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-toperform 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.

The utility of glomerular C4d immunostaining in renal biopsies in patients with immunoglobulin A nephropathy. A clinicopathological study

“…In the study by Espinosa et al [16] C4d-positive patients were more numerous: 32.2% and 67.8%, respectively. In the latter study by Espinosa et al [15] these percentages were 38.5% and 61.5%, respectively. Similarly to our results, Roos et al [5] found 25% of IgAN patients to be C4d-positive and 75% C4d-negative.…”

“…Recently mesangial deposition of C4d is regarded as a prognostic factor in IgAN [5,15,16]. Roos et al [5] revealed that patients with IgAN are divided into two groups on the basis of the pattern of complement activation.…”

“…Some clinical and histological factors, such as arterial hypertension, proteinuria, renal function, and Oxford classification score, determine the final outcome of patients with IgAN [14]. The identification of new prognostic markers could provide insights into pathogenesis of IgAN and unveil new therapeutic avenues [15]. Glomerular deposition of C4d is a marker of activation of the lectin pathway of complement [5].…”

“…Glomerular deposition of C4d is a marker of activation of the lectin pathway of complement [5]. It is thought that activation of the lectin pathway in IgAN is associated with more severe renal damage, and more severe histological findings [5,15,16].…”

Glomerulonefritis rápidamente progresiva asociada a ANCA en un paciente con nefropatía por IgA, reporte de caso

“…El depósito de C3 y C4, en las biopsias renales de NIgA, sugiere la activación de la vía alternativa y de las lectinas. Desde el punto de vista clínico, el depósito de C4d en el mesangio y C3d en células peritubulares se ha asociado a formas agresivas de la enfermedad 21,22 . Ya se han evaluado bloqueadores del complemento en pacientes con nefritis lúpica y vasculitis ANCA e incluso se reportó el uso de eculizumab en un paciente NIgA refractaria a esteroide, ciclofosfamida y plasmaféresis [23][24][25] .…”