Local immunosuppression with reduced systemic toxicity in a canine renal allograft model

Scott A. Gruber, William J.M. Hrushesky, Robert J. Cipolle, Gary R. Erdmann, Barbara A. Burke, Kristi L. Skjei, Roger P. Mueller, David S. Fryd, Arthur J. Matas, Richard L. Simmons, Daniel M. Canafax

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21 Scopus citations


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 hep- arin-treated or untreated controls (MST = 7 days for both groups) when administered either locally or sys- temically. 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 > 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 < 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.

Original languageEnglish (US)
Pages (from-to)936-943
Number of pages8
Issue number6
StatePublished - Dec 1989


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