Combined Serologic and Genetic Risk Score and Prognostication of PLA2R-Associated Membranous Nephropathy

Introduction:The aim of this study was to test whether a combined risk score based on genetic risk and serology can improve the prediction of kidney failure in PLA2R-associated primary membranous nephropathy. Methods:We performed a retrospective analysis of 519 biopsy-proven PLA2R-associated primary membranous nephropathy patients with baseline eGFR >= 25ml/min/1.73m2. The combined risk score was calculated by combining the genetic risk score with PLA2R ELISA antibody titers. The primary endpoint was kidney disease progression defined as a 50% reduction in eGFR or kidney failure. Cox proportional hazard regression analysis and C-statistics were applied to compare the performance of PLA2R antibody, genetic risk score, and combined risk score, as compared to clinical factors alone, in predicting primary outcomes. Results:Median age was 56 years (range 15-82 years); male-to-female ratio was 1:0.6, median eGFR at biopsy was 99 ml/min/1.73m2 (range: 26-167 ml/min/1.73m2) and median proteinuria was 5.3 g/24h (range: 1.5-25.8 g/24h). During a median follow-up of 67 (5-200) months, 66 (13%) had kidney disease progression. In Cox proportional hazard regression models, PLA2R antibody titers, genetic risk score and combined risk score were all individually associated with kidney disease progression with and without adjustments for age, sex, proteinuria, eGFR and tubulo-interstitial lesions. The best-performing clinical model to predict kidney disease progression included age, eGFR, proteinuria, serum albumin, diabetes, and tubule-interstitial lesions [C-statistic 0.76 (0.69-0.82), adjusted R2 0.51]. While the addition of PLA2R antibody titer improved the performance of this model [C-statistic: 0.78 (0.72-0.84), adjusted R2 0.61], replacing PLA2R antibody with the combined risk score improved the model further [C-statistic: 0.82 (0.77-0.87), adjusted R2 0.69, difference of C-statistics with clinical model = 0.06 (0.03-0.10), P<0.001; difference of C-statistics with clinical-serological model = 0.04 (0.01-0.06), P<0.001 ]. Conclusion:In patients with PLA2R-associated membranous nephropathy, the combined risk score incorporating inherited risk alleles and PLA2R antibody enhanced prediction of kidney disease progression compared to PLA2R serology and clinical factors alone.