Insights into chronic cyclosporine nephrotoxicity.
Cyclosporine has proven to be an invaluable immunosuppressive agent in solid organ transplantation. However, its major side effect is dose-related acute and chronic nephrotoxicity. The acute effects of cyclosporine are predominantly hemodynamic and mediated by a variety of vasoactive compounds, including endothelin, thromboxane A2, and/or inhibition of nitric oxide synthase. The chronic lesion of cyclosporine nephropathy which consists of afferent arteriolopathy combined with striped tubulointerstitial fibrosis and glomerulosclerosis has been much more difficult to understand. An experimental model using the salt-depleted rat has been developed which reproduces the structural and functional changes of chronic cyclosporine nephropathy. Furthermore, it has been shown in this animal model that the renin angiotensin system within the kidney is activated and is important in the pathogenesis of this lesion. Inhibition of the renin angiotensin system with angiotensin II receptor blockade or ACE inhibition markedly reduces the tubulointerstitial fibrosis and arteriolopathy while leaving the glomerular and hemodynamic effects of the drug unchanged. Thus, in the chronic animal model, the vascular and tubulointerstitial effect of cyclosporine can be dissociated. Recent studies have shown the involvement of TGF-beta 2 and osteopontin in the scarring process. Interestingly, the TGF-beta 2 and osteopontin response can also be markedly abrogated by inhibition of the renin angiotensin system. This is of great interest since recent information has suggested that the immunosuppressive effect of cyclosporine is at least partially mediated through TGF-beta 2. The therapeutic and clinical implications of further work in this area are obvious and may lead to better management strategies for the patient who must necessarily be on long-term cyclosporine therapy.
Bennett
W M
WM
Department of Medicine and Pharmacology, Oregon Health Sciences University 97201 Portland, USA.
D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000009:adverse effects*; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced*; D051381:Rats
D007166:Immunosuppressive Agents; D016572:Cyclosporine