IgA nephropathy (IgAN) is increasingly understood as an autoimmune glomerular disease in which complement activation helps convert mesangial immune-complex deposition into progressive kidney injury. The accepted disease model begins with mucosal immune dysregulation and production of galactose-deficient IgA1, followed by autoantibody formation, circulating immune complexes, and mesangial deposition. Complement—particularly the alternative pathway, with lectin pathway involvement in a subset of patients—then amplifies inflammation through C3 and C5 activation. This contributes to mesangial and endothelial injury, podocyte dysfunction, proteinuria, and tubulointerstitial fibrosis. Complement markers such as glomerular C4d, C3, C5b-9, factor B, and factor H-related proteins have also been associated with more active or severe histologic features, including crescents, although their role in routine risk stratification remains investigational.
This mechanistic understanding is driving development of pathway-selective therapies. In phase 3 data, factor B inhibition reduced proteinuria by 38.3% versus placebo at 9 months, while phase 2 C5 inhibition produced a 30.1% relative reduction in proteinuria at approximately 6 months. Other approaches targeting lectin, alternative, and terminal complement pathways are in various stages of clinical development, reflecting a shift from broad immunosuppression toward more mechanism-based treatment. However, important questions remain: most biomarker evidence is observational or cross-sectional, long-term effects on eGFR and kidney survival are still being established, and optimal patient selection has not been defined. Complement inhibition also requires attention to infection risk, including vaccination against encapsulated bacteria. For clinical practice, complement is emerging as an important therapeutic layer alongside optimized supportive care, not a replacement for it.
Reference: Lu CL, Yang CC, Wu CC, Lu KC. Breaking tolerance in the glomerulus: complement as a driver and therapeutic target in IgA nephropathy. Front Med (Lausanne). 2026 Aug 3;13:1896069. doi: 10.3389/fmed.2026.1896069.
