Renal Complement C3 Deposition is Associated with Glomerular Prothrombotic Milieu in Patients with IgA Nephropathy

Complement activation plays a central role in the pathogenesis of IgA nephropathy (IgAN); however, not all patients exhibit renal C3 deposition. Accumulating evidence suggests that complement activation is closely linked to coagulation activation and prothrombotic cellular responses.

This retrospective study was conducted using clinical and laboratory data obtained from the institutional clinical database of the Affiliated Hospital of Guangdong Medical University. This study investigated the association between renal C3 deposition and an intraglomerular prothrombotic milieu in 890 biopsy-proven IgAN patients categorized by C3 deposition status. Histological glomerular prothrombotic lesions reflecting a prothrombotic milieu were defined by pathological features, including intraglomerular erythrocyte aggregation and/or glomerular capillary microthrombus-like lesions. The primary outcome was a composite of a ≥30% decline in eGFR from baseline or kidney failure, defined as initiation of maintenance dialysis, kidney transplantation, or eGFR ≤15 mL/min/1.73 m². Firth's penalized logistic regression was used to assess associations with histological glomerular prothrombotic lesions, and Cox proportional hazards regression was used to evaluate renal outcomes; cumulative incidence curves were generated using the survival and survminer packages in R.

Among 890 patients, 852 (95.7%) exhibited C3 deposition and 38 (4.3%) did not; 324 patients experienced histological glomerular prothrombotic lesions indicative of an intraglomerular prothrombotic milieu. In multivariable analyses, glomerular C3 deposition remained independently associated with histological glomerular prothrombotic lesions (OR 8.22, 95% CI 2.01-75.72, P = 0.001). During follow-up, 110 patients reached the primary outcome. In unadjusted Cox analysis, renal C3 deposition was associated with a lower risk of the composite outcome (HR 0.53, 95% CI 0.28-0.99, P = 0.048); however, this association was attenuated and no longer significant after sequential adjustment for clinical variables, pathological lesions, and treatment (fully adjusted HR 0.86, 95% CI 0.35-2.11, P = 0.74).

Renal C3 deposition is associated with intraglomerular coagulation abnormalities and a heightened prothrombotic milieu in IgAN. Although an apparent association with better renal outcomes was observed in unadjusted analysis, renal C3 deposition was not independently associated with long-term renal prognosis after adjustment for potential confounders.