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.
Almond
P S
PS
Department of Surgery, University of Minnesota, Minneapolis 55455.
Moss
A
A
Nakhleh
R E
RE
Melin
M
M
Chen
S
S
Salazar
A
A
Shirabe
K
K
Matas
A J
AJ
D000818:Animals; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity / Q000209:etiology / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D011090:Polyenes / Q000009:adverse effects / Q000494:pharmacology*; D020123:Sirolimus; D013552:Swine; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus