Reduction of chronic ciclosporin nephrotoxicity by thromboxane synthase inhibition with OKY-046

Abstract

Ciclosporin A (CsA) is a potent immunosuppressive agent which is extremely effective in controlling allograft rejection and in the treatment of autoimmune disease and nephrotic syndrome. Unfortunately, its use is limited by chronic, irreversible nephrotoxicity. Administration of CsA induces renal vasoconstriction, causing a reduction in renal blood flow. An alteration of the prostaglandin-thromboxane cascade may be involved in the vasoconstriction. We studied the role of thromboxane A2 in CsA nephrotoxicity and the ability of a thromboxane synthase inhibitor, OKY-046, to reduce the CsA nephrotoxicity. Daily administration of CsA 25 mg/kg for 28 days to Sprague-Dawley rats resulted in increased excretion of urinary thomboxane B2 (47.9+/-11.5 vs. 27.2+/-9.7 ng/24 h; p<0.05) and decreased creatinine clearance (0.25+/-0.07 vs. 0.43+/-0.17ml/min/100 g; p<0.01) as compared with administration of vehicle only. Histologically, large numbers of lysosomes in the tubular epithelium were characteristic. Coadministration of OKY-046 prevented both the rise in urinary thromboxane B2 excretion (40.0+/-11.8 ng/24 h) and the reduction in the creatinine clearance (0.44+/-0.11 ml/min/100 g). The severity of the histological changes was significantly diminished. Selective inhibition of thromboxane production with OKY-046 may be valuable in the attenuation of CsA nephrotoxicity.