C4d-positive renal allograft rejection biopsies in cyclosporine-treated patients:single-center incidence and outcome

T cell-mediated acute rejection (ATCMR) in renal transplant patients can have an antibody-mediated component. The aim of this study was to evaluate the incidence of renal biopsies showing ATCMR with C4d immunoreactivity and the correlation between C4d-positive ATCMRs and graft outcomes. We studied 216 renal transplant patients receiving cyclosporine-based immunosuppression (mean follow-up = 203.5 +/- 42.5 months). Of these, 79 experienced biopsy-proven ATCMR (group 1), whereas 137 did not show clinical or laboratory evidence of ATCMR (group 2). Mean serum creatinine levels were evaluated at 6 months, as well as 2 and 5 years after transplantation. The number of graft losses due to interstitial fibrosis and tubular atrophy (IF/TA) was greater in group 1 than in group 2 (P < .001 and P < .02, respectively), while graft survival was lower (P < .03). Staining with anti-C4d antibody was performed in 61/77 type I ATCMR biopsies: seven cases showed diffuse C4d positivity with CD68(+) monocytes in peritubular capillaries observed in all cases. Three cases showed focal C4d positivity. Two ATCMRs were steroid, resistant. Graft loss due to IF/TA occurred in 4/7 patients (57.1%) who had previously experienced ATCMRs with diffuse C4d positivity; whereas it occurred in 5/51 patients (9.8%) with previous C4d negative ATCMRs (P < .001). Patients with focal C4d positivity did not undergo graft loss due to IF/TA. In conclusion, at our center the diffuse C4d positivity that occurred in 11.4% of type I ATCMRs was associated with a poor prognosis.