Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• IgA nephropathy (IgAN) is a leading cause of primary glomerulonephritis globally, characterized by IgA deposition and complement component 3 (C3) co-deposition.
• Asian populations with IgAN often present with more severe clinical phenotypes, active kidney lesions, and faster progression.
• A prior genome-wide association study identified the complement factor H (CFH) variant rs6677604, linked to ΔCFHR3-1 deletion, as a susceptibility factor for IgAN, impacting complement regulation.

Purpose of the Study:

• To investigate the impact of the CFH variant rs6677604 on IgA nephropathy progression in a Chinese cohort.
• To analyze the correlation between genotype, C3 deposition, and clinical/pathological manifestations in IgAN patients.
• To determine the prognostic value of rs6677604 genotype and mesangial C3 deposition on IgAN outcomes.

Main Methods:

• Enrolled 1781 Chinese IgA nephropathy patients with regular follow-up.
• Genotyped the rs6677604 variant and analyzed genotype-phenotype correlations using statistical tests.
• Assessed mesangial C3 deposition intensity and correlated it with clinical/pathological scores (Oxford classification).
• Utilized Kaplan-Meier analysis and Cox regression to evaluate the association between rs6677604, C3 deposition, and IgAN prognosis.

Main Results:

• Patients with the rs6677604-GG genotype exhibited stronger mesangial C3 deposition compared to AA/AG genotypes.
• Higher C3 deposition intensity correlated with more severe clinical (lower eGFR) and pathological (higher Oxford scores M/S/T/C) features.
• Survival analysis revealed that intense mesangial C3 deposition, but not the rs6677604-GG genotype, predicted poor long-term kidney outcomes.

Conclusions:

• In Chinese IgAN patients, the rs6677604 variant is associated with mesangial C3 deposition.
• Mesangial C3 deposition intensity, rather than the rs6677604 genotype, is significantly linked to IgAN severity and progression.
• These findings highlight C3 deposition as a critical factor in IgAN pathogenesis and prognosis.