Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake.
In addition to its well-recognized ability to provoke acute renal dysfunction by promoting intense renal vasoconstriction, cyclosporine produces a chronic tubulointerstitial nephropathy characterized by striped interstitial fibrosis in humans. With a model of chronic cyclosporine nephropathy in which striped fibrosis develops in the uninephrectomized salt-depleted rat, the relationship between renal functional impairment and structural changes was studied during cyclosporine treatment and after its withdrawal in order to ascertain the natural history of this lesion. Groups of uninephrectomized rats maintained on a salt-depleted (-NaCl) or salt-replete (+NaCl) diet were treated with cyclosporine, 15 mg/kg per day, or vehicle by sc injection. GFR and morphology were assessed at 14 and 28 days of treatment and at intervals up to 28 days after drug withdrawal. Although GFR was similarly depressed in cyclosporine-treated animals on either diet (P < 0.001 versus vehicle), tubulointerstitial injury was largely confined to cyclosporine-treated rats on the -NaCl diet (P < 0.001 versus cyclosporine/+NaCl and vehicle). At 28 days after the withdrawal of cyclosporine, there was a marked discordance between renal structure and function in the cyclosporine/-NaCl group as GFR returned toward normal (P > 0.05 versus cyclosporine/+NaCl) but prominent tubulointerstitial injury persisted and, in some instances, even progressed (P < 0.001 versus cyclosporine/+NaCl and vehicle). Thus, sodium intake emerges as an important determinant of structural tubulointerstitial changes, whereas reductions in GFR during cyclosporine therapy are equivalent in sodium-depleted or sodium-replete animals.
Division of Nephrology and Hypertension, Oregon Health Sciences University, Portland 97201.
L W
LW
Elzinga
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S
Rosen
W M
WM
Bennett
D000818:Animals; D001284:Atrophy; D016572:Cyclosporine / Q000494:pharmacology / Q000633:toxicity*; D005665:Furosemide / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006984:Hypertrophy; D008138:Loop of Henle / Q000187:drug effects / Q000473:pathology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000097:blood; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*
D012982:Sodium, Dietary; D005665:Furosemide; D016572:Cyclosporine; D012964:Sodium