The Role of Complement C3 Deposition in ANCA-Associated Glomerulonephritis: a Registry-Based Study of Clinical, Histopathological, and Prognostic Insights

Abstract

Background: ANCA-associated glomerulonephritis (ANCA-GN) is a leading cause of pauci-immune crescentic GN. Recent evidence indicates that complement activation, marked by C3 deposition in glomeruli, may contribute to more severe renal injury and influence renal outcomes. We aim to evaluate the clinical, histopathological, and prognostic implications of C3 deposition in ANCA-GN. Methods: We retrospectively analyzed 195 patients with biopsy-proven ANCA-GN from the Turkish Society of Nephrology Glomerular Diseases registry from 2002 to 2022. Patients were classified as C3-positive or C3-negative according to kidney biopsy immunofluorescence findings. Clinical characteristics, histopathologic lesion profiles, and follow-up outcomes (remission, relapse, and survival) were compared between the two groups. Results: Of 195 patients, 54 (27.7%) had C3 deposition. The C3-negative group was more likely to exhibit PR3-ANCA positivity, whereas the C3-positive group was strongly associated with the presence of MPO-ANCAs (22.2% vs. 77.8%; p = 0.001). Compared with C3-negative patients, C3-positive patients had higher levels of proteinuria (2026 mg/day vs. 1790 mg/day; p = 0.049) and lower HDL levels (30 mg/dL vs. 37 mg/dL; p = 0.009). Fibrocellular crescents were more common in C3-positive patients than in C3-negative patients (p < 0.001). Immune complex deposits, including IgG (26.4% vs. 3.5%; p < 0.001), IgA (14.8% vs. 0.7%; p < 0.001), IgM (25.0% vs. 3.5%; p < 0.001), and C1q (13.7% vs. 0.8%; p < 0.001) were significantly greater in the C3-positive group. However, no significant difference was detected in overall survival (85.8% for C3-negative patients vs. 88.9% for C3-positive patients; p = 0.249). Similarly, the remission (62.1% vs. 59.4%; p = 0.786) and relapse rates (14.8% vs. 11.1%; p = 0.532) did not differ between the groups. Conclusion: In ANCA-GN, glomerular C3 deposition is associated with an MPO-ANCA serotype, greater proteinuria, and more severe renal histology (including immune-complex deposition and more fibrocellular crescents), indicating more pronounced complement activation and tissue injury. However, C3 deposition did not predict worse patient or renal survival in our cohort. Clinical trial number: Not applicable. © The Author(s) 2025.