Local immunosuppression with reduced systemic toxicity in a canine renal allograft model.
We compared the efficacy of continuous intraarterial versus intravenous 6-mercaptopurine (6-MP) infusion in a mongrel canine renal allograft model with regard to overall survival, incidence of systemic and renal toxicity, and systemic drug exposure. Arterial anastomoses were done end-to-end, and infusion catheters were placed in the iliac artery or vena cava and connected to a subcutaneously placed programmable pump. A dose of 0.5 mg/kg/day 6-MP did not prolong survival over heparin-treated or untreated controls (MST = 7 days for both groups) when administered either locally or systemically. However, 0.75 mg/kg/day 6-MP i.a. (MST = 20 days) significantly prolonged survival over both untreated (P = 0.007) and heparin-treated controls (P = 0.02), with all dogs eventually dying of rejection. In contrast, 0.75 mg/kg/day i.v. (MST = 7 days) failed to prolong survival over controls (P greater than 0.1) and produced death from systemic toxicity in 3 of 7 animals. Six of 7 dogs receiving 2.0 mg/kg/day 6-MP i.a. (MST = 12 days) developed azotemia secondary to drug-induced nephrotoxicity. Identical renal histologic changes occurred in the same time frame in autotransplants treated similarly. Of 7 animals receiving 2.0 mg/kg/day i.v. (MST = 12 days), 5 died from early, severe systemic drug toxicity and 2 from early rejection. During 6-MP infusion at 0.5 mg/kg/day, systemic exposure was significantly less in the locally treated than in the systemically treated dogs when Cr concentrations were normal or moderately elevated (P less than 0.0005 and P = 0.01, respectively) but not when renal function became severely impaired (P = 0.34). In contrast to i.v. infusion, i.a. 6-MP delivery dissociated immunosuppressive efficacy from systemic toxicity, supporting previous work demonstrating high first-pass renal elimination of 6-MP. We conclude that tightly controlled local delivery of an immunosuppressive agent can effectively prolong graft survival with reduced systemic toxicity in a large animal model employing a pump/catheter system applicable to man.
Gruber
S A
SA
Department of Surgery, University of Minnesota, Minneapolis 55455.
Hrushesky
W J
WJ
Cipolle
R J
RJ
Erdmann
G R
GR
Burke
B A
BA
Skjei
K L
KL
Mueller
R P
RP
Fryd
D S
DS
Matas
A J
AJ
Simmons
R L
RL
D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007165:Immunosuppression Therapy; D007668:Kidney / Q000187:drug effects; D016030:Kidney Transplantation; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000633:toxicity; D014184:Transplantation, Homologous
D006493:Heparin; D015122:Mercaptopurine