An Outcomes-Based Definition of Proteinuria Remission in Focal Segmental Glomerulosclerosis

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.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_02_20_CJASNPodcast_18_3_T.mp3.

Keywords: Cohort Studies; FSGS; Glomerulosclerosis, Focal Segmental; Goals; Humans; Kidney Failure, Chronic; Prognosis; Propensity Score; Proportional Hazards Models; Renal Insufficiency; creatinine; glomerular filtration rate; kidney; proteinuria; surrogate endpoint.

Figure 1.

Flow diagram of included patients from 5 FSGS cohorts. C-PROBE, Clinical Phenotyping Resource and Biobank Core; FSGS-CT, National Institutes of Health-funded National Institute of Diabetes and Digestive and Kidney Diseases FSGS Clinical Trial; NACI, NephCure Accelerating Cures Network; NEPTUNE, Nephrotic Syndrome Study Network; NS-REG, University of Michigan Nephrotic Syndrome Registry; UP:C, urine protein:creatinine ratio.

Figure 2.

No improvement in kidney survival in children and adults with primary FSGS in the NEPTUNE study by conventional definitions of partial proteinuria remission at 4 months after biopsy. Complete remission, urine protein-to-creatinine ratio (UP:C) <0.3 g/g; partial remission, UP:C 0.3 to <3.5 g/g; no remission includes all other patients.

Figure 3.

Pooled analysis of 4 FSGS cohorts demonstrate kidney survival is better for patients achieving the novel FSGS partial proteinuria remission or complete remission compared to no remission by month 4, and month 8, but not month 1. Kidney survival is better for patients achieving the novel FSGS partial proteinuria remission or complete remission compared with no remission by month 4 and month 8, but not month 1. UP:C, urine protein:creatinine ratio.