Does Mineralocorticoid Receptor Antagonism Prevent Calcineurin Inhibitor-Induced Nephrotoxicity?

Abstract

Calcineurin inhibitors have markedly reduced acute rejection rates in renal transplantation, thus significantly improved short-term outcome. The beneficial effects are, however, tampered by acute and chronic nephrotoxicity leading to interstitial fibrosis and tubular atrophy, which impairs long-term allograft survival. The mineralocorticoid hormone aldosterone induces fibrosis in numerous organs, including the kidney. Evidence from animal models suggests a beneficial effect of aldosterone antagonism in reducing calcineurin inhibitor-induced nephrotoxicity. This review summarizes current evidence of mineralocorticoid receptor antagonism in animal models of calcineurin inhibitor-induced nephrotoxicity and the results from studies of mineralocorticoid antagonism in renal transplant patients.

Keywords: IF/TA; aldosterone; cyclosporine A; fibrosis; mineralocorticoid; tacrolimus.

Figure 1

Calcineurin inhibitors induce afferent arteriolar vasoconstriction through an effect on both mediators of endothelial dysfunction and a direct stimulatory effect on the RAAS-system. Vasoconstriction leads to reduced renal blood flow (acute CNI nephrotoxicity) and renal ischemia, which ultimately leads to inflammation and fibrosis (chronic CNI nephrotoxicity). The latter is further induced by a direct stimulatory effect on the major pro-fibrotic cytokine TGF-β. Simplified from Naesens et al. (3). CNI, calcineurin inhibitor; NO, nitric oxide; ET1, endothelin 1; RAAS, renin-angiotensin-aldosterone system; TGF-β, transforming growth factor β; ROS, reactive oxygen species; IF/TA, interstitial fibrosis and tubular atrophy.

Figure 2

Aldosterone induces vasoconstriction via MR in vascular smooth muscle cells and through reduced bioavailability of nitric oxide. Also, aldosterone stimulates the formation of ROS further worsened by vasoconstriction. Activation of pro-inflammatory transcription factors as well as the direct stimulation of cytokines and leukocyte adhesion to the vessel wall leads to inflammation, which contributes to tissue fibrosis. A, aldosterone; MR, mineralocorticoid receptor; MRA, MR antagonist; ROS, reactive oxygen species; TGF-β, transforming growth factor β; PAI-1, plasminogen activator inhibitor 1; ET-1, endothelin 1; CTFG, colony transforming growth factor; ICAM-1, intercellular adhesion molecule 1; NFκβ, nuclear factor κβ; AP-1, activator protein 1.