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Acquired drivers of C3 glomerulopathy
Seth J Welsh1, Yuzhou Zhang1, Richard J H Smith1
1Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Insights
C3 glomerulopathy (C3G) involves complement alternative pathway overactivation due to autoantibodies called nephritic factors. Current treatments are limited, highlighting the need for research into these acquired drivers.
Area of Science:
- Nephrology
- Immunology
- Complement System Biology
Background:
- C3 glomerulopathy (C3G) is a rare kidney disease driven by complement alternative pathway (AP) dysregulation.
- Diagnosis involves kidney biopsy showing C3 deposition, distinguishing dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).
- Acquired autoantibodies, nephritic factors (NFs), stabilize complement convertases, causing overactivation.
Purpose of the Study:
- To review acquired drivers of C3G, focusing on nephritic factors (NFs).
- To highlight challenges in C3G diagnosis and treatment.
- To identify research gaps concerning NF origins, mechanisms, and pathogenic roles.
Main Methods:
- Review of literature on C3G pathogenesis, focusing on acquired drivers.
- Emphasis on autoantibodies like C3Nefs and C5Nefs.
- Discussion of diagnostic challenges and current therapeutic limitations.
Main Results:
- Nephritic factors (C3Nefs, C4Nefs, C5Nefs) are key acquired drivers of AP dysregulation in C3G.
- Existing therapies, including eculizumab, show limited efficacy.
- Variability in autoantibody detection and lack of standardized assays complicate clinical interpretation.
Conclusions:
- Acquired drivers, particularly nephritic factors, are central to C3G pathogenesis.
- Further research is needed to understand NF origins, mechanisms, and therapeutic targeting.
- Comprehensive assessment including autoantibodies, biomarkers, and genetics is crucial for understanding C3G.
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.
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