Clinical Predictors of Long-term Outcomes in C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis within the UK RaDaR Registry

Abstract

Background C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare disorders that often result in kidney failure over the long-term. While there is much interest in the therapeutic potential of complement inhibition, the limited duration and necessarily small size of controlled trials, means there is a need to define how well short-term changes in eGFR and proteinuria predict clinically important outcomes such as kidney failure. We aimed to address this using longitudinal data from the UK National Registry of Rare Kidney Diseases (RaDaR). Methods 287 patients with biopsy-proven C3G (135, 47%) or IC-MPGN (152, 53%) were included. Analyses of kidney survival were conducted using Kaplan Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope. Results 85/135 (63%) C3G and 107/152 (70%) IC-MPGN patients reached kidney failure over follow-up after a median of 9.7 years (95% CI 7.6-12.4). Median time to first allograft loss following transplantation was 4.9 years (95% CI 1.7-6.5). Kidney survival was strongly associated with eGFR at baseline and 12-month timepoints (p<0.001). Proteinuria at diagnosis, although high, was not associated with long-term kidney failure risk. In contrast, both a time averaged 0.44g/g (50mg/mmol) and 50% reduction in UPCR at 12 months (from either diagnosis or 6 months) was strongly associated with a lower risk of kidney failure (≤0.002). Most notably those with a UPCR <0.88g/g (<100mg/mmol) at 12 months had a substantially lower rate of progression to kidney failure (HR adjusted for eGFR 0.13 (95% CI 0.03-0.56), p=0.007). Conclusions We quantified the relationships between early changes in both eGFR and proteinuria with long-term kidney survival. We demonstrate that proteinuria a short time after diagnosis is a strong predictor of long-term outcomes and that a UPCR <0.88g/g (<100mg/mol) at 1 year is associated with a substantially lower kidney failure risk.