Clinical significance of serum complement levels and C3/C4 ratio in IgA nephropathy: histopathological correlates and prognostic implications

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Complement activation plays a central role in its pathogenesis; however, the prognostic significance of serum complement levels remains unclear. In this single-center retrospective study, we evaluated the prognostic value of serum C3, C4 levels, and C3/C4 ratio in 116 biopsy-proven primary IgAN patients with available complement measurements, followed for a median of 37.5 months. Poor prognosis was defined as a ≥ 50% decline in estimated glomerular filtration rate (eGFR) or progression to end-stage renal disease; 39 patients (33.6%) reached this endpoint. Serum C3 was significantly lower in the poor prognosis group (113.0 vs. 128.0 mg/dL, p = 0.0004), as was the C3/C4 ratio (3.39 vs. 4.27, p = 0.0009), while serum C4 did not differ significantly (p = 0.520). ROC analysis identified serum C3 (AUC = 0.703, 95% CI: 0.595-0.801, cutoff 121.1 mg/dL) and C3/C4 ratio (AUC = 0.689, 95% CI: 0.575-0.791, cutoff 3.62) as significant predictors. Bootstrap validation confirmed cutoff robustness (C3: 97.0-144.0 mg/dL; C3/C4: 3.03-4.31). Kaplan-Meier analysis demonstrated significantly worse renal survival with low C3 (p = 0.011) and low C3/C4 ratio (p = 0.001). Serum C3 correlated with tubular atrophy score (r = -0.197, p = 0.036) and C3/C4 ratio with crescent score (r = -0.272, p = 0.003). In expanded multivariate Cox regression, ACE inhibitor/ARB use was independently associated with better prognosis (HR = 0.136, 95% CI: 0.031-0.605, p = 0.009). Serum C3 and C3/C4 ratio at diagnosis are associated with renal prognosis and histopathological severity in IgAN and may serve as adjunctive prognostic markers alongside established parameters.