Cyclosporine arteriolopathy: effects of drug withdrawal

Renal arteriolopathy in chronic cyclosporine-induced nephrotoxicity is characterized by an eosinophilic granular transformation of vascular smooth muscle cells of afferent glomerular arterioles that is thought to eventually progress to necrosis of individual muscle cells and hyalinization of the vessel wall. Although the lesion is highly specific for cyclosporine-induced injury in humans, it has been difficult to reproduce in normotensive animals. To study the natural history of the cyclosporine arteriolopathy, we conducted sequential studies in salt-depleted Sprague-Dawley rats using cyclosporin A (15 mg/kg subcutaneously) treatment for 35 days, 49 days, 35 days plus 14 or 56 days of drug washout, or placebo (olive oil). Cyclosporin A produced a progressive decrease in renal function that significantly improved after discontinuation of the drug. The arteriolopathy, scored semiquantitatively, was present by day 35 and did not improve with cyclosporine withdrawal within 2 weeks but did dramatically regress after 56 days. However, tubulointerstitial changes did not regress with drug discontinuation and were present despite improvement in renal function. We conclude that cyclosporine-induced arteriolopathy may be reversible and associated with improving renal function. Thus, the morphological evidence of arteriolopathy is dissociable from the progressive tubulointerstitial scarring.