Clinical and Histologic Predictors of Kidney Outcomes in C3 Glomerulopathy and Idiopathic Membranoproliferative GN

Key Points Lower eGFR, paraprotein presence, and interstitial fibrosis were associated with a higher risk of kidney outcome. Native disease (versus recurrence post-transplantation), White ethnicity, and lower C4 levels were associated with a lower risk of kidney outcome. A 50% reduction in proteinuria from baseline to a value <1 g/d was associated with a lower risk of kidney outcome. Background C3 glomerulopathy (C3G) is a rare disease caused by abnormalities in the alternative complement pathway with significant overlap with idiopathic immune complex membranoproliferative GN (IC-MPGN). The risk factors of kidney outcomes in these conditions remain controversial, limited by small studies. We aimed to identify and assess risk factors associated with kidney outcomes. Methods Using a cohort of 225 patients with C3G or idiopathic IC-MPGN from three international centers, we evaluated the association between clinical and histologic variables and a composite outcome of a 30% decline in eGFR or ESKD, using Cox proportional hazards models. A prediction model was derived and internally validated through bootstrap resampling. Results In a multivariable model, lower eGFR, paraprotein presence, and interstitial fibrosis were associated with a higher outcome risk, whereas native disease (versus recurrence post-transplantation), White ethnicity, and lower C4 levels were associated with lower risk. The prediction model including these variables performed well (R 2 D : 53%, C-statistic: 0.84 [95% confidence interval, 0.82 to 0.86], integrated calibration index: 0.31) and maintained robustness after internal validation. A 50% reduction in proteinuria from baseline to a value <1 g/d was associated with a lower risk of outcome independent of other risk factors (hazard ratio, 0.35; 95% confidence interval, 0.12 to 0.97). Conclusions Our study evaluated the baseline clinical and histologic parameters associated with kidney outcomes using the largest C3G/idiopathic IC-MPGN cohort to date. These factors were included in a prediction model to assess individual patient risk. Our results provide an evidence-based definition of proteinuria remission that can be used for patient care and in clinical trials. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2025_08_27_CJASNAugust.20.8.82.mp3