CYCLOSPORINE-A-INDUCED ARTERIOLOPATHY IN A RAT MODEL OF CHRONIC CYCLOSPORINE NEPHROPATHY

Chronic cyclosporine (CsA) nephrotoxicity is a major complication of heart, bone marrow, and renal transplantation, and is characterized in humans by striped interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of hilar arterioles. This last feature is highly specific for cyclosporine injury and has been difficult to reproduce in normotensive animal models. Salt-depletion has been shown to sensitize rodents to the effects of CsA and accelerate the disease process. We conducted sequential studies in chronically salt depleted, pair fed rats treated with CsA (15 mg/kg, s.c.) or an equivalent dose of olive oil vehicle, and found a histologic lesion associated with CsA that consisted of striped cortical interstitial fibrosis, tubular dilatation and atrophy, and hyalinization of many afferent arterioles. The arteriolopathy was first detected at day 10 with progressive hyalinization of arterioles continuing until termination of the study at day 35. The arteriolopathy consisted initially of eosinophilic granular transformation of smooth muscle cells comprising afferent hilar glomerular arterioles, and progressed to foci of smooth muscle cell vacuolization and accumulation of discrete hyaline deposits in vessel walls. Electron microscopy demonstrated marked accumulation of typical renin granules throughout the smooth muscle cell cytoplasm, corresponding to the eosinophilic granular transformation revealed histologically. Immunocytochemistry confirmed the up-regulated production of renin in these vessels. This study documents a rodent model for CsA arteriolopathy and CsA-associated interstitial fibrosis that strikingly reproduces the most characteristic nephropathic effects of cyclosporine found in human patients treated with this agent. This model offers an opportunity to test therapeutic interventions that might block or ameliorate the most serious nephrotoxic effects of this drug.