Current and Emerging Therapies for C3 Glomerulopathy and Primary (Idiopathic) Immune Complex Membranoproliferative Glomerulonephritis.

C3 glomerulopathy (C3G) and primary (idiopathic) immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare kidney diseases characterized by dysregulation of the complement system and progressive deposition of C3 and its breakdown products in the glomeruli, ultimately leading to kidney failure in up to 50% of patients within 10 years. Until recently, standard approaches to treatment included supportive measures common to many kidney diseases and immunosuppression to mitigate inflammation, rather than specific therapies addressing the underlying C3 dysregulation. However, recent advances in targeted complement inhibitor therapy have been made in these diseases with positive results from phase 3 clinical trials of both the factor B inhibitor, iptacopan (in adults with native kidney C3G) and the C3/C3b inhibitor, pegcetacoplan (in adults and adolescents with native or posttransplant C3G or primary IC-MPGN). In this review, we summarize what is known and what questions still remain regarding the effect of complement inhibitors on widely accepted surrogate end points for efficacy in C3G/primary IC-MPGN (proteinuria, estimated glomerular filtration rate [eGFR], and kidney biopsy histology). Additional controversies, including candidate patient populations, optimal treatment duration, and how best to monitor patients on complement inhibitor therapy are also discussed, in an effort to prepare the nephrology community for innovative therapeutic options for patients whose long-term prognosis has generally been dismal.