Lower serum C3 levels are associated with glomerulosclerosis in membranous nephropathy and ANCA-glomerulonephritis
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 (antineutrophil cytoplasmic antibody)-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 = .015) and combined global and segmental glomerulosclerosis (9.5% vs 0%, p = .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 < .001), crescentic (127 [107–151] mg/dl, p = .003), or mixed (123 [101–140] mg/dl, p = .018). Furthermore, ANCA-GN patients in the C3-low group showed lower estimated glomerular filtration rate at presentation and serum C3 was inversely associated with the risk of kidney failure, independently of several confounders (Hazard ratio [HR] for 10 mg/dl increase in C3: 0.91, 95% Confidence Interval [CI] 0.83–1.00, p = .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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BibTeX
@article{tedesco2026lower,
title = {{Lower serum C3 levels are associated with glomerulosclerosis in membranous nephropathy and ANCA-glomerulonephritis}},
author = {Martina Tedesco and Elisa Delbarba and Martina Uzzo and Gianmarco Lugli and Chiara Bedognè and Marta Salti and Francesco Ravelli and Corrado Damilano and Eva Sestagalli and Marta Arrighini and Simona Fisogni and Vincenzo L’Imperio and Fabio Pagni and Jennifer Scott and Jennifer Scott and Jennifer O’Brien and Kresimir Galesic and Simonetta Genovesi and Giorgio Trivioli and Marco Allinovi and Iva Gunnarsson and Anna Juto and Robert Hall and Silke R. Brix and Federica Maritati and Anisa Idrizi and Anna Ricchiuto and Annette Bruchfeld and Gaetano La Manna and Mario Cozzolino and Renato A Sinico and Augusto Vaglio and Giacomo Emmi and Ingeborg Bajema and Andreas Kronbichler and Matija Crnogorac and Stephen McAdoo and Mark A Little and David R W Jayne and Federica Mescia and Federico Alberici},
journal = {Clinical kidney journal},
year = {2026},
month = oct,
doi = {10.1093/ckj/sfag350},
url = {https://europepmc.org/article/PMC/PMC13724270},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lower serum C3 levels are associated with glomerulosclerosis in membranous nephropathy and ANCA-glomerulonephritis
AU - Martina Tedesco
AU - Elisa Delbarba
AU - Martina Uzzo
AU - Gianmarco Lugli
AU - Chiara Bedognè
AU - Marta Salti
AU - Francesco Ravelli
AU - Corrado Damilano
AU - Eva Sestagalli
AU - Marta Arrighini
AU - Simona Fisogni
AU - Vincenzo L’Imperio
AU - Fabio Pagni
AU - Jennifer Scott
AU - Jennifer Scott
AU - Jennifer O’Brien
AU - Kresimir Galesic
AU - Simonetta Genovesi
AU - Giorgio Trivioli
AU - Marco Allinovi
AU - Iva Gunnarsson
AU - Anna Juto
AU - Robert Hall
AU - Silke R. Brix
AU - Federica Maritati
AU - Anisa Idrizi
AU - Anna Ricchiuto
AU - Annette Bruchfeld
AU - Gaetano La Manna
AU - Mario Cozzolino
AU - Renato A Sinico
AU - Augusto Vaglio
AU - Giacomo Emmi
AU - Ingeborg Bajema
AU - Andreas Kronbichler
AU - Matija Crnogorac
AU - Stephen McAdoo
AU - Mark A Little
AU - David R W Jayne
AU - Federica Mescia
AU - Federico Alberici
PY - 2026
DA - 2026/10/05
JO - Clinical kidney journal
DO - 10.1093/ckj/sfag350
UR - https://europepmc.org/article/PMC/PMC13724270
AB - 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 (antineutrophil cytoplasmic antibody)-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 = .015) and combined global and segmental glomerulosclerosis (9.5% vs 0%, p = .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 < .001), crescentic (127 [107–151] mg/dl, p = .003), or mixed (123 [101–140] mg/dl, p = .018). Furthermore, ANCA-GN patients in the C3-low group showed lower estimated glomerular filtration rate at presentation and serum C3 was inversely associated with the risk of kidney failure, independently of several confounders (Hazard ratio [HR] for 10 mg/dl increase in C3: 0.91, 95% Confidence Interval [CI] 0.83–1.00, p = .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.
SN - 2048-8505
SN - 2048-8513
ER -