MIF Matters: The Macrophage Migration Inhibitory Factor and Kidney Injury

Acute kidney injury (AKI) is a common complication of cardiac surgery involving cardiopulmonary bypass. There are nearly 2 million cardiac surgeries annually worldwide, with AKI incidence rates between 5% and 42%.¹ AKI in the setting of cardiac surgery has been associated with longer hospital stays and increased mortality risk. The relationship between cardiac surgery and AKI in humans has served as a natural experiment; cardiac surgery is common and often used for biomarker discovery, yet our understanding of the mechanism of AKI following it has been evolving. Hypoperfusion may directly contribute to tubular cell damage and death. However, recent work has suggested that hypoperfusion alone cannot fully explain the damage at a cellular and tissue level and that oxidative stress, inflammation, and other factors may contribute to kidney damage in this setting.¹ Even the type of cell death in AKI has been further delineated, with the concept of apoptosis evolving to include a combination of necroinflammatory cell death phenotypes, including ferroptosis influencing signaling and immune response.² Although the science continues to progress, therapies that mitigate the risk for AKI after cardiac surgery are urgently needed.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine shown to have a protective role in the heart during ischemia-reperfusion injury after cardiac surgery.³ Multiple cell types store MIF in intracellular pools and release it in response to stress and other mediators. After liberation from the cell, MIF may bind to various receptors, including CXCR2, CXCR4, and CD74. These various interactions involving different cells at different times may differentially influence the downstream events related to the binding and thus the responses to stress. When binding CXCR2 or CXCR4, MIF promotes inflammation.⁴ MIF binding to CD74 appears to have beneficial effects in the heart during ischemia-reperfusion injury by an antioxidant mechanism through the CD74/CD44/AMP-activated protein kinase (AMPK) pathway.^5,6 However, during sepsis, increased MIF levels appear to exacerbate kidney injury.⁷

What Does This Important Study Show?

A recent study by Stoppe et al⁸ examined the association between circulating MIF levels and incidence of AKI in patients who had undergone cardiac surgery with cardiopulmonary bypass. Patients in the postoperative period had significantly increased serum MIF levels from baseline. Patients with MIF levels higher than the median following cardiac surgery had lower rates of AKI (as determined by AKI Network [AKIN] criteria). Moreover, higher MIF levels correlated with lower levels of the urinary AKI biomarker neutrophil gelatinase-associated lipocalin (NGAL) and enhanced antioxidant capacity in serum. The quantity of MIF released into the bloodstream correlated with renal protection. These hypothesis-generating observations led the investigators to examine the relation of MIF to AKI and potential underlying mechanisms in a series of mouse and in vitro experiments.

Stoppe et al⁸ tested the hypothesis that MIF deficiency would increase AKI using multiple models: ischemia reperfusion injury and rhabdomyolysis, comparing MIF-deficient (MIF^−/−) and wild-type mice. MIF^−/− mice demonstrated a higher propensity and severity of AKI than wild-type controls as measured using serum creatinine level. Furthermore, MIF^−/− mice had greater tubular cell injury and increased inflammatory cell infiltration across all conditions.

To examine the protective mechanisms of MIF, primary mouse kidney epithelial cells were stressed with hydrogen peroxide and treated with recombinant MIF (rMIF). These rMIF-treated cells demonstrated markedly elevated intracellular reduced glutathione (GSH) and lower lipid peroxidation levels. Additionally, supplementation of primary mouse kidney epithelial cells with rMIF attenuated the cell death caused by hypoxia treatment for 24 hours. However, rMIF supplementation in MIF^−/− primary cells failed to improve the degree of cell death associated with hypoxic conditions. When MIF^−/− mice were challenged with either ischemia-reperfusion injury or rhabdomyolysis, there was greater GSH depletion and higher thiobarbituric acid reactive substance levels (an indicator of lipid peroxidation; ie, more oxidative stress) as compared with wild-type mice. Similarly, rMIF treatment given to wild-type mice before and after ischemia-reperfusion injury conferred renal protection (as assessed by lessened tubular injury and lower increases in creatinine). Again, MIF^−/− mice given rMIF under the same conditions did not show significant protection from AKI. The findings that rMIF failed to rescue MIF^−/− cells and mice from injury in these experiments suggests that there may be compensatory changes in downstream signaling pathways caused by constitutive MIF knockout that render the cells unresponsive to MIF (eg, downregulation of CD44).

Treatment with the soluble CD74 receptor (sCD74), a concentration-dependent modulator of MIF signaling, enhanced the protective effects of MIF on hypoxic injury of primary mouse kidney epithelial cells in vitro and on tubular injury in wild-type mice undergoing ischemiareperfusion injury. Further studies using an inducible MIF knockout mouse model and/or specific acute inhibitors of the MIF/CD74 pathway (eg, 4-IPP) could be very informative to better define mechanisms that mediate the protective effects observed in these studies.

How Does This Study Compare With Prior Studies?

The downstream mechanisms that underlie MIF-induced renoprotection in the setting of ischemic injury are not yet clear. Although Mount et al⁹ found no significant effect on ischemia-reperfusion injury in constitutive AMPK-b1 knockout mice, other studies have found that AMPK activation (or pre-activation, mimicking ischemic preconditioning) has beneficial effects in dampening kidney injury in rodent ischemia-reperfusion injury models and transplant models.^10,11 Moreover, MIF mediates hepatoprotection through the CD74/AMPK pathway in hepatocytes in metabolic models of liver injury.¹² Defining the precise mechanisms and time dependent effects of MIF modulation are important goals for future work.

What Are the Implications for Nephrologists?

The work of Stoppe and colleagues provides a number of other opportunities for study, particularly given that sCD74 enhanced the beneficial effects of MIF.⁸ Further mechanistic studies are warranted to begin to understand the reasons that MIF level becomes elevated, the extent to which MIF inhibitors block the effects, and the timing of MIF changes in relationship to kidney injury. The observation relating higher MIF levels to lower risk for AKI in humans could be strengthened by looking at a wider range of conditions and in larger populations. Although previous work demonstrated that MIF exacerbated AKI in the setting of sepsis, perhaps sCD74 would be an alternative. Additional upstream or downstream targets of MIF also deserve further exploration.

It will be helpful to understand the potential sources of variability in MIF responses to injury across multiple patient demographics and the role of timing in the reduction of AKI associated with MIF levels. The timing is particularly important given that our interventions for AKI tend to come late in the natural history of the disease due to late detection afforded by monitoring of serum creatinine levels. It is possible that there are certain therapeutic time windows during which MIF therapy may be optimally effective in treating AKI. This issue could be explored by using specific MIF agonists or inhibitors for in vitro or in vivo studies or potentially inducible MIF knockdown or overexpression mouse models.

The incidence of AKI has dramatically increased in the past decade, concomitant with an aging population, more burdensome diseases, increasingly invasive interventions, and higher levels of monitoring. Despite numerous ongoing trials, there are still no proven pharmacologic treatments for AKI. This may stem from the heterogeneity of the causes and consequences of AKI. Different causes of AKI should necessitate different treatments. The work by Stoppe et al suggests that focusing on treatments based on the specific pathophysiology of kidney injury is a promising approach.⁸ This work suggests that MIF mitigates AKI in the setting of ischemia, but it may have detrimental effects in other settings, such as sepsis or liver failure. The underlying cause or causes of AKI are often unclear, which further complicates the identification of rational therapies such as rMIF or MIF agonists.