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 prolonging renal allograft survival in pigs. Untreated and triple therapy groups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped. Rapamycin whole-blood concentrations were followed weekly. Chemistry, hematology, and lipid values were monitored post-transplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of rejection seen on necropsy. After rejection, pneumonia was the most common cause of death. No specific end-organ toxicity was noted on histopathologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated controls--however, all values were within normal limits. Mean ALT levels increased in weeks 2 to 4 in the higher-dose rapamycin groups but returned to baseline in pigs surviving after the drug was stopped. ALT levels did not increase above twice normal in any group. Creatinine levels correlated with the degree of rejection seen on biopsy. We noted no other toxicities. We conclude that rapamycin, given as oral monotherapy, is an effective and safe immunosuppressant in our large animal renal allograft model. Outcome correlated with dose and whole-blood levels.
Department of Surgery, University of Minnesota, Minneapolis 55455.
D K
DK
Granger
J W
JW
Cromwell
S C
SC
Chen
J J
JJ
Goswitz
D T
DT
Morrow
F A
FA
Beierle
S N
SN
Sehgal
D M
DM
Canafax
A J
AJ
Matas
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008954:Models, Biological; D009336:Necrosis; D011090:Polyenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D020123:Sirolimus; D013552:Swine; D013997:Time Factors
D007166:Immunosuppressive Agents; D011090:Polyenes; D000410:Alanine Transaminase; D020123:Sirolimus