Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome

• Rare pathogenic variants and a common SNP of THBD predispose to C3 glomerulopathy.
• Mutations increase the risk of Ig-MPGN/C3 G only when combined with common SNPs.
• Patients with complement gene mutations or C3NeF have a lower risk of ESRD.

BackgroundMembranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephropathy recently reclassified into immunoglobulin-associated MPGN (Ig-MPGN) and C3 glomerulopathy (C3G). In this study we aimed: (1) to evaluate the complement genetic and biochemical profile in patients with Ig-MPGN/C3G; (2) to investigate whether genetic variants and different patterns of complement activation (i.e., fluid versus solid phase) correlate with disease manifestations and outcomes.MethodsIn 140 patients with idiopathic Ig-MPGN or C3G we performed complement biochemical and genetic screening and correlated genetic, biochemical and histology data with clinical features.ResultsMutations in genes encoding alternative pathway complement proteins were found in both Ig-MPGN and C3G, and mutations in the two components of the C3 convertase are the most prevalent. We also report a mutation in THBD encoding thrombomodulin in a C3G patient. The presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants (CD46 c.-366A in Ig-MPGN; CFH V62 and THBD A473 in C3G). Finally, patients without complement gene mutations or C3NeFs – autoantibodies that stabilize the alternative pathway C3 convertase – have a higher risk of progressing to end-stage renal disease than patients with identified mutations and/or C3NeFs, suggesting the existence of different pathogenetic mechanisms that lead to renal disease.ConclusionsWe provide new insights into the pathogenesis of Ig-MPGN/C3G that underscore the complex nature of these diseases and suggest that the current C3G classification may miss many cases associated with abnormalities of the complement alternative pathway.