Research ArticleKidney Disease

The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery

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Science Translational Medicine  16 May 2018:
Vol. 10, Issue 441, eaan4886
DOI: 10.1126/scitranslmed.aan4886

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MIF muffles kidney injury

Patients undergoing open-heart surgery are susceptible to complications, including acute kidney injury (AKI). Stoppe et al. observed that patients who had high serum concentrations of macrophage migration inhibitory factor (MIF) after cardiac surgery had lower risk of AKI. Renal ischemia-reperfusion injury induced more inflammation and kidney cell death in mice lacking Mif than in wild-type mice. Treating isolated kidney cells with MIF protected against hypoxia-induced cell death. Mice treated with MIF or a soluble form of CD74 (MIF receptor) showed reduced kidney injury after ischemia-reperfusion. This study suggests that MIF may protect the kidney from ischemia-reperfusion injury.

Abstract

Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif−/− mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.

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