Acquired drivers of C3 glomerulopathy.

Abstract

C3 glomerulopathy (C3G) is a group of heterogeneous ultrarare kidney diseases characterized by dysregulated activation of the complement alternative pathway (AP) leading to excessive C3 cleavage. Diagnosis relies on kidney biopsy showing predominant C3 deposition in the glomerular basement membrane, with electron microscopy differentiating between dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The main drivers of AP dysregulation in C3G are acquired rather than genetic and consist primarily of autoantibodies called nephritic factors (C3Nefs, C4Nefs and C5Nefs) that bind to and stabilize complement convertases, causing complement overactivation. Current therapies are largely supportive, and existing complement-targeting treatments, such as eculizumab, demonstrate limited efficacy. Challenges in studying C3G include variability in autoantibody detection and a lack of standardized assays, which complicates clinical interpretation. Comprehensive assessment involving autoantibody panels, complement biomarkers, functional assays and genetic testing provides a more complete understanding of disease dynamics; however, key knowledge gaps remain regarding Nef origins, mechanisms and their pathogenic role. In this review we discuss acquired drivers of C3G with an emphasis on C3Nefs and C5Nefs and suggest areas of interest that might benefit from future research.