Lower serum C3 levels are associated with glomerulosclerosis in membranous nephropathy and ANCA-glomerulonephritis

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ID: 331519
2026
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Abstract
Abstract Background Despite the key pathogenetic role of the complement cascade in various immune-mediated kidney diseases, the clinical significance of serum C3/C4 levels in conditions where most patients exhibit complement levels within normal limits, such as membranous nephropathy (MN) and ANCA-glomerulonephritis (ANCA-GN), remains underexplored. This study focused on the clinico-pathological correlates of serum complement C3/C4 levels in two cohorts of patients with biopsy-proven MN and ANCA-GN. Methods Based on median C3 and C4 levels at time of diagnostic biopsy, the cohorts were stratified into four groups, referred to as ‘complement component-high’ and ‘-low’. Clinico-pathological features were compared between these groups and correlated with C3/C4 levels. Results In the MN cohort (n = 44), patients in the C3-low group showed a higher degree of global (8.3% vs 0%, p = 0.015) and combined global and segmental glomerulosclerosis (9.5% vs 0%, p = 0.032) compared to the C3-high group. In the ANCA-GN cohort (n = 198), serum C3 levels were lower in cases with the sclerotic class according to Berden classification (107 [98–123] mg/dL) compared to those classified as focal (138 [112–151] mg/dL, p < 0.001), crescentic (127 [107–151] mg/dL, p = 0.003) or mixed (123 [101–140] mg/dL, p = 0.018). Furthermore, ANCA-GN patients in the C3-low group showed lower eGFR at presentation and serum C3 was inversely associated with the risk of kidney failure, independently of several confounders (HR for 10 mg/dL increase in C3: 0.91, 95%CI 0.83 -1.00, p = 0.049). Conclusions Serum C3 levels in the low-normal range were associated with glomerulosclerosis in both ANCA-GN and MN, and with poorer kidney outcome in ANCA-GN, supporting a potentially cross-disease role of the complement cascade in mediating glomerular injury.
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Authors Martina Tedesco, Elisa Delbarba, Martina Uzzo, Gianmarco Lugli, Chiara Bedognè, Marta Salti, Francesco Ravelli, Corrado Damilano, Eva Sestagalli, Marta Arrighini, Simona Fisogni, Vincenzo L'Imperio, Fabio Pagni, The Reassess Study Group, Annette N. Bruchfeld, Gaetano La Manna, Mario Gennaro Cozzolino, Renato Alberto Sinico, Augusto Vaglio, Giacomo Emmi, Ingeborg M. Bajema, Andreas Kronbichler, Matija Crnogorac, Stephen Paul McAdoo, Mark Alan Little, David R.W. Jayne, Federica Mescia, Federico Alberici
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Journal clinical kidney journal
Year 2026
DOI
10.1093/ckj/sfag350
URL
https://doi.org/10.1093/ckj/sfag350
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