The protective role of Macrophage Migration Inhibitory Factor (MIF) in acute kidney injury after cardiac surgery
Background: Acute kidney injury (AKI) is a common complication after cardiac surgery, which is triggered by inflammation and oxidative stress. Within inflammation, macrophage migration inhibitory factor (MIF) represents a stress-regulating cytokine that may protect from myocardial ischemia-reperfusion (I/R) injury, by reducing oxidative stress. Therefore, we tested the hypothesis, if MIF is protective against AKI by cytoprotective and antioxidant effects.
Methods: Serum and urine samples were collected from 60 patients scheduled for cardiac surgery with aortic-cross-clamping. The concentrations of MIF and urinary neutrophil gelatinase-associated lipocalin (NGAL) were quantified.
In vivo, one- or two-sided renal ischemia was induced for 30 min in wildtyp (WT) and MIF-/- mice. After 6 or 24 h, serum creatinine, tubular injury, cleaved caspase-3 positive cells and phosphorylated mixed lineage kinase domain-like (pMLKL) positive tubuli were quantified. The oxidative markers glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were measured. Primary murine tubular (pmTEC) cells were treated with MIF or PBS under hypoxic conditions. LDH, GSH and TBARS were measured.
Results: We found that cardiac surgery triggered a significant increase in MIF serum levels that inversely correlated with urinary levels of NGAL (p=0.01; r=-0.4088), indicating a protective role of MIF. Patients with high circulating MIF levels 12 h after surgery had a significantly reduced risk for the development of AKI (rel. risk reduction 0.72, p=0.03). After renal I/R injury, MIF-/- mice showed a significantly aggravated extent of renal failure (increased creatinine) due to increased tubular cell injury. We found more cleaved caspase-3 positive, apoptotic, (p=0.003) and pMLKL positive, necroptotic, cells (p=0.001) in MIF-/- mice. Additionally, oxidative stress was strikingly increased indicated by reduced GSH and increased TBARS, a marker of lipid peroxidation and ferroptosis. Treatment of pmTEC with MIF in vitro confirmed its cytoprotective (LDH) and antioxidant (GSH, TBARS) effects. 
Conclusion: Our data suggest a novel, renoprotective role of MIF in pathogenesis of AKI in patients after cardiac surgery by counteracting programmed cell death pathways and oxidative stress that could open therapeutic perspectives to reduce the incidence of AKI.