Search

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address.

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-[alpha] kinase 2/eukaryotic translation initiation factor 2[alpha] (EIF2AK2/ eIF2[alpha]) 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 in sepsisThe development of acute kidney injury (AKI) remains a major cause of increased mortality among critically ill patients with bacterial sepsis (1). Despite the availability of [...]

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. Keywords Macrophage activation * Ischemia/reperfusion * Acute kidney injury * Repair, Introduction Ischemic renal injury remains a major cause of acute kidney injury, contributing to an increased risk of in-hospital mortality as well as long-term risk of chronic kidney disease, end-stage [...]

Mitochondrial hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme in ketogenesis. The liver expresses high levels of HMGCS2 constitutively as the main ketogenic organ. It has been suggested that the kidney could be ketogenic as HMGCS2 is expressed in the kidney during fasting and diabetic conditions. However, definitive proof of the capacity for the kidney to produce ketones is lacking. We demonstrated that during fasting, HMGCS2 expression is induced in the proximal tubule of the kidney and is peroxisome proliferator activated receptor-a dependent. Mice with kidney-specific Hmgcs2 deletion showed a minor, likely physiologically insignificant, decrease in circulating ketones during fasting. Conversely, liver-specific Hmgcs2 knockout mice exhibited a complete loss of fasting ketosis. Together, these findings indicate that renal HMGCS2 does not significantly contribute to global ketone production and that during fasting, the increase in circulating ketones is solely dependent on hepatic HMGCS2. Proximal tubule HMGCS2 serves functions other than systemic ketone provision. [ABSTRACT FROM AUTHOR]

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 correspondingmetabolic programs to actuate tissueprotective 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 vehicletreated 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 2DGtreated 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. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common hospital complication. There are no effective treatments to minimize kidney injury or limit associated morbidity and mortality. Currently, serum creatinine and urine output remain the gold standard used clinically in the diagnosis of AKI. Several novel biomarkers can diagnose AKI earlier than elevations of serum creatinine and changes in urine output. Recent long-term observational studies have elucidated a subgroup of patients who have positive biomarkers of AKI but do not meet criteria for AKI by serum creatinine or urine output, termed subclinical AKI. These patients with subclinical AKI have increased risk of both short- and long-term mortality. In this review, we will highlight the implications of what these patients may represent and the need for better phenotyping of AKI by etiology, severity of injury, and ability to recover. We will discuss two AKI biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and breast regression protein-39 (BRP-39)/YKL-40, that exemplify the need to characterize the complexity of the biological meaning behind the biomarker, beyond elevated levels reporting on tissue injury. Ultimately, careful phenotyping of AKI will lead to identification of therapeutic targets and appropriate patient populations for clinical trials. [ABSTRACT FROM AUTHOR]

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury. [ABSTRACT FROM AUTHOR]

The metabolic health of the kidney is a primary determinant of the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel kidney functions is limited by the kidney's structural and functional heterogeneity. As the kidney contains many different cell types, we hypothesize that intra-renal mitochondrial heterogeneity contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique to isolate kidney cell-type specific mitochondria. Here, we investigate mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag allele was combined with Slc34a1-CreERT2 , Ggt1-Cre , or Pvalb-Cre alleles to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. Changes with mitochondrial metabolomes induced by fasting suggest that the late PT significantly increases FAO during fasting. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting., Translational Statement: While the renal cortex is often considered a single metabolic compartment, we discovered significant diversity of mitochondrial metabolomes and functional capacities across the proximal tubule and the distal convoluted tubule. As mitochondrial dysfunction is a major biochemical pathway related to kidney disease progression, understanding the differences in mitochondrial metabolism across distinct kidney cell populations is thus critical in the development of effective and targeted therapeutic therapies for acute and chronic kidney disease.