C3 glomerulopathy in transplant "like yet unlike native": Pathophysiology, recent advances in therapeutics and evolving paradigms.

Abstract

This review provides an in-depth examination of the recurrence and management of glomerular diseases after kidney transplantation, with particular emphasis on C3 glomerulopathy (C3G). Among post-transplant glomerular diseases, C3G exhibits the highest recurrence rates, reported between 30% and 89% across studies. The review outlines the complex pathophysiology of C3G, driven by dysregulation of the complement system - whether from genetic variants, autoantibodies, monoclonal gammopathy, or other acquired factors. It highlights the diagnostic challenges posed by overlapping features with hemolytic uremic syndrome and membranoproliferative glomerulonephritis, as well as the difficulty in distinguishing complement overactivation from true regulatory failure. Key mechanisms of complement activation and the role of regulatory proteins are discussed, along with operative and clinical risk factors such as ischemia-reperfusion injury, delayed graft function, viral infections, and monoclonal gammopathy. The review describes the histopathologic spectrum of C3G in the allograft and underscores the importance of early protocol biopsies for timely detection. Management strategies include conservative measures, nonspecific immunosuppression, and emerging complement-targeted therapies. Recent Food and Drug Administration approvals of iptacopan and pegcetacoplan represents major advances. The review concludes by emphasizing personalized medicine, improved biomarkers, comprehensive genetic and autoantibody testing, and continued research to refine surveillance and treatment strategies for transplant recipients with C3G.