C3 Glomerulopathy

Recent advances in our understanding of the disease pathology of membranoproliferative glomerulonephritis has resulted in its re-classification as complement C3 glomerulopathy (C3G) and immune complex-mediated glomerulonephritis (IC-GN). The new consensus is based on its underlying pathomechanism, with a key pathogenetic role for the complement alternative pathway (AP), rather than on histomorphological characteristics. In C3G, loss of AP regulation leads to predominant glomerular C3 deposition, which distinguishes C3G from IC-GN with predominant immunoglobulin G staining. Electron microscopy further subdivides C3G into C3 glomerulonephritis and dense deposit disease depending on the presence and distribution pattern of electron-dense deposits within the glomerular filter. Mutations or autoantibodies affecting the function of AP activators or regulators, in particular the decay of the C3 convertase (C3 nephritic factor), have been detected in up to 80 % of C3G patients. The natural outcome of C3G is heterogeneous, but 50 % of patients progress slowly and reach end-stage renal disease within 10-15 years. The new classification not only marks significant advancement in the pathogenic understanding of this rare disease, but also opens doors towards more specific treatment with the potential for improved outcomes.