Cyclosporine-induced renal dysfunction: correlations between cellular events and whole kidney function.
The main adverse reaction to the immunosuppressive drug cyclosporine is dose-dependent renal dysfunction. Although renal vasoconstriction without major tubular dysfunction is usually noted, recent studies have demonstrated an inhibition of renal cortical microsomal protein synthesis. Sprague-Dawley rats and appropriate pair-fed controls were given cyclosporine orally in doses of 5, 10, 25, and 50 mg/kg/day for periods up to 10 days. A dose-dependent decline in glomerular filtration rate and effective renal plasma flow was maximal by day 3 and did not worsen despite continued dosing. Microsomal protein synthesis as measured by [3H]leucine incorporation was also depressed in a dose-dependent fashion; however, inhibition did not reach the nadir until day 4, 1 day after renal dysfunction was established. When cyclosporine was discontinued, microsomal protein synthesis was normalized by 4 days after drug withdrawal; in contrast, the return of glomerular filtration rate and effective renal plasma flow to normal required 8 days after drug discontinuation. Tubular function as measured by fractional excretion of lithium, enzymuria, and urinary osmolality was well maintained despite the depression of renal hemodynamics. There was no evidence of tubular necrosis by light or electron microscopy. Although cyclosporine produces reductions in renal microsomal protein synthesis, measured by "run-off" translation assays, these effects appear unlikely to be the direct cause of acute renal dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
Bennett
W M
WM
Department of Medicine, Oregon Health Sciences University, Portland 97201.
Houghton
D C
DC
Buss
W C
WC
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008854:Microscopy, Electron; D008861:Microsomes / Q000378:metabolism; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects
D016572:Cyclosporine