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

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.