MODULATION OF EXPERIMENTAL CYCLOSPORINE NEPHROTOXICITY BY INHIBITION OF THROMBOXANE SYNTHESIS
- 1 October 1990
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Transplantation
- Vol. 50 (4), 558-563
- https://doi.org/10.1097/00007890-199010000-00005
Abstract
The clinical usefulness of Cyclosporine is limited by its intrinisic nephrotoxicity. A potential mechanism of CsA-mediated renal injury may involve an alteration in the prostaglandin-thromboxane (PG-TX) cascade. In our studies, pharmacological manipulation of the PG-TX system in normal and nephrotoxic animals was conducted using a specific thromboxane synthetase inhibitory U63,557A, and the cyclooxygenase inhibitor indomethacin. Administration of CsA 50 mg/kg/day for 7 days to Sprague Dawley rats resulted in a 99% increase in urinary thromboxane B2 excretion compared with controls (48.2 .+-. 3.1 vs. 24.2 .+-. 2.6 ng/24 hr, P<0.001), while plasma levels remained unchanged. Glomerular and tubular function was significantly reduced at this time, with a 48% decrease in creatinine clearance (CCr), and a 25% reduction in the fractional excretion of sodium (FeNa) (P<0.001). Histological injury included cortical tubular vacuolization and necrosis. Administration of indomethacin 8 mg/kg/day to both normal and CsA-treated rats resulted in a significant reduction in prostanoid excretion. Indomethacin alone had no adverse effect on glomerular function; however, when coadministered with CsA an exaggerated decrease in renal function was observed. CCr in this group fell by a further 27% compared with the CsA-50 group, while FeNa decreased by 76% (P<0.001). Histologic injury intensified, with an increase in vacuolization and necrosis. In contrast, coadministration of U63,557A with CsA prevented the rise in urinary TXB2 excretion, improved CCr by 20% (P<0.05), and restored FeNa to control levels. The severity of CsA-induced vacuolization was significantly diminished. Selective inhibition of thromboxane production may therefore be valuable in mitigating the clinical nephrotoxicity of CsA.This publication has 2 references indexed in Scilit:
- Effect of cyclosporine administration on renal hemodynamics in conscious ratsKidney International, 1985
- Cyclosporine NephrotoxicityAnnals of Internal Medicine, 1983