@article{656320ed11bb466fa2c380318245ecd9,
title = "Proteinuria Reduction and Kidney Survival in Focal Segmental Glomerulosclerosis",
abstract = "Rationale & Objective: Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival. Study Design: Cohort analysis of clinical trial participants. Setting & Participants: Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone. Predictors: Reduction in proteinuria measured during 26 weeks after initiating treatment. Outcomes: Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization. Analytical Approach: Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome. Results: 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90 mL/min/1.73 m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44). Limitations: Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years. Conclusions: These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.",
keywords = "Focal segmental glomerulosclerosis (FSGS), clinical outcome assessment, clinical trials, eGFR slope, estimated glomerular filtration rate (eGFR), proteinuria, remission, renal failure",
author = "Troost, {Jonathan P.} and Howard Trachtman and Cathie Spino and Kaskel, {Frederick J.} and Aaron Friedman and Moxey-Mims, {Marva M.} and Fine, {Richard N.} and Gassman, {Jennifer J.} and Kopp, {Jeffrey B.} and Liron Walsh and Rong Wang and Gipson, {Debbie S.}",
note = "Funding Information: Jonathan P. Troost, PhD, Howard Trachtman, MD, Cathie Spino, ScD, Frederick J. Kaskel, MD, Aaron Friedman, MD, Marva M. Moxey-Mims, MD, Richard N. Fine, MD, Jennifer J. Gassman, PhD, Jeffrey B. Kopp, MD, Liron Walsh, MD, Rong Wang, MS, and Debbie S. Gipson, MD, MS. FSGS-CT study design, conduct, enrollment of participants: HT, FJK, AF, MM-M, RNF, JJG, DSG; conception of overall research question and approach for secondary analyses of FSGS-CT data: JPT, HT, CS, DSG; statistical analyses: JPT; interpretation of results: all authors. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. This study was supported by the National Center for Advancing Translational Sciences (grant no. UL1TR002240) for the Michigan Institute for Clinical and Health Research. The FSGS Clinical Trial was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) grants U01- DK063385, DK063490, DK063455, and DK063549. Dr Kopp was supported by the NIDDK Intramural Research Program. This study was supported by many Clinical and Translational Science Award/NIH-funded institutions for the conduct of study visits, nursing, laboratory, and outpatient research facilities throughout the trial. The NIH had a role in the original study design and data collection, but no funders had a role in the analyses, reporting, or the decision to submit these analyses for publication. These analyses are investigator initiated. Several investigators on this study serve on scientific advisory boards and have funded clinical trials consulting agreements with several companies having active or in development FSGS trials: Pfizer Inc, Complexa, Goldfinch Bio, and Vertex. Drs Troost and Gipson have research funding through the University of Michigan with Complexa Inc, Retrophin Inc, and Goldfinch Bio; Dr Gipson has past research funding through the University of Michigan with Bristol-Meyers Squibb and Zyversa; Dr Troost, through the University of Michigan with Vertex Pharmaceuticals and Pfizer Inc. Dr Trachtman has research funding through the NYU with Retrophin Inc and Goldfinch Bio. Dr Walsh is an employee of Goldfinch Bio. Mr Wang is an employee of Pfizer Inc. We are indebted to the patients and families who graciously participated in this research; thank all site coordinators who assisted with patient identification, enrollment, treatment, and follow-up; acknowledge Norman Siegel (deceased) for leadership as the first FSGS-CT Steering Committee Chair; and thank members of the US Food and Drug Administration for review and advice on content. Received September 6, 2019. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form April 18, 2020. Funding Information: This study was supported by the National Center for Advancing Translational Sciences (grant no. UL1TR002240 ) for the Michigan Institute for Clinical and Health Research . The FSGS Clinical Trial was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) grants U01- DK063385 , DK063490 , DK063455 , and DK063549 . Dr Kopp was supported by the NIDDK Intramural Research Program. This study was supported by many Clinical and Translational Science Award/ NIH -funded institutions for the conduct of study visits, nursing, laboratory, and outpatient research facilities throughout the trial. The NIH had a role in the original study design and data collection, but no funders had a role in the analyses, reporting, or the decision to submit these analyses for publication. Publisher Copyright: {\textcopyright} 2020 National Kidney Foundation, Inc.",
year = "2021",
month = feb,
doi = "10.1053/j.ajkd.2020.04.014",
language = "English (US)",
volume = "77",
pages = "216--225",
journal = "American Journal of Kidney Diseases",
issn = "0272-6386",
publisher = "W.B. Saunders Ltd",
number = "2",
}