Acute cyclosporine A nephrotoxicity in rats: which role for renin-angiotensin system and glomerular prostaglandins?

Cyclosporine A (CsA) is a recently introduced immunosuppressive agent that represents a significant advance in the clinical control of graft rejection. However despite the remarkable effectiveness, one of the limiting factors to a more extensive use of CsA appears to be its nephrotoxicity. CsA is reported to induce a tubular epithelial damage whereas histological examination of glomeruli does not reveal abnormalities unless particularly high doses of the drug are used. On the other hand a decrease in glomerular filtration rate (GFR) has been reported in association with acute administration of CsA. Relatively few studies are available to compare structural and functional abnormalities in the same animals after an acute administration of CsA. Here we evaluated morphological abnormalities and renal function in the same animals treated for 20 days with CsA. Moreover in the attempt to find a link between tubular damage and decrease in GFR we studied the effect of CsA on the renin-angiotensin system as well as on glomerular synthesis of prostacyclin (PGI2) and prostaglandin E2 (PGE2). Our results confirmed that CsA induces a focal damage of tubular epithelial cells with isometric vacuolization of cytoplasm. No glomerular or vascular changes have been detected at histological examination. Serum creatinine was significantly elevated after 20 days of treatment, whereas creatinine clearance showed a progressive tendency to decrease without reaching a statistical significance. Plasma renin activity was found to progressively increase during CsA administration, whereas the synthesis of PGI2 and PGE2 by isolated glomeruli was not modified in CsA-treated animals in respect to animals receiving the solvent alone.(ABSTRACT TRUNCATED AT 250 WORDS)