Chronic cyclosporine nephrotoxicity. A rodent model

Abstract

The lack of a suitable rodent model has hampered the study of chronic cyclosporine nephrotoxicity. Proximal tubule vacuolization and inclusions are consistently reported in rat studies, but changes associated with chronic CsA nephrotoxicity in humans (interstitial fibrosis, tubular atrophy, arteriolopathy) are difficult to reproduce. Using male Sprague-Dawley (SD) rats we have administered CsA in olive oil (o.o.) at 25 mg/kg/d i.p. for 28 consecutive days. This protocol consistently results in a lesion of patchy interstitial fibrosis, tubular atrophy, interstitial inflammation, and marked juxtaglomerular apparatus (JGA) hypertrophy and hyperplasia. Control animals were pair-fed and received only o.o. i.p. Despite pair feeding, CsA-treated animals gained only 9.4 +/- 12 g, while controls gained 69 +/- 18 g. Minimal JGA hypertrophy was noted in some control animals, but no other significant changes were identified. The protocol was well tolerated and did not result in peritonitis. GFR was significantly depressed in the CsA-treated animals at the end of the 28-day period (0.44 +/- .26 vs. 1.12 +/- .13 ml/min) and BP tended to be lower, but this difference did not achieve statistical significance. We conclude that this model results in a reproducible lesion with many of the features of chronic CsA nephrotoxicity in humans, and that it will permit study of this problem to advance.