LONG-TERM CYCLOSPORINE-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 we eks. Control rats (n = 45) received CyA vehicle. All rats were given e ither isradipine (ISRA) 1 or 5 mg/kg/day orally, or isradipine vehicle . Fifteen rats died from interstitial pneumonia caused by Staphylococc us xylosus. A predefined morphological CyA nephrotoxicity scoring syst em, based on semiquantitative scores for basophilic tubules and for in terstitial fibrosis, performed on hematoxylin-eosin-stained tissue, yi elded mean scores for basophilic tubules of 0.2 (range 0-1) in control s, 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 interstiti al 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 tubule s 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 ra ts scored above 1. Thus, this CyA nephrotoxicity scoring system provid ed an easy, efficacious, and reproducible identification of rats with morphological CyA nephrotoxicity, and may be of clinical interest in t he assessment of CyA nephrotoxicity. Kidney tissue from rats not treat ed with isradipine was further investigated with periodic acid-Schiff (PAS) with and without diastase treatment, and with Sirius Red. The la tter confirmed the increase in connective tissue following tubular atr ophy in CyA-treated rats. PAS reaction disclosed diastase-resistant po sitivity in the glomerular arterioles (score in controls: mean 0.4, ra nge 0-1, in CyA 12.5 mg/kg/day mean 2.2, range 1-3, p<0.001 as compare d to controls; in CyA 25 mg/kg/day mean 1.1, range 0-2, p<0.005 as com pared to controls, p<0.05 as compared to CyA 12.5 mg/kg/day). Furtherm ore, 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 previo us results since CyA decreased inulin clearance (C(in)) from 1.2 +/- 0 .5 to 0.8 +/- 0.3 ml/min/g kidney weight (kW) (p<0.05), and lithium cl earance (C(Li)) was reduced from 263 +/- 113 to 119 +/- 61 mul/min/gKW (p<0.001). Isradipine had no significant effect.