Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10⁻¹²) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10⁻¹⁴), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10⁻¹⁰³) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10⁻⁴⁹), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10⁻⁹³), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10⁻²³ and OR = 3.39, P = 5.2 × 10⁻⁸², respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Key Points: ACCOLADE was the first randomized trial in patients with complement 3 glomerulopathy investigating the use of avacopan, a complement component 5a receptor blocker. The trial did not meet its primary end point of change in disease activity index from baseline to 26 weeks. No new safety signals were reported; the results suggest a potential role of avacopan in milder forms of complement 3 glomerulopathy. Background: Complement 3 (C3) glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with isolated or dominant complement 3 deposition in glomeruli. Patients with C3 glomerulopathy may develop progressive deterioration in kidney function and kidney failure. Methods: We studied the safety and efficacy of avacopan 30 mg twice daily in patients with C3 glomerulopathy (N=57) with elevated (>244 ng/ml) and normal (≤244 ng/ml) levels of membrane attack complex or terminal complement complex (C5b-9) in a randomized, double-blind, placebo-controlled, phase 2 trial, with kidney biopsies performed prerandomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in C3 Glomerulopathy Histological Index for disease activity. Results: The study was conducted in patients with C3 glomerulopathy, including C3 GN and dense deposit disease. The median study duration was 60.0 weeks (interquartile range, 59.9–61.0). There were no significant differences in the primary outcome between the avacopan and the placebo group—least squares mean treatment difference (95% confidence interval)= −0.0 (−1.9 to 1.8). The secondary measures of efficacy including C3 Glomerulopathy Histological Index for disease chronicity, urine protein:creatinine ratio, and eGFR were not different between treatment groups. The overall incidence and type of adverse events for both treatment groups were comparable. No deaths were reported during the study, and no new safety signals were detected. Conclusions: The primary end point for the study was not met; other clinical effects of avacopan to improve certain key kidney function parameters and slow disease progression were variable and require further evaluation. Clinical Trial registry name and registration number: Controlled Trial Evaluating Avacopan in C3 Glomerulopathy (ACCOLADE), NCT03301467.