Acute kidney injury (AKI) is a growing global health concern, yet no treatment is currently available to prevent it or to promote kidney repair after injury. Animal models demonstrate that the ...macrophage is a major contributor to the inflammatory response to AKI. Emerging data from human biopsies also corroborate the presence of macrophages in AKI and their persistence in progressive chronic kidney disease. Macrophages are phagocytic innate immune cells that are important mediators of tissue homeostasis and host defense. In response to tissue injury, macrophages become activated based on specific signals from the damaged microenvironment. The activation and functional state of the macrophage depends on the stage of tissue injury and repair, reflecting a dynamic and diverse spectrum of macrophage phenotypes. In this review, we highlight our current understanding of the mechanisms by which macrophages contribute to injury and repair after AKI.
Sepsis is a significant cause for mortality among critically ill patients. Metabolic derangements that develop in sepsis are often considered to be pathologic, contributing to sepsis morbidity and ...mortality. However, alterations in metabolism during sepsis are multifaceted and are incompletely understood. Acute anorexia during infection is an evolutionarily conserved response, suggesting a potential protective role of anorexia in the host response to infection. In animal models of bacterial inflammation, fasting metabolic programs associated with acute anorexia such as those regulated by fibroblast growth factor 21 and ketogenesis are associated with improved survival. Other fasting metabolic pathways such as fatty acid oxidation and autophagy are also implicated in preventing acute kidney injury (AKI). Global metabolic changes during sepsis and current clinical interventions can potentially affect disease tolerance mechanisms and modify the risk of AKI.
Acute infections are associated with a set of stereotypic behavioral responses, including anorexia, lethargy, and social withdrawal. Although these so-called sickness behaviors are the most common ...and familiar symptoms of infections, their roles in host defense are largely unknown. Here, we investigated the role of anorexia in models of bacterial and viral infections. We found that anorexia was protective while nutritional supplementation was detrimental in bacterial sepsis. Furthermore, glucose was necessary and sufficient for these effects. In contrast, nutritional supplementation protected against mortality from influenza infection and viral sepsis, whereas blocking glucose utilization was lethal. In both bacterial and viral models, these effects were largely independent of pathogen load and magnitude of inflammation. Instead, we identify opposing metabolic requirements tied to cellular stress adaptations critical for tolerance of differential inflammatory states.
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•Fasting metabolism is protective in bacterial, but not viral, inflammation•Ketone bodies limit ROS-induced neuronal damage during bacterial inflammation•Glucose utilization prevents UPR-mediated neuronal damage during viral inflammation
Starve a fever, stuff a cold: why anorexia helps the organism to tolerate bacterial infections but makes viral infections hard to endure.
The development of acute kidney injury (AKI) in patients with sepsis causes significant morbidity and mortality. The pathogenesis of AKI in sepsis is incompletely understood. In this issue of the ...JCI, Hato et al. investigate the renal translatome during bacterial sepsis and identify the global shutdown of renal protein translation mediated by the eukaryotic translation initiation factor 2-α kinase 2/eukaryotic translation initiation factor 2α (EIF2AK2/eIF2α) axis as a major pathway in mediating septic AKI. The results of this study suggest that inhibiting this pathway could be a potential therapeutic strategy for preventing septic AKI.
Acute kidney injury (AKI) after cardiac surgery confers a significant increased risk of death. Several risk models have been developed to predict postoperative kidney failure after cardiac surgery. ...This systematic review evaluated the available risk models for AKI after cardiac surgery. Literature searches were performed in the Web of Science/Knowledge, Scopus, and MEDLINE databases for articles reporting the primary development of a risk model and articles reporting validation of existing risk models for AKI after cardiac surgery. Data on model variables, internal or external validation (or both), measures of discrimination, and measures of calibration were extracted. The systematic review included 7 articles with a primary development of a prediction score for AKI after cardiac surgery and 8 articles with external validation of established models. The models for AKI requiring dialysis are the most robust and externally validated. Among the prediction rules for AKI requiring dialysis after cardiac surgery, the Cleveland Clinic model has been the most widely tested thus far and has shown high discrimination in most of the tested populations. A validated score to predict AKI not requiring dialysis is lacking. Further studies are required to develop risk models to predict milder AKI not requiring dialysis after cardiac surgery. Standardizing risk factor and AKI definitions will facilitate the development and validation of risk models predicting AKI.
Acute ischemic kidney injury is a common complication in hospitalized patients. No treatment is yet available for augmenting kidney repair or preventing progressive kidney fibrosis. Animal models of ...acute kidney injury demonstrate that activation of the innate immune system plays a major role in the systemic response to ischemia/reperfusion injury. Macrophage depletion studies suggest that macrophages, key participants in the innate immune response, augment the initial injury after reperfusion but also promote tubular repair and contribute to long-term kidney fibrosis after ischemic injury. The distinct functional outcomes seen following macrophage depletion at different time points after ischemia/reperfusion injury suggest heterogeneity in macrophage activation states. Identifying the pathways that regulate the transitions of macrophage activation is thus critical for understanding the mechanisms that govern both macrophage-mediated injury and repair in the postischemic kidney. This review examines our understanding of the complex and intricately controlled pathways that determine monocyte recruitment, macrophage activation, and macrophage effector functions after renal ischemia/reperfusion injury. Careful delineation of repair and resolution pathways could provide therapeutic targets for the development of effective treatments to offer patients with acute kidney injury.
Sepsis continues to cause significant morbidity and mortality despite technological advancements in medical management. While sepsis is defined as organ dysfunction owing to the dysregulated host ...response to infection, our understanding of the dysregulation of the host response remains incomplete.
Many metabolic derangements that occur during sepsis, including those associated with anorexia, hyperglycemia, and proteolysis, have largely been considered maladaptive. Supportive medical and nutritional interventions targeted at correcting these metabolic derangements have not led to improved outcomes, suggesting a reappraisal of our approach to metabolism and nutrition in critically ill septic patients is needed.
Explanations of the lack of efficacy of these clinical interventions may include targeting the wrong metric or patient population, or the possibility that some of these metabolic changes could be protective. In this mini-review, we propose a paradigm shift that is needed in metabolism and nutrition management in sepsis.
Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) increases mortality significantly. Endoplasmic reticulum stress is activated in many cell ...types upon microbial infection and modulates inflammation. The role of endoplasmic reticulum signaling in the kidney during septic AKI is unknown. Here we tested the role of the spliced X-box binding protein 1 (Xbp1s), a key component of the endoplasmic reticulum stress-activated pathways, in the renal response to sepsis in the lipopolysaccharide (LPS) model. Xbp1s was increased in the kidneys of mice treated with LPS but not in other models of AKI, or several chronic kidney disease models. The functional significance of Xbp1s induction was examined by genetic manipulation in renal tubules. Renal tubule-specific overexpression of Xbp1s caused severe tubule dilation and vacuolation with expression of the injury markers Kim1 and Ngal, the pro-inflammatory molecules interleukin-6 (Il6) and Toll-like receptor 4 (Tlr4), decreased kidney function and 50% mortality in five days. Renal tubule-specific genetic ablation of Xbp1 had no phenotype at baseline. However, after LPS, Xbp1 knockdown mice displayed lower renal NGAL, pro-apoptotic factor CHOP, serum creatinine levels, and a tendency towards lower Tlr4 compared to LPS-treated mice with intact Xbp1s. LPS treatment in Xbp1s-overexpressing mice caused a mild increase in NGAL and CHOP compared to LPS-treated mice without genetic Xbp1s overexpression. Thus, increased Xbp1s signaling in renal tubules is unique to sepsis-induced AKI and contributes to renal inflammation and injury. Inhibition of this pathway may be a potential portal to alleviate injury.
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After kidney ischemia/reperfusion (I/R) injury, monocytes home to the kidney and differentiate into activated macrophages. Whereas proinflammatory macrophages contribute to the initial kidney damage, ...an alternatively activated phenotype can promote normal renal repair. The microenvironment of the kidney during the repair phase mediates the transition of macrophage activation from a proinflammatory to a reparative phenotype. In this study, we show that macrophages isolated from murine kidneys during the tubular repair phase after I/R exhibit an alternative activation gene profile that differs from the canonical alternative activation induced by IL-4-stimulated STAT6 signaling. This unique activation profile can be reproduced in vitro by stimulation of bone marrow-derived macrophages with conditioned media from serum-starved mouse proximal tubule cells. Secreted tubular factors were found to activate macrophage STAT3 and STAT5 but not STAT6, leading to induction of the unique alternative activation pattern. Using STAT3-deficient bone marrow-derived macrophages and pharmacologic inhibition of STAT5, we found that tubular cell-mediated macrophage alternative activation is regulated by STAT5 activation. Both in vitro and after renal I/R, tubular cells expressed GM-CSF, a known STAT5 activator, and this pathway was required for in vitro alternative activation of macrophages by tubular cells. Furthermore, administration of a neutralizing antibody against GM-CSF after renal I/R attenuated kidney macrophage alternative activation and suppressed tubular proliferation. Taken together, these data show that tubular cells can instruct macrophage activation by secreting GM-CSF, leading to a unique macrophage reparative phenotype that supports tubular proliferation after sterile ischemic injury.
Sickness behaviors are a conserved set of stereotypic responses to inflammatory diseases. We recently demonstrated that interfering with inflammation-induced anorexia led to metabolic changes that ...had profound effects on survival of acute inflammatory conditions. We found that different inflammatory states needed to be coordinated with corresponding-metabolic programs to actuate tissue-protective mechanisms. Survival of viral inflammation required intact glucose utilization pathways, whereas survival of bacterial inflammation required alternative fuel substrates and ketogenic programs. We thus hypothesized that organismal metabolism would be important in other classes of infectious inflammation and sought to understand its role in the prototypic parasitic disease malaria. Utilizing the cerebral malaria model, Plasmodium berghei ANKA (PbA) infection in C57BL/6J male mice, we unexpectedly found that inhibition of glycolysis using 2-deoxy glucose (2DG) conferred protection from cerebral malaria. Unlike vehicle-treated animals, 2DG-treated animals did not develop cerebral malaria and survived until ultimately succumbing to fatal anemia. We did not find any differences in parasitemia or pathogen load in affected tissues. There were no differences in the kinetics of anemia. We also did not detect differences in immune infiltration in the brain or in blood–brain barrier permeability. Rather, on pathological analyses performed on the entire brain, we found that 2DG prevented the formation of thrombi and thrombotic complications. Using thromboelastography (TEG), we found that 2DG-treated animals formed clots that were significantly less strong and stable. Together, these data suggest that glucose metabolism is involved in inflammation-induced hemostasis and provide a potential therapeutic target in treatment of cerebral malaria.
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