PROLONGATION OF RENAL-ALLOGRAFT SURVIVAL IN A LARGE ANIMAL-MODEL BY ORAL RAPAMYCIN MONOTHERAPY

We assessed the efficacy of 5 dose levels of oral rapamycin for prolon ging renal allograft survival in pigs, Untreated and triple therapy gr oups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped, Rapamycin whole-blood concentrations were followed weekly, C hemistry, hematology, and lipid values were monitored posttransplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of r ejection seen on necropsy. After rejection, pneumonia was the most com mon cause of death, No specific endorgan toxicity was noted on histopa thologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated co ntrols - however, all values were within normal limits. Mean ALT level s increased in weeks 2 to 4 in the higher-dose rapamycin groups but re turned to baseline in pigs surviving after the drug was stopped. ALT l evels did not increase above twice normal in any group. Creatinine lev els correlated with the degree of rejection seen on biopsy. We noted n o other toxicities. We conclude that rapamycin, given as oral monother apy, is an effective and safe immunosuppressant in our large animal re nal allograft model. Outcome correlated with dose and whole-blood leve ls.