The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory ...(M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.
To discuss how nutritional management could be optimized to promote protective metabolism in sepsis and associated acute kidney injury.
Recent evidence suggests that sepsis is a metabolically ...distinct critical illness and that certain metabolic alterations, such as activation of fasting metabolism, may be protective in bacterial sepsis. These findings may explain the lack of survival benefit in recent randomized controlled trials of nutrition therapy for critical illness. These trials are limited by cohort heterogeneity, combining both septic and nonseptic critical illness, and the use of inaccurate caloric estimates to determine energy requirements. These energy estimates are also unable to provide information on specific substrate preferences or the capacity for substrate utilization. As a result, high protein feeding beyond the capacity for protein synthesis could cause harm in septic patients. Excess glucose and insulin exposures suppress fatty acid oxidation, ketogenesis and autophagy, of which emerging evidence suggest are protective against sepsis associated organ damage such as acute kidney injury.
Distinguishing pathogenic and protective sepsis-related metabolic changes are critical to enhancing and individualizing nutrition management for critically ill patients.
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-α dependent. Mice with kidney-specific
deletion showed a minor, likely physiologically insignificant, decrease in circulating ketones during fasting. Conversely, liver-specific
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.
The mitochondrial enzyme hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) catalyzes the rate-limiting step of ketogenesis. Although the liver constitutively expresses HMGCS2 and is considered the main ketogenic organ, HMGCS2 is induced in the kidney during fasting, leading to the proposal that the kidney contributes to fasting ketosis. We showed kidney HMGCS2 does not contribute to circulating ketones during fasting and cannot compensate for hepatic ketogenic insufficiency.
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.
Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to ...survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.
In response to bacterial inflammation, anorexia of acute illness is protective and is associated with the induction of fasting metabolic programs such as ketogenesis. Forced feeding during the ...anorectic period induced by bacterial inflammation is associated with suppressed ketogenesis and increased mortality. As ketogenesis is considered essential in fasting adaptation, we sought to determine the role of ketogenesis in illness-induced anorexia.
A mouse model of inducible hepatic specific deletion of the rate limiting enzyme for ketogenesis (HMG-CoA synthase 2, Hmgcs2) was used to investigate the role of ketogenesis in endotoxemia, a model of bacterial inflammation, and in prolonged starvation.
Mice deficient of hepatic Hmgcs2 failed to develop ketosis during endotoxemia and during prolonged fasting. Surprisingly, hepatic HMGCS2 deficiency and the lack of ketosis did not affect survival, glycemia, or body temperature in response to endotoxemia. Mice with hepatic ketogenic deficiency also did not exhibit any defects in starvation adaptation and were able to maintain blood glucose, body temperature, and lean mass compared to littermate wild-type controls. Mice with hepatic HMGCS2 deficiency exhibited higher levels of plasma acetate levels in response to fasting.
Circulating hepatic-derived ketones do not provide protection against endotoxemia, suggesting that alternative mechanisms drive the increased mortality from forced feeding during illness-induced anorexia. Hepatic ketones are also dispensable for surviving prolonged starvation in the absence of inflammation. Our study challenges the notion that hepatic ketogenesis is required to maintain blood glucose and preserve lean mass during starvation, raising the possibility of extrahepatic ketogenesis and use of alternative fuels as potential means of metabolic compensation.
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•Ketosis induced by sickness-induced anorexia does not provide a survival benefit.•Hepatic ketogenesis is not required for starvation adaptation.•Alternative pathways compensate for hepatic ketogenic deficiency during fasting.
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.
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.
Acute kidney injury (AKI) is a common and morbid complication in patients with severe burn. The reported incidence of AKI and mortality in this population varies widely due to inconsistent and ...changing definitions. They aimed to examine the incidence, severity, and hospital mortality of patients with AKI after burn using consensus criteria. This is a retrospective cohort study of adults with thermal injury admitted to the Parkland burn intensive care unit (ICU) from 2008 to 2015. One thousand forty adult patients with burn were admitted to the burn ICU. AKI was defined by KDIGO serum creatinine criteria. Primary outcome includes hospital death and secondary outcome includes length of mechanical ventilation, ICU, and hospital stay. All available serum creatinine measurements were used to determine the occurrence of AKI during the hospitalization. All relevant clinical data were collected. The median total body surface area (TBSA) of burn was 16% (IQR: 6%-29%). AKI occurred in 601 patients (58%; AKI stage 1, 60%; stage 2, 19.8%; stage 3, 10.5%; and stage 3 requiring renal replacement therapy 3-RRT, 9.7%). Patients with AKI had larger TBSA burn (median 20.5% vs 11.0%; P < .001) and more mechanical ventilation and hospitalization days than patients without AKI. The hospital death rate was higher in those with AKI vs those without AKI (19.7% vs 3.9%; P < .001) and increased by each AKI severity stage (P trend < .001). AKI severity was independently associated with hospital mortality in the small burn group (for TBSA ≤ 10%: stage 1 adjusted OR 9.3; 95% CI, 2.6-33.0; stage 2-3 OR, 35.0; 95% CI, 9.0-136.8; stage 3-RRT OR, 30.7; 95% CI, 4.2-226.4) and medium burn group (TBSA 10%-40%: stage 2-3 OR, 6.5; 95% CI, 1.9-22.1; stage 3-RRT OR, 35.1; 95% CI, 8.2-150.3). AKI was not independently associated with hospital death in the large burn group (TBSA > 40%). Urine output data were unavailable. AKI occurs frequently in patients after burn. Presence of and increasing severity of AKI are associated with increased hospital mortality. AKI appears to be independently and strongly associated with mortality in patients with TBSA ≤ 40%. Further investigation to develop risk-stratification tools tailoring this susceptible population is direly needed.
Peritoneal dialysis–associated peritonitis from such resistant organisms as vancomycin-resistant enterococci increasingly is occurring and is challenging to treat. We describe 2 cases of ...vancomycin-resistant entercoccus peritonitis successfully treated with intraperitoneal daptomycin. Both patients were on automated peritoneal dialysis therapy with culture-positive vancomycin-resistant Enterococcus faecium peritonitis and were treated with 10 to 14 days of intraperitoneal daptomycin given every 4 hours through manual peritoneal dialysate exchanges. Despite the known degradation in dextrose solutions, intraperitoneal daptomycin was effective in clearing both infections. Neither patient experienced a relapse or repeated peritonitis. Additional studies of dosing and pharmacokinetics of intraperitoneal daptomycin in the treatment of patients with vancomycin-resistant enterococcus peritonitis are needed.
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