title: Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity.
abstract: Recent studies in liver and kidney transplant recipients revealed a nephrotoxic adverse effect of the new macrolide immunosuppressant FK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was investigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK-506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels.
authors.affiliation: Laboratory of Nephropathology, Odense University Hospital, Denmark.
authors.forename: F T
authors.initials: FT
authors.lastname: Nielsen
authors.forename: P P
authors.initials: PP
authors.lastname: Leyssac
authors.forename: E
authors.initials: E
authors.lastname: Kemp
authors.forename: H
authors.initials: H
authors.lastname: Starklint
authors.forename: H
authors.initials: H
authors.lastname: Dieperink
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control; D007444:Inulin / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology; D008094:Lithium / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D016038:Skin Transplantation / Q000473:pathology; D016559:Tacrolimus / Q000627:therapeutic use / Q000633:toxicity*; D014554:Urination / Q000187:drug effects
chemical_list: D007444:Inulin; D008094:Lithium; D016559:Tacrolimus