Effects of Defibrotide on Renal Function and Urinary Prostanoid Excretion in Ciclosporin-Treated Rats

Abstract

Defibrotide (DF) has been proposed as a new antithrombotic agent in renal transplantation. Because it was also found to increase prostacyclin synthesis, a reduction in ciclosporin (CS) nephrotoxicity could be supposed. To ascertain this hypothesis, renal function and urinary prostanoids were evaluated in four groups of rats after 10 days of oral treatment (doses in mg/kg/day): CS 50 (group A), CS 50 + DF 400 (group B), DF 400 (group C) and controls (group D). Compared to controls, creatinine clearance (CCR) was significantly lower in groups A and B (In CCr: A = 6.62 +/- 0.28, B = 6.83 +/- 0.24 vs. 8.17 +/- 0.13 microliters/min, p less than 0.01), whereas it did not change in group C (8.03 +/- 0.24 microliters/min). The urinary excretion of prostaglandin E2 (PGE2) was significantly (p less than 0.05) higher in group A (In PGE2: 3.98 +/- 0.98 nmol/mol Cr) and more evidently in groups B and C (6.89 +/- 0.38 and 6.01 +/- 0.32 nmol/mol Cr, respectively) compared to controls (1.43 +/- 0.45 nmol/mol Cr). The urinary excretion of 6-keto-PGF1 alpha and of thromboxane B2 (TxB2) were higher only in groups A and B (ln 6-keto-PGF1 alpha and ln TxB2: A = 6.45 +/- 0.22 and 4.97 +/- 0.20, B = 7.06 +/- 0.31 and 5.43 +/- 0.41 vs. group D = 5.53 +/- 0.22 and 3.79 +/- 0.42 nmol/mol Cr; p less than 0.05). The 6-keto-PGF1 alpha/Tx molar ratio was not significantly affected, although a trend for a reduction in the ratio was found in the treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)