clinical classification of these diseases is widely believed to be inadequate by the scientific community. Given the poor understanding of MCD/FSGS and MN biology, it is not surprising that the available therapies are imperfect. The therapies lack a clear biological basis, and as many families have experienced, they are often not beneficial, and in fact may be significantly toxic. Given these observations, it is essential that research be conducted that address these serious obstacles to effectively caring for patients. In response to a request for applications by the National Institutes of Health, Office of Rare Diseases (NIH, ORD) for the creation of Rare Disease Clinical Research Consortia, a number of affiliated universities joined together with The NephCure Foundation the NIDDK, the ORDR, and the University of Michigan in collaboration towards the establishment of a Nephrotic Syndrome (NS) Rare Diseases Clinical Research Consortium. Through this consortium the investigators hope to understand the fundamental biology of these rare diseases and aim to bank long-term observational data and corresponding biological specimens for researchers to access and further enrich.

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  • Phase 2/3 Open-Label Trial of Sibeprenlimab in the Treatment of Immunoglobulin A Nephropathy Recruiting

    This is a phase 2/3 open-label study to evaluate the long-term safety, tolerability, and efficacy of sibeprenlimab administered subcutaneously (SC) in subjects with IgAN.

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  • Study of Ravulizumab in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN) Recruiting

    The objectives of this study are to evaluate the safety and efficacy of ravulizumab administered by intravenous (IV) infusion compared to placebo and demonstrate proof-of-concept of the efficacy of terminal complement inhibition in participants with LN (LN Cohort) or IgAN (IgAN Cohort).

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  • Transformative Research in Diabetic Nephropathy Recruiting

    This is a prospective, observational, cohort study of patients with a clinical diagnosis of diabetes who are undergoing clinically indicated kidney biopsy. The intent is to collect, process, and study kidney tissue and to harvest blood, urine and genetic materials to elucidate molecular pathways and link them to biomarkers that characterize those patients have a rapid decline in kidney function (> 5 mL/min/1.73m2/year) from those with lesser degrees of kidney function change over the period of observation. High through-put genomic analysis associated with genetic and biomarker testing will serve to identify key potential therapeutic targets for DKD by comparing patients with rapid and slow progression patterns. Each participating clinical site will search for, consent, harvest the biopsy sample, and enroll the participants as required for the TRIDENT protocol.

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  • Visionary Study: Phase 3 Trial of Sibeprenlimab in Immunoglobulin A Nephropathy (IgAN) Recruiting

    This is a phase 3 study to evaluate effects on proteinuria and glomerular filtration rate of sibeprenlimab 400 mg subcutaneously (s.c.) Q 4 weeks in adults with IgAN who are receiving maximally tolerated standard-of-care therapy.

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  • A Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy Not Recruiting

    To determine the long-term (approximately 2 years) nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with immunoglobulin A nephropathy (IgAN).

    Stanford is currently not accepting patients for this trial. For more information, please contact Brittany Yeung, 650-498-3116.

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  • A Study To Evaluate The Efficacy And Safety Of Obinutuzumab In Patients With ISN/RPS 2003 Class III Or IV Lupus Nephritis Not Recruiting

    This study will evaluate the efficacy, safety, and pharmacokinetics of obinutuzumab compared with placebo in patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV lupus nephritis (LN) when added on to standard-of-care therapy consisting of mycophenolate mofetil (MMF) and corticosteroids.

    Stanford is currently not accepting patients for this trial. For more information, please contact Elizabeth Chen, (650) 721-3848.

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  • Atrasentan in Patients With IgA Nephropathy Not Recruiting

    The ALIGN Study is a phase 3, double-blind, placebo-controlled study to compare the efficacy and safety of atrasentan to placebo in patients with IgA nephropathy (IgAN) at risk of progressive loss of renal function.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shiktj Dave, 650-723-2240.

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  • Atrasentan in Patients With Proteinuric Glomerular Diseases Not Recruiting

    The AFFINITY Study is a phase 2, open-label, basket study to evaluate the efficacy and safety of atrasentan in patients with proteinuric glomerular disease who are at risk of progressive loss of renal function.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shiktj Dave, 650-723-2240.

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  • Belimumab With Rituximab for Primary Membranous Nephropathy Not Recruiting

    The primary objective of this study is to evaluate the effectiveness of belimumab and intravenous rituximab co-administration at inducing a complete remission (CR) compared to rituximab alone in participants with primary membranous nephropathy. Background: Primary membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults. MN affects individuals of all ages and races. The peak incidence of MN is in the fifth decade of life. Primary MN is recognized to be an autoimmune disease, a disease where the body's own immune system causes damage to kidneys. This damage can cause the loss of too much protein in the urine. Drugs used to treat MN aim to reduce the attack by one's own immune system on the kidneys by blocking inflammation and reducing the immune system's function. These drugs can have serious side effects and often do not cure the disease. There is a need for new treatments for MN that are better at improving the disease while reducing fewer treatment associated side effects. In this study, researchers will evaluate if treatment with a combination of two different drugs, belimumab and rituximab, is effective at blocking the immune attacks on the kidney compared to rituximab alone. Rituximab works by decreasing a type of immune cell, called B cells. B cells are known to have a role in MN. Once these cells are removed, disease may become less active or even inactive. However, after stopping treatment, the body will make new B cells which may cause disease to become active again. Belimumab works by decreasing the new B cells produced by the body and, may even change the type of new B cells subsequently produced. Belimumab is approved by the US Food and Drug Administration (FDA) to treat systemic lupus erythematosus (also referred to as lupus or SLE). Rituximab is approved by the FDA to treat some types of cancer, rheumatoid arthritis, and vasculitis. Neither rituximab nor belimumab is approved by the FDA to treat MN. Treatment with a combination of belimumab and rituximab has not been studied in individuals with MN, but has been tested in other autoimmune diseases, including lupus nephritis and Sjögren's syndrome.

    Stanford is currently not accepting patients for this trial. For more information, please contact Brittany Yeung, 650-498-3116.

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  • Study of Ravulizumab in Immunoglobulin A Nephropathy (IgAN) Not Recruiting

    The primary objective of this study to evaluate the efficacy of ravulizumab compared with placebo to reduce proteinuria and slow the rate of eGFR decline in adult participants with IgAN who are at risk of disease progression.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shiktj Dave, 650-723-2240.

    View full details

2023-24 Courses


Graduate and Fellowship Programs


All Publications


  • Targeting APRIL in the Treatment of IgA Nephropathy. Clinical journal of the American Society of Nephrology : CJASN Cheung, C. K., Barratt, J., Carroll, K., Lafayette, R. A., Liew, A., Suzuki, Y., Tesar, V., Trimarchi, H., Wong, M. G., Zhang, H., Perkovic, V., Rizk, D. V. 2023

    View details for DOI 10.2215/CJN.0000000000000338

    View details for PubMedID 37801688

  • Expert Discussion on Challenges in C3G Diagnosis: A Podcast Article on Best Practices in Kidney Biopsies. Advances in therapy Lafayette, R. A., Charu, V. 2023

    Abstract

    Complement 3 glomerulopathy (C3G) is an ultra-rare, progressive kidney disease resulting from dysregulation of the alternative complement pathway. Clinical presentation of C3G is heterogeneous and definitive diagnosis relies on kidney biopsy and immunofluorescence staining. The term C3G encompasses two subgroups, dense deposit disease and C3 glomerulonephritis, distinguished via electron microscopy. In this podcast article, the authors discuss the challenges associated with C3G diagnosis and the central role of kidney biopsy. Using an illustrative case study, key histological observations are described, and best practices are discussed from the perspectives of a nephrologist and a nephropathologist. Podcast Audio (MP4 141866 KB).

    View details for DOI 10.1007/s12325-023-02654-3

    View details for PubMedID 37751024

  • Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet (London, England) Lafayette, R., Kristensen, J., Stone, A., Floege, J., Tesař, V., Trimarchi, H., Zhang, H., Eren, N., Paliege, A., Reich, H. N., Rovin, B. H., Barratt, J. 2023

    Abstract

    IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy.In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed.Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported.A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product.Calliditas Therapeutics.

    View details for DOI 10.1016/S0140-6736(23)01554-4

    View details for PubMedID 37591292

  • Considering the Treatment of IgA Nephropathy. Clinical journal of the American Society of Nephrology : CJASN Lafayette, R. A., S Kamal, F. 2023

    View details for DOI 10.2215/CJN.0000000000000261

    View details for PubMedID 37533148

  • Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy. Clinical journal of the American Society of Nephrology : CJASN Barbour, S. J., Fervenza, F. C., Induruwage, D., Brenchley, P. E., Rovin, B., Hladunewich, M., Reich, H. N., Lafayette, R., Aslam, N., Appel, G. B., Zand, L., Kiryluk, K., Liu, L., Cattran, D. C., MENTOR Trial investigators 2023

    Abstract

    BACKGROUND: The 2021 KDIGO guidelines recommend following anti-PLA2R antibody levels as a marker of treatment response in membranous nephropathy, however the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown.METHODS: We used a cohort of 85 patients from the MENTOR trial with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline, and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike Information Criterion (AIC), R2).RESULTS: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared to the model at baseline, the model at 3 months had better model fit (AIC 70.9 vs 96.4, R2 51.8% vs 30.1%) and higher C-statistic (0.93 vs 0.83, p=0.008). The model at 6 months had no difference in performance compared to the model at 3 months (AIC 68.6, R2 53.0%, C-statistic 0.94 p=0.67).CONCLUSIONS: Using the MENTOR clinical trial cohort of patients with membranous nephropathy treated with standardized cyclosporine or rituximab, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment.

    View details for DOI 10.2215/CJN.0000000000000237

    View details for PubMedID 37471101

  • DIFFERENCES IN HEALTHCARE RESOURCE UTILIZATION FOR THE MANAGEMENT OF IMMUNOGLOBULIN A NEPHROPATHY IN EUROPE, THE US, CHINA AND JAPAN Kroes, M., Aldworth, C., George, A., Ndife, B., Prieto, L., Lafayette, R., De Courcy, J., Chatterton, E. ELSEVIER SCIENCE INC. 2023: S385
  • IgA Nephropathy: the Lectin Pathway and Implications for Targeted Therapy. Kidney international Barratt, J., Lafayette, R. A., Zhang, H., Tesar, V., Rovin, B. H., Tumlin, J. A., Reich, H. N., Floege, J. 2023

    Abstract

    Many patients with IgA nephropathy (IgAN) progress to end-stage kidney disease even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system - particularly the lectin and alternative pathways of complement - have emerged as key mediators of kidney injury in IgAN and possible targets for investigational therapy. This review will focus on the lectin pathway. Examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (one of six pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN, and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients.

    View details for DOI 10.1016/j.kint.2023.04.029

    View details for PubMedID 37263354

  • Budesonide delayed-release capsules to reduce proteinuria in adults with primary immunoglobulin A nephropathy. Expert review of clinical immunology Barratt, J., Lafayette, R. A., Rovin, B. H., Fellstrom, B. 2023

    Abstract

    INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is characterized by mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1). This Gd-IgA1 is believed to originate from mucosally sited B cells, which are abundant in the Peyer's patches-rich distal ileum. Nefecon is a targeted-release form of budesonide developed to act in the distal ileum, thereby exerting a direct action on the mucosal tissue implicated in the pathogenesis of the disease.AREAS COVERED: This review discusses IgAN pathophysiology and provides an overview of the current therapeutic landscape, focusing on Nefecon, the first drug to receive accelerated US approval and conditional EU approval for the treatment of patients with IgAN at risk of rapid disease progression.EXPERT OPINION: Nefecon trial data thus far have demonstrated a promising efficacy profile, with a predictable pattern of adverse events. Treatment with Nefecon for 9 months reduces proteinuria substantially (Part A of the Phase 3 trial and the Phase 2b trial). A nearly complete prevention of deterioration of renal function has been observed at 12 months in patients at greatest risk of rapid disease progression. Long-term data from Part B of the Phase 3 study will provide 24-month data, furthering understanding of the durability of the 9-month treatment course.

    View details for DOI 10.1080/1744666X.2023.2206119

    View details for PubMedID 37103889

  • Class I and II Human Leukocyte Antigen Serotypes Associated with End-Stage Kidney Disease due to Membranoproliferative Glomerulonephritis and Dense Deposit Disease Afolabi, H., Zhang, B., O'Shaughnessy, M., Chertow, G., Lafayette, R., Charu, V. ELSEVIER SCIENCE INC. 2023: S1422-S1423
  • Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis. Kidney international Mariani, L. H., Eddy, S., AlAkwaa, F. M., McCown, P. J., Harder, J. L., Nair, V., Eichinger, F., Martini, S., Ademola, A. D., Boima, V., Reich, H. N., El Saghir, J., Godfrey, B., Ju, W., Tanner, E. C., Vega-Warner, V., Wys, N. L., Adler, S. G., Appel, G. B., Athavale, A., Atkinson, M. A., Bagnasco, S. M., Barisoni, L., Brown, E., Cattran, D. C., Coppock, G. M., Dell, K. M., Derebail, V. K., Fervenza, F. C., Fornoni, A., Gadegbeku, C. A., Gibson, K. L., Greenbaum, L. A., Hingorani, S. R., Hladunewich, M. A., Hodgin, J. B., Hogan, M., Holzman, L. B., Jefferson, J. A., Kaskel, F. J., Kopp, J. B., Lafayette, R. A., Lemley, K. V., Lieske, J. C., Lin, J. J., Menon, R., Meyers, K. E., Nachman, P. H., Nast, C. C., O'Shaughnessy, M. M., Otto, E. A., Reidy, K. J., Sambandam, K. K., Sedor, J. R., Sethna, C. B., Singer, P., Srivastava, T., Tran, C. L., Tuttle, K. R., Vento, S., Wang, C. S., Ojo, A. O., Adu, D., Gipson, D. S., Trachtman, H., Kretzler, M. 2022

    Abstract

    The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.

    View details for DOI 10.1016/j.kint.2022.10.023

    View details for PubMedID 36442540

  • Results from part A of the multi-center, double-blind, randomized, placebo-controlled NefIgArd trial evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney international Barratt, J., Lafayette, R., Kristensen, J., Stone, A., Cattran, D., Floege, J., Tesar, V., Trimarchi, H., Zhang, H., Eren, N., Paliege, A., Rovin, B. H., NefIgArd Trial Investigators 2022

    Abstract

    The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated, included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.

    View details for DOI 10.1016/j.kint.2022.09.017

    View details for PubMedID 36270561

  • Racial and Ethnic Disparities in Acute Care Utilization Among Patients With Glomerular Disease. American journal of kidney diseases : the official journal of the National Kidney Foundation Krissberg, J. R., O'Shaughnessy, M. M., Smith, A. R., Helmuth, M. E., Almaani, S., Aviles, D. H., Brathwaite, K. E., Cai, Y., Cattran, D., Gbadegesin, R., Glenn, D. A., Greenbaum, L. A., Iragorri, S., Jain, K., Khalid, M., Kidd, J., Kopp, J., Lafayette, R., Lane, J. C., Lugani, F., Nestor, J. G., Parekh, R. S., Reidy, K., Selewski, D. T., Sethna, C. B., Sperati, C. J., Katherine Tuttle, Twombley, K., Vasylyeva, T. L., Weaver, D. J., Wenderfer, S. E., Gibson, K., CureGN Consortium 2022

    Abstract

    RATIONALE & OBJECTIVE: The effects of race, ethnicity, socioeconomic status, and disease severity on acute care utilization (ACU) in patients with glomerular disease (GD) are unknown.STUDY DESIGN: A prospective cohort study.SETTING: & Participants: 1,456 adults and 768 children with biopsy proven GD enrolled in the Cure Glomerulonephropathy cohort.EXPOSURE: Race and ethnicity as a participant-reported social factor.OUTCOME: ACU defined as hospitalizations or emergency department visits.ANALYTICAL APPROACH: Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and ACU.RESULTS: Black or Hispanic participants had lower socioeconomic status and more severe GD compared to White or Asian participants. ACU rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared to White race (reference group): Black race was significantly associated with ACU in adults (rate ratio (RR) 1.76, 95% Confidence Interval (CI) 1.37-2.27), although this finding was attenuated after multivariable adjustment (RR 1.31, 95% CI 1.03-1.68). Black race was not significantly associated with ACU in children; Asian race was significantly associated with lower ACU in children (RR 0.32, 95% CI 0.14-0.70); no significant associations between Hispanic ethnicity and ACU were identified.LIMITATIONS: We used proxies for socioeconomic status and lacked direct information on income, household unemployment or disability.CONCLUSIONS: Significant differences in ACU rates were observed across racial and ethnic groups in persons with prevalent GD, although many of these difference were explained by differences in socioeconomic status and disease severity. Measures to combat socioeconomic disadvantage in Black patients, and more effectively prevent and treat glomerular disease, are needed to reduce disparities in ACU, improve patient wellbeing, and reduce healthcare costs.

    View details for DOI 10.1053/j.ajkd.2022.08.010

    View details for PubMedID 36191724

  • Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis. JAMA network open Gipson, D. S., Troost, J. P., Spino, C., Attalla, S., Tarnoff, J., Massengill, S., Lafayette, R., Vega-Warner, V., Adler, S., Gipson, P., Elliott, M., Kaskel, F., Fermin, D., Moxey-Mims, M., Fine, R. N., Brown, E. J., Reidy, K., Tuttle, K., Gibson, K., Lemley, K. V., Greenbaum, L. A., Atkinson, M. A., Hingorani, S., Srivastava, T., Sethna, C. B., Meyers, K., Tran, C., Dell, K. M., Wang, C., Yee, J. L., Sampson, M. G., Gbadegesin, R., Lin, J. J., Brady, T., Rheault, M., Trachtman, H. 2022; 5 (8): e2228701

    Abstract

    Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials.Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS.Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022.Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy.Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria.Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50).Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

    View details for DOI 10.1001/jamanetworkopen.2022.28701

    View details for PubMedID 36006643

  • C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study. Clinical kidney journal Bruchfeld, A., Magin, H., Nachman, P., Parikh, S., Lafayette, R., Potarca, A., Miao, S., Bekker, P. 2022; 15 (5): 922-928

    Abstract

    Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody-associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin-angiotensin-aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria.This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 or >45 mL/min/1.73 m2 if eGFR has not declined >10 mL/min/1.73 m2 over the previous 24 weeks. If the UPCR remained at >1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period.A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of ∼50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan.This short-term pilot study showed an improvement in the slope of the UPCR, with ∼50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit.

    View details for DOI 10.1093/ckj/sfab294

    View details for PubMedID 35498891

    View details for PubMedCentralID PMC9050557

  • REAL-WORLD SIGNS AND SYMPTOMS AT DIAGNOSIS IN PATIENTS WITH IGA NEPHROPATHY Roccatello, D., Kattlun, J., Przybysz, R., George, A., Aldworth, C., Proudfoot, C., Wang, W., Decourcy, J., Lafayette, R. OXFORD UNIV PRESS. 2022: I159-I160
  • A Focus Group Study of Self-Management in Patients With Glomerular Disease. Kidney international reports Carter, S. A., Teng, C., Gutman, T., Logeman, C., Cattran, D., Lightstone, L., Bagga, A., Barbour, S. J., Barratt, J., Boletis, J., Caster, D. J., Coppo, R., Fervenza, F. C., Floege, J., Hladunewich, M. A., Hogan, J. J., Kitching, A. R., Lafayette, R. A., Malvar, A., Radhakrishnan, J., Rovin, B. H., Scholes-Robertson, N., Trimarchi, H., Zhang, H., Azukaitis, K., Cho, Y., Viecelli, A. K., Dunn, L., Harris, D., Johnson, D. W., Kerr, P. G., Laboi, P., Ryan, J., Shen, J. I., Ruiz, L., Wang, A. Y., Lee, A. H., Ka Shun, S. F., Ka-Hang Tong, M., Teixeira-Pinto, A., Wilkie, M., Alexander, S. I., Craig, J. C., Martin, A., Tong, A. 1800; 7 (1): 56-67

    Abstract

    Introduction: Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease.Methods: We conducted 16 focus groups involving adult patients with glomerular disease (n= 101) and their care partners (n= 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically.Results: We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); overwhelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance).Conclusion: Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease.

    View details for DOI 10.1016/j.ekir.2021.10.011

    View details for PubMedID 35005314

  • Improving data quality in observational research studies: Report of the Cure Glomerulonephropathy (CureGN) network. Contemporary clinical trials communications Gillespie, B. W., Laurin, L., Zinsser, D., Lafayette, R., Marasa, M., Wenderfer, S. E., Vento, S., Poulton, C., Barisoni, L., Zee, J., Helmuth, M., Lugani, F., Kamel, M., Hill-Callahan, P., Hewitt, S. M., Mariani, L. H., Smoyer, W. E., Greenbaum, L. A., Gipson, D. S., Robinson, B. M., Gharavi, A. G., Guay-Woodford, L. M., Trachtman, H. 2021; 22: 100749

    Abstract

    Background: High data quality is of crucial importance to the integrity of research projects. In the conduct of multi-center observational cohort studies with increasing types and quantities of data, maintaining data quality is challenging, with few published guidelines.Methods: The Cure Glomerulonephropathy (CureGN) Network has established numerous quality control procedures to manage the 70 participating sites in the United States, Canada, and Europe. This effort is supported and guided by the activities of several committees, including Data Quality, Recruitment and Retention, and Central Review, that work in tandem with the Data Coordinating Center to monitor the study. We have implemented coordinator training and feedback channels, data queries of questionable or missing data, and developed performance metrics for recruitment, retention, visit completion, data entry, recording of patient-reported outcomes, collection, shipping and accessing of biological samples and pathology materials, and processing, cataloging and accessing genetic data and materials.Results: We describe the development of data queries and site Report Cards, and their use in monitoring and encouraging excellence in site performance. We demonstrate improvements in data quality and completeness over 4 years after implementing these activities. We describe quality initiatives addressing specific challenges in collecting and cataloging whole slide images and other kidney pathology data, and novel methods of data quality assessment.Conclusions: This paper reports the CureGN experience in optimizing data quality and underscores the importance of general and study-specific data quality initiatives to maintain excellence in the research measures of a multi-center observational study.

    View details for DOI 10.1016/j.conctc.2021.100749

    View details for PubMedID 33851061

  • y A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY OF ATRASENTAN IN PATIENTS WITH IGA NEPHROPATHY (THE ALIGN STUDY) Heerspink, H., Kohan, D., Lafayette, R., Levin, A., Zhang, H., Glicklich, A., Camargo, M., King, A., Barratt, J. OXFORD UNIV PRESS. 2021: 194
  • APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis. Pediatric nephrology (Berlin, Germany) Zee, J., McNulty, M. T., Hodgin, J. B., Zhdanova, O., Hingorani, S., Jefferson, J. A., Gibson, K. L., Trachtman, H., Fornoni, A., Dell, K. M., Reich, H. N., Bagnasco, S., Greenbaum, L. A., Lafayette, R. A., Gipson, D. S., Brown, E., Kretzler, M., Appel, G., Sambandam, K. K., Tuttle, K. R., Chen, D., Atkinson, M. A., Hogan, M. C., Kaskel, F. J., Meyers, K. E., O'Toole, J., Srivastava, T., Sethna, C. B., Hladunewich, M. A., Lin, J. J., Nast, C. C., Derebail, V. K., Patel, J., Vento, S., Holzman, L. B., Athavale, A. M., Adler, S. G., Lemley, K. V., Lieske, J. C., Hogan, J. J., Gadegbeku, C. A., Fervenza, F. C., Wang, C., Matar, R. B., Singer, P., Kopp, J. B., Barisoni, L., Sampson, M. G. 2021

    Abstract

    BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging.METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes.RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features.CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

    View details for DOI 10.1007/s00467-021-04990-4

    View details for PubMedID 33646395

  • Documentation of Reproductive Health Counseling Among Women With CKD: A Retrospective Chart Review. American journal of kidney diseases : the official journal of the National Kidney Foundation Okundaye, I. O., Stedman, M. R., Rhee, J. J., O'Shaughnessy, M., Lafayette, R. A. 2021

    View details for DOI 10.1053/j.ajkd.2021.08.012

    View details for PubMedID 34571063

  • Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. American journal of kidney diseases : the official journal of the National Kidney Foundation Bomback, A. S., Appel, G. B., Gipson, D. S., Hladunewich, M. A., Lafayette, R., Nester, C. M., Parikh, S. V., Smith, R. J., Trachtman, H., Heeger, P. S., Ram, S., Rovin, B. H., Ali, S., Arceneaux, N., Ashoor, I., Bailey-Wickins, L., Barratt, J., Beck, L., Cattran, D. C., Cravedi, P., Erkan, E., Fervenza, F., Frazer-Abel, A. A., Fremeaux-Bacchi, V., Fuller, L., Gbadegesin, R., Hogan, J. J., Kiryluk, K., le Quintrec-Donnette, M., Licht, C., Mahan, J. D., Pickering, M. C., Quigg, R., Rheault, M., Ronco, P., Sarwal, M. M., Sethna, C., Spino, C., Stegall, M., Vivarelli, M., Feldman, D. L., Thurman, J. M. 2021

    Abstract

    Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents a myriad of questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anti-complement therapy trials either planned or underway, the National Kidney Foundation (NKF) facilitated an all-virtual format scientific workshop entitled, "Improving Clinical Trials for Anti-complement Therapies in Complement-mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anti-complement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, subject risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.

    View details for DOI 10.1053/j.ajkd.2021.07.025

    View details for PubMedID 34571062

  • Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP-2 Inhibitor for the Treatment of IgA Nephropathy. Kidney international reports Lafayette, R. A., Rovin, B. H., Reich, H. N., Tumlin, J. A., Floege, J., Barratt, J. 2020; 5 (11): 2032–41

    Abstract

    Introduction: Narsoplimab is a human monoclonal antibody against mannan-associated lectin-binding serine protease-2 (MASP-2). Now in a phase 3 study, narsoplimab was evaluated in a staged phase 2 study assessing safety and effectiveness in high-risk patients with IgA nephropathy (IgAN).Methods: Substudy 1 was a single-arm open-label study of 12 weekly infusions and tapered corticosteroids, with 6 weeks of follow-up. In substudy 2, patients were randomized 1:1 to receive a course of treatment consisting of once-weekly narsoplimab or vehicle infusions for 12 weeks. After 6 weeks of follow-up, both substudy 2 groups could continue in an open-label extension, receiving 1 or more narsoplimab courses at the investigator's discretion.Results: The most commonly reported adverse events (AEs) included headache, upper respiratory infection, and fatigue. Most AEs were mild or moderate and transient. No treatment-related serious AEs were reported. All 4 patients who were enrolled in substudy 1 had reductions in 24-hour urine protein excretion (UPE) at week 18, ranging from 54% to 95% compared with baseline. In substudy 2, the vehicle and narsoplimab groups had similar proteinuria reductions at week 18. Eight patients (3 vehicle, 5 narsoplimab) continued in the dosing extension; all received narsoplimab. Median reduction in 24-hour UPE in these 8 patients was 61.4% at 31 to 54 weeks postbaseline. Estimated glomerular filtration rates (eGFR) remained stable in both substudies.Conclusion: This interim analysis suggests that narsoplimab treatment is safe, is well tolerated, and may result in clinically meaningful reductions in proteinuria and stability of eGFR in high-risk patients with advanced IgAN.

    View details for DOI 10.1016/j.ekir.2020.08.003

    View details for PubMedID 33163724

  • Assessing the Impact of Losmapimod on Proteinuria in Idiopathic Focal Segmental Glomerulosclerosis. Kidney international reports Gipson, D. S., Hladunewich, M. A., Lafayette, R., Sedor, J. R., Rovin, B. H., Barbour, S. J., McMahon, A., Jennette, J. C., Nachman, P. H., Willette, R. N., Paglione, M., Gao, F., Ross Terres, J. A., Vallow, S., Holland, M. C., Thorneloe, K. S., Sprecher, D. L. 2020; 5 (8): 1228–39

    Abstract

    Introduction: Idiopathic focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. In preclinical models and biopsies of human FSGS kidneys, p38 mitogen-activated protein kinase (MAPK) has demonstrated enhanced activity; and p38 MAPK inhibition has improved disease markers. This proof-of-concept trial aimed to assess efficacy, safety,tolerability, and pharmacokinetics of losmapimod, an oral p38 MAPK inhibitor, in humans with FSGS.Methods: A single-arm, multicenter, open-label, Phase II trial (NCT02000440) was conducted in adults with FSGS; proteinuria≥2.0 g/d; estimated glomerular filtration rate (eGFR)≥45 ml/min per 1.73 m2; blood pressure<140/90 mmHg. Collapsing and genetic forms of FSGS were excluded. The primary endpoint was number of patients with≥50% proteinuria reduction and eGFR≥70% of baseline after receiving losmapimod twice-daily for 16 to 24 weeks.Results: Seventeen patients received≥1 losmapimod dose. No patients achieved the primary endpoint; therefore, the study was terminated following a prespecified interim analysis. At week 24, proteinuria reductions between 20% and<50% were observed in 4 patients and proteinuria increases >20% in 3 patients. One patient achieved a proteinuria response (≥50% reduction) at week 2 but subsequently relapsed. Losmapimod pharmacokinetics were consistent with prior studies. No serious adverse events (AEs) were reported.Conclusion: p38 MAPK inhibition with losmapimod did not result in≥50% reduction of proteinuria in patients with FSGS. However, study population heterogeneity may have contributed to our negative findings and therefore this does not eliminate the potential to demonstrate benefit in a population more sensitive to p38 MAPK inhibition if identifiable in the future by precision-medicine methods.

    View details for DOI 10.1016/j.ekir.2020.05.024

    View details for PubMedID 32775822

  • MASP-2 inhibition as a potential strategy for the management of IgA nephropathy DRUGS OF THE FUTURE Barratt, J., Lafayette, R. 2020; 45 (6): 389–96
  • JAK-STAT Activity in Peripheral Blood Cells and Kidney Tissue in IgA Nephropathy. Clinical journal of the American Society of Nephrology : CJASN Tao, J., Mariani, L., Eddy, S., Maecker, H., Kambham, N., Mehta, K., Hartman, J., Wang, W., Kretzler, M., Lafayette, R. A. 2020

    Abstract

    BACKGROUND AND OBJECTIVES: IgA nephropathy is the most common primary glomerular disease in the world. Marked by mesangial inflammation and proliferation, it generally leads to progressive kidney fibrosis. As the Janus kinase signal transducer and activator of transcription pathway has been implicated as an important mediator of diabetic kidney disease and FSGS, detailed investigation of this pathway in IgA nephropathy was undertaken to establish the basis for targeting this pathway across glomerular diseases.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Well characterized patients with IgA nephropathy and controls were studied, allowing us to compare 77 patients with biopsy-proven IgA nephropathy with 45 healthy subjects. STAT phosphorylation was assessed in peripheral blood monocytes (PBMCs) by phosphoflow before and after cytokine stimulation. Kidney Janus kinase signal transducer and activator of transcription activity was studied by immunofluorescence and by transcriptomic studies. An STAT1 activity score was established using downstream transcriptional targets of pSTAT1 and associated with disease and clinical outcomes.RESULTS: We found PBMCs to have upregulated pSTAT production at baseline in patients with IgA nephropathy with a limited reserve to respond to cytokine stimulation compared with controls. Increased staining in glomerular mesangium and endothelium was seen for Jak-2 and pSTAT1 and in the tubulointerstitial for JAK2, pSTAT1, and pSTAT3. Activation of the Janus kinase signal transducer and activator of transcription pathway was further supported by increased pSTAT1 and pSTAT3 scores in glomerular and tubulointerstitial sections of the kidney (glomerular activation Z scores: 7.1 and 4.5, respectively; P values: <0.001 and <0.001, respectively). Clinically, phosphoflow results associated with proteinuria and kidney function, and STAT1 activation associated with proteinuria but was not associated with progression.CONCLUSIONS: Janus kinase signal transducer and activator of transcription signaling was activated in patients with IgA nephropathy compared with controls. There were altered responses in peripheral immune cells and increased message and activated proteins in the kidney. These changes variably related to proteinuria and kidney function.

    View details for DOI 10.2215/CJN.11010919

    View details for PubMedID 32354727

  • Identifying Outcomes Important to Patients with Glomerular Disease and Their Caregivers. Clinical journal of the American Society of Nephrology : CJASN Carter, S. A., Gutman, T., Logeman, C., Cattran, D., Lightstone, L., Bagga, A., Barbour, S. J., Barratt, J., Boletis, J., Caster, D., Coppo, R., Fervenza, F. C., Floege, J., Hladunewich, M., Hogan, J. J., Kitching, A. R., Lafayette, R. A., Malvar, A., Radhakrishnan, J., Rovin, B. H., Scholes-Robertson, N., Trimarchi, H., Zhang, H., Azukaitis, K., Cho, Y., Viecelli, A. K., Dunn, L., Harris, D., Johnson, D. W., Kerr, P. G., Laboi, P., Ryan, J., Shen, J. I., Ruiz, L., Wang, A. Y., Lee, A. H., Fung, S., Tong, M. K., Teixeira-Pinto, A., Wilkie, M., Alexander, S. I., Craig, J. C., Tong, A., SONG-GD Investigators 2020

    Abstract

    BACKGROUND AND OBJECTIVES: Shared decision making in patients with glomerular disease remains challenging because outcomes important to patients remain largely unknown. We aimed to identify and prioritize outcomes important to patients and caregivers and to describe reasons for their choices.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We purposively sampled adult patients with glomerular disease and their caregivers from Australia, Hong Kong, the United Kingdom, and the United States. Participants identified, discussed, and ranked outcomes in focus groups using the nominal group technique; a relative importance score (between zero and one) was calculated. Qualitative data were analyzed thematically.RESULTS: Across 16 focus groups, 134 participants (range, 19-85 years old; 51% women), including 101 patients and 33 caregivers, identified 58 outcomes. The ten highest-ranked outcomes were kidney function (importance score of 0.42), mortality (0.29), need for dialysis or transplant (0.22), life participation (0.18), fatigue (0.17), anxiety (0.13), family impact (0.12), infection and immunity (0.12), ability to work (0.11), and BP (0.11). Three themes explained the reasons for these rankings: constraining day-to-day experience, impaired agency and control over health, and threats to future health and family.CONCLUSIONS: Patients with glomerular disease and their caregivers highly prioritize kidney health and survival, but they also prioritize life participation, fatigue, anxiety, and family impact.

    View details for DOI 10.2215/CJN.13101019

    View details for PubMedID 32354728

  • Facing the Vexing Problem of Recurrent FSGS after Kidney Transplantation. Clinical journal of the American Society of Nephrology : CJASN Lafayette, R. A. 2020

    View details for DOI 10.2215/CJN.14841219

    View details for PubMedID 31995516

  • Organ responses with daratumumab therapy in previously treated AL amyloidosis. Blood advances Chung, A. n., Kaufman, G. P., Sidana, S. n., Eckhert, E. n., Schrier, S. L., Lafayette, R. A., Arai, S. n., Witteles, R. M., Liedtke, M. n. 2020; 4 (3): 458–66

    Abstract

    Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)-free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

    View details for DOI 10.1182/bloodadvances.2019000776

    View details for PubMedID 32027745

  • An Open-Label Pilot Study of Adrenocorticotrophic Hormone in the Treatment of IgA Nephropathy at High Risk of Progression. Kidney international reports Zand, L., Canetta, P., Lafayette, R., Aslam, N., Jan, N., Sethi, S., Fervenza, F. C. 2020; 5 (1): 58-65

    Abstract

    IgA nephropathy (IgAN) is the most common glomerulonephritis with high risk of progression to end-stage renal disease in patients with proteinuria >1 g/24 hours. There are no known effective treatments in patients with IgAN.We conducted a prospective open-label pilot study in patients with IgAN using adrenocorticotrophic hormone (ACTH) (Acthar Gel, Mallinckrodt Pharmaceuticals, Bedminster, NJ) at a dosage of 80 units subcutaneously twice weekly for a total of 6 months and followed patients for a total of 12 months. Patients had to have urinary protein >1 g/24 hours despite adequate renin-angiotensin-aldosterone system (RAAS) blockade and estimated glomerular filtration rate (eGFR) >30 ml/min at enrollment.A total of 19 patients were recruited and followed for 1 year. At baseline, the mean age was 34.9 ± 10.5 years with 11 men and 8 women, and 14 Caucasian and 5 Asian individuals. At 12 months, there was a statistically significant decline in 24-hour urinary protein from 2.6 to 1.3 g (P = 0.007) and significant increase in serum albumin (3.79 to 3.93, P = 0.02). There was no significant change in eGFR (65.5 to 61.1 ml/min, P = 0.1). There were 0 complete remissions and 8 partial remissions (42%). There were a total of 6 infections: 2 were viral and 4 required antibiotic therapy (2 sinusitis, 1 pneumonia, 1 otitis media). The most common adverse events included acne, hot flashes, soreness, and anxiety.In summary, patients with IgAN with >1 g/24-hour urinary protein and eGFR >30 ml/min had a significant reduction in 24-hour urinary protein with stable eGFR at 12-month follow-up after being treated with 6 months of ACTH.

    View details for DOI 10.1016/j.ekir.2019.10.007

    View details for PubMedID 31922061

    View details for PubMedCentralID PMC6943772

  • Rationale and design of the Transformative Research in Diabetic Nephropathy (TRIDENT) Study KIDNEY INTERNATIONAL Townsend, R. R., Guarnieri, P., Argyropoulos, C., Blady, S., Boustany-Kari, C. M., Devalaraja-Narashimha, K., Morton, L., Mottl, A. K., Patel, U., Palmer, M., Ross, M. J., Sarov-Blat, L., Steinbugler, K., Susztak, K., Luciano, R., Ross, M., Canetta, P., Campbell, K., Hogan, J., Mottl, A., Lenz, O., Szerlip, H., Bansal, S., Brosius, C., Schelling, J., Almaani, S., Kretzler, M., Isakova, T., Avasare, R., Lafayette, R., Argyropoulos, C., TRIDENT Study Investigators 2020; 97 (1): 10–13

    View details for DOI 10.1016/j.kint.2019.09.020

    View details for Web of Science ID 000505044800003

    View details for PubMedID 31901339

  • An Open-Label Pilot Study of Adrenocorticotrophic Hormone in the Treatment of IgA Nephropathy at High Risk of Progression KIDNEY INTERNATIONAL REPORTS Zand, L., Canetta, P., Lafayette, R., Aslam, N., Jan, N., Sethi, S., Fervenza, F. C. 2020; 5 (1): 58–65
  • The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network. Clinical kidney journal Troost, J. P., Waldo, A. n., Carlozzi, N. E., Murphy, S. n., Modersitzki, F. n., Trachtman, H. n., Nachman, P. H., Reidy, K. J., Selewski, D. T., Herreshoff, E. G., Srivastava, T. n., Gibson, K. L., Derebail, V. K., Lin, J. J., Hingorani, S. n., Fornoni, A. n., Fervenza, F. C., Sambandam, K. n., Athavale, A. M., Kopp, J. B., Reich, H. N., Adler, S. G., Greenbaum, L. A., Dell, K. M., Appel, G. n., Wang, C. S., Sedor, J. n., Kaskel, F. J., Lafayette, R. A., Atkinson, M. A., Lieske, J. C., Sethna, C. B., Kretzler, M. n., Hladunewich, M. A., Lemley, K. V., Brown, E. n., Meyers, K. E., Gadegbeku, C. A., Holzman, L. B., Jefferson, J. A., Tuttle, K. R., Singer, P. n., Hogan, M. C., Cattran, D. C., Barisoni, L. n., Gipson, D. S. 2020; 13 (4): 597–606

    Abstract

    Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS).FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied.There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (-7.6 points, P = 0.02) and mobility (-4.2, P = 0.02), the number of reported symptoms was associated with worse depression (-2.7 per symptom, P = 0.009) and anxiety (-2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (-2.8 per visit, P < 0.001) and fatigue (-2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P = 0.03).PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

    View details for DOI 10.1093/ckj/sfz092

    View details for PubMedID 32905199

    View details for PubMedCentralID PMC7467600

  • Time to Initiation of Antihypertensive Therapy After Onset of Elevated Blood Pressure in Patients With Primary Proteinuric Kidney Disease. Kidney medicine Weaver, D. J., Waldo, A. n., Oh, G. J., Kamil, E. S., Elliott, M. n., Adler, S. n., Pesenson, A. n., Modes, M. M., Gipson, P. n., Lafayette, R. A., Selewski, D. T., Attalla, S. E., Eikstadt, R. n., Troost, J. P., Gipson, D. S., Massengill, S. F. 2020; 2 (2): 131–38

    Abstract

    The objective of the study was to estimate the prevalence of hypertension in patients with proteinuric kidney disease and evaluate blood pressure (BP) control.Retrospective cohort study.Data from adults and children with proteinuric kidney disease enrolled in the multicenter Kidney Research Network Registry were used for this study.Proteinuric kidney disease.Hypertension and BP control.Patients with white-coat hypertension were excluded. Patients were censored at end-stage kidney disease onset. Patients were defined as hypertensive either by hypertension diagnosis code, having 2 or more encounters with elevated BPs, or treatment with antihypertensive therapy excluding renin-angiotensin-aldosterone system blockade. Elevated BP was defined as greater than 95th percentile for children and >140/90 mm Hg in adults. Sustained BP control was defined as 2 or more consecutive encounters with BPs lower than 95th percentile for children and <140/90 mm Hg for adults. Kaplan-Meier and Cox proportional hazards analyses were used to evaluate the time to initiation of antihypertensive therapy.842 patients, 69% adults and 31% children, with a total observation period of 6,722 patient-years were included in the analysis. 644 (76%) had hypertension during observation. There was no difference in the prevalence of hypertension between children and adults (74% vs 78%; P = 0.3). Hypertension was most common among those of African American race compared with other races (90% vs 72%-75%; P = 0.003). 504 (78%) patients with hypertension achieved BP control but only 51% achieved control within 1 year. 140 (22%) patients with hypertension never achieved BP control during a median of 41 (IQR, 24-73) months of observation.Differing BP control goals that may lead to overestimation of the controlled patient population.Hypertension affects most patients with proteinuric kidney disease regardless of age. Time to BP control exceeded 1 year in 50% of patients with hypertension and 22% did not demonstrate control. This study highlights the need to address hypertension early and completely in disease management of patients with proteinuric kidney disease.

    View details for DOI 10.1016/j.xkme.2019.10.012

    View details for PubMedID 32734234

    View details for PubMedCentralID PMC7380443

  • Steroid-Associated Side Effects in Patients With Primary Proteinuric Kidney Disease. Kidney international reports Oh, G. J., Waldo, A., Paez-Cruz, F., Gipson, P. E., Pesenson, A., Selewski, D. T., Kamil, E. S., Massengill, S. F., Lafayette, R. A., Modes, M., Adler, S. G., Desmond, H., Eikstadt, R., Attalla, S., Modi, Z. J., Troost, J. P., Gipson, D. S. 2019; 4 (11): 1608-1616

    Abstract

    The goal of this study was to assess the occurrence of steroid-associated adverse events (SAAE) in patients with primary proteinuric kidney disease.The Kidney Research Network Registry consists of children and adults with primary proteinuric kidney disease. SAAEs of interest were hypertension, hyperglycemia and diabetes, overweight and obesity, short stature, ophthalmologic complications, bone disorders, infections, and psychosis. Events were identified using International Classification of Diseases, Ninth Revision/Tenth Revision codes, blood pressures, growth parameters, laboratory values, and medications. Poisson generalized estimating equations tested the association between steroid onset and dose on SAAE risk.A total of 884 participants were included in the analysis; 534 (60%) were treated with steroids. Of these, 62% had at least one SAAE. The frequency of any SAAE after initiation of steroids was 293 per 1000 person-years. The most common SAAEs were hypertension (173.7 per 1000 person-years), diabetes (78.7 per 1000 person-years), obesity (66.8 per 1000 person-years), and infections (46.1 per 1000 person-years). After adjustment for demographics, duration of kidney disease, estimated glomerular filtration rate (eGFR), proteinuria, and other therapies, steroid exposure was associated with a 40% increase in risk of any SAAE (Relative risk [RR]: 1.4; 95% confidence interval [CI]: 1.3-1.6). A 1-mg/kg per day increase in steroid dose was associated with a 2.5-fold increase in risk of any SAAE.Most patients with primary proteinuric kidney disease treated with steroids experienced at least one SAAE. Steroid therapy increased risk of hypertension, diabetes, weight gain, short stature, fractures, and infections after adjusting for disease-related factors. This study highlights the importance of surveillance and management of SAAE and provides rationale for the development of steroid minimization protocols.

    View details for DOI 10.1016/j.ekir.2019.08.019

    View details for PubMedID 31891002

    View details for PubMedCentralID PMC6933464

  • Steroid-Associated Side Effects in Patients With Primary Proteinuric Kidney Disease KIDNEY INTERNATIONAL REPORTS Oh, G. J., Waldo, A., Paez-Cruz, F., Gipson, P. E., Pesenson, A., Selewski, D. T., Kamil, E. S., Massengill, S. F., Lafayette, R. A., Modes, M., Adler, S. G., Desmond, H., Eikstadt, R., Attalla, S., Modi, Z. J., Troost, J. P., Gipson, D. S. 2019; 4 (11): 1608–16
  • INTERIM RESULTS FROM AN ONGOING PHASE 2 STUDY EVALUATING THE USE OF A MASP-2 INHIBITOR FOR THE TREATMENT OF IGA NEPHROPATHY (IGAN) Barratt, J., Leifke, E., Whitaker, S., DeTulleo, L., Lafayette, R. OXFORD UNIV PRESS. 2019
  • Standardized Outcomes in Nephrology-Glomerular Disease (SONG-GD): establishing a core outcome set for trials in patients with glomerular disease. Kidney international Carter, S. A., Lightstone, L., Cattran, D., Bagga, A., Barbour, S. J., Barratt, J., Boletis, J., Caster, D., Coppo, R., Fervenza, F. C., Floege, J., Hladunewich, M., Hogan, J. J., Kitching, A. R., Lafayette, R., Malvar, A., Radhakrishnan, J., Rovin, B. H., Zhang, H., Gutman, T., Howell, M., Logeman, C., Shen, J. I., Teixeira-Pinto, A., Alexander, S. I., Cho, Y., Craig, J. C., Harris, D., Johnson, D. W., Kerr, P. G., Ryan, J., Viecelli, A. K., Wang, A. Y., Wilkie, M., Scholes-Robertson, N., Tong, A., SONG-GD Initiative 2019; 95 (6): 1280–83

    View details for DOI 10.1016/j.kint.2019.01.047

    View details for PubMedID 31122702

  • Plasma Zonulin Levels in Childhood Nephrotic Syndrome FRONTIERS IN PEDIATRICS Trachtman, H., Gipson, D. S., Lemley, K. V., Troost, J. P., Faul, C., Morrison, D. J., Vento, S. M., Ahn, D., Goldberg, J. D., Sedor, J., Dell, K., Schachere, M., Lemley, K., Whitted, L., Srivastava, T., Haney, C., Sethna, C., Grammatikopoulos, K., Appel, G., Toledo, M., Greenbaum, L., Wang, C., Lee, B., Adler, S., Nast, C., La Page, J., Athavale, A., Itteera, M., Neu, A., Boynton, S., Fervenza, F., Hogan, M., Lieske, J., Chernitskiy, V., Kaskel, F., Kumar, N., Flynn, P., Kopp, J., Castro-Rubio, E., Brede, E., Trachtman, H., Zhdanova, O., Modersitzki, F., Vento, S., Lafayette, R., Mehta, K., Gadegbeku, C., Johnstone, D., Pfeffer, Z., Cattran, D., Hladunewich, M., Reich, H., Ling, P., Romano, M., Fornoni, A., Barisoni, L., Bidot, C., Kretzler, M., Gipson, D., Williams, A., Pitter, R., Nachman, P., Gibson, K., Grubbs, S., Froment, A., Holzman, L., Meyers, K., Kallem, K., Cerecino, F. J., Sambandam, K., Brown, E., Johnson, N., Jefferson, A., Hingorani, S., Tuttle, K., Klepach, K., Dismuke, S., Cooper, A., Freedman, B., Lin, J. J., Spainhour, M., Gray, S., Kretzler, M., Barisoni, L., Gadegbeku, C., Gillespie, B., Gipson, D., Gizinski, B., Holzman, L., Mariani, L., Sampson, M., Song, P., Troost, J., Zee, J., Herreshoff, E., Kincaid, C., Lienczewski, C., Mainieri, T., Williams, A., NEPTUNE Cohort Study 2019; 7
  • Health-related quality of life in glomerular disease KIDNEY INTERNATIONAL Canetta, P. A., Troost, J. P., Mahoney, S., Kogon, A. J., Carlozzi, N., Bartosh, S. M., Cai, Y., Davis, T., Fernandez, H., Fornoni, A., Gbadegesin, R. A., Herreshoff, E., Mahan, J. D., Nachman, P. H., Selewski, D. T., Sethna, C. B., Srivastava, T., Tuttle, K. R., Wang, C., Falk, R. J., Gharavi, A. G., Gillespie, B. W., Greenbaum, L. A., Holzman, L. B., Kretzler, M., Robinson, B. M., Smoyer, W. E., Guay-Woodford, L. M., Reeve, B., Gipson, D. S., Ahn, W., Appel, G. B., Babayev, R., Batal, I., Bomback, A. S., Brown, E., Campenot, E. S., Canetta, P., Carlassara, L., Chan, B., Chatterjee, D., D'Agati, V. D., Delbarba, E., Dogra, S., Foroncewicz, B., Ghiggeri, G., Hines, W. H., Husain, S., Jain, N. G., Khairallah, P., Kil, B., Kiryluk, K., Jeyabalan, A., Lau, W. L., Lin, F., Lugani, F., Marasa, M., Markowitz, G., Mohan, S., Mu, X., Mucha, K., Nickolas, T. L., Piva, S., Radhakrishnan, J., Rao, M. K., Renu, R., Sanna-Cherchi, S., Santoriello, D., Shirazian, S., Stokes, M. B., Uy, N., Valeri, A. M., Al-Uzri, A., Ambruzs, J., Ashoor, I., Aviles, D., Baracco, R., Barcia, J., Bartosh, S., Belsha, C., Bowers, C., Braun, M. C., Chernitskiy, V., Chishti, A., Claes, D., Clark, K., Cramer, C., Davis, K., Erkan, E., Feig, D., Freundlich, M., Gaut, J., Gbadegesin, R., Hanna, M., Hidalgo, G., Hooper, D., Hunley, T. E., Jain, A., Kallash, M., Kamel, M., Khalid, M., Klein, J. B., Kump, T., Lane, J. C., Liapis, H., Mahan, J., Mathews, N., Nester, C., Pan, C., Patterson, L., Patel, H., Raad, A., Revell, A., Rheault, M. N., Silva, C., Sreedharan, R., Steinke, J., Sumner, S., Twombley, K., Wenderfer, S. E., Vasylyeva, T. L., Weaver, D. J., Wong, C. S., Yin, H., Achanti, A., Almaani, S., Ayoub, I., Budisavljevic, M., D'Angelo, M., Fatima, H., Falk, R., Fogo, A., Gibson, K., Glenn, D., Hogan, S., Jennette, J., Julian, B., Kidd, J., Laurin, L., Massey, H., Mottl, A., Murphy, S., Nachman, P., Nadasdy, T., Novak, J., Parikh, S., Poulton, C., Powell, T., Renfrow, M., Reynolds, M., Rizk, D., Rovin, B., Royal, V., Sanghani, N., Self, S., Adler, S., Alachkar, N., Alpers, C., Matar, R., Avila-Casado, C., Bagnasco, S., Brede, E., Brown, E., Cattran, D., Choi, M., Dell, K. M., Dewalt, D., Denburg, M., Dukkipati, R., Fervenza, F. C., Gadegbeku, C., Gipson, P., Gonzalez-Zea, A., Hasely, L., Hendren, E., Hingorani, S., Hladunewich, M., Hogan, J., Hou, J., Jefferson, J., Jhaveri, K., Johnstone, D. B., Kaskel, F., Kogan, A., Kopp, J., Lafayette, R., Lemley, K., Malaga-Dieguez, L., Meyers, K., Neu, A., O'Shaughnessy, M., O'Toole, J. F., Oliverio, A., Palmer, M., Parekh, R., Pitter, R., Reich, H., Reidy, K., Rondon, H., Sambandam, K. K., Sampson, M., Sedor, J. R., Schelling, J., Sperati, J. C., Swiatecka-Urban, A., Trachtman, H., Waldman, M., Weisstuch, J., Wiggins, R., Williams, D., Winkler, C., Vento, S., Young, E., Zhdanova, O., Barisoni, L., Beil, C., Eikstadt, R., Gillespie, B., Graff, J., Hewitt, S., Hill-Callahan, P., Helmuth, M., Lienczewski, C., Mansfield, S., Mariani, L., McCullough, K., Moore, N., Nast, C. C., Sexton, M., Troost, J., Wladkowski, M., Zee, J., Zinsser, D., CureGN Consortium 2019; 95 (5): 1209–24

    Abstract

    There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

    View details for DOI 10.1016/j.kint.2018.12.018

    View details for Web of Science ID 000465213400024

    View details for PubMedID 30898342

  • Cause of kidney disease and cardiovascular events in a national cohort of US patients with end- stage renal disease on dialysis: a retrospective analysis EUROPEAN HEART JOURNAL O'Shaughnessy, M. M., Liu, S., Montez-Rath, M. E., Lafayette, R. A., Winkelmayer, W. C. 2019; 40 (11): 887-+
  • CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease AMERICAN JOURNAL OF KIDNEY DISEASES Mariani, L. H., Bomback, A. S., Canetta, P. A., Flessner, M. F., Helmuth, M., Hladunewich, M. A., Hogan, J. J., Kiryluk, K., Nachman, P. H., Nast, C. C., Rheault, M. N., Rizk, D., Trachtman, H., Wenderfer, S. E., Bowers, C., Hill-Callahan, P., Marasa, M., Poulton, C. J., Revell, A., Vento, S., Barisoni, L., Cattran, D., D'Agati, V., Jennette, J., Klein, J. B., Laurin, L., Twombley, K., Falk, R. J., Gharavi, A. G., Gillespie, B. W., Gipson, D. S., Greenbaum, L. A., Holzman, L. B., Kretzler, M., Robinson, B., Smoyer, W. E., Guay-Woodford, L. M., Ahn, W., Appel, G. B., Babayev, R., Batal, I., Brown, E., Campenot, E. S., Canetta, P., Carlassara, L., Chan, B., Chatterjee, D., D'Agati, V. D., Delbarba, E., Dogra, S., Fernandez, H., Foroncewicz, B., Ghiggeri, G., Hines, W. H., Husain, S., Jain, N. G., Khairallah, P., Kil, B., Jeyabalan, A., Lau, W. L., Lin, F., Lugani, F., Markowitz, G., Mohan, S., Mu, X., Mucha, K., Nickolas, T. L., Piva, S., Radhakrishnan, J., Rao, M. K., Regunathan-Shenk, R., Sanna-Cherchi, S., Santoriello, D., Shirazian, S., Stokes, M. B., Yu, N., Valeri, A. M., Zviti, R., Al-Uzri, A., Ambruzs, J., Ashoor, I., Aviles, D., Baracco, R., Barcia, J., Bartosh, S., Belsha, C., Braun, M. C., Cai, Y., Chernitskiy, V., Chishti, A., Claes, D., Clark, K., Cramer, C., Davis, K., Dutcher, A., Erkan, E., Feig, D., Freundlich, M., Gaut, J., Gbadegesin, R., Hanna, M., Hidalgo, G., Hooper, D., Hunley, T. E., Jain, A., Kallash, M., Kamel, M., Khalid, M., Kump, T., Lane, J. C., Liapis, H., Mahan, J., Mathews, N., Nester, C., Pan, C., Patterson, L., Patel, H., Raad, A., Silva, C., Sreedharan, R., Srivastava, T., Steinke, J., Sumner, S., Vasylyeva, T. L., Wang, C., Weaver, D. J., Wong, C. S., Yin, H., Achanti, A., Almaani, S., Ayoub, I., Budisavljevic, M., D'Angelo, M., Derebail, V., Fatima, H., Falk, R., Fogo, A., Gibson, K., Glenn, D., Hogan, S., Jain, K., Julian, B., Kidd, J., Massey, H., Mottl, A., Murphy, S., Nadasdy, T., Novak, J., Parikh, S., Poulton, C., Powell, T., Reeve, B., Renfrow, M., Reynolds, M., Rizk, D., Rovin, B., Royal, V., Saha, M., Sanghani, N., Self, S., Adler, S., Alachkar, N., Alpers, C., Matar, R., Avila-Casado, C., Bagnasco, S., Brede, E., Brown, E., Cattran, D., Choi, M., Contreras, G., Dell, K. M., Dewalt, D., Denburg, M., Dukkipati, R., Fervenza, F. C., Fornoni, A., Gadegbeku, C., Gipson, P., Gonzalez-Zea, A., Hasely, L., Hendren, E., Hingorani, S., Hladunewich, M., Hogan, J., Hou, J., Jefferson, J., Jhaveri, K., Johnstone, D. B., Kaskel, F., Kogan, A., Kopp, J., Lafayette, R., Lemley, K., Malaga-Dieguez, L., Meyers, K., Neu, A., O'Shaughnessy, M., O'Toole, J. F., Oliverio, A., Palmer, M., Parekh, R., Pitter, R., Reich, H., Reidy, K., Rondon, H., Sambandam, K. K., Sampson, M., Sedor, J. R., Selewski, D. T., Sethna, C. B., Schelling, J., Sperati, J. C., Swiatecka-Urban, A., Tuttle, K. R., Waldman, M., Weisstuch, J., Wiggins, R., Williams, D., Winkler, C., Young, E., Zhdanova, O., Beil, C., Eikstadt, R., Gillespie, B., Graff, J., Hewitt, S., Herreshoff, E., Lienczewski, C., Mansfield, S., Mariani, L., McCullough, K., Moore, N., Robinson, B. M., Sexton, M., Troost, J., Wladkowski, M., Zee, J., Zinsser, D., CureGN Consortium 2019; 73 (2): 218–29

    Abstract

    Glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A (IgA) nephropathy, share clinical presentations, yet result from multiple biological mechanisms. Challenges to identifying underlying mechanisms, biomarkers, and new therapies include the rarity of each diagnosis and slow progression, often requiring decades to measure the effectiveness of interventions to prevent end-stage kidney disease (ESKD) or death.Multicenter prospective cohort study.Cure Glomerulonephropathy (CureGN) will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (including IgA vasculitis) and a first diagnostic kidney biopsy within 5 years. Patients with ESKD and those with secondary causes of glomerular disease are excluded.Clinical data, including medical history, medications, family history, and patient-reported outcomes, are obtained, along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year.Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment, including infection, malignancy, cardiovascular, and thromboembolic events.The study design supports multiple longitudinal analyses leveraging the diverse data domains of CureGN and its ancillary program. At 2,400 patients and an average of 2 years' initial follow-up, CureGN has 80% power to detect an HR of 1.4 to 1.9 for proteinuria remission and a mean difference of 2.1 to 3.0mL/min/1.73m2 in estimated glomerular filtration rate per year.Current follow-up can only detect large differences in ESKD and death outcomes.Study infrastructure will support a broad range of scientific approaches to identify mechanistically distinct subgroups, identify accurate biomarkers of disease activity and progression, delineate disease-specific treatment targets, and inform future therapeutic trials. CureGN is expected to be among the largest prospective studies of children and adults with glomerular disease, with a broad goal to lessen disease burden and improve outcomes.

    View details for PubMedID 30420158

    View details for PubMedCentralID PMC6348011

  • Organoid single cell profiling identifies a transcriptional signature of glomerular disease JCI INSIGHT Harder, J. L., Menon, R., Otto, E. A., Zhou, J., Eddy, S., Wys, N. L., O'Connor, C., Luo, J., Nair, V., Cebrian, C., Spence, J. R., Bitzer, M., Troyanskaya, O. G., Hodgin, J. B., Wiggins, R. C., Freedman, B. S., Kretzler, M., Cohen, C., Schmid, H., Fischereder, M., Weber, L., Schloendorff, D., Sraer, J., Ronco, P., Rastaldi, M., D'Amico, G., Doran, P., Brady, H., Moenks, D., Wanner, C., Rees, A., Strutz, F., Mueller, G., Mertens, P., Floege, J., Braun, N., Risler, T., Gesualdo, L., Schena, F., Wolf, G., Oberbauer, R., Kerjaschki, D., Banas, B., Kraemer, B., Saleem, M., Wuethrich, R., Samtleben, W., Peters, H., Neumayer, H., Daha, M., Ivens, K., Grabensee, B., Mampaso, F., Oh, J., Schaefer, F., Zeier, M., Groene, H., Gross, P., Tonolo, G., Tesar, V., Rupprecht, H., Pavenstaedt, H., Marti, H., Gerth, J., Sedor, J., Dell, K., Schachere, M., Lemley, K., Whitted, L., Srivastava, T., Haney, C., Sethna, C., Gurusinghe, S., Appel, G., Toledo, M., Greenbaum, L., Wang, C., Lee, B., Adler, S., Nast, C., La Page, J., Athavale, A., Itteera, M., Neu, A., Boynton, S., Fervenza, F., Hogan, M., Lieske, J., Chernitskiy, Kaskel, F., Kumar, N., Flynn, P., Kopp, J., Castro-Rubio, E., Brede, E., Trachtman, H., Zhdanova, O., Modersitzki, F., Vento, S., Lafayette, R., Mehta, K., Gadegbeku, C., Johnstone, D., Pfeffer, Z., Cattran, D., Hladunewich, M., Reich, H., Ling, P., Romano, M., Fornoni, A., Barisoni, L., Bidot, C., Kretzler, M., Gipson, D., Williams, A., Pitter, R., Nachman, P., Gibson, K., Grubbs, S., Froment, A., Holzman, L., Meyers, K., Kallem, K., Cerecino, F. J., Sambandam, K., Brown, E., Johnson, N., Jefferson, A., Hingorani, S., Tuttle, K., Klepach, K., Kelton, M., Cooper, A., Freedman, B., Lin, J. J., Spainhour, M., Gray, S., Gillespie, B., Mariani, L., Sampson, M., Song, P., Troost, J., Zee, J., Herreshoff, E., Kincaid, C., Lienczewski, C., Mainieri, T., Abbott, K., Roy, C., Urv, T., Brooks, P. J., European Renal cDNA Bank ERCB, Nephrotic Syndrome Study Network N 2019; 4 (1)

    Abstract

    Podocyte injury is central to many forms of kidney disease, but transcriptional signatures reflecting podocyte injury and compensation mechanisms are challenging to analyze in vivo. Human kidney organoids derived from pluripotent stem cells (PSCs), a potentially new model for disease and regeneration, present an opportunity to explore the transcriptional plasticity of podocytes. Here, transcriptional profiling of more than 12,000 single cells from human PSC-derived kidney organoid cultures was used to identify robust and reproducible cell lineage gene expression signatures shared with developing human kidneys based on trajectory analysis. Surprisingly, the gene expression signature characteristic of developing glomerular epithelial cells was also observed in glomerular tissue from a kidney disease cohort. This signature correlated with proteinuria and inverse eGFR, and it was confirmed in an independent podocytopathy cohort. Three genes in particular were further characterized as potentially novel components of the glomerular disease signature. We conclude that cells in human PSC-derived kidney organoids reliably recapitulate the developmental transcriptional program of podocytes and other cell lineages in the human kidney and that transcriptional profiles seen in developing podocytes are reactivated in glomerular disease. Our findings demonstrate an approach to identifying potentially novel molecular programs involved in the pathogenesis of glomerulopathies.

    View details for DOI 10.1172/jci.insight.122697

    View details for Web of Science ID 000455454900004

    View details for PubMedID 30626756

  • A Changing Landscape of Mortality for Systemic Light Chain Amyloidosis. JACC. Heart failure Barrett, C. D., Dobos, K. n., Liedtke, M. n., Tuzovic, M. n., Haddad, F. n., Kobayashi, Y. n., Lafayette, R. n., Fowler, M. B., Arai, S. n., Schrier, S. n., Witteles, R. M. 2019

    Abstract

    The purpose of this study was to address the overall trends in mortality since the adoption of modern therapies for treatment of systemic amyloidosis, and to reconsider the prognostic significance of individual components of the current staging system.Systemic light chain (AL) amyloidosis involves deposition of immunoglobulin light chains in organs throughout the body and is known to have the highest mortality when significant cardiac involvement is present. Survival has historically been poor but may be improving as systemic therapies continue to advance. This study assesses whether recent advancements in light chain directed therapy have led to improved survival in patients with systemic AL amyloidosis.We reviewed all cases of patients who were evaluated for a new diagnosis of AL amyloidosis at the Stanford Amyloid Center between 2009 and 2016. Patients' stage at diagnosis was determined according to the most commonly used staging system. Clinical data, overall survival from diagnosis, and the independent influence of each component of the staging system were analyzed.At total of 194 patients were identified with a new diagnosis of systemic AL amyloidosis. Median overall survival was 59 months and 6 months for stage 3 and 4 patients, respectively. Median overall survival was not reached in stage 1 and 2 groups, as survival was >50% by the end of the study. Mean overall survival was 118 months, 76 months, 64 months, and 27 months in Stages 1, 2, 3, and 4 patients, respectively. Although N-terminal pro-B-type natriuretic peptide and troponin I concentrations had large effects on prognosis, differences in serum free light chains (dFLC) on initial staging laboratory results ≥18 mg/dl, part of the current staging system, did not contribute significantly to prognosis for values ≥5 mg/dl.Survival for patients with systemic AL amyloidosis has improved for patients at all stages of disease in the present era of rapid advancements in light chain-reducing therapies. Cardiac biomarkers at diagnosis, but not baseline dFLC ≥18 mg/dl, continue to provide important prognostic information.

    View details for DOI 10.1016/j.jchf.2019.07.007

    View details for PubMedID 31606365

  • Noninvasive Urinary Monitoring of Progression in IgA Nephropathy. International journal of molecular sciences Yang, J. Y., Sarwal, R. D., Fervenza, F. C., Sarwal, M. M., Lafayette, R. A. 2019; 20 (18)

    Abstract

    Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies.

    View details for DOI 10.3390/ijms20184463

    View details for PubMedID 31510053

  • Increasing Options for First-Line Therapy in Primary FSGS? Kidney international reports Lafayette, R. A. 2019; 4 (1): 8–10

    View details for PubMedID 30596161

  • Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. The New England journal of medicine Fervenza, F. C., Appel, G. B., Barbour, S. J., Rovin, B. H., Lafayette, R. A., Aslam, N. n., Jefferson, J. A., Gipson, P. E., Rizk, D. V., Sedor, J. R., Simon, J. F., McCarthy, E. T., Brenchley, P. n., Sethi, S. n., Avila-Casado, C. n., Beanlands, H. n., Lieske, J. C., Philibert, D. n., Li, T. n., Thomas, L. F., Green, D. F., Juncos, L. A., Beara-Lasic, L. n., Blumenthal, S. S., Sussman, A. N., Erickson, S. B., Hladunewich, M. n., Canetta, P. A., Hebert, L. A., Leung, N. n., Radhakrishnan, J. n., Reich, H. N., Parikh, S. V., Gipson, D. S., Lee, D. K., da Costa, B. R., Jüni, P. n., Cattran, D. C. 2019; 381 (1): 36–46

    Abstract

    B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06).Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).

    View details for DOI 10.1056/NEJMoa1814427

    View details for PubMedID 31269364

  • A rare case of Alport syndrome, atypical hemolytic uremic syndrome and Pauci-immune crescentic glomerulonephritis. BMC nephrology Tao, J., Lieberman, J., Lafayette, R. A., Kambham, N. 2018; 19 (1): 355

    Abstract

    BACKGROUND: Renal thrombotic microangiopathy (TMA) is occasionally seen in biopsies with pauci-immune necrotizing crescentic glomerulonephritis (PCGN). Recent study indicated that the complement activation is more prominent in the ANCA-negative glomerulonephritis.CASE PRESENTATION: We report a case of concurrent TMA and PCGN without ANCA positivity. Interestingly, our patient also had biopsy features supportive of Alport syndrome (AS). Genetic studies identified variants and polymorphisms in alternative complement pathway genes that confer substantial risk of developing atypical hemolytic uremic syndrome (aHUS).CONCLUSIONS: Abnormal activation in complement pathway may represent a common pathogenic link between these three distinct entities.

    View details for PubMedID 30541482

  • Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study KIDNEY INTERNATIONAL REPORTS Selewski, D. T., Ambruzs, J. M., Appel, G. B., Bomback, A. S., Matar, R., Cai, Y., Cattran, D. C., Chishti, A. S., D'Agati, V. D., D'Alessandri-Silva, C. J., Gbadegesin, R. A., Hogan, J. J., Iragorri, S., Jennette, J., Julian, B. A., Khalid, M., Lafayette, R. A., Liapis, H., Lugani, F., Mansfield, S. A., Mason, S., Nachman, P. H., Nast, C. C., Nester, C. M., Noone, D. G., Novak, J., O'Shaughnessy, M. M., Reich, H. N., Rheault, M. N., Rizk, D., Saha, M. K., Sanghani, N. S., Sperati, C., Sreedharan, R., Srivastava, T., Swiatecka-Urban, A., Twombley, K., Vasylyeva, T. L., Weaver, D. J., Yin, H., Zee, J., Falk, R. J., Gharavi, A. G., Gillespie, B. W., Gipson, D. S., Greenbaum, L. A., Holzman, L. B., Kretzler, M., Robinson, B. M., Smoyer, W. E., Flessner, M., Guay-Woodford, L. M., Kiryluk, K., CureGN Consortium 2018; 3 (6): 1373–84

    Abstract

    The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients.Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment.A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001).This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies.

    View details for PubMedID 30450464

  • JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis. Kidney international Tao, J., Mariani, L., Eddy, S., Maecker, H., Kambham, N., Mehta, K., Hartman, J., Wang, W., Kretzler, M., Lafayette, R. A. 2018

    Abstract

    Focal segmental glomerular sclerosis (FSGS) is a devastating disease with limited treatment options and poor prognosis. Activated JAK-STAT signaling has been implicated in other kidney diseases. Since new technologies allow us to better evaluate changes in systemic and renal JAK-STAT activity as it relates to kidney function, we examined this in 106 patients with biopsy-proven FSGS compared to 47 healthy control individuals. Peripheral immune function was assessed in peripheral blood mononuclear cells by phosphoflow studies before and after cytokine stimulation. Kidney JAK-STAT activity was measured by immunofluorescence and by transcriptomics. A STAT1 activity score was calculated by evaluating message status of downstream targets of pSTAT1. Peripheral blood mononuclear cells were found to be upregulated in terms of pSTAT production at baseline in FSGS and to have limited reserve to respond to various cytokines. Increased staining for components of the JAK-STAT system in FSGS by microscopy was found. Furthermore, we found transcriptomic evidence for activation of JAK-STAT that increased pSTAT 1 and pSTAT 3 in glomerular and tubulointerstitial sections of the kidney. Some of these changes were associated with the likelihood of remission of proteinuria and progression of disease. JAK-STAT signaling is altered in patients with FSGS as compared to healthy controls with activated peripheral immune cells, increased message in the kidney and increased activated proteins in the kidney. Thus, our findings support immune activation in this disease and point to the JAK-STAT pathway as a potential target for treatment of FSGS.

    View details for PubMedID 30093081

  • Cause of kidney disease and cardiovascular events in a national cohort of US patients with end-stage renal disease on dialysis: a retrospective analysis. European heart journal O'Shaughnessy, M. M., Liu, S., Montez-Rath, M. E., Lafayette, R. A., Winkelmayer, W. C. 2018

    Abstract

    Aims: End-stage renal disease (ESRD) is a strong cardiovascular risk factor. We aimed to determine the extent to which cause of kidney disease independently contributes to this risk.Methods and results: Using a national US ESRD registry, we selected patients with eight different causes of ESRD who initiated dialysis 1997-2014. We used proportional sub-distribution hazard models, with non-cardiovascular death or kidney transplantation as competing risks, to estimate hazard ratios (HRs) for a first composite cardiovascular event (myocardial infarction, ischaemic stroke, or cardiovascular or cerebrovascular death), by cause of ESRD. The population was restricted to those using Medicare insurance at Day 91 after dialysis initiation (when most patients become Medicare eligible). Outcomes were ascertained from Medicare claims or Death Notifications. Among the 658168 patients identified, composite event rates ranged from 3.5/100 person-years in IgA nephropathy to 14.6/100 person-years in diabetic nephropathy (DN). After adjusting for demographics, socioeconomic factors, comorbidities, dialysis modality, and laboratory values, cardiovascular event HRs differed significantly by cause of ESRD. Comparing to IgA nephropathy, the adjusted HR was highest for DN [aHR=2.97, 95% confidence interval (CI) 2.77-3.20], next highest for lupus nephritis (aHR=1.86, 95% CI 1.71-2.03), and thereafter ranged from 1.29 (95% CI 1.19-1.39) in autosomal dominant polycystic kidney disease to 1.67 (95% CI 1.52-1.83) in membranous nephropathy.Conclusion: High cardiovascular event rates in dialysis patients vary considerably by cause of ESRD. Determining underlying reasons for these differences might provide new insights in to cardiovascular disease mechanisms as well as inform future drug development and clinical trial design.

    View details for PubMedID 30085056

  • NephCure Accelerating Cures Institute: A Multidisciplinary Consortium to Improve Care for Nephrotic Syndrome KIDNEY INTERNATIONAL REPORTS Gipson, D. S., Selewski, D. T., Massengill, S. F., Modes, M., Desmond, H., Lee, L., Kamil, E., Elliott, M. R., Adler, S. G., Oh, G., Lafayette, R. A., Gipson, P. E., Sinha, A., Bagga, A., Pesenson, A., Courtlandt, C., Spino, C., Eikstadt, R., Pitter, R., Attalla, S., Waldo, A., Winneker, R., Carlozzi, N. E., Troost, J. P., Smokler, I., Stone, M. 2018; 3 (2): 439–46
  • Immunoglobulin A Nephropathy: Advances in Understanding of Pathogenesis and Treatment. American journal of nephrology Lafayette, R. A., Kelepouris, E. 2018; 47 Suppl 1: 43–52

    Abstract

    BACKGROUND: Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis and has clinical associations with a wide range of inflammatory and infectious diseases. There is a substantial variation in clinical course and outcomes, with many patients not diagnosed until they present with sequelae, which may include gross hematuria, hypertension, renal insufficiency, and/or significant proteinuria. Treatment options are currently limited and directed mainly toward control of these sequelae and have limited ability to reduce the incidence of end-stage renal disease or treat the primary IgA defect.SUMMARY: Growing knowledge about the pathogenesis of IgA nephropathy and research into its genetic basis are helping to elucidate the course of this widely variable disease. IgA accumulation in the kidneys is thought to be the result of a number of different pathways in a "multi-hit" process that includes an initial traumatic trigger (often infection related) and subsequent memory responses that are amplified in those with a genetic predisposition to the disease and lead to an inflammatory response in susceptible individuals. Genome-wide association studies are providing new insights into the genetic variance of this autoimmune disease and are yielding information that may address both its causes and consequences. Key Messages: New treatment approaches are urgently required for the management of patients with IgA nephropathy. Novel interventions based around its inflammatory nature and "multi-hit" pathogenesis are being investigated to potentially limit disease progression.

    View details for PubMedID 29852501

  • A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lafayette, R. A., Canetta, P. A., Ravin, B. H., Appel, G. B., Novak, J., Nath, K. A., Sethi, S., Tumlin, J. A., Mehta, K., Hogan, M., Erickson, S., Julian, B. A., Leung, N., Enders, F. T., Brown, R., Knoppova, B., Hall, S., Fervenza, F. C. 2017; 28 (4): 1306-1313

    Abstract

    IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m(2), to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.

    View details for Web of Science ID 000397832900032

  • Validating identification of patients with small vessel vasculitis, with or without renal involvement, using administrative healthcare records. Clinical nephrology O'Shaughnessy, M. M., Cheng, X. S., Montez-Rath, M. E., Lafayette, R. A., Winkelmayer, W. C. 2017; 87 (2017) (3): 159-162

    View details for DOI 10.5414/CN109035

    View details for PubMedID 28102817

  • Kidney Transplantation Rates Across Glomerulonephritis Subtypes in the United States. Transplantation O'Shaughnessy, M. M., Liu, S., Montez-Rath, M. E., Lafayette, R. A., Winkelmayer, W. C. 2017

    Abstract

    Whether kidney transplantation rates differ by glomerulonephritis (GN) subtype remains largely unknown.Using the US Renal Data System, we identified all adult patients with ESRD attributed to 1 of 6 GN subtypes who initiated dialysis in the US (1996-2013). Patients with diabetic nephropathy (DN) and autosomal-dominant polycystic kidney disease (ADPKD) served as "external" non-GN comparators. Using Cox proportional hazards regression, with death considered a competing risk, we estimated hazard ratios [HRs (95% confidence intervals)] for first kidney transplantation, controlling for year, demographics, comorbidities, socioeconomic factors, and Organ Procurement Organization (OPO).Among 718,480 patients studied, unadjusted and multivariable-adjusted transplant rates differed considerably across GN subtypes. Adjusted transplant rates were highest for patients with IgA nephropathy (IgAN, referent) and lower for all other groups: focal segmental glomerulosclerosis, HR=0.80 (0.77-0.82); membranous nephropathy, HR=0.88 (0.83-0.93); membranoproliferative GN, HR=0.84 (0.76-0.92); lupus nephritis, HR=0.69 (0.66-0.71); vasculitis, HR=0.66 (0.61-0.70); DN, HR=0.50 (0.47-0.52); ADPKD, HR=0.85 (0.82-0.88). Reduced kidney transplantation rates among comparator groups were driven more so by lower rates of waitlisting [HRs, vs. IgAN, ranged from 0.49 for DN to 0.92 for membranous nephropathy or ADPKD] than by lower rates of deceased donor kidney transplantation after waitlisting [rates were only significantly lower, vs. IgAN, for those with secondary GN subtypes: lupus nephritis, HR=0.91 (0.86-0.97), vasculitis, HR=0.85 (0.76-0.94); DN, HR=0.73 (0.69-0.77)].Identifying underlying reasons for apparent disease-specific barriers to kidney transplantation might inform center-specific transplant candidate selection procedures, along with national organ allocation policies, leading to more equitable patient care and improved patient outcomes.

    View details for DOI 10.1097/TP.0000000000001657

    View details for PubMedID 28207635

  • Kidney Transplantation Outcomes across GN Subtypes in the United States JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY O'Shaughnessy, M. M., Liu, S., Montez-Rath, M. E., Lenihan, C. R., Lafayette, R. A., Winkelmayer, W. C. 2017; 28 (2): 632-644

    Abstract

    Differences in kidney transplantation outcomes across GN subtypes have rarely been studied. From the US Renal Data System, we identified all adult (≥18 years) first kidney transplant recipients (1996-2011) with ESRD attributed to one of six GN subtypes or two comparator kidney diseases. We computed hazard ratios (HRs) for death, all-cause allograft failure, and allograft failure excluding death as a cause (competing risks framework) using Cox proportional hazards regression. Among the 32,131 patients with GN studied, patients with IgA nephropathy (IgAN) had the lowest mortality rates and patients with IgAN or vasculitis had the lowest allograft failure rates. After adjusting for patient- and transplant-related factors, compared with IgAN (referent), FSGS, membranous nephropathy, membranoproliferative GN, lupus nephritis, and vasculitis associated with HRs (95% confidence intervals) for death of 1.57 (1.43 to 1.72), 1.52 (1.34 to 1.72), 1.76 (1.55 to 2.01), 1.82 (1.63 to 2.02), and 1.56 (1.34 to 1.81), respectively, and with HRs for allograft failure excluding death as a cause of 1.20 (1.12 to 1.28), 1.27 (1.14 to 1.41), 1.50 (1.36 to 1.66), 1.11 (1.02 to 1.20), and 0.94 (0.81 to 1.09), respectively. Considering external comparator groups, and comparing with IgAN, autosomal dominant polycystic kidney disease (ADPKD) and diabetic nephropathy associated with higher HRs for mortality [1.22 (1.12 to 1.34) and 2.57 (2.35 to 2.82), respectively], but ADPKD associated with a lower HR for allograft failure excluding death as a cause [0.85 (0.79 to 0.91)]. Reasons for differential outcomes by GN subtype and cause of ESRD should be examined in future research.

    View details for DOI 10.1681/ASN.2016020126

    View details for Web of Science ID 000393017600025

    View details for PubMedID 27432742

  • Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M. n., Kobayashi, Y. n., Wheeler, M. n., Barrett, C. n., Liedtke, M. n., Lafayette, R. n., Schrier, S. n., Haddad, F. n., Witteles, R. n. 2017; 120 (8): 1381–86

    Abstract

    Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

    View details for PubMedID 28844519

  • Differences in Initial Hemodialysis Vascular Access Use Among Glomerulonephritis Subtypes in the United States AMERICAN JOURNAL OF KIDNEY DISEASES O'Shaughnessy, M. M., Montez-Rath, M. E., Zheng, Y., Lafayette, R. A., Winkelmayer, W. C. 2016; 67 (4): 638-647

    Abstract

    The type of vascular access used for hemodialysis affects patient morbidity and mortality. Whether vascular access types differ by glomerulonephritis (GN) subtype in the US hemodialysis population has not been investigated.Cross-sectional observational study.We identified all adult (aged ≥ 18 years) patients within the US Renal Data System who initiated hemodialysis therapy from July 2005 through December 2011 with a diagnosis of end-stage renal disease attributed to any of 4 primary (focal segmental glomerulosclerosis, immunoglobulin A nephropathy [reference group], membranous nephropathy, and membranoproliferative GN) or 2 secondary (lupus nephritis and vasculitis) GN subtypes.GN subtype.ORs with 95% CIs for arteriovenous fistula versus central venous catheter (CVC) use and for arteriovenous graft versus CVC use were computed using multinomial logistic regression, with adjustment for demographic, socioeconomic, comorbidity, and duration of nephrology care covariates.Among 29,015 patients, CVC use at initiation of hemodialysis therapy was substantially higher in patients with lupus nephritis (89.2%) or vasculitis (91.2%) compared with patients with primary GN subtypes (72.7%-79.8%). After adjustment and compared with patients with immunoglobulin A nephropathy, patients with lupus nephritis or vasculitis were as likely to have used an arteriovenous graft (ORs of 0.94 [95% CI, 0.70-1.27] and 0.80 [95% CI, 0.56-1.13], respectively) but significantly less likely to have used an arteriovenous fistula (ORs of 0.66 [95% CI, 0.57-0.76] and 0.54 [95% CI, 0.45-0.63], respectively), whereas patients with any comparator primary GN subtype were at least as likely to have used either of these 2 access types.Potential misclassification of exposure; residual confounding by unmeasured covariates; inability to determine causes of observed associations; lacking longitudinal data for vascular access use.Significant differences in vascular access distributions at initiation of hemodialysis therapy are apparent among GN subtypes. The unacceptably high use of CVCs in patients with lupus nephritis and vasculitis is particularly concerning. Further studies are needed to identify any potentially modifiable factors underlying these findings.

    View details for DOI 10.1053/j.ajkd.2015.11.019

    View details for Web of Science ID 000372720300019

  • Differences in initial treatment modality for end-stage renal disease among glomerulonephritis subtypes in the USA. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association O'Shaughnessy, M. M., Montez-Rath, M. E., Lafayette, R. A., Winkelmayer, W. C. 2016; 31 (2): 290-298

    Abstract

    Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD), while peritoneal dialysis affords certain benefits over hemodialysis. Distributions and determinants of first ESRD treatment modality have not been compared across glomerulonephritis (GN) subtypes.We identified all adult (18-75 years) patients with ESRD attributed to any of six GN subtypes [focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous nephropathy (MN), membranoproliferative GN (MPGN), lupus nephritis (LN) and vasculitis] who were first registered in the US Renal Data System (USRDS) between 1996 and 2011. We used multinomial logistic regression-adjusting for temporal, geographic, demographic, socioeconomic and comorbid factors-to determine odds ratios (ORs) with 95% confidence intervals (CIs) for transplantation versus hemodialysis, and for peritoneal dialysis versus hemodialysis, comparing other GN subtypes to IgAN.Among the 75 278 patients studied, patients with comparator GN subtypes were significantly less likely than those with IgAN to receive either transplantation or peritoneal dialysis. After adjusting for potentially confounding covariates, patients with comparator primary GN subtypes (FSGS, MN, MPGN) were at least as likely to receive transplantation [FSGS OR 0.98 (95% CI 0.93-1.15), MN OR 1.19 (95% CI 1.01-1.39), MPGN OR 1.08 (95% CI 0.93-1.26)] or peritoneal dialysis [FSGS OR 1.05 (95% CI 0.98-1.12), MN OR 1.30 (95% CI 1.18-1.43), MPGN OR 0.95 (95% CI 0.85-1.06)] as patients with IgAN. Conversely, patients with the secondary GN subtypes LN and vasculitis remained significantly less likely to receive either modality [transplantation OR 0.49 (95% CI 0.43-0.56) for LN and 0.27 (95% CI 0.22-0.34) for vasculitis, peritoneal dialysis OR 0.76 (95% CI 0.70-0.82) for LN and 0.54 (95% CI 0.48-0.60) for vasculitis].Significant differences in ESRD treatment practice patterns are apparent among GN subtypes. To ensure equitable care for all patients, regardless of GN subtype, reasons for observed disparities should be elucidated and-if appropriate-eliminated.

    View details for DOI 10.1093/ndt/gfv386

    View details for PubMedID 26610594

  • Complete Remission in the Nephrotic Syndrome Study Network CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Gipson, D. S., Troost, J. P., Lafayette, R. A., Hladunewich, M. A., Trachtman, H., Gadegbeku, C. A., Sedor, J. R., Holzman, L. B., Moxey-Mims, M. M., Perumal, K., Kaskel, F. J., Nelson, P. J., Tuttle, K. R., Bagnasco, S. M., Hogan, M. C., Dell, K. M., Appel, G. B., Lieske, J. C., Ilori, T. O., Sethna, C. B., Fervenza, F. C., Hogan, S. L., Nachman, P. H., Rosenberg, A. Z., Greenbaum, L. A., Meyers, K. E., Hewitt, S. M., Choi, M. J., Kopp, J. B., Zhdanova, O., Hodgin, J. B., Johnstone, D. B., Adler, S. G., Avila-Casado, C., Neu, A. M., Hingorani, S. R., Lemley, K. V., Nast, C. C., Brady, T. M., Barisoni-Thomas, L., Fornoni, A., Jennette, J. C., Cattran, D. C., Palmer, M. B., Gibson, K. L., Reich, H. N., Mokrzycki, M. H., Sambandam, K. K., Zilleruelo, G. E., Licht, C., Sampson, M. G., Song, P., Mariani, L. H., Kretzler, M. 2016; 11 (1): 81-89

    Abstract

    This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever).We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever.We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis.In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.

    View details for DOI 10.2215/CJN.02560315

    View details for Web of Science ID 000367766200014

    View details for PubMedID 26656320

  • Clinicopathological features of membranoproliferative glomerulonephritis under a new classification CLINICAL NEPHROLOGY Nargund, P., Kambham, N., Mehta, K., Lafayette, R. A. 2015; 84 (6): 323-330

    Abstract

    A recent classification of membranoproliferative glomerulonephritis (MPGN) utilizes the presence of immunoglobulin and complements to simplify diagnosis and point towards disease etiology. Here, we evaluate a historic cohort of patients with idiopathic MPGN using the new classification system and correlate it with clinical outcome.We identified 281 patients diagnosed with MPGN at Stanford from 2000 to 2012. Patients with hepatitis, systemic lupus erythematosis, lymphomas, and plasma cell dyscrasias were excluded. The clinicopathologic findings of the remaining 71 patients were further analyzed and differences between immunoglobulin dominant (IM) and complement dominant (CM) disease were evaluated.Using the new classification system, 51 subjects were characterized as CM MPGN and 20 as IM MPGN. In the CM MPGN group, there was a non-significant trend towards lower proteinuria but higher serum creatinine values. At biopsy, most subjects had less than 50% global sclerosis or cortical scarring. The majority of subjects in the CM MPGN group (41%) had C3 nephropathy while 60% of subjects in IM MPGN group had C3 dominant disease. Treatment and outcomes: During follow-up (median 2 years), 20 patients reached a clinical end point of dialysis or death. The mean creatinine was significantly higher while the baseline proteinuria also trended slightly higher. Prednisone use was statistically higher in the survivor group.Our study highlights the clinicopathological features of patients with biopsy proven MPGN with no known etiological factors and sheds some light on the incidence and outcomes of various categories of MPGN under the new criteria, including MPGN with "dominant C3" deposits, rapidly becoming a descriptive diagnosis.

    View details for DOI 10.5414/CN108619

    View details for Web of Science ID 000369249900002

    View details for PubMedID 26445002

  • Patient Characteristics and Outcomes by GN Subtype in ESRD. Clinical journal of the American Society of Nephrology O'Shaughnessy, M. M., Montez-Rath, M. E., Lafayette, R. A., Winkelmayer, W. C. 2015; 10 (7): 1170-1178

    Abstract

    Outcomes-based research rarely focuses on patients with ESRD caused by GN. The hypotheses were that the GN subtype would clinically discriminate patient groups and independently associate with survival after ESRD therapy initiation.Data were extracted from the US Renal Data System for adult patients with incident (1996-2011) ESRD attributed to six GN subtypes: FSGS, IgA nephropathy (IgAN), membranous nephropathy, membranoproliferative glomeruonephritis, lupus nephritis (LN), and vasculitis. ESRD attributed to diabetes and autosomal dominant polycystic kidney disease served as non-GN comparators. Unadjusted and adjusted mortality hazard ratios (aHRs) with 95% confidence intervals (95% CIs) were estimated using Cox regression (reference, IgAN). Models sequentially adjusted for sociodemographic (model 2), comorbidity/laboratory (model 3), and ESRD treatment modality (model 4) variables.Among 84,301 patients with ESRD attributed to GN, the median age ranged from 39 (LN) to 66 (vasculitis) years, male sex ranged from 18% (LN) to 68% (IgAN), and black race ranged from 7% (IgAN) to 49% (LN). Patients with IgAN had the fewest comorbidities and lowest use of hemodialysis (70.1%). After a median follow-up of 2.5 (interquartile range, 1.0-4.9) years, crude mortality was lowest in IgAN (3.7 deaths/100 person years). Compared to IgAN, adjusted mortality was highest in LN (model 4 aHR=1.75; 95% CI, 1.68 to 1.83) and in diabetes (aHR=1.73; 95% CI, 1.67 to 1.79), and was also higher in all other GN subtypes (membranous nephropathy: aHR=1.23; 95% CI, 1.17 to 1.29; FSGS: aHR=1.37; 95% CI, 1.32 to 1.42; membranoproliferative GN: aHR=1.38; 95% CI, 1.31 to 1.45; vasculitis: aHR=1.51; 95% CI, 1.45 to 1.58) and in autosomal dominant polycystic kidney disease (aHR=1.22; 95% CI, 1.18 to 1.27).This study exposes substantial heterogeneity across GN subtypes at ESRD therapy initiation and identifies independent associations between GN subtype and post-ESRD mortality. These survival discrepancies warrant further study, and the utility of current research practice to group GN subtypes together when evaluating ESRD outcomes should be questioned.

    View details for DOI 10.2215/CJN.11261114

    View details for PubMedID 26092830

    View details for PubMedCentralID PMC4491300

  • Red blood cell transfusion, hyperkalemia, and heart failure in advanced chronic kidney disease PHARMACOEPIDEMIOLOGY AND DRUG SAFETY Gill, K., Fink, J. C., Gilbertson, D. T., Monda, K. L., Muntner, P., Lafayette, R. A., Petersen, J., Chertow, G. M., Bradbury, B. D. 2015; 24 (6): 654-662

    Abstract

    In recent years, the use of red blood cell (RBC) transfusion for the treatment of chronic kidney disease (CKD)-related anemia has increased. We used the OptumInsight medical claims database to study the association between receiving a transfusion and hyperkalemia and heart failure events.Persons 18-64 years of age with diagnosed stage 4 or 5 CKD (not requiring dialysis) between 2006 and 2010 were followed until their first hospitalization or emergency room visit with a diagnosis of hyperkalemia or heart failure, termination of insurance coverage, or death. We used a case-only design and conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CIs) describing associations between RBC transfusion and the risks of hyperkalemia or heart failure. We used single (1:1) and variable (1:m) self-control matching intervals, with adjustment for time-varying confounders.Seven thousand eight hundred twenty-nine individuals met our inclusion criteria; two-thirds were age 50 years or older; 43% were women and 51% had diabetes. Rates of hyperkalemia and heart failure were 7.9/100 person-years (95%CI: 7.3, 8.5) and 16.3/100 person-years (95%CI: 15.5, 17.2), respectively. RBC transfusion was associated with an increased risk of both hyperkalemia (single interval matched RR = 12.0, 95%CI: 1.3, 109; multiple interval matched RR = 6.1, 95%CI: 2.5, 15.1) and heart failure (single interval matched RR = 1.7, 95%CI: 0.3, 9.2; multiple interval matched RR = 3.8, 95%CI: 1.4, 10.3).In patients with advanced CKD, RBC transfusion appears to be associated with an elevated risk of hyperkalemia and heart failure; further investigation into these risks is warranted. Copyright © 2015 John Wiley & Sons, Ltd.

    View details for DOI 10.1002/pds.3779

    View details for PubMedID 25903095

  • Mapping novel immunogenic epitopes in IgA nephropathy. Clinical journal of the American Society of Nephrology Woo, S. H., Sigdel, T. K., Dinh, V. T., Vu, M., Sarwal, M. M., Lafayette, R. A. 2015; 10 (3): 372-381

    Abstract

    IgA plays a key role in IgA nephropathy (IgAN) by forming immune complexes and depositing in the glomeruli, leading to an inflammatory response. However, the antigenic targets and functional characterization of IgA have been incompletely defined in this disease.This study was performed in sera from patients who were studied as part of a prospective, observational study of IgAN. These patients (n=22) all had biopsy-proven IgAN within 3 years of study initiation, complete clinical data, annual urinary inulin clearance for GFRs, and at least 5 years of follow-up. Progression was defined as loss of >5 ml/min per 1.73 m(2) per year of inulin clearance measured over at least 5 years. A protein microarray was used for detection of IgAN-specific IgA autoantibodies in blood across approximately 9000 human antigens to specifically identify the most immunogenic protein targets that drive IgA antibodies in IgAN (n=22), healthy controls (n=10), and non-IgAN glomerular diseases (n=17). Results were validated by ELISA assays in sera and by immunohistochemistry in IgAN kidney biopsies. IgA-specific antibodies were correlated with clinical and histologic variables to assess their effect on disease progression and prognosis.Fifty-four proteins mounted highly significant IgA antibody responses in patients with IgAN with a false discovery rate (q value) of ≤10%; 325 antibodies (P≤0.05) were increased overall. Antitissue transglutaminase IgA was significantly elevated in IgAN (P<0.001, q value of 0%). IgA antibodies to DDX4 (r=-0.55, P=0.01) and ZADH2 (r=-0.48, P=0.02) were significantly correlated with the decline of renal function. Specific IgA autoantibodies are elevated in IgAN compared with normal participants and those with other glomerular diseases.In this preliminary study, IgA autoantibodies target novel proteins, highly expressed in the kidney glomerulus and tubules. These IgA autoantibodies may play important roles in the pathogenesis of IgAN.

    View details for DOI 10.2215/CJN.02390314

    View details for PubMedID 25542908

  • Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

    Abstract

    We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

    View details for DOI 10.1111/ajt.13025

    View details for PubMedID 25648766

  • A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR) NEPHRON Fervenza, F. C., Canetta, P. A., Barbour, S. J., Lafayette, R. A., Rovin, B. H., Aslam, N., Hladunewich, M. A., Irazabal, M. V., Sethi, S., Gipson, D. S., Reich, H. N., Brenchley, P., Kretzler, M., Radhakrishnan, J., Hebert, L. A., Gipson, P. E., Thomas, L. F., McCarthy, E. T., Appel, G. B., Jefferson, J. A., Eirin, A., Lieske, J. C., Hogan, M. C., Greene, E. L., Dillon, J. J., Leung, N., Sedor, J. R., Rizk, D. V., Blumenthal, S. S., Lasic, L. B., Juncos, L. A., Green, D. F., Simon, J., Sussman, A. N., Philibert, D., Cattran, D. C. 2015; 130 (3): 159-168

    Abstract

    Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria.Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with IV rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study.This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy. © 2015 S. Karger AG, Basel.

    View details for DOI 10.1159/000430849

    View details for Web of Science ID 000358976400002

    View details for PubMedID 26087670

  • Maternal proteinuria in twin compared with singleton pregnancies. Obstetrics and gynecology Osmundson, S. S., Lafayette, R. A., Bowen, R. A., Roque, V. C., Garabedian, M. J., Aziz, N. 2014; 124 (2): 332-337

    Abstract

    To compare 24-hour urinary protein excretion in twin and singleton pregnancies not complicated by hypertension.We prospectively evaluated mean 24-hour urinary protein excretion in twin and singleton pregnancies between 24 0/7 weeks and 36 0/7 weeks of gestation. Women with urinary tract infections, chronic hypertension, pregestational diabetes, and renal or autoimmune diseases were excluded. Collection adequacy was assessed by urinary creatinine excretion adjusted for maternal weight.Adequate samples were obtained from 50 twin and 49 singleton pregnancies at a mean gestational age of 30 weeks. At collection, the two groups were similar with regard to maternal age, gestational age, body mass index, and blood pressure. Mean urinary protein excretion was higher in twin compared with singleton pregnancies (269.3±124.1 mg compared with 204.3±92.5 mg, P=.004). Proteinuria (300 mg/day protein or greater) occurred in 38.0% (n=19) of twin and 8.2% (n=4) of singleton pregnancies (P<.001). After adjusting for confounding variables, the difference in mean total protein excretion remained significant (P=.004) and twins were more likely to have proteinuria compared with singleton pregnancies (adjusted odds ratio 9.1, 95% confidence interval 2.1-38.5). Nineteen participants developed a hypertensive disorder at a mean of 7.7 weeks after the urine collection (range 2.6-14.5 weeks). After excluding these women, proteinuria was present in 43% of twin and 7% of singleton pregnancies (P<.001).Mean 24-hour urinary protein excretion in twin pregnancies is greater than in singletons. These data suggest a reevaluation of the diagnostic criteria for preeclampsia in twin pregnancies.: II.

    View details for DOI 10.1097/AOG.0000000000000383

    View details for PubMedID 25004349

  • Anemia Management Trends in Hospital-Based Dialysis Centers (HBDCs), 2010 to 2013. Clinical therapeutics Coritsidis, G. N., Maglinte, G. A., Acharya, A., Saxena, A., Chang, C., Hill, J., Gitlin, M., Lafayette, R. A. 2014; 36 (3): 408-418

    Abstract

    Few data have been reported on anemia management practices in hospital-based dialysis centers (HBDCs), which are uniquely different from other freestanding dialysis centers. Examining data from HBDCs would help determine if HBDCs and the general US dialysis population have similar trends related to how anemia is managed in dialysis patients.Given recent changes in the prescribing information of erythropoiesis-stimulating agents (ESAs) and in end-stage renal disease-related health policy and reimbursement, this study describes trends in anemia management practices in HBDCs from January 2010 through March 2013.Electronic medical records of 5404 adult hemodialysis patients in 50 US-based HBDCs were analyzed retrospectively. Patients included in the study cohort were aged ≥18 years and had at least 1 hemoglobin (Hb) measurement and 1 dose of an ESA between January 2010 and March 2013. End points included Hb concentration, darbepoetin alfa dosing, epoetin alfa dosing, and iron biomarkers (transferrin saturation and ferritin) and dosing.From 2010 to 2013, mean monthly Hb levels declined from 11.4 to 10.7 g/dL; the percentage of patients with mean monthly Hb levels <10 g/dL increased from 11.3% to 24.4%; and the percentage of patients with mean monthly Hb levels >12 g/dL declined from 30.1% to 11.2%. The median darbepoetin alfa cumulative 4-week dose also declined 38.8%, and the weekly epoetin alfa dose declined 24%. From January 2010 to March 2013, the percentage of patients with transferrin saturation >30% increased from 35.8% to 43.6%, the percentage of patients with ferritin levels >500 ng/mL increased from 62.0% to 77.9%, the percentage of patients with ferritin levels ≥800 ng/mL increased from 28.9% to 47.3%, and the median cumulative 4-week intravenous iron dose increased 50%.These study results support growing evidence that meaningful changes have occurred over the last 3 years in how anemia is clinically managed in US hemodialysis patients. Study limitations include that changes in patient clinical/demographic characteristics over time were not controlled for and that study findings may not be applicable to HBDCs that have different patient populations and/or do not use an electronic medical record system. Continuing to evaluate anemia management practices in HBDCs would provide additional information on the risks and benefits of anemia care. Consistent with national data, the findings from this study indicate that from 2010 to 2013, HBDCs modified anemia management practices for dialysis patients, as evidenced by reductions in mean monthly Hb levels and ESA dosing and by increases in iron biomarkers and dosing.

    View details for DOI 10.1016/j.clinthera.2014.01.015

    View details for PubMedID 24582713

  • Renal function in normal and disordered pregnancy CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION Hussein, W., Lafayette, R. A. 2014; 23 (1): 46-53

    Abstract

    Renal dysfunction during pregnancy is a common and serious complication. Understanding normal physiology during pregnancy provides a context to further describe changes in pregnancy that lead to renal dysfunction and may provide clues to better management.Hormonal changes during pregnancy allow for increased blood flow to the kidneys and altered autoregulation such that glomerular filtration rate (GFR) increases significantly through reductions in net glomerular oncotic pressure and increased renal size. The mechanisms for maintenance of increased GFR change through the trimesters of pregnancy, continuing into the postpartum period. Important causes of pregnancy-specific renal dysfunction have been further studied, but much needs to be learned. Pre-eclampsia is due to abnormal placentation, with shifts in angiogenic proteins and the renin-angiotensin-aldosterone system leading to endothelial injury and clinical manifestations of hypertension and organ dysfunction. Other thrombotic microangiopathies occurring during pregnancy have been better defined as well, with new work focusing on the contribution of the complement system to these disorders.Advances have been made in understanding the physiology of the kidney in normal pregnancy. Diseases that affect the kidney during pregnancy alter this physiology in various ways that inform clinicians on pathogenesis and may lead to improved therapeutic approaches and better outcomes of pregnancy.

    View details for DOI 10.1097/01.mnh.0000436545.94132.52

    View details for Web of Science ID 000327996700007

    View details for PubMedID 24247824

  • Incidence and Relevance of Proteinuria in Bevacizumab-Treated Patients: Pooled Analysis from Randomized Controlled Trials AMERICAN JOURNAL OF NEPHROLOGY Lafayette, R. A., McCall, B., Li, N., Chu, L., Werner, P., Das, A., Glassock, R. 2014; 40 (1): 75-83

    Abstract

    This analysis evaluated the incidence of and risk factors for bevacizumab-related proteinuria and assessed for any associated clinical sequelae, including renal function changes.Patient-level adverse event and laboratory data from a pooled safety database were used to characterize alterations in urine protein excretion following interventional therapy ± bevacizumab in 17 randomized trials across multiple tumor types. Severity of renal function change was assessed using changes in serum creatinine concentration from baseline values. Potential predictors of proteinuria and the association between proteinuria and other adverse events were also investigated.Among 14,548 patients, the incidence of any-grade proteinuria was 8.2% (733/8,917) and 4.6% (257/5,631) in the bevacizumab and control groups, respectively; rates of grade ≥3 proteinuria were 1.4 and 0.2%. Post-baseline proteinuria grade and bevacizumab were associated with increased rates of renal dysfunction. Patients developing proteinuria had an increased rate of any-grade infection but not thromboembolic events. History of diabetes was the only examined risk factor that appeared to have a significant association with proteinuria development.This analysis confirmed a significant increase in the development of proteinuria during bevacizumab treatment. We also observed an increased rate of renal dysfunction associated with bevacizumab treatment and among subjects with proteinuria, although the dysfunction was generally mild. The development of proteinuria was also associated with a modest increase in risk of infection.

    View details for DOI 10.1159/000365156

    View details for PubMedID 25059491

  • Immunoglobulin A nephropathy: insights and progress. Translational research Lafayette, R. A. 2014; 163 (1): 3-7

    View details for DOI 10.1016/j.trsl.2013.08.007

    View details for PubMedID 24064200

  • Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis HEART RHYTHM Varr, B. C., Zarafshar, S., Coakley, T., Liedtke, M., Lafayette, R. A., Arai, S., Schrier, S. L., Witteles, R. M. 2014; 11 (1): 158-162

    View details for DOI 10.1016/j.hrthm.2013.10.026

    View details for PubMedID 24121001

  • Treatment of Idiopathic FSGS with Adrenocorticotropic Hormone Gel CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Hogan, J., Bomback, A. S., Mehta, K., Canetta, P. A., Rao, M. K., Appel, G. B., Radhakrishnan, J., Lafayette, R. A. 2013; 8 (12): 2072-2081

    Abstract

    Adrenocorticotropic hormone (ACTH) has shown efficacy as primary and secondary therapy for nephrotic syndrome due to membranous nephropathy. The data on using ACTH to treat idiopathic FSGS are limited. This report describes our experience using ACTH for nephrotic syndrome due to idiopathic FSGS in the United States.Twenty-four patients with nephrotic syndrome from idiopathic FSGS were treated with ACTH gel at two academic medical centers between 2009 and 2012, either as part of investigator-initiated pilot studies (n=16) or by prescription for treatment-resistant FSGS (n=8). The primary outcome was remission of proteinuria. The median dose of ACTH was 80 units injected subcutaneously twice weekly. Treatment durations were not uniform.Twenty-two patients had received immunosuppression (mean, 2.2 medications) before ACTH therapy. Six patients had steroid-dependent and 15 had steroid-resistant FSGS. At the time of ACTH initiation, the median serum creatinine (interquartile range) was 2.0 (1.1-2.7) mg/dl, estimated GFR was 36 (28-78) ml/min per 1.73 m(2), and urine protein-to-creatinine ratio was 4595 (2200-8020) mg/g. At the end of ACTH therapy, 7 of 24 patients (29%) experienced remission (n=2 complete remissions, n=5 partial remissions). All remitters had steroid-resistant (n=5) or steroid-dependent (n=2) FSGS. Two responders relapsed during the follow-up period (mean ± SD, 70±31 weeks). Adverse events occurred in 21 of 24 patients, including one episode of new-onset diabetes that resolved after stopping ACTH and two episodes of AKI.Response to ACTH treatment among steroid-resistant or steroid-dependent patients with FSGS is low, but ACTH gel may be a viable treatment option for some patients with resistant nephrotic syndrome due to idiopathic FSGS. Further research is necessary to determine which patients will respond to therapy.

    View details for DOI 10.2215/CJN.02840313

    View details for Web of Science ID 000327951100008

    View details for PubMedID 24009220

    View details for PubMedCentralID PMC3848392

  • High-potency statins and acute kidney injury-associated hospitalizations. American journal of kidney diseases Lenihan, C. R., Lafayette, R. A. 2013; 62 (5): 877-879

    View details for DOI 10.1053/j.ajkd.2013.07.006

    View details for PubMedID 23972947

    View details for PubMedCentralID PMC4090769

  • Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement. Haematologica Dinner, S., Witteles, W., Afghahi, A., Witteles, R., Arai, S., Lafayette, R., Schrier, S. L., Liedtke, M. 2013; 98 (10): 1593-1599

    Abstract

    Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).

    View details for DOI 10.3324/haematol.2013.084574

    View details for PubMedID 23716538

  • Red blood cell transfusion use in patients with chronic kidney disease NEPHROLOGY DIALYSIS TRANSPLANTATION Gill, K. S., Muntner, P., Lafayette, R. A., Petersen, J., Fink, J. C., Gilbertson, D. T., Bradbury, B. D. 2013; 28 (6): 1504-1515

    Abstract

    BACKGROUND: There is limited data available on the use of red blood cell (RBC) transfusions in younger chronic kidney disease patients not on dialysis (CKD-ND), for whom the consequences of developing antibodies to foreign antigens (allosensitization) may be particularly relevant. METHODS: We used the Ingenix medical claims database, comprising data on ∼40 million commercially insured US individuals, to identify annual (2002-08) cohorts of patients 18-64 years of age with newly diagnosed CKD. We followed each cohort for 1 year to estimate RBC transfusion rates and used Cox proportional hazards regression to identify patient characteristics associated with time to first transfusion. RESULTS: We identified 120 790 newly diagnosed CKD patients for the years 2002-08; 54% were 50-64 years of age. Overall, the transfusion rate was 2.64/100 person-years (PYs) (95% CI: 2.52-2.77). Rates were higher among those with diagnosed anemia [9.80/100 PYs (95% CI: 9.31-10.3)] and among those who progressed to end-stage renal disease (ESRD) [28.0/100 PYs (95% CI: 23.7-33.0)]. For those progressing to ESRD, transfusion rates more than doubled between 2002 and 2008. Of the factors evaluated, transfusion history and the presence of heart failure and diabetes were most strongly associated with a receipt of a transfusion. CONCLUSIONS: RBC transfusions are relatively common and on the rise among younger CKD-ND patients who are anemic and progress to ESRD. Efforts to decrease the use of transfusions may be important for potential transplant candidates who progress to ESRD.

    View details for DOI 10.1093/ndt/gfs580

    View details for Web of Science ID 000321057700031

    View details for PubMedID 23389999

  • The prognostic value of diagnosing concurrent multiple myeloma in immunoglobulin light chain amyloidosis BRITISH JOURNAL OF HAEMATOLOGY Dinner, S., Witteles, W., Witteles, R., Lam, A., Arai, S., Lafayette, R., George, T. I., Schrier, S. L., Liedtke, M. 2013; 161 (3): 367-372

    Abstract

    The prevalence and prognostic value of a concomitant diagnosis of symptomatic or asymptomatic multiple myeloma (MM), as defined by the current International Myeloma Working Group (IMWG) criteria, in patients with immunoglobulin light chain amyloidosis (AL), are unknown. We studied 46 consecutive patients with AL who underwent quantification of serum M-protein and clonal bone marrow plasma cells, as well as a comprehensive evaluation for end organ damage by MM. Using standard morphology and CD138 immunohistochemical staining, 57% and 80% of patients were found to have concomitant MM, respectively. Nine patients exhibited end organ damage consistent with a diagnosis of symptomatic MM. While overall survival was similar between AL patients with or without concurrent myeloma (1-year overall survival 68% vs. 87%; P = 0.27), a diagnosis of symptomatic myeloma was associated with inferior outcome (1-year overall survival 39% vs. 81%; P = 0.005). Quantification of bone marrow plasma cells by both standard morphology and CD138 immunohistochemistry identified a much higher prevalence of concurrent MM in patients with AL than previously reported. Evaluation of bone marrow plasma cell infiltration and presence of myeloma associated end organ damage could be clinically useful for prognostication of patients with AL.

    View details for DOI 10.1111/bjh.12269

    View details for PubMedID 23432783

  • Renal Physiology of Pregnancy ADVANCES IN CHRONIC KIDNEY DISEASE Cheung, K. L., Lafayette, R. A. 2013; 20 (3): 209-214

    Abstract

    Pregnancy involves remarkable orchestration of physiologic changes. The kidneys are central players in the evolving hormonal milieu of pregnancy, responding and contributing to the changes in the environment for the pregnant woman and fetus. The functional impact of pregnancy on kidney physiology is widespread, involving practically all aspects of kidney function. The glomerular filtration rate increases 50% with subsequent decrease in serum creatinine, urea, and uric acid values. The threshold for thirst and antidiuretic hormone secretion are depressed, resulting in lower osmolality and serum sodium levels. Blood pressure drops approximately 10 mmHg by the second trimester despite a gain in intravascular volume of 30% to 50%. The drop in systemic vascular resistance is multifactorial, attributed in part to insensitivity to vasoactive hormones, and leads to activation of the renin-aldosterone-angiostensin system. A rise in serum aldosterone results in a net gain of approximately 1000 mg of sodium. A parallel rise in progesterone protects the pregnant woman from hypokalemia. The kidneys increase in length and volume, and physiologic hydronephrosis occurs in up to 80% of women. This review will provide an understanding of these important changes in kidney physiology during pregnancy, which is fundamental in caring for the pregnant patient.

    View details for DOI 10.1053/j.ackd.2013.01.012

    View details for Web of Science ID 000318464100003

    View details for PubMedID 23928384

  • INCIDENCE AND RELEVANCE OF PROTEINURIA IN BEVACIZUMAB (BV)-TREATED PATIENTS (PTS): POOLED ANALYSIS FROM RANDOMIZED CONTROLLED TRIALS (RCTS) 37th Congress of the European-Society-for-Medical-Oncology (ESMO) Lafayette, R., McCall, B., Li, N. F., Chu, L., Werner, P., Das, A., Glassock, R. J. OXFORD UNIV PRESS. 2012: 171–171
  • More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Stevenson, R., Witteles, R., Damrose, E., Arai, S., Lafayette, R. A., Schrier, S., Afghahi, A., Liedtke, M. 2012; 138 (5): 509-511

    View details for PubMedID 22652951

  • ADRENOCORTICOTROPIN HORMONE (ACTH) FOR THE TREATMENT OF PRIMARY FOCAL GLOMERULOSCLEROSIS (FSGS) Spring Clinical Meeting of the National-Kidney-Foundation Lafayette, R. A., Root, C., Mehta, K. W B SAUNDERS CO-ELSEVIER INC. 2012: A49–A49
  • Heart transplantation and cardiac amyloidosis: Approach to screening and novel management strategies JOURNAL OF HEART AND LUNG TRANSPLANTATION Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. 2012; 31 (3): 325-331

    Abstract

    Limited data exist regarding screening methods and outcomes for orthotopic heart transplantation (OHT) in cardiac amyloidosis. As a result, uncertainty exists over the best approach to OHT for cardiac amyloidosis and for the timing of critical post-transplant therapies. This article reviews 6 patients who underwent OHT for cardiac amyloidosis at the Stanford University Amyloid Center from 2008 to present. All patients with light-chain amyloidosis received chemotherapy in the interval between OHT and autologous hematopoietic stem cell transplant. Five patients remain alive up to 25 months after OHT, without evidence of recurrent cardiac amyloid deposition. A novel strategy of OHT, followed by light-chain suppressive chemotherapy before autologous hematopoietic stem cell transplant, is feasible for patients with light-chain amyloidosis.

    View details for DOI 10.1016/j.healun.2011.09.010

    View details for PubMedID 22051505

  • Profiling of Autoantibodies in IgA Nephropathy, an Integrative Antibiomics Approach CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Sigdel, T. K., Woo, S. H., Dai, H., Khatri, P., Li, L., Myers, B., Sarwal, M. M., Lafayette, R. A. 2011; 6 (12): 2775-2784

    Abstract

    IgG commonly co-exists with IgA in the glomerular mesangium of patients with IgA nephropathy (IgAN) with unclear clinical relevance. Autoantibody (autoAb) biomarkers to detect and track progression of IgAN are an unmet clinical need. The objective of the study was to identify IgA-specific autoAbs specific to IgAN.High-density protein microarrays were evaluated IgG autoAbs in the serum of IgAN patients (n = 22) and controls (n = 10). Clinical parameters, including annual GFR and urine protein measurements, were collected on all patients over 5 years. Bioinformatic data analysis was performed to select targets for further validation by immunohistochemistry (IHC).One hundred seventeen (1.4%) specific antibodies were increased in IgAN. Among the most significant were the autoAb to the Ig family of proteins. IgAN-specific autoAbs (approximately 50%) were mounted against proteins predominantly expressed in glomeruli and tubules, and selected candidates were verified by IHC. Receiver operating characteristic analysis of our study demonstrated that IgG autoAb levels (matriline 2, ubiquitin-conjugating enzyme E2W, DEAD box protein, and protein kinase D1) might be used in combination with 24-hour proteinuria to improve prediction of the progression of IgAN (area under the curve = 0.86, P = 0.02).IgAN is associated with elevated IgG autoAbs to multiple proteins in the kidney. This first analysis of the repertoire of autoAbs in IgAN identifies novel, immunogenic protein targets that are highly expressed in the kidney glomerulus and tubules that may bear relevance in the pathogenesis and progression of IgAN.

    View details for DOI 10.2215/CJN.04600511

    View details for Web of Science ID 000297948900009

    View details for PubMedID 22157707

    View details for PubMedCentralID PMC3255376

  • Cardiac Amyloidosis: Screening Criteria for Heart Transplantation and New Strategies for Post-Transplant Therapy 15th Annual Scientific Meeting of the Heart-Failure-Society-of-America Varr, B. C., Liedtke, M., Arai, S., Lafayette, R. A., Schrier, S. L., Witteles, R. M. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2011: S45–S46
  • Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia CLINICAL NEPHROLOGY Lafayette, R. A., Hladunewich, M. A., Derby, G., Blouch, K., Druzin, M. L., Myers, B. D. 2011; 75 (3): 226-232

    Abstract

    Relaxin, a potent pregnancy-related hormone, has been proposed to be a major mediator of renal physiology in normal pregnancy. We wished to test relaxin levels in pregnancy and preeclampsia.We performed precise physiologic measurements of kidney function in 38 normal peripartum women and 58 women with preeclampsia. We measured serum relaxin levels prior to delivery and over the first 4 postpartum weeks utilizing a modern, validated ELISA. Results were compared to those of 18 normal women of childbearing age.Relaxin levels were substantially elevated in women prior to delivery (364 ± 268 vs. 15 ± 16 pg/ml) and fell rapidly over the first postpartum week reaching normal non pregnant levels by Week 2 (32 ± 64 vs. 15 ± 16 pg/ml). No differences were seen between relaxin levels in normal pregnancy as compared to preeclampsia (364 ± 268 vs. 376 ± 241 pg/ml) despite substantial and persistent abnormalities in GFR (149 ± 33 vs. 89 ± 25 ml/min), albuminuria (14 vs. 687 mg/g) and mean arterial pressure (80 ± 8 vs. 111 ± 18). Furthermore no correlation could be established between physiologic measures (GFR, MAP, RBF, RVR) and relaxin levels (p > 0.3), either in the overall population or any of the subgroups.Relaxin is indeed significantly elevated in the serum of women during late pregnancy and the early puerperium. However, serum relaxin does not appear to influence BP, renal vascular resistance, renal blood flow or GFR in late pregnancy or in women with preeclampsia.

    View details for DOI 10.5414/CNP75226

    View details for Web of Science ID 000288817800007

    View details for PubMedID 21329633

  • A Pilot Study of Melphalan, Lenalidomide and Dexamethasone In AL Amyloidosis: Interim Results 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Afghahi, A., Witteles, W., Witteles, R., Liedtke, M., Lafayette, R., Arai, S., Schrier, S. L. AMER SOC HEMATOLOGY. 2010: 810–11
  • Hemoglobinuria and Acute Kidney Injury Requiring Hemodialysis Following Intravenous Immunoglobulin Infusion AMERICAN JOURNAL OF KIDNEY DISEASES Welles, C. C., Tambra, S., Lafayette, R. A. 2010; 55 (1): 148-151

    Abstract

    Intravenous immunoglobulin (IVIG), a product initially developed for patients with immunodeficiencies, now has multiple other indications and increasing off-label use. IVIG generally is well tolerated, with few adverse effects. Antibody-mediated (Coombs-positive) hemolysis is known to occur after IVIG infusion, but often is subclinical and previously has not been reported to lead to acute kidney injury (AKI). The predominantly known mechanism of AKI after IVIG infusion has been osmotic nephrosis, primarily associated with sucrose-containing formulations. We present a case of a bone marrow transplant recipient who was treated with a sucrose-free IVIG product and subsequently developed Coombs-positive hemolysis leading to AKI requiring hemodialysis, who ultimately died secondary to infectious complications. The severity of this case emphasizes the importance of identifying populations who may be at increased risk of pigment-mediated kidney injury before consideration of IVIG therapy.

    View details for DOI 10.1053/j.ajkd.2009.06.013

    View details for Web of Science ID 000273958000020

    View details for PubMedID 19628320

  • Protocol adherence and the ability to achieve target haemoglobin levels in haemodialysis patients 40th Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week Chan, K., Moran, J., Hlatky, M., Lafayette, R. OXFORD UNIV PRESS. 2009: 1956–62

    Abstract

    Anemia management remains complicated in patients with endstage renal disease on hemodialysis. We wished to evaluate the effect of protocol adherence to EPO and intravenous iron dosing on achieving the desired range of hemoglobin levels.A cohort of hemodialysis patients was studied to evaluate the rate of adherence to EPO and iron dosing protocols over a 5 month period. A database was completed to evaluate all known comorbidities, demographic factors, and facility issues that might affect hemoglobin levels. A logistic regression model was employed to evaluate the effect of adherence to the anemia protocols on the probability of achieving a hemoglobin level below, within or above the targeted range of 11-12.5 g/dl.Among 2114 patients, we found that adherence to both the EPO and iron dosing protocol resulted in the greatest probability of achieving the target hemoglobin range (56 +/- 5% in anemia protocol adherent patients versus 42 +/- 7% in non adherent patients). This was predominantly due to a lowered risk of having above target hemoglobin levels rather than below. The use of the anemia protocols was associated with lower rates of hospitalization (9 +/- 0.7 visits/100 months in adherent group vs 15 +/- 2 in non adherent group) and lower utilization of both EPO and intravenous iron. Furthermore, patients in the adherent groups had less variability of their hemoglobin levels month by month, at least as judged by standard deviation.Adherence to anemia protocols, as practiced in the dialysis units included in this cohort, may improve hemodialysis patients' ability to achieve target hemoglobin levels, and by avoiding above target hemoglobin values, lower drug utilization and reduce variability of hemoglobin levels.

    View details for DOI 10.1093/ndt/gfn780

    View details for Web of Science ID 000266355500040

    View details for PubMedID 19176685

  • Imatinib in the Treatment of Nephrogenic Systemic Fibrosis AMERICAN JOURNAL OF KIDNEY DISEASES Chandran, S., Petersen, J., Jacobs, C., Forentino, D., Doeden, K., Lafayette, R. A. 2009; 53 (1): 129-132

    Abstract

    Nephrogenic systemic fibrosis is a disabling progressive condition that is being reported with increased frequency in patients with kidney disease. Treatment is extremely limited and largely supportive. We report a case of severe nephrogenic systemic fibrosis in a dialysis patient exposed to multiple doses of gadolinium who improved clinically and histologically with treatment with imatinib.

    View details for DOI 10.1053/j.ajkd.2008.08.029

    View details for Web of Science ID 000262172200018

    View details for PubMedID 19012999

  • Facility factors dominate the ability to achieve target haemoglobin levels in haemodialysis patients NEPHROLOGY DIALYSIS TRANSPLANTATION Chan, K. E., Lafayette, R. A., Whittemore, A. S., Hlatky, M. A., Moran, J. 2008; 23 (9): 2948-2956

    Abstract

    Our objective was to determine whether patient factors, processes of care and measures of erythropoietin (EPO) responsiveness were associated with successful anemia management at the individual patient level.We retrospectively reviewed laboratory and demographic data from 1499 patients receiving hemodialysis in 15 units operated by the same dialysis provider. We performed univariate and multivariate logistic regression analysis to determine predictors of an average 3-month hemoglobin level below or above the target interval of 11.0-12.5 g/dL. To explain the effect of facility on anemia performance, we calculated correlations between measures of EPO responsiveness and the probability of achieving the target interval by facility.Patients above the target hemoglobin range demonstrated an association with parathyroid hormone (PTH) (OR = 0.96 per 100 pg/mL increase), female gender (OR = 0.68), EPO protocol use (OR = 0.94 per 10% increase in use) and facility (range of OR = 0.26-2.59 for 15 participating sites). Patients below the target hemoglobin range demonstrated an association with CRP (OR = 1.10 per mg/L increase), PTH (OR = 1.07 per 100 pg/mL increase), iron deficiency (OR = 1.07 per 10% increase), EPO protocol use (OR = 0.89 per 10% increase in use), iron protocol use (OR = 0.93 per 10% increase in use) and facility (range of OR = 0.58-3.41 over 15 units). EPO index (r = 0.71), EPO dose (r = 0.73), hemoglobin (r = -0.60) and EPO per unit weight (r = 0.76) were significantly correlated with the probability of achieving the target hemoglobin by facility.The facility significantly influences the outcome of anemia management in patients with ESRD. In part, this is due to the patients' EPO responsiveness, which may be influenced by facility care patterns.

    View details for DOI 10.1093/ndt/gfn172

    View details for Web of Science ID 000259372400039

    View details for PubMedID 18469314

  • Course of preeclamptic glomerular injury after delivery AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Hladunewich, M. A., Myers, B. D., Derby, G. C., Blouch, K. L., Druzin, M. L., Deen, W. M., Naimark, D. M., Lafayette, R. A. 2008; 294 (3): F614-F620

    Abstract

    We evaluated the early postpartum recovery of glomerular function over 4 wk in 57 women with preeclampsia. We used physiological techniques to measure glomerular filtration rate (GFR), renal plasma flow, and oncotic pressure (pi(A)) and computed a value for the two-kidney ultrafiltration coefficient (K(f)). Compared with healthy, postpartum controls, GFR was depressed by 40% on postpartum day 1, but by only 19% and 8% in the second and fourth postpartum weeks, respectively. Hypofiltration was attributable solely to depression, at corresponding postpartum times, of K(f) by 55%, 30%, and 18%, respectively. Improvement in glomerular filtration capacity was accompanied by recovery of hypertension to near-normal levels and significant improvement in albuminuria. We conclude that the functional manifestations of the glomerular endothelial injury of preeclampsia largely resolve within the first postpartum month.

    View details for DOI 10.1152/ajprenal.00470.2007

    View details for Web of Science ID 000253574500019

    View details for PubMedID 18199600

  • Prediction of early progression in recently diagnosed IgA nephropathy NEPHROLOGY DIALYSIS TRANSPLANTATION Lemley, K. V., Lafayette, R. A., Derby, G., Blouch, K. L., Anderson, L., Efron, B., Myers, B. D. 2008; 23 (1): 213-222

    Abstract

    Most studies of prognosis in IgA nephropathy (IgAN) have tried to predict dichotomous outcomes based on a small number of clinical or semi-quantitative histological variables in large numbers of patients.We pursued a quite different approach. We measured GFR annually for 4-5 years in 22 adult patients with recently diagnosed IgAN. Quantitative morphology was performed on the diagnostic biopsy specimens and baseline glomerular filtration dynamics were performed at study entry. An initial set of 30 plausible predictor variables (half demographic or physiological, half structural) was reduced to 22 using phylogenetic trees. Least-angle regression (LARS) was used to predict the rate of GFR change from these variablesThe rate of GFR change ranged from a loss of 41 ml/min/year to a gain of 8.6 ml/min/year. We found an optimum predictor set of five baseline variables: the percentage of glomeruli with global sclerosis, the fractional interstitial area, the serum creatinine, the average tuft volume of non-sclerotic glomeruli and the renal plasma flow.The strong predictive relationship of the three structural variables with the slope of GFR in our subjects suggests that even at the time of their initial diagnosis many patients with IgAN already manifest a 'remnant kidney' phenomenon. The distinctive pathophysiological insights derived from this study suggest some of the advantages of intense quantitative investigations applied to a small number of subjects.

    View details for DOI 10.1093/ndt/gfm560

    View details for Web of Science ID 000253022100034

    View details for PubMedID 17890749

  • Pathophysiology of the clinical manifestations of preeclampsia CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Hladunewich, M., Karumanchi, S. A., Lafayette, R. 2007; 2 (3): 543-549

    View details for DOI 10.2215/CJN.03761106

    View details for Web of Science ID 000246049100021

    View details for PubMedID 17699462

  • Effect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial. Obstetrics and gynecology Hladunewich, M. A., Derby, G. C., Lafayette, R. A., Blouch, K. L., Druzin, M. L., Myers, B. D. 2006; 107 (4): 886-895

    Abstract

    To assess the benefit of l-arginine, the precursor to nitric oxide, on blood pressure and recovery of the glomerular lesion in preeclampsia.Forty-five women with preeclampsia were randomized to receive either l-arginine or placebo until day 10 postpartum. Primary outcome measures including mean arterial pressure, glomerular filtration rate, and proteinuria were assessed on the third and 10th days postpartum by inulin clearance and albumin-to-creatinine ratio. Nitric oxide, cyclic guanosine 3'5' monophosphate, endothelin-1, and asymmetric-dimethyl-arginine and arginine levels were assayed before delivery and on the third and 10th days postpartum. Healthy gravid women provided control values. Assuming a standard deviation of 10 mm Hg, the study was powered to detect a 10-mm Hg difference in mean arterial pressure (alpha .05, beta .20) between the study groups.No significant differences existed between the groups with preeclampsia before randomization. Compared with the gravid control group, women with preeclampsia exhibited significantly increased serum levels of endothelin-1, cyclic guanosine 3'5' monophosphate, and asymmetric-dimethyl-arginine before delivery. Despite a significant increase in postpartum serum arginine levels due to treatment, no differences were found in the corresponding levels of nitric oxide, endothelin-1, cyclic guanosine 3'5' monophosphate, or asymmetric-dimethyl-arginine between the two groups with preeclampsia. Further, there were no significant differences in any of the primary outcome measures with both groups demonstrating similar levels in glomerular filtration rate and equivalent improvements in both blood pressure and proteinuria.Blood pressure and kidney function improve markedly in preeclampsia by the 10th day postpartum. Supplementation with l-arginine does not hasten this recovery.I.

    View details for PubMedID 16582128

  • Effect of L-arginine therapy on the glomerular injury of preeclampsia - A randomized controlled trial OBSTETRICS AND GYNECOLOGY Mladunewich, M. A., Derby, G. C., Lafayette, R. A., Blouch, K. L., Druzin, M. L., Myers, B. D. 2006; 107 (4): 886-895

    Abstract

    To assess the benefit of l-arginine, the precursor to nitric oxide, on blood pressure and recovery of the glomerular lesion in preeclampsia.Forty-five women with preeclampsia were randomized to receive either l-arginine or placebo until day 10 postpartum. Primary outcome measures including mean arterial pressure, glomerular filtration rate, and proteinuria were assessed on the third and 10th days postpartum by inulin clearance and albumin-to-creatinine ratio. Nitric oxide, cyclic guanosine 3'5' monophosphate, endothelin-1, and asymmetric-dimethyl-arginine and arginine levels were assayed before delivery and on the third and 10th days postpartum. Healthy gravid women provided control values. Assuming a standard deviation of 10 mm Hg, the study was powered to detect a 10-mm Hg difference in mean arterial pressure (alpha .05, beta .20) between the study groups.No significant differences existed between the groups with preeclampsia before randomization. Compared with the gravid control group, women with preeclampsia exhibited significantly increased serum levels of endothelin-1, cyclic guanosine 3'5' monophosphate, and asymmetric-dimethyl-arginine before delivery. Despite a significant increase in postpartum serum arginine levels due to treatment, no differences were found in the corresponding levels of nitric oxide, endothelin-1, cyclic guanosine 3'5' monophosphate, or asymmetric-dimethyl-arginine between the two groups with preeclampsia. Further, there were no significant differences in any of the primary outcome measures with both groups demonstrating similar levels in glomerular filtration rate and equivalent improvements in both blood pressure and proteinuria.Blood pressure and kidney function improve markedly in preeclampsia by the 10th day postpartum. Supplementation with l-arginine does not hasten this recovery.I.

    View details for Web of Science ID 000241296200022

  • Associations of serologic markers of infection and inflammation with vascular disease events and mortality in American dialysis patients. Clinical and experimental nephrology Lentine, K. L., Parsonnet, J., Taylor, I., Wrone, E. M., Lafayette, R. A. 2006; 10 (1): 55-62

    Abstract

    Inflammatory markers predict cardiovascular risk and mortality in endstage renal disease. The relationship of chronic infections to inflammation and vascular disease events has not been reported among American dialysis patients.We performed a cross-sectional and prospective study of a multiracial cohort of 97 chronic hemodialysis patients in California. Anti-Chlamydia pneumoniae IgA and IgG antibodies (Cp-IgA and Cp-IgG), anti-Helicobacter pylori antibodies (Hp-IgG), and highly sensitive C-reactive protein (hsCRP) levels were measured at enrollment. We ascertained the prevalence of atherosclerotic vascular (coronary artery, cerebrovascular, and peripheral vascular) disease (AVD) events, and observed participants for at least 1 year for incident events and mortality. We defined statistical significance as P < 0.01.Elevated hsCRP levels (77%) and seropositivity to C. pneumoniae were common (Cp-IgA, 49%; Cp-IgG, 64%), whereas the seroprevalence of Hp-IgG was relatively low (25%). The hsCRP levels did not vary with infection status. In bivariate analysis, Cp-IgA and Cp-IgG were each associated with approximately fourfold higher odds of prevalent AVD (P < 0.01). Although anti-chlamydial antibodies maintained nearly significant associations with AVD after covariate adjustment (P < 0.05), antibodies did not predict outcomes over the period of observation. However, hsCRP was a nearly significant independent predictor of prevalent AVD (P = 0.02) and of mortality during follow-up (P = 0.01). We did not detect an association of Hp-IgG with any study outcome.Our findings generalize a possible link between C. pneumoniae and prevalent atherosclerosis in American hemodialysis patients and confirm the importance of hsCRP as a prognostic indicator. Our work does not support H. pylori as an important mediator of cardiovascular risk in dialysis patients.

    View details for PubMedID 16544178

  • Renal tubular injury associated with anagrelide NEPHROLOGY DIALYSIS TRANSPLANTATION Rodwell, G. E., Troxell, M. L., Lafayette, R. A. 2005; 20 (5): 988-990

    View details for DOI 10.1093/ndt/gfh726

    View details for Web of Science ID 000229083800022

    View details for PubMedID 15728271

  • The kidney in preeclampsia KIDNEY INTERNATIONAL Lafayette, R. 2005; 67 (3): 1194-1203

    View details for Web of Science ID 000227013500049

    View details for PubMedID 15698468

  • Examining chronic kidney disease management in a single center CLINICAL NEPHROLOGY Lafayette, R. A., Lai, G. 2004; 62 (4): 260-266

    Abstract

    The management of patients with chronic kidney disease in outpatient clinics was assessed for the ability to achieve targets of care advocated in clinical practice guidelines.272 records of outpatients with increased serum creatinine (> or = 1.5 mg/dl for women, > or = 2.0 mg/dl for men) were reviewed for details of their assessment and management. Prevailing data on blood pressure, anemia, bone disease and lipid status as well as therapeutic changes were evaluated.The subjects were aged 64 +/- 18 years, serum creatinine 2.6 +/- 1.1 mg/dl, and calculated GFR (MDRD formula) 19.2 +/- 9.9 ml/min. Median UproV was 1.0 (0.024 - 12.4) g/day. Causes of CKD were diabetes (33.5%), HTN (8.8%), GN (19.5%), and adult PKD (3.3%). Treatment targets were BP < 130/85 mmHg, Hct > or = 36%, serum Ca++ > or = 8.5 mg/dl, serum Po4 < 4.5 mg/dl and cholesterol < 200 mg/dl. Of the patients with abnormal findings, mean values for SBP were 153 +/- 17 mmHg, DBP 93 +/- 6 mmHg, Hct 31.7 +/- 2.9%, Ca++ 8.0 +/- 0.7 mg/dl, PO4 5.6 +/- 1.0 mg/dl, and cholesterol 236 +/- 37 mg/dl. Only a minority of patients with abnormal values had their treatment altered. Furthermore, only 54% of patients with hypertension were treated with either ACEi or ARB therapy. Finally, only 6% of patients with hypercholesterolemia had fasting lipid levels measured.This data suggests that treatment of patients with CKD has improved, but that many opportunities exist to optimize their care.

    View details for Web of Science ID 000224247300002

    View details for PubMedID 15524055

  • The dynamics of glomerular filtration in the puerperium AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Hladunewich, M. A., Lafayette, R. A., Derby, G. C., Blouch, K. L., Bialek, J. W., Druzin, M. L., Deen, W. M., Myers, B. D. 2004; 286 (3): F496-F503

    Abstract

    We evaluated the glomerular filtration rate (GFR) during the second postpartum week in 22 healthy women who had completed an uncomplicated pregnancy. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (K(f)). We compared these findings with those in pregnant women previously studied on the first postpartum day as well as nongravid women of reproductive age. Healthy female transplant donors of reproductive age permitted the morphometric analysis of glomeruli and computation of the single-nephron K(f). The aforementioned physiological and morphometric measurements were utilized to estimate transcapillary hydraulic pressure (Delta P) from a mathematical model of glomerular ultrafiltration. We conclude that postpartum day 1 is associated with marked glomerular hyperfiltration (+41%). A theoretical analysis of GFR determinants suggests that depression of glomerular capillary oncotic pressure, the force opposing the formation of filtrate, is the predominant determinant of early elevation of postpartum GFR. A reversal of the gestational hypervolemia and hemodilution, still evident on postpartum day 1, eventuates by postpartum week 2. An elevation of oncotic pressure in the plasma that flows axially along the glomerular capillaries to supernormal levels ensues; however, GFR remains modestly elevated (+20%) above nongravid levels. An analysis of filtration dynamics at this time suggests that a significant increase in Delta P by up to 16%, an approximately 50% increase in K(f), or a combination of smaller increments in both must be invoked to account for the persistent hyperfiltration.

    View details for DOI 10.1152/ajprenal.00194.2003

    View details for Web of Science ID 000188707500009

    View details for PubMedID 14612381

  • Podocytopenia and disease severity in IgA nephropathy KIDNEY INTERNATIONAL Lemley, K. V., Lafayette, R. A., Safai, M., Derby, G., Blouch, K., Squarer, A., Myers, B. D. 2002; 61 (4): 1475-1485

    Abstract

    IgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy.Glomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and 3H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers.The patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 +/- 29 SD vs. 104 +/- 23 mL/min/1.73 m2, P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells.Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.

    View details for Web of Science ID 000174465100030

    View details for PubMedID 11918755

  • How does knocking out angiotensin II activity reduce renal injury in mice? Discussion AMERICAN JOURNAL OF KIDNEY DISEASES Lafayette, R. A. 2000; 35 (1): 166-169

    View details for Web of Science ID 000084572400027

    View details for PubMedID 10620561

  • The dynamics of glomerular filtration after caesarean section JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lafayette, R. A., Malik, T., Druzin, M., Derby, G., Myers, B. D. 1999; 10 (7): 1561-1565

    Abstract

    The objective of this study was to determine whether the glomerular hyperfiltration of pregnancy is maintained even after Caesarean section and, if so, to define the responsible hemodynamics. The dynamics of glomerular filtration were evaluated in 12 healthy women who had just completed an uncomplicated pregnancy and were delivered by Caesarean section. Age-matched but non-gravid female volunteers (n = 22) served as control subjects. GFR in postpartum women was elevated above control values by 41%; 149+/-10 versus 106+/-3 ml/min per 1.73 m2, respectively (P < 0.001). In contrast, corresponding renal plasma flow was the same in the two groups, such that the postpartum filtration fraction was significantly elevated by 20%. Computation of glomerular intracapillary oncotic pressure (piGC) from knowledge of plasma oncotic pressure and the filtration fraction revealed this quantity to be significantly reduced in postpartum women, 20.6+/-1.7 versus 26.1+/-2.0 mmHg in control subjects (P < 0.001). A theoretical analysis of glomerular ultrafiltration suggests that depression of piGC, the force opposing the formation of filtrate, is predominantly or uniquely responsible for the observed postpartum hyperfiltration.

    View details for Web of Science ID 000081143900017

    View details for PubMedID 10405212

  • Nature of glomerular dysfunction in pre-eclampsia KIDNEY INTERNATIONAL Lafayette, R. A., Druzin, M., Sibley, R., Derby, G., Malik, T., Huie, P., Polhemus, C., Deen, W. M., Myers, B. D. 1998; 54 (4): 1240-1249

    Abstract

    Pre-eclampsia is characterized by hypertension, proteinuria and edema. Simultaneous studies of kidney function and structure have not been reported. We wished to explore the degree and nature of glomerular dysfunction in pre-eclampsia.Physiologic techniques were used to estimate glomerular filtration rate (GFR), renal plasma flow and afferent oncotic pressure immediately after delivery in consecutive patients with pre-eclampsia (PET; N = 13). Healthy mothers completing an uncomplicated pregnancy served as functional controls (N = 12). A morphometric analysis of glomeruli obtained by biopsy and mathematical modeling were used to estimate the glomerular ultrafiltration coefficient (Kf). Glomeruli from healthy female kidney transplant donors served as structural controls (N = 8).The GFR in PET was depressed below the control level, 91 +/- 23 versus 149 +/- 34 ml/min/1.73 m2, respectively (P < 0.0001). In contrast, renal plasma flow and oncotic pressure were similar in the two groups (P = NS). A reduction in the density and size of endothelial fenestrae and subendothelial accumulation of fibrinoid deposits lowered glomerular hydraulic permeability in PET compared to controls, 1.81 versus 2.58 x 10(-9) m/sec/PA. Mesangial cell interposition also curtailed effective filtration surface area. Together, these changes lowered the computed single nephron Kf in PET below control, 4.26 versus 6.78 nl/min x mm Hg, respectively.The proportionate (approximately 40%) depression of Kf for single nephrons and GFR suggests that hypofiltration in PET does not have a hemodynamic basis, but is a consequence of structural changes that lead to impairment of intrinsic glomerular ultrafiltration capacity.

    View details for Web of Science ID 000076096900022

    View details for PubMedID 9767540

  • Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis 27th Annual Meeting of the American-Society-of-Nephrology Chertow, G. M., Lazarus, J. M., Paganini, E. P., Allgren, R. L., Lafayette, R. A., Sayegh, M. H. AMER SOC NEPHROLOGY. 1998: 692–98

    Abstract

    To explore the natural history of critically ill patients with acute renal failure due to acute tubular necrosis, we evaluated 256 patients enrolled in the placebo arm of a randomized clinical trial. Death and the composite outcome, death or the provision of dialysis, were determined with follow-up to 60 d. The relative risks (RR) and 95% confidence intervals (95% CI) associated with routinely available demographic, clinical, and laboratory variables were estimated using proportional hazards regression. Ninety-three (36%) deaths were documented; an additional 52 (20%) patients who survived received dialysis. Predictors of mortality included male gender (RR, 2.01; 95% CI, 1.21 to 3.36), oliguria (RR, 2.25; 95% CI, 1.43 to 3.55), mechanical ventilation (RR, 1.86; 95% CI, 1.18 to 2.93), acute myocardial infarction (RR, 3.14; 95% CI, 1.85 to 5.31), acute stroke or seizure (RR, 3.08; 95% CI, 1.56 to 6.06), chronic immunosuppression (RR, 2.37; 95% CI, 1.16 to 4.88), hyperbilirubinemia (RR, 1.06; 95% CI, 1.03 to 1.08 per 1 mg/dl increase in total bilirubin) and metabolic acidosis (RR, 0.95; 95% CI, 0.90 to 0.99 per 1 mEq/L increase in serum bicarbonate concentration). Predictors of death or the provision of dialysis were oliguria (RR, 5.95; 95% CI, 3.96 to 8.95), mechanical ventilation (RR, 1.53; 95% CI, 1.07 to 2.21), acute myocardial infarction (RR, 1.95; 95% CI, 1.24 to 3.07), arrhythmia (RR, 1.51; 95% CI, 1.04 to 2.19), and hypoalbuminemia (RR, 0.56; 95% CI, 0.42 to 0.74 per 1 g/dl increase in serum albumin concentration). Neither mortality nor the provision of dialysis was related to patient age. These observations can be used to estimate risk early in the course of acute tubular necrosis. Furthermore, these and related models may be used to adjust for case-mix variation in quality improvement efforts, and to objectively stratify patients in future intervention trials aimed at favorably altering the course of hospital-acquired acute renal failure.

    View details for Web of Science ID 000072776600020

    View details for PubMedID 9555672

  • Renal artery stenosis in kidney transplants AMERICAN JOURNAL OF KIDNEY DISEASES Fervenza, F. C., Lafayette, R. A., Alfrey, E. J., Petersen, J. 1998; 31 (1): 142-148

    Abstract

    Transplant renal artery stenosis (TRAS) is an increasingly recognized complication of renal transplantation, with a reported incidence of between 1% and 23%. The clinical features include refractory hypertension, new-onset hypertension, allograft dysfunction, and the presence of a bruit over the graft. In this report, we describe the investigation and treatment of one such patient and review the current diagnostic approaches and therapy in this setting.

    View details for Web of Science ID 000071345700024

    View details for PubMedID 9428466

  • Pretransplant renal dysfunction predicts poorer outcome in liver transplantation CLINICAL NEPHROLOGY Lafayette, R. A., Pare, G., Schmid, C. H., King, A. J., Rohrer, R. J., Nasraway, S. A. 1997; 48 (3): 159-164

    Abstract

    The postoperative courses of 115 liver transplant recipients were reviewed to monitor for outcomes of acute renal failure and mortality. An analysis of baseline (preoperative) variables with particular attention to baseline renal function was accomplished to establish predictive variables for a complicated postoperative course. Acute renal failure requiring dialysis occurred in 27 cases (23%) and was associated with a prolonged ICU stay, greater infectious complications, greater hospital charges and a high mortality rate (46 +/- 11% vs. 9 +/- 3%) as compared to patients who did not experience acute renal failure. Death occurred in 20 patients (17%) overall prior to discharge. In order to assess the contribution of renal function, the population was divided arbitrarily into two groups based on preoperative serum creatinine. Group 1 (n = 50) had a preoperative serum creatinine < 1.0 mg/dl (mean +/- SD = 2.2 +/- 0.2 mg/dl) and Group 2 (n = 65) had a preoperative serum creatinine < or = 1.0 mg/dl (0.7 +/- 0.1 mg/dl). The groups experienced similar operative courses. Group 1 patients experienced significantly longer ICU stays (18 +/- 3 vs. 10 +/- 2 days), higher rates of acute renal failure requiring dialysis (52 +/- 7 vs. 5 +/- 2%), higher hospital charges (231,454 +/- 17,088 vs. 178,755 +/- 14,744 $, US) and a greatly increased mortality rate (32 +/- 1 vs. 6 +/- 1%), as compared to Group 2 patients. A multifactorial regression analysis demonstrated that of all pretransplant factors analyzed, elevation in the serum creatinine was significantly associated and was the strongest predictor of both outcomes: acute renal failure requiring dialysis (ROC = 0.89) and death (ROC = 0.83). The presence or absence of hepatorenal syndrome did not influence the results of this analysis. This study demonstrates that cirrhotic patients with renal dysfunction, as indicated by an elevated serum creatinine, experience a poor surgical outcome following liver transplantation. These patients may require special attention in the perioperative period. Alternatively, these data may influence the selection of ideal candidates for liver transplantation, where scarce resources need to be applied appropriately.

    View details for Web of Science ID A1997XV89900005

    View details for PubMedID 9342487

  • Anaritide in acute tubular necrosis 27th Annual Meeting of the American-Society-of-Nephrology Allgren, R. L., Marbury, T. C., Rahman, S. N., Weisberg, L. S., Fenves, A. Z., Lafayette, R. A., Sweet, R. M., Genter, F. C., Kurnik, B. R., Conger, J. D., Sayegh, M. H. MASS MEDICAL SOC. 1997: 828–34

    Abstract

    Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide.We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 microgram per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality.The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, < 400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03).The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis.

    View details for Web of Science ID A1997WN37100003

    View details for PubMedID 9062091

  • Profound hypophosphatemia and isolated hyperphosphaturia in two cases of multiple myeloma AMERICAN JOURNAL OF KIDNEY DISEASES Dash, T., Parker, M. G., Lafayette, R. A. 1997; 29 (3): 445-448

    Abstract

    We describe the development of severe hypophosphatemia and urinary phosphate wasting in two patients with multiple myeloma. In both cases, the serum phosphorus was repeatedly less than 1.0 mg/dL despite vigorous replacement, and the calculated fractional excretion of urinary phosphorus was greater than 100%. Neither patient demonstrated other tubular defects typical of Fanconi's syndrome. With treatment of the myeloma, both patients achieved normalization of the serum phosphorus and no longer required phosphorus supplementation. We believe that multiple myeloma should be considered in the differential diagnosis in patients with profound hypophosphatemia, urinary phosphate wasting, and otherwise intact tubular function.

    View details for Web of Science ID A1997WK38800016

    View details for PubMedID 9041222

  • Acute renal failure due to postinfectious glomerulonephritis during pregnancy AMERICAN JOURNAL OF KIDNEY DISEASES Fervenza, F., Green, A., Lafayette, R. A. 1997; 29 (2): 273-276

    Abstract

    Acute renal failure is a rare but potentially devastating complication of pregnancy. Among its many potential causes is acute postinfectious glomerulonephritis. We describe a case of acute renal failure during pregnancy, provide the histologic features of the renal biopsy, and discuss the differential diagnosis. Postinfectious glomerulonephritis can present rapidly after clinical infection and cause acute renal failure in pregnancy.

    View details for Web of Science ID A1997WH36400014

    View details for PubMedID 9016900

  • PREVENTING DISEASE PROGRESSION IN CHRONIC-RENAL-FAILURE AMERICAN FAMILY PHYSICIAN Lafayette, R. A. 1995; 52 (6): 1783-1791

    Abstract

    Progression toward end-stage renal disease is usually inexorable in patients with diabetic and nondiabetic nephropathy. These patients can be identified at an early stage based on history, abnormal urinalysis or reduced glomerular filtration. Recent advances have made it possible to slow the progression of chronic renal failure. Major interventions include antihypertensive therapy, dietary protein restriction and, in patients with diabetes, strict glycemic control and angiotensin-converting enzyme inhibitor therapy. Collaboration with a nephrologist can help guide the family physician in the appropriate use of these modalities and help avoid common complications. Major efforts in slowing the progression of renal failure may lead to a decreased incidence of end-stage renal disease, with savings in morbidity, mortality and cost.

    View details for Web of Science ID A1995TC86900021

    View details for PubMedID 7484688

  • RENAL ACID-BASE TRANSPORT - THE REGULATORY ROLE OF THE INNER MEDULLARY COLLECTING DUCT KIDNEY INTERNATIONAL Schwartz, J. H., Madias, N. E., Harrington, J. T., Perrone, R., Lafayette, R., Borkan, S. 1995; 47 (1): 333-341

    View details for Web of Science ID A1995PZ59700044

    View details for PubMedID 7731167

  • MORBIDITY AND MORTALITY IN DIALYSIS PATIENTS KIDNEY INTERNATIONAL Port, F. K., Harrington, J. T., Lafayette, R., Brown, R. S., Levey, A. S., STEINMAN, T. L., Meyer, K., Madias, N. E., NEURINGER, J. R. 1994; 46 (6): 1728-1737

    View details for Web of Science ID A1994PT27200053

    View details for PubMedID 7700033

  • ACUTE-RENAL-FAILURE IN THE SETTING OF BONE-MARROW TRANSPLANTATION KIDNEY INTERNATIONAL Zager, R. A., Madias, N. E., Harrington, J. T., Singh, A., Perrone, R., King, A., Lafayette, R., Natov, S. N. 1994; 46 (5): 1443-1458

    View details for Web of Science ID A1994PM51400025

    View details for PubMedID 7853806

  • LIPIDS AND THE KIDNEY KIDNEY INTERNATIONAL Keane, W. F., Madias, N. E., Harrington, J. T., Pereira, B., Singh, A., Lafayette, R., Neuringer, J., Natov, S. N. 1994; 46 (3): 910-920

    View details for Web of Science ID A1994PC21700039

    View details for PubMedID 7996813

  • INCREASED SERUM CREATININE IN THE ABSENCE OF RENAL-FAILURE IN PROFOUND HYPOTHYROIDISM AMERICAN JOURNAL OF MEDICINE Lafayette, R. A., Costa, M. E., King, A. J. 1994; 96 (3): 298-299

    View details for Web of Science ID A1994ND10900019

    View details for PubMedID 8154519

  • RENIN PROFILING FOR DIAGNOSIS, RISK ASSESSMENT, AND TREATMENT OF HYPERTENSION KIDNEY INTERNATIONAL Laragh, J. H., Madias, N. E., Harrington, J. T., Strom, J., Singh, A. K., Lafayette, R., Levey, A. S., Cahan, D. 1993; 44 (5): 1163-1175

    View details for Web of Science ID A1993MB44800031

    View details for PubMedID 8264150

  • THE EFFECTS OF BLOOD-PRESSURE REDUCTION ON CYCLOSPORINE NEPHROTOXICITY IN THE RAT JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lafayette, R. A., Mayer, G., Meyer, T. W. 1993; 3 (12): 1892-1899

    Abstract

    The effects of blood pressure reduction on cyclosporine nephrotoxicity were studied over 12 months in four groups of rats. Group 1 received no drugs and served as controls. Groups 2, 3, and 4 received cyclosporine (CyA), approximately 9 mg/kg.day, in their food. In addition, Group 3 received enalapril and Group 4 received minoxidil, hydrochlorothiazide, and reserpine. Time-averaged monthly systolic blood pressure was equal in Groups 1 and 2 (136 +/- 1 and 135 +/- 1 mm Hg, respectively). Antihypertensive agents reduced average systolic blood pressure in Groups 3 and 4 (116 +/- 1 and 117 +/- 1 mm Hg, respectively). Morphometric studies showed that 12 months of CyA treatment caused interstitial fibrosis with an increase in the fractional volume of cortical interstitium (VvInt: Group 2, 20 +/- 1%; Group 1, 11 +/- 1%) and a reduction in mean glomerular volume (VG. Group 2, (2.00 +/- 0.06) x 10(6) mu 3; Group 1, (2.48 +/- 0.06) x 10(6) mu 3). These structural changes were accompanied by a significant reduction in GFR (Group 2, 2.27 +/- 0.10 mL/min; Group 1, 2.76 +/- 0.10 mL/min). Cotreatment with enalapril reduced interstitial fibrosis (VvInt, 14 +/- 1%) and maintained VG (2.23 +/- 0.08 x 10(6) mu 3) and GFR (2.56 +/- 0.08 mL/min) at near-normal values in Group 3. In contrast, the combination antihypertensive regimen increased the extent of interstitial fibrosis (VvInt, 24 +/- 1%) and further lowered VG (1.72 +/- 0.05 x 10(6) mu 3) and GFR (1.72 +/- 0.05 mL/min) in Group 4. These results show that sustained treatment with a moderate dose of CyA causes interstitial fibrosis and impairs renal function in rats. The administration of enalapril, but not minoxidil, reserpine, and hydrochlorothiazide, limits renal injury in this model.

    View details for Web of Science ID A1993LJ29800007

    View details for PubMedID 8338921

  • EFFECTS OF ANGIOTENSIN-II RECEPTOR BLOCKADE ON REMNANT GLOMERULAR PERMSELECTIVITY KIDNEY INTERNATIONAL Mayer, G., Lafayette, R. A., Oliver, J., Deen, W. M., Myers, B. D., Meyer, T. W. 1993; 43 (2): 346-353

    Abstract

    This study examined the mechanisms by which angiotensin II (Ang II) receptor blockade improves glomerular barrier function in rats with reduced nephron number. Proteinuria was measured at four weeks after 5/6 renal ablation, and rats were then divided into a group which received the Ang II receptor blocker MK954 and a group which received no treatment. Studies performed one week later showed that Ang II receptor blockade reduced proteinuria without altering GFR in renal ablated rats. Micropuncture studies showed that Ang II blockade reduced both mean arterial pressure (142 +/- 7 mm Hg, ablation without treatment; 105 +/- 2 mm Hg, ablation with treatment) and glomerular transcapillary pressure (54 +/- 3 mm Hg, ablation without treatment; 43 +/- 1 mm Hg, ablation with treatment). Dextran sieving studies showed that untreated rats developed a size-selective defect characterized by increased transglomerular passage of neutral dextrans with radii 54 to 76 A and a charge-selective defect characterized by an increased transglomerular passage of anionic dextran sulfate with a radius of approximately 18 A. Ang II blockade reduced fractional clearance values for large neutral dextrans near to values observed in normal rats but had no effect on the fractional clearance of dextran sulfate (0.68 +/- 0.11, ablation without treatment; 0.66 +/- 0.08, ablation with treatment; 0.46 +/- 0.05, normal rats). These findings indicate that reducing Ang II activity improves size-selectivity without affecting charge-selectivity in injured remnant glomeruli.

    View details for Web of Science ID A1993KH90700009

    View details for PubMedID 7680077

  • ANGIOTENSIN-II RECEPTOR BLOCKADE LIMITS GLOMERULAR INJURY IN RATS WITH REDUCED RENAL MASS JOURNAL OF CLINICAL INVESTIGATION Lafayette, R. A., Mayer, G., Park, S. K., Meyer, T. W. 1992; 90 (3): 766-771

    Abstract

    The effects of angiotensin II (AII) blockade were compared with the effects of angiotensin converting enzyme inhibition in rats with reduced nephron number. Rats were subjected to five-sixths renal ablation and divided into four groups with similar values for blood pressure and serum creatinine after 2 wk. Group 1 then served as untreated controls, while group 2 received the AII receptor antagonist MK954 (which has previously been designated DuP753), group 3 received the converting enzyme inhibitor enalapril, and group 4 received a combination of reserpine, hydralazine, and hydrochlorothiazide. Micropuncture and morphologic studies were performed 10 wk later. Converting enzyme inhibition, AII receptor blockade, and the combination regimen were equally effective in reversing systemic hypertension (time-averaged systolic blood pressure: group 1, 185 +/- 5 mmHg; group 2, 125 +/- 2 mmHg; group 3, 127 +/- 2 mmHg; group 4, 117 +/- 4 mmHg). Micropuncture studies showed that glomerular transcapillary pressure was reduced significantly by converting enzyme inhibition and by AII blockade but not by the combination regimen (delta P: group 1, 49 +/- 1 mmHg; group 2, 42 +/- 1 mmHg; group 3, 40 +/- 2 mmHg, group 4, 47 +/- 1 mmHg). Reduction of systemic blood pressure was associated with the development of markedly less proteinuria and segmental glomerular sclerosis in rats receiving enalapril and MK954 but not in rats receiving the combination regimen (prevalence of glomerular sclerotic lesions: group 1, 41 +/- 4%; group 2, 9 +/- 1%; group 3, 9 +/- 1%; group 4, 33 +/- 6%). These results indicate that the effects of converting enzyme inhibition on remnant glomerular function and structure depend on reduction in AII activity and are not attributable simply to normalization of systemic blood pressure.

    View details for Web of Science ID A1992JN95900012

    View details for PubMedID 1522231