MODIFICATION OF EXPERIMENTAL NEPHROTOXICITY WITH FISH OIL AS THE VEHICLE FOR CYCLOSPORINE

Abstract

Cyclosporine-associated renal dysfunction is well recognized. While renal vasoconstriction appears to be a major pathogenic factor, the precise mechanism responsible for the altered hemodynamics is unclear. To investigate whether alterations in renal eicosanoid metabolism could be involved, we substituted fish oil rich in eicosapentaenoic acid (EPA), an inhibitor of cyclooxygenase metabolites, for the conventional olive oil cyclosporine vehicle. Male rats were pretreated with 1.0 cc fish oil or olive oil by gavage. After 14 days, cyclosporine (12.5 mg/cc vehicle) was added to the oil and animals received cyclosporine 50 mg/kg for an additional 14 days. Pair-fed control animals received fish oil or olive oil alone. Glomerular filtration rate (GFR) was severely reduced in the cyclosporine-in-olive-oil (CSA + OO) group (0.28 +/- .05 ml/min/100 g) vs. olive oil (OO) controls (0.70 +/- .04) (P less than 0.001). While GFR was reduced in the cyclosporine-in-fish oil group (CSA + FO) vs. fish oil (FO) controls (0.47 +/- .07 vs. 0.74 +/- .04), it was significantly higher than in the CSA + OO group (P less than 0.05). Trough whole-blood cyclosporine levels were not significantly different in the two groups. While CSA + OO appeared to elevate renal cortical content of thromboxane B2 (65.7 +/- 7.3 pg/mg tissue vs. 46.9 +/- 5.3 for OO), both the CSA + FO and FO groups had reduced levels (31.1 +/- 2.7 and 29.5 +/- 2.3, respectively). In addition, there was a striking reduction in proximal tubular vacuolar changes in the CSA +/- FO vs. CSA + OO group. We conclude that the use of EPA-rich fish oil as the vehicle for cyclosporine results in improved renal function and morphology and is associated with depressed renal cortical levels of vasoconstrictor thromboxane B2.