Decreased Circulating C3 Levels and Mesangial C3 Deposition Predict Renal Outcome in Patients with IgA Nephropathy

Abstract

Background and AimsMesangial C3 deposition is frequently observed in patients with IgA nephropathy (IgAN). However, the role of complement in the pathogenesis or progression of IgAN is uncertain. In this observational cohort study, we aimed to identify the clinical implications of circulating C3 levels and mesangial C3 deposition and to investigate their utility as predictors of renal outcomes in patients with IgAN.MethodsA total of 343 patients with biopsy-proven IgAN were enrolled between January 2000 and December 2008. Decreased serum C3 level (hypoC3) was defined as C3 <90 mg/dl. The study endpoint was end-stage renal disease (ESRD) and a doubling of the baseline serum creatinine (D-SCr).ResultsOf the patients, there were 66 patients (19.2%) with hypoC3. During a mean follow-up of 53.7 months, ESRD occurred in 5 patients (7.6%) with hypoC3 compared with 9 patients (3.2%) with normal C3 levels (P = 0.11). However, 12 patients (18.2%) with hypoC3 reached D-SCr compared with 17 patients (6.1%) with normal C3 levels [Hazard ratio (HR), 3.59; 95% confidence interval (CI), 1.33–10.36; P = 0.018]. In a multivariable model in which serum C3 levels were treated as a continuous variable, hypoC3 significantly predicted renal outcome of D-SCr (per 1 mg/dl increase of C3; HR, 0.95; 95% CI, 0.92–0.99; P = 0.011). The risk of reaching renal outcome was significantly higher in patients with mesangial C3 deposition 2+ to 3+ than in patients without deposition (HR 9.37; 95% CI, 1.10–80.26; P = 0.04).ConclusionsThis study showed that hypoC3 and mesangial C3 deposition were independent risk factors for progression, suggesting that complement activation may play a pathogenic role in patients with IgAN.

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

“…Recently, Kim et al 39 showed that mesangial C3 deposition predicted renal outcome in patients with IgAN. However, owing to the slowly progressive nature of IgAN and our relatively small follow-up population, we failed to draw any convincing conclusions regarding the predictive value of rs6677604 and mesangial C3 deposition in our study.…”

C4d deposits in IgA nephropathy: where does complement activation come from?

“…However, in addition to this in situ activation, a systemic complement activation has been suggested by several studies, including a negative correlation between circulating C3 and mesangial C3 deposition [12]. C3 levels in Caucasian patients with progressive IgAN are not noticeably reduced, while in Chinese and Japanese patients slightly reduced levels of complement (<90 mg/dl) have been detected in similar cases [12,13]. The ratio between IgA levels (frequently increased in patients with IgAN) and C3 levels (seldom changed and then only slightly decreased) has been reported to be of prognostic value in adults and children [14].…”

“…Complement inhibiting factors acting in fluid phase according to the hypothesis of systemic activation have been investigated in patients with IgAN. In Asiatic patients an association was reported between C3 and FH levels, suggesting an active regulation of the alternative complement pathway even in cases of subclinical activation [12,13].…”

“…The prognostic value of the presence and intensity of C3 deposits for outcome has been reported by some but not all authors [12]. The detection of glomerular C4d deposits has been proposed by Espinosa et al as an early biomarker for progressive IgAN in a cohort of children and adults [5].…”

Eculizumab treatment for rescue of renal function in IgA nephropathy

“…C3 levels in serum are usually normal but degradation products, such as iC3b-C3d, may be elevated, suggesting activation of the alternative pathway [13]. Furthermore, decreased circulatory C3 levels and increased C3 deposition were suggested to be predictors of worse outcome [14]. Complement activation may thus contribute to renal inflammation during progressive IgA nephropathy [15].…”