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Effect of cyclosporine on urinary prostanoid excretion, renal blood flow, and glomerulotubular function
R Petric1, D Freeman, C Wallace
1Department of Medicine, University Hospital, London, Ontario, Canada.
Abstract:
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.
Insights
Cyclosporine (CsA) causes kidney damage by increasing thromboxane B2 (TXB2) and altering sodium reabsorption in rat kidneys. This mechanism involves vasoconstriction and tubular injury, limiting CsA
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cyclosporine (CsA) is crucial for organ transplantation and autoimmune diseases.
- CsA's clinical use is restricted by its significant nephrotoxicity.
- Understanding CsA's renal impairment mechanisms is vital for patient safety.
Purpose of the Study:
- To investigate the mechanism of cyclosporine-induced nephrotoxicity.
- To examine the role of prostanoids, particularly thromboxane A2 (TXA2), in CsA renal injury.
- To correlate functional and morphological changes with biochemical markers in a rat model.
Main Methods:
- Male Sprague-Dawley rats were administered varying doses of oral CsA.
- Urinary prostanoid excretion (TXB2, PGE2, 6-keto-PGF1α) was measured.
- Renal function was assessed by measuring fractional sodium excretion, renal blood flow, and creatinine/urea clearance.
- Renal morphology was examined for signs of tubular damage.
Main Results:
- CsA administration significantly increased urinary thromboxane B2 (TXB2) excretion.
- A concurrent increase in proximal tubular sodium reabsorption was observed.
- Renal blood flow and creatinine/urea clearance decreased significantly.
- Histological examination revealed severe vacuolization and necrosis in proximal tubules.
Conclusions:
- Increased urinary TXB2 excretion is a key marker of CsA-induced nephrotoxicity.
- CsA-induced renal impairment involves vasoconstriction and proximal tubular damage.
- These findings highlight the role of thromboxane A2 in CsA's detrimental effects on kidney function.