An outcomes-based definition of proteinuria remission in focal segmental glomerulosclerosis

Jonathan P. Troost, Howard Trachtman, Patrick H. Nachman, Matthias Kretzler, Cathie Spino, Radko Komers, Sarah Tuller, Kalyani Perumal, Susan F. Massengill, Elaine S. Kamil, Gia Oh, David T. Selewski, Patrick Gipson, Debbie S. Gipson

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background and objectives Proteinuria is used as an indicator of FSGS disease activity, but its use as a clinical trial end point is not universally accepted. The goal of this study was to refine proteinuria definitions associated with long-term kidney survival. Design, setting, participants, & measurements Data on 466 patients with primary FSGS with proteinuria (urine protein-to-creatinine ratio >1 g/g) were analyzed from five independent cohorts. Proteinuria by months 1, 4, and 8 after study baseline was categorized by conventional definitions of complete (<0.3 g/g) and partial remission (<3.5 g/g and 50% reduction in proteinuria). Novel remission definitions were explored using receiver operating curves. Kaplan–Meier methods were used to estimate the associations of proteinuria with progression to ESRD or a 50% loss in kidney function. Propensity score–adjusted Cox proportional hazards models were used to adjust for baseline proteinuria, eGFR, and therapy. Results In the initial derivation cohort, conventional partial remission was not associated with kidney survival. A novel definition of partial remission (40% proteinuria reduction and proteinuria<1.5 g/g) on the basis of receiver operating curve analyses of 89 patients was identified (Sensitivity=0.70; Specificity=0.77). In the validation cohort analyses, complete remission was associated with better prognosis (6 out of 41 patients progressed to kidney failure; 6.6 per 100 patient-years) as was the novel partial remission (13 out of 71 progressed; 8.5 per 100 patient-years), compared with those with no response (51 out of 116 progressed; 20.1 per 100 patient-years). Conventional partial remission at month 8, but not month 4, was also associated with better response (19 out of 85 patients progressed; risk=10.4 per 100 patient-years). Propensity score–adjusted analyses showed the novel partial remission was associated with less progression at months 4 and 8 (month 4: hazard ratio, 0.50; P=0.01; month 8: hazard ratio, 0.30; P=0.002). Conclusions Reaching either a complete or partial remission using a novel or conventional definition was associated with better long-term outcomes in patients with FSGS.

Original languageEnglish (US)
Pages (from-to)414-421
Number of pages8
JournalClinical Journal of the American Society of Nephrology
Volume13
Issue number3
DOIs
StatePublished - Mar 7 2018

Bibliographical note

Funding Information:
This investigator-initiated work was supported by Retrophin, Inc. and was conducted as an ancillary study to the Nephrotic Syndrome Study Network, Clinical Phenotyping Resource and Biobank Core study, and the NephCure Accelerating Cures Network. The study investigators report the following disclosures: R.K. and S.T. are employees of Retrophin; D.S.G. as part of her employment at University of Michigan is the principal investigator of the NephCure Accelerating Cures Institute Coordinating Center and has research funding from NephCure Kidney International, the National Institutes of Health, the Patient Centered Outcomes Research Institute, Retrophin, Bristol-Myers Squibb, Complexa, and Pfizer.

Funding Information:
The Nephrotic Syndrome Study Network (NEPTUNE) is spon-soredbytheNationalInstitutes ofHealth(NIH)/NationalCenterfor Advancing Translational Sciences and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U54DK083912), NephCureKidneyInternational,andtheUniversityofMichigan.Most NEPTUNE participating sites are supported by the NIH-sponsored Clinical and Translational Science Awards and their clinical research– supportedfacilities.TheFSGSClinicalTrialwassupportedbyNIDDK, NIH. The NephCure Accelerating Cures Institute is supported by NephCure Kidney International and the University of Michigan Department of Pediatrics and Communicable Diseases. The University of Michigan Nephrotic Syndrome Registry was supported in part by the NIH/NIDDK O’Brien Kidney Center (2P30-DK-081943) summer research internship (Grace Tsai), the University of Michigan Department of Pediatrics and Communicable Diseases and Honest Broker Office, and the NephCure Accelerating Cures Institute. The Clinical Phenotyping Resource and Biobank Core study is supported, in part, by the O’BrienRenalCenterNIHGrantP30-DK081943-01,andtheUniversity of Michigan School of Medicine, Department of Internal Medicine, and Department of Pediatrics and Communicable Diseases.

Funding Information:
We are indebted to the patients and families who graciously participated in these research studies. We would like to thank Lynn Holvenski for her help with the data extractions and dataset preparation. The Nephrotic Syndrome Study Network (NEPTUNE) is sponsored by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U54DK083912), NephCure KidneyInternational, and the University of Michigan. Most NEPTUNE participating sites are supported by the NIH-sponsored Clinical and Translational Science Awards and their clinical research– supported facilities. The FSGSClinical Trial was supported by NIDDK, NIH. The NephCure Accelerating Cures Institute is supported by NephCure Kidney International and the University of Michigan Department of Pediatrics and Communicable Diseases. The University of Michigan Nephrotic Syndrome Registry was supported in part by the NIH/NIDDK O’Brien Kidney Center (2P30-DK-081943) summer research internship (Grace Tsai), the University of Michigan Department of Pediatrics and Communicable Diseases and Honest Broker Office, and the NephCure Accelerating Cures Institute. The Clinical Phenotyping Resource and Biobank Core study is supported, in part, by the O’BrienRenal Center NIH Grant P30-DK081943-01, andthe University of Michigan School of Medicine, Department of Internal Medicine, and Department of Pediatrics and Communicable Diseases.

Publisher Copyright:
© 2018 by the American Society of Nephrology.

Keywords

  • Cohort Studies
  • Creatinine
  • Fsgs
  • Glomerular filtration rate
  • Goals
  • Humans Glomerulosclerosis, Focal Segmental
  • Kidney
  • Kidney Failure, Chronic
  • Prognosis
  • Propensity Score
  • Proportional Hazards Models
  • Proteinuria
  • Renal Insufficiency
  • Surrogate endpoint

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