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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 (C<sub>Cr</sub>) was significantly lower in groups A and B (In C<sub>Cr</sub>: A = 6.62 ± 0.28, B = 6.83 ± 0.24 vs. 8.17 ± 0.13 μl/min, p < 0.01), whereas it did not change in group C (8.03 ± 0.24 μl/min). The urinary excretion of prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) was significantly (p < 0.05) higher in group A (In PGE<sub>2</sub>: 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-PGF<sub>1</sub>α and of thromboxane B<sub>2</sub> (TxB<sub>2</sub>) were higher only in groups A and B (In 6-keto-PGF<sub>1α</sub> and In TxB<sub>2</sub>: 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 < 0.05). The 6-keto-PGF<sub>1α</sub>/Tx molar ratio was not significantly affected, although a trend for a reduction in the ratio was found in the treated rats. In conclusion, DF enhanced urinary prostanoid excretion in CS-treated rats but did not significantly affect renal function.