This study was performed to investigate the clinical and pathologic features of C4d-positive steroid-resistant acute rejection (AR) at different phases after renal transplantation. Fifty-six kidney allograft recipients with C4d-positive AR were divided into three groups, very early rejection (VER, occurring < or =14 days following transplantation, n=28), early rejection (ER, occurring 15-180 days following transplantation, n=5), and late rejection (LR, occurring >180 days following transplantation, n=23). Clinical and pathological features were evaluated. Significantly more patients in the ER and LR groups were associated with a reduction or withdrawal of immunosuppressants. More patients in the ER and LR groups experienced a significant (>3 g/l) decrease in serum albumin (80% ER, 91.3% LR, 7.1% VER, P<0.001) and a decrease in hemoglobin (>1 g/dl) (80, 100 vs 17.9%, P<0.001). Most VER patients reported a fever and had very rapid graft dysfunction requiring dialysis. Significantly more patients (87%) had interstitial fibrosis and tubular atrophy in the LR group compared with the other groups and 13% had transplant glomerulopathy. Most cases of VER were reversed with tacrolimus and mycophenolate mofetil treatment, with or without immunoadsorption, with a 1-year survival rate of 96.4%, compared with only 60 and 52.2% in the ER and LR groups. In conclusion, C4d-positive steroid-resistant AR at different time points is associated with unique clinico-histopathological manifestations requiring distinct treatment strategies. Late episodes are usually associated with significantly reduced serum albumin and hemoglobin levels and a poorer outcome. A more specialized treatment protocol should be established for these patients.

Anti-endothelial cell antibodies (AECAs) are thought to be involved in the development of renal allograft rejection. To explore this further, we determine whether AECAs play a role both in predicting the incidence of allograft rejection and long-term outcomes by analysis of serum samples from 226 renal allograft recipients for AECAs pre- and post-transplant. Surprisingly, the presence of pre-existing AECAs was not associated with either an increased risk of rejection or a detrimental impact on recipient/graft survival. Subsequent de novo AECAs, however, were associated with a significantly increased risk of early acute rejection. Moreover, these rejections tended to be more severe with a significantly increased incidence of both steroid-resistant and multiple episodes of acute rejection. The acute rejections associated with de novo AECAs did not correlate with C4d deposition at the time of renal biopsy, but did demonstrate an association with the presence of glomerulitis and peritubular capillary inflammation. Significantly more patients with de novo AECAs developed graft dysfunction. Thus, our prospective study suggests the emergence of de novo AECAs is associated with transplant rejection that may lead to allograft dysfunction.

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