C3 Glomerulopathy

Abstract

Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a new classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN. Immune complex-mediated MPGN results from the deposition of immunoglobulin deposits and complements component C3 driven by classical complement pathway activation, while complement-mediated disease may be associated with complement alternative pathway dysregulation and is a new entity, C3 glomerulopathy. C3 glomerulopathy is an umbrella term, encompassing dense deposit disease (DDD), former MPGN type II, and C3 glomerulonephritis. C3 glomerulonephritis comprises examples of MPGN types I and III, in which immunofluorescence reveals predominant C3 deposits. By light microscopy, distinctive histologic patterns can be observed in both entities, including membranoproliferative, mesangial proliferative, crescentic and acute proliferative and exudative patterns, of which the membranoproliferative pattern seems to be the most common. DDD is defined by the presence of dense osmiophilic transformation of the glomerular basement membrane (GBM) on electron microscopy (EM). Only EM enables definite distinction of DDD from C3 glomerulonephritis. C3 glomerulopathy is a heterogeneous disease; genetic or acquired complement alternative pathway abnormalities have been identified in up to 40% of patients, including mutations in complement factors or autoantibodies directed against them.