Association of C4d deposition with clinical outcomes in IgA nephropathy

Abstract

Background and objectives: Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.

Design, setting, participants, & measurements: This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.

Results: There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P<0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m(2) increase, 0.96; 95% CI, 0.94 to 0.97; P<0.001), T2 Oxford classification (tubular atrophy/interstitial fibrosis, >50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).

Conclusions: C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.

Keywords: IgA nephropathy; complement; survival.

Figure 1.

The complement system and C4d. C4d can be derived from the classic and lectin pathway activation. In patients in whom C1q deposits are not detected, the classic pathway of complement activation can be ruled out. MBL, mannose-binding lectin.

Figure 2.

Renal tissue from patients with IgAN was stained for the presence of C4d. Representative images are shown. (A and B) A patient with a negative C4d staining. (C and D) A representative patient with a positive C4d staining in mesangial areas. No staining is detected in peritubular capillaries. Tubular staining is observed. IgAN, IgA nephropathy. Original magnification, ×100 in A; ×200 in B; ×40 in C; ×400 in D.

Figure 3.

Renal survival according to C4d staining.