Decreased circulating C3 levels and mesangial C3 deposition predict renal outcome in patients with IgA nephropathy

Abstract

Background and aims: Mesangial 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.

Methods: A 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).

Results: Of 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).

Conclusions: This 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.

Figure 1. Flow diagram of the study.

IgA nephropathy was diagnosed in 436 patients between January 2000 and December 2008. Excluding 93 patients, a total of 343 patients were enrolled. eGFR, estimated glomerular filtration rate; GN, glomerulonephritis; SLE, systemic lupus erythematosus.

Figure 2. Representative pictures of immunofluorescence staining of mesangial C3 1+ to 3+.

Immunofluorescence intensity was quantified by ImageJ software.

Figure 3. A scattered plot of each level of serum C3 between patients with C3 levels <90 mg/dl and patients with C3 levels ≥90 mg/dl.

Figure 4. The histopathologic grades such as (A) mesangial hypercellularity, (B) segmental glomerulosclerosis, (C) endocapillary hypercellularity, and (D) tubular atrophy/interstitial fibrosis according to mesangial C3 deposition.

Mesangial hypercellularity (C3 deposition 0, 9.4%; 1+, 29.7%; 2+∼3+, 49.3%; P<0.001) and high-grade tubular atrophy/interstitial fibrosis (C3 deposition 0, 7.5%; 1+, 10.5%; 2+∼3+, 14.1%; P<0.001) were more prominent as the mesangial area of C3 deposition increased.

Figure 5. Comparison of serum C3 levels according to mesangial C3 deposition.

Serum C3 levels decreased significantly from 0 to 2+∼3+ mesangial C3 deposition (0, 111.7±18.0; 1+, 104.3±17.1; 2+∼3+, 98.6±14.2 mg/dl; P<0.001).

Figure 6. Kaplan-Meier analyses of cumulative renal survival of patients with IgA nephropathy based on (A) serum C3 level and (B) mesangial C3 deposition.

(A) A 10-year renal survival rate was significantly lower in patients with C3 levels <90 mg/dl than those with C3 levels ≥90 mg/dl (P = 0.006). (B) A 10-year survival in patients with 2+ and 3+ mesangial deposition of C3 was lower than in those without C3 deposition (P = 0.04).

Figure 7. ROC curve analysis for renal outcome of the doubling of the baseline serum creatinine.

Serum C3 levels had a significant predictive value for renal outcome (AUC = 0.642, P = 0.011), although the predictive value of serum C3 was lower than UPCR (AUC = 0.819, P<0.001) or eGFR (AUC = 0.781, P<0.001).

Figure 8. Kaplan-Meier analyses of cumulative renal survival of patients with IgA nephropathy according to histopathologic features including (A) mesangial hypercellularity, (B) segmental glomerulosclerosis, (C) endocapillary hypercellularity, and (D) tubular atrophy/interstitial fibrosis.

Patients with mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity, and tubular atrophy/interstitial fibrosis had significantly lower renal survival than those without such findings (P<0.05).

Figure 9. The decline rate of eGFR. Error bars indicate standard error.