Cyclosporine nephropathy: pathophysiology and clinical impact

Abstract

Cyclosporine (CsA) has markedly improved the results of transplantation, and its use has been extended to include autoimmune and primary renal diseases. However, the major limitation to its nephrotoxicity. Acutely, a reversible form of renal vasoconstriction can occur in all patients receiving CsA. In addition, progressive renal insufficiency owing to CsA has also been well documented. Clinically, long-term CsA nephrotoxicity is characterized by slowly progressive azotemia, proteinuria, and hypertension. Histologically, there is striped tubulointerstitial fibrosis, tubular atrophy, and afferent arteriolopathy. New evidence suggests that the histological changes in long-term CsA nephropathy are independent of the functional changes. Recently transforming growth factor (TGF)-beta was shown to be upregulated along with matrix proteins in a model of CsA nephrotoxicity. Because TGF-beta has immunosuppressive activities, it was suggested that it may contribute not only to CsA nephrotoxicity, but also to the mechanism of action of CsA. A number of strategies have been devised to try to minimize CsA nephrotoxicity, but remain inconclusive. Presently, it is not clear what role CsA therapy plays in the chronic failure of renal allografts. Continued research should give new insights into measures to overcome CsA-induced scarring in the kidney.