Prevention of Experimental Cyclosporine Nephrotoxicity by Dietary Supplementation with LSL 90202, a Lysine Salt of Eicosapentaenoic Acid

Abstract

Cyclosporine (CsA) nephrotoxicity is partially mediated by renal vasoconstriction due to an imbalance between vasodilator and vasoconstrictor eicosanoids. LSL 90202 is a purified lysine salt of eicosapentaenoic acid which is a known inhibitor of renal eicosanoid synthesis. The aim of the present work was to determine if chronic dietary supplementation with LSL 90202 prevented CsA nephrotoxicity and to establish the role of thromboxane and prostacyclin in renal tissue. Thirty-three male Sprague-Dawley rats were divided into 4 groups: group 1, CsA in olive oil (n = 10); group 2, isovolumetric olive oil (n = 7); group 3, CsA in olive oil plus LSL 90202 (n = 8); group 4, isovolumetric olive oil plus LSL 90202 (n = 8). CsA and LSL 90202 were given at 20 mg/kg/day. Weight and creatinine clearance (CrCl) were determined before and on days 14 and 30. On day 30 whole-blood CsA was determined and renal tissue processed for renal malondialdehyde, thromboxane B2 and 6-keto-PGF_1α measurement and for conventional histology. CrCl was severely reduced in the CsA in olive oil group compared to olive oil and LSL 90202 control groups. On day 30, CrCl in the CsA in olive oil plus LSL 90202 group showed a slight decrease, but the mean CrCl was significantly higher than in the CsA in olive oil group. Trough whole blood CsA levels were not significantly different in both groups given the drug. No morphological differences were found between groups. Renal content of thromboxane B2 and 6-keto-PGF_1α (the stable metabolites of thromboxane A2 and prostacyclin, respectively) was higher in CsA in olive oil group than in olive oil control group. In contrast, both eicosanoids were similarly low in both groups receiving LSL 90202. The difference between group 1 and group 3 was statistically significant. In summary, our results suggest that LSL 90202 modifies CsA nephrotoxicity and that its benefitial effect may be due to its influence on intrarenal biosynthesis of thomboxane A2 and prostacyclin.