RAPAMYCIN - IMMUNOSUPPRESSION, HYPORESPONSIVENESS, AND SIDE-EFFECTS IN A PORCINE RENAL-ALLOGRAFT MODEL

Rapamycin prolongs allograft survival and induces donor-specific tolerance in some small animal transplant models. Large animal studies, however, are limited. We studied rapamycin in a porcine renal allograft model. Donor-recipient combinations were chosen based on high response in pretransplant MLCs. Allografts were anastomosed to the aorta and vena cava and the native kidneys removed. There were 5 treatment groups: (a) no immunosuppression; (b) triple therapy (CsA, 1 mg/kg/day; AZA, 2-3 mg/kg/day; and PRED, 3-4 mg/kg/day); (c) rapamycin (0.75 mg/kg/day i.m.) in carboxymethylcellulose (CMC); (d) rapamycin (0.25 mg/kg/day i.m. in CMC); and (e) a vehicle (CMC) control. Serum creatinine levels were determined every other day. Most allografts were biopsied once a week. Immunosuppression was stopped after 30 days. Mean graft survival in nonimmunosuppressed recipients was 6.8+/-3.6 days. Mean graft survival in triple therapy recipients (n=10) was 45.7+/-36 days vs. 59.6+/-11.4 days in rapamycin (0.25 mg/kg/day) recipients (n=7) (P=0.51). Both triple therapy and rapamycin improved renal allograft survival versus nonimmunosuppressed controls (P=0.0025 and 0.001, respectively). Serum creatinine levels were significantly lower (P<0.05) in rapamycin versus triple therapy recipients. We conclude that rapamycin is a potent immunosuppressant in a porcine renal allograft model and may avoid the elevated serum creatinine levels associated with CsA.