Acquired and genetic determinants of disease phenotype and therapeutic strategies in C3 glomerulopathy and immunoglobulin-associated MPGN

Abstract C3 glomerulopathy (C3G), a prototype of complement mediated disease, is characterized by significant heterogeneity, not only in terms of clinical, histological and biological presentation but also of prognosis, and response to existing therapies. Recent advancements in understanding the factors responsible for alternative pathway dysregulation in the disease have highlighted its even more complex nature. Here, we propose a reexamination of the diversity of C3G presentations in light of the drivers of complement activation. Autoantibodies targeting complement proteins, genetic abnormalities in complement genes and monoclonal immunoglobulins are now well-known to drive disease occurrence. This review discusses how these drivers contribute to the heterogeneity in disease phenotype and outcomes, providing insights into tailored diagnostic and therapeutic approaches. In recent years, a broad spectrum of complement inhibitory therapies has emerged, soon to be available in clinical practice. The recognition of specific clinical, biological, and histological patterns associated with different forms of C3G is crucial for personalized management, particularly treatment strategies.