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

• Published in: Science translational medicine Vol. 10; no. 441
• Main Authors: Stoppe, Christian, Averdunk, Luisa, Goetzenich, Andreas, Soppert, Josefin, Marlier, Arnaud, Kraemer, Sandra, Vieten, Jil, Coburn, Mark, Kowark, Ana, Kim, Bong-Song, Marx, Gernot, Rex, Steffen, Ochi, Akinobu, Leng, Lin, Moeckel, Gilbert, Linkermann, Andreas, El Bounkari, Omar, Zarbock, Alexander, Bernhagen, Jürgen, Djudjaj, Sonja, Bucala, Richard, Boor, Peter
• Format: Journal Article
• Language: English
• Published: United States 16.05.2018
• Subjects: Acute Kidney Injury - blood; Acute Kidney Injury - epidemiology; Acute Kidney Injury - etiology; Acute Kidney Injury - urine; Animals; Antigens, Differentiation, B-Lymphocyte - chemistry; Antigens, Differentiation, B-Lymphocyte - metabolism; Antioxidants - metabolism; Cardiac Surgical Procedures - adverse effects; Cell Death; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - metabolism; Humans; Incidence; Inflammation - pathology; Kidney - blood supply; Kidney - pathology; Lipid Peroxidation; Lipocalin-2 - urine; Macrophage Migration-Inhibitory Factors - blood; Macrophage Migration-Inhibitory Factors - deficiency; Macrophage Migration-Inhibitory Factors - urine; Mice, Inbred C57BL; Oxidative Stress; Protective Agents - metabolism; Protein Domains; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Reperfusion Injury - complications; Reperfusion Injury - pathology; Rhabdomyolysis - pathology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aan4886

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%; = 0.03). Experimental AKI was induced in wild-type and mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. -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.