Pathophysiology of Cyclosporine-Induced Nephrotoxicity in Humans: A Role for Nitric Oxide?

Abstract

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 (10 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 µmol/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 µmol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E₂ and 6-keto-prostaglandin F_1α 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)]. Urinary thromboxane B₂ 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 E₂ and 6-keto-prostaglandin F_1α and possibly nitric oxide.

Cyclosporine A Suppresses Cyclooxygenase-2 Expression in the Rat Kidney

“…An inhibition of COX-2 expression and consequently an inhibition of prostanoid formation by calcineurin inhibitors also fits well with in vitro and in vivo data. In this context, it has been found that CsA decreases PGE 2 formation in cultures of vascular smooth muscle cells (33) and that calcineurin inhibitors decrease the renal excretion of vasodilatory prostanoids, like PGE 2 and prostacyclin, in rats and humans (34,35).…”

Protective Effect of Docosahexaenoic Acid Against Cyclosporine A-Induced Nephrotoxicity in Rats: A Possible Mechanism of Action

“…However, participation of NO, an important renal vasodilator, is highly suggested to participate in CsA-induced nephrotoxicity. Gossmann et al 5 reported that acetylcholine-induced vasodilatation is impaired in vascular beds of CsAtreated animals, which may indicate deficiency of endothelial NO synthesis. However, this conclusion can also be referred to the enhanced generation of free radicals in CsA-induced nephrotoxicity which is able to inactivate NO.…”

“…Renal vasoconstriction is attributed to a disturbance in the complex dynamic interaction of predominating vasoconstrictors with counteracting vasoactive substances. 2,[4][5][6][7][8] Moreover, the oxidative damage in the body induced by reactive oxygen species and lipid peroxidation products is frequently reported in the CsA nephrotoxicity. [9][10][11] The involvement of free radical species in CsA nephrotoxicity was supported by the fact that many antioxidants and free radical scavengers provide marked functional protection.…”

Cyclosporine A Impairs Norepinephrine-Induced Vascular Contractility

“…Thereby, CsA causes several pathophysiological changes that have been regarded crucial for the side effects such as direct vasoconstriction [7], increased sympathetic and angiotensin activities [8,9], endothelin release [10] as well as endothelin-mediated vasoconstriction [11] and altered renal metabolism of arachidonic acid favoring a vasoconstrictor prostanoid profile [12]. Endothelial dysfunction may also contribute to the side effects of CsA resulting in renal arterial vasoconstriction and subsequent nephrotoxicity [13,14] and hypertension [15]. Vascular relaxation elicited by acetylcholine [16], bradykinin [17], substance P [18], calcium ionophore A23187 [17], and prostaglandin E 1 [19] are remarkably impaired by CsA.…”