Long-term cyclosporin A nephrotoxicity in the rat. Evaluation of a morphological scoring system and of co-treatment with isradipine.
Cyclosporin A (CyA) nephrotoxicity was examined in Spraque-Dawley rats given CyA (12.5 (n = 45) or 25 (n = 45) mg/kg/day perorally for 16 weeks. Control rats (n = 45) received CyA vehicle. All rats were given either isradipine (ISRA) 1 or 5 mg/kg/day orally, or isradipine vehicle. Fifteen rats died from interstitial pneumonia caused by Staphylococcus xylosus. A predefined morphological CyA nephrotoxicity scoring system, based on semiquantitative scores for basophilic tubules and for interstitial fibrosis, performed on hematoxylin-eosin-stained tissue, yielded mean scores for basophilic tubules of 0.2 (range 0-1) in controls, 1.4 (range 0-3) in rats given CyA 12.5 mg/kg/day (p < 0.001), and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001 as compared to controls). Rats given CyA were grouped according to their score for interstitial fibrosis: 0.2 (range 0-1) in CyA 12.5 mg/kg/day and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001). When scores for basophilic tubules and interstitial fibrosis were pooled, none of the control rats had a score above 1, while 47% of the low-dose and 95% of the high-dose rats scored above 1. Thus, this CyA nephrotoxicity scoring system provided an easy, efficacious, and reproducible identification of rats with morphological CyA nephrotoxicity, and may be of clinical interest in the assessment of CyA nephrotoxicity. Kidney tissue from rats not treated with isradipine was further investigated with periodic acid-Schiff (PAS) with and without diastase treatment, and with Sirius Red. The latter confirmed the increase in connective tissue following tubular atrophy in CyA-treated rats. PAS reaction disclosed diastase-resistant positivity in the glomerular arterioles (score in controls: mean 0.4, range 0-1, in CyA 12.5 mg/kg/day mean 2.2, range 1-3, p < 0.001 as compared to controls; in CyA 25 mg/kg/day mean 1.1, range 0-2, p < 0.005 as compared to controls, p < 0.05 as compared to CyA 12.5 mg/kg/day). Furthermore, the straight part of the distal tubules of rats given the highest CyA dose contained considerable amounts of glycogen. The significance of this finding is unknown. Renal functional studies confirmed previous results since CyA decreased inulin clearance (Cin) from 1.2 +/- 0.5 to 0.8 +/- 0.3 ml/min/g kidney weight (kW) (p < 0.05), and lithium clearance (CLi) was reduced from 263 +/- 113 to 119 +/- 61 microliters/min/gKW (p < 0.001). Isradipine had no significant effect.
Starklint
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H
Laboratory of Nephropathology, Odense University Hospital, Denmark.
Hansen
H V
HV
Kemp
M
M
Leyssac
P P
PP
Kemp
E
E
Dieperink
H
H
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D017275:Isradipine / Q000494:pharmacology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D016572:Cyclosporine; D017275:Isradipine