Effect of cyclosporine on urinary prostanoid excretion, renal blood flow, and glomerulotubular function.
The clinical usefulness of cyclosporine (CsA) in organ transplantation and autoimmune diseases is limited by its intrinsic nephrotoxicity. The mechanism of this renal impairment was examined utilizing an animal model in which male Sprague-Dawley rats were administered oral CsA in doses of 25, 37.5, and 50 mg/kg/day for 7 days and 50 mg/kg/day for 2, 4, and 7 days. Urinary thromboxane B2 (TXB2) excretion increased from 30.6 +/- 2.3 to 60.8 +/- 4.4 ng/24 hr P less than 0.001, following 48 hr of CsA dosing. In addition, a concomitant rise in proximal tubular sodium reabsorption was observed with fractional excretion of sodium decreasing from 0.502 +/- 0.091 to 0.223 +/- 0.037% P less than 0.05. Urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion increased two-fold, although plasma levels of all 3 prostanoids did not vary from controls. Functional changes included decreases in the relative renal blood flow of 53% P less than 0.05, and the clearance of creatinine and urea of 46% and 42%, respectively on day 7 of treatment, while renal morphology showed severe vacuolization and necrosis confined to the proximal tubular region of the cortex. Thromboxane A2, the active precursor of TXB2, is a potent vasoconstrictor and promoter of platelet aggregation and may alter proximal tubular handling of sodium. The rise in urinary TXB2 excretion may contribute to the renal vasoconstriction leading to functional impairment and histologic injury.
Petric
R
R
Department of Medicine, University Hospital, London, Ontario, Canada.
Freeman
D
D
Wallace
C
C
McDonald
J
J
Stiller
C
C
Keown
P
P
D001921:Brain / Q000098:blood supply; D003524:Cyclosporins / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply*; D007684:Kidney Tubules / Q000187:drug effects; D008099:Liver / Q000098:blood supply; D009318:Natriuresis / Q000187:drug effects*; D011453:Prostaglandins / Q000652:urine*; D012039:Regional Blood Flow / Q000187:drug effects; D013154:Spleen / Q000098:blood supply; D013997:Time Factors
D003524:Cyclosporins; D011453:Prostaglandins