Tacrolimus versus cyclosporin A: a comparative study on rat renal allograft survival

Although tacrolimus has been studied in a wide variety of experimental animal models, we are the first group to systematically study the effect of tacrolimus on rat renal allograft survival, as primary therapy and as anti-rejection therapy, in comparison with cyclosporin A (CyA). Renal grafts were transplanted from BN to LEW rats. Tacrolimus and CyA were administrated orally from day 0 for 50 days as primary therapy after grafting. Allografts were rejected after a median survival time (MST) of 8 days. Both tacrolimus und CyA significantly prolonged renal allograft survival, in a dose-dependent manner compared with the allograft controls. The most effective dose was 3.2 mg/kg, per day for tacrolimus, and 10 mg/kg per day for CyA. There was no significant difference in renal function between the group treated with the most effective dose of tacrolimus and the CyA-treated group. The percentage of detectable serum IL-2 level was 45% in the allograft control group, but was undetectable in groups treated with the most effective dose of tacrolimus or CyA at days 3 and 6 after grafting. On the other hand, no side effects were noted in recipient rats by daily inspection, body weight change, and histological studies, although minimal tubular vacuolation was encountered in the group treated with CyA 32 mg/kg per day. In addition, the most effective doses of tacrolimus and CyA were studied as anti-rejection therapy. All of the 5 recipients treated with tacrolimus from days 2-14, and 3 of the 5 treated from days 4-16 after grafting, survived for more than 50 days. However, the MST was 19 days for recipients treated with CyA from days 2-14, and 13 days for those treated from days 4-16 after grafting. In summary, tacrolimus as primary therapy induced rat renal allograft survival with renal function and side effects comparable with those of CyA. Interestingly, when both agents were used as anti-rejection therapy, tacrolimus, but not CyA, could significantly overcome ongoing renal allograft rejection in the rat.