Complement 3 Glomerulopathy (C3G) in Native and Posttransplant Kidneys: Pathophysiology, Prognosis, and Treatment.

Abstract

Complement 3 glomerulopathy (C3G) is a rare, complement-mediated kidney disease characterized by overactivation of the alternative pathway (AP). C3G encompasses 2 subtypes-dense deposit disease and C3 glomerulonephritis-both of which lead to C3 deposition in the glomeruli, progressive kidney dysfunction, and, ultimately, kidney failure. The pathophysiology of C3G and the underlying complement AP overactivation are often driven by genetic mutations and/or acquired autoantibodies. These systemic drivers can affect both native and transplanted kidneys; thus, C3G is associated with a high risk of recurrence in allografts. Recurrence of C3G in posttransplant kidneys has a particularly poor prognosis and leads to a high rate of graft loss. Therapeutic strategies for both native and posttransplant recurrent C3G that are largely supportive have shown limited benefit in improving kidney survival, as have therapies targeting the terminal complement cascade, downstream of pathogenic AP overactivation. In contrast, emerging therapies that target AP overactivation are showing promise for more effective disease modification. In light of the evolving treatment landscape, this review provides an update on the current state of knowledge regarding the pathophysiology, prognosis, and treatment options for native and posttransplant recurrent C3G.