title: Cyclosporine toxicity in immunosuppressed streptozotocin-diabetic nonhuman primates.
abstract: Streptozotocin (STZ) is widely applied in animal models of insulin-dependent diabetes mellitus. Adverse effects of STZ mainly concern liver and kidney. In nonhuman primates a single 100-150 mg/kg dose invariably induces diabetes with only rare adverse effects. We report one animal with renal failure necessitating sacrifice. Body weight (age) might be a confounding factor, i.e. older animals might be more vulnerable to STZ-related toxicity. We therefore recommended to administer STZ on a mg/m2 basis and not on a mg/kg basis. In our islet transplantation program nonhuman primates with STZ-induced diabetes received transplants under chronic immunosuppression including calcineurin inhibitors (cyclosporine, tacrolimus), drugs in the rapamycin class affecting growth factor-induced cell proliferation, and the sphingosine 1-phosphate receptor antagonist FTY720. Four animals developed renal failure and had to be sacrificed, most likely caused by cyclosporine. Kidney histology was typical for cyclosporine toxicity including thrombotic microangiopathy in glomeruli and fibrinoid necrosis of arteries, and for STZ toxicity including acute tubular necrosis and accumulations of erythroid precursors. This adverse effect was observed at a pharmacologically active cyclosporine exposure. Additionally, six diabetic animals without major adverse effects during cyclosporine or tacrolimus treatment are presented. We conclude that cyclosporine facilitates renal dysfunction in animals with STZ-induced diabetes, presumably related to an increased vulnerability to a toxic insult after STZ administration.
authors.affiliation: Department of Surgery, Diabetes Institute for Immunology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Wijkstrom
authors.forename: Nicole
authors.initials: N
authors.lastname: Kirchhof
authors.forename: Melanie
authors.initials: M
authors.lastname: Graham
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ingulli
authors.forename: Robert B
authors.initials: RB
authors.lastname: Colvin
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Hering
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Schuurman
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use / Q000633:toxicity*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D016867:Immunocompromised Host / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use / Q000633:toxicity*; D016381:Islets of Langerhans Transplantation; D008252:Macaca fascicularis; D008297:Male; D051437:Renal Insufficiency / Q000209:etiology* / Q000473:pathology; D013311:Streptozocin / Q000633:toxicity*
chemical_list: D007166:Immunosuppressive Agents; D013311:Streptozocin; D016572:Cyclosporine