Pathophysiology of cyclosporine-induced nephrotoxicity in humans:: A role for nitric oxide?

Background: The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. Methods: We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO2/NO3) in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA 110 mg/kg b.w.), Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA, Blood pressure, heart rate, and CsA blood levels were also determined. Results: Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased, Nitric oxide plasma levels decreased in nearly all patients from 21.0 +/- 2.8 to 19.1 +/- 2.6 (p = 0.003) and then rose slightly to 19.5 +/- 2.5 mu mol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO2/NO3 decreased nonsignificantly from 269 +/- 38.8 to 259 +/- 27.7 and 254 +/- 41.6 mu mol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E-2 and 6-keto-prostaglandin F-1 alpha excretion rate declined significantly [from 1,187 +/- 254 to 1,186 +/- 351 and 730 +/- 148 pg/min (p = 0.27 and 0.02) and from 697 +/- 115 to 645 +/- 134 and 508 +/- 58.2 pg/min (p = 0.34 and 0.05)1, Urinary thromboxane BZ and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 +/- 2.5 to 110 +/- 2.6 and 114 +/- 3.4 mm Hg (p = 0.1 and 0.05). Conclusion: The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E-2 and 6-keto-prostaglandin fl, and possibly nitric oxide. Copyright (C) 2001 S. Karger AG. Basel.