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Cyclosporine and tacrolimus nephrotoxicity

William M Bennett, MD
Section Editor
Daniel C Brennan, MD, FACP
Deputy Editor
Albert Q Lam, MD


Patients treated with the calcineurin inhibitors cyclosporine and tacrolimus are at high risk of developing renal injury [1]. Calcineurin inhibitor nephrotoxicity (CIN) is manifested either as acute azotemia, which is largely reversible after reducing the dose, or as chronic progressive renal disease, which is usually irreversible [2-5]. Other renal effects of the calcineurin inhibitors include tubular dysfunction and, rarely, a hemolytic uremic syndrome (HUS) that can lead to acute graft loss [2]. A similar pattern of renal injury from cyclosporine is seen with the use of tacrolimus, thereby suggesting a drug class effect. (See 'Tacrolimus nephrotoxicity' below.)

Attention must also be paid to drug dose, other side effects, and drug interactions to minimize toxicity and maximize efficacy. (See "Pharmacology of cyclosporine and tacrolimus".)


Most data in this field pertains to cyclosporine, although the effects of tacrolimus are thought to be similar. In the earliest clinical renal transplant trials using cyclosporine, a high incidence of oliguric acute kidney injury (AKI) and primary nonfunction was observed; the risk was greatest with prolonged ischemia time of the donated kidney prior to transplantation [6]. Subsequent trials using lower doses of cyclosporine showed that these problems were dose related, although there was considerable variability in the incidence of AKI in various centers.

Studies have demonstrated that cyclosporine causes vasoconstriction of the afferent and efferent glomerular arterioles [7] and reductions in renal blood flow and glomerular filtration rate (GFR). The exact mechanism of vasoconstriction is unclear, but there appears to be substantial impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane) [7-10]. Increased sympathetic tone also may be present [11], although renal vasoconstriction occurs even in denervated kidneys. In addition, transforming growth factor (TGF)-beta-1, endothelin-1, and the production of reactive oxygen and nitrogen species have also been implicated [10].

There may also be an intrinsic renal susceptibility to cyclosporine-induced renal vasoconstriction. Experimental support for this hypothesis is derived from a study examining the effect of raising the cyclosporine dose in eight pairs of stable, unrelated renal transplant recipients who had received a cadaver kidney from the same donor [12]. Seven of the eight pairs showed a parallel response to increasing the cyclosporine dose (four pairs showed an elevation in the plasma creatinine concentration, while three pairs showed no change, p<0.05).


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Literature review current through: Sep 2016. | This topic last updated: Sep 11, 2015.
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