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Acquired drivers of C3 Glomerulopathy
Journal article   Open access   Peer reviewed

Acquired drivers of C3 Glomerulopathy

Seth J Welsh, Yuzhou Zhang and Richard J H Smith
Clinical kidney journal, Vol.18(3), sfaf022
03/04/2025
DOI: 10.1093/ckj/sfaf022
PMCID: PMC11883229
PMID: 40052168
url
https://doi.org/10.1093/ckj/sfaf022View
Published (Version of record) Open Access

Abstract

C3 glomerulopathy (C3G) is a group of heterogeneous ultra-rare 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) which bind to and stabilize complement convertases, causing complement over-activation. Current therapies are largely supportive, with limited efficacy from existing complement-targeting treatments like eculizumab. Challenges in studying C3G include variability in autoantibody detection and 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 drives of C3G with an emphasis on C3Nefs and C5Nefs and suggest areas of interest that might benefit from future research.
 complement C3 glomerulopathy nephritic factor autoimmune disease C3 convertase

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