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Acute kidney injury (AKI) is common in critically ill children and adults, and sepsis-associated AKI (SA-AKI) is the most frequent cause of AKI in the ICU. To date, no mechanistically targeted therapeutic interventions have been identified. High-throughput 'omic' technologies (e.g., genomics, proteomics, metabolomics, etc.) offer a new angle of approach to achieve this end. In this review, we provide an update on the current understanding of SA-AKI pathophysiology. Omic technologies themselves are briefly discussed to facilitate interpretation of studies using them. We next summarize the body of SA-AKI research to date that has employed omic technologies. Importantly, omic studies are helping to elucidate a pathophysiology of SA-AKI centered around cellular stress responses, metabolic changes, and dysregulation of energy production that underlie its clinical features. Finally, we propose opportunities for future research using clinically relevant animal models, integrating multiple omic technologies and ultimately progressing to translational human studies focusing therapeutic strategies on targeted disease mechanisms., Author(s): Denise Hasson [sup.1] , Stuart L. Goldstein [sup.2] [sup.3] , Stephen W. Standage [sup.1] [sup.3] Author Affiliations: (1) grid.239573.9, 0000 0000 9025 8099, Division of Critical Care Medicine, Cincinnati [...]

The Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100) is a hemoperfusion device designed to adsorb bacteria, viruses, and toxins when added to extracorporeal circuits. The FDA granted emergency use authorization in adults, but this device had never been utilized in children. A 17-year-old patient with asthma presented with respiratory distress due to COVID-19. His course was complicated by respiratory failure, rhabdomyolysis, and stage 3 AKI requiring initiation of continuous kidney replacement therapy (CKRT) on ICU day 3. The Seraph® 100 filter was added on ICU day 4. He was treated with 3 filters from ICU day 4 to 8. On ICU day 8, he was extubated and CKRT discontinued. He required no further kidney replacement therapy but did not have laboratory work post-discharge. In conclusion, this adolescent patient with COVID-19 and AKI requiring CKRT tolerated treatment with the Seraph® 100 Microbind® Affinity Blood Filter without significant adverse events. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is common in critically ill patients, and sepsis is its leading cause. Sepsis-associated AKI (SA-AKI) causes greater morbidity and mortality than other AKI etiologies, yet the underlying mechanisms are incompletely understood. Metabolomic technologies can characterize cellular energy derangements, but few discovery analyses have evaluated the metabolomic profile of SA-AKI. To identify metabolic derangements amenable to therapeutic intervention, we assessed plasma and urine metabolites in septic mice and critically ill children and compared them by AKI status. Metabolites related to choline and central carbon metabolism were differentially abundant in SA-AKI in both mice and humans. Gene expression of enzymes related to choline metabolism was altered in the kidneys and liver of mice with SA-AKI. Treatment with intraperitoneal choline improved renal function in septic mice. Because pediatric patients with sepsis displayed similar metabolomic profiles to septic mice, choline supplementation may attenuate pediatric septic AKI. NEW & NOTEWORTHY Altered choline metabolism plays a role in both human and murine sepsis-associated acute kidney injury (SA-AKI), and choline administration in experimental SA-AKI improved renal function. These findings indicate that 1) mouse models can help interrogate clinically relevant mechanisms and 2) choline supplementation may ameliorate human SA-AKI. Future research will investigate clinically the impact of choline supplementation on human renal function in sepsis and, using model systems, how choline mediates its effects. [ABSTRACT FROM AUTHOR]

Objective. Acute asphyxial asthma (AAA) is well described in adult patients and is characterized by a sudden onset that may rapidly progress to a near-arrest state. Despite the initial severity of AAA, mechanical ventilation often restores gas exchange promptly, resulting in shorter durations of ventilation. We believe that AAA can occur in children and can lead to respiratory failure that requires mechanical ventilation. Furthermore, children with rapid-onset respiratory failure that requires intubation in the emergency department (ED) are more likely to have AAA and a shorter duration of mechanical ventilation than those intubated in the pediatric intensive care unit (PICU). Methods. An 11-year retrospective chart review (1991-2002) was conducted of all children who were aged 2 through 18 years and had the primary diagnosis of status asthmaticus and required mechanical ventilation. Results. During the study period, 33 (11.4%) of 290 PICU admissions for status asthmaticus required mechanical ventilation. Thirteen children presented with rapid respiratory failure en route, on arrival, or within 30 minutes of arrival to the ED versus 20 children who progressed to respiratory failure later in their ED course or in the P|CU. Mean duration of mechanical ventilation was significantly shorter in the children who presented with rapid respiratory failure versus those with progressive respiratory failure (29 [+ or -] 43 hours vs 88 [+ or -] 72 hours). Children with rapid respiratory failure had greater improvements in ventilation and oxygenation than those with progressive respiratory failure as measured by pre-and postintubation changes in arterial carbon dioxide pressure, arterial oxygen pressure/fraction of inspired oxygen ratio, and alveolar-arterial gradient. According to site of intubation, 23 children required intubation in the ED, whereas 10 were intubated later in the PICU. Mean duration of mechanical ventilation was significantly shorter in the ED group versus the PICU group (42 [+ or -] 63 hours vs 118 [+ or -] 46 hours). There were significantly greater improvements in ventilation and oxygenation in the ED group versus the PICU group as measured by pre- and postintubation changes in arterial carbon dioxide pressure and arterial oxygen pressure/fraction of inspired oxygen ratio. Conclusions. AAA occurs in children and shares characteristics seen in adult counterparts. Need for early intubation is a marker for AAA and may not represent a failure to maximize preintubation therapies. AAA represents a distinct form of life-threatening asthma and requires additional study in children. Pediatrics 2004;114: 762-767; acute asphyxial asthma, rapid onset near-fatal asthma, respiratory failure, mechanical ventilation., ABBREVIATIONS. AAA, acute asphyxial asthma; GCHaS, Golisano Children's Hospital at Strong; PICU, pediatric intensive care unit; RRF, rapid respiratory failure; PRF, progressive respiratory failure; ED, emergency department; Pa[O.sub.2], arterial oxygen [...]

Sepsis-associated acute kidney injury (SA-AKI) is a significant problem in the critically ill that causes increased death. Emerging understanding of this disease implicates metabolic dysfunction in its pathophysiology. This study sought to identify specific metabolic pathways amenable to potential therapeutic intervention. Using a murine model of sepsis, blood and tissue samples were collected for assessment of systemic inflammation, kidney function, and renal injury. Nuclear magnetic resonance (NMR)-based metabolomics quantified dozens of metabolites in serum and urine that were subsequently submitted to pathway analysis. Kidney tissue gene expression analysis confirmed the implicated pathways. Septic mice had elevated circulating levels of inflammatory cytokines and increased levels of blood urea nitrogen and creatinine, indicating both systemic inflammation and poor kidney function. Renal tissue showed only mild histological evidence of injury in sepsis. NMR metabolomic analysis identified the involvement of mitochondrial pathways associated with branched-chain amino acid metabolism, fatty acid oxidation, and de novo NAD+ biosynthesis in SA-AKI. Renal cortical gene expression of enzymes associated with those pathways was predominantly suppressed. Renal cortical fatty acid oxidation rates were lower in septic mice with high inflammation, and this correlated with higher serum creatinine levels. Similar to humans, septic mice demonstrated renal dysfunction without significant tissue disruption, pointing to metabolic derangement as an important contributor to SA-AKI pathophysiology. Metabolism of branchedchain amino acid and fatty acids and NAD+ synthesis, which all center on mitochondrial function, appeared to be suppressed. Developing interventions to activate these pathways may provide new therapeutic opportunities for SA-AKI. NEW & NOTEWORTHY NMR-based metabolomics revealed disruptions in branched-chain amino acid metabolism, fatty acid oxidation, and NAD+ synthesis in sepsis-associated acute kidney injury. These pathways represent essential processes for energy provision in renal tubular epithelial cells and may represent targetable mechanisms for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Sepsis‐associated acute kidney injury (AKI) is a significant problem in critically ill children and adults resulting in increased morbidity and mortality. Fundamental mechanisms contributing to sepsis‐associated AKI are poorly understood. Previous research has demonstrated that peroxisome proliferator‐activated receptor α (PPARα) expression is associated with reduced organ system failure in sepsis. Using an experimental model of polymicrobial sepsis, we demonstrate that mice deficient in PPARα have worse kidney function, which is likely related to reduced fatty acid oxidation and increased inflammation. Ultrastructural evaluation with electron microscopy reveals that the proximal convoluted tubule is specifically injured in septic PPARα deficient mice. In this experimental group, serum metabolomic analysis reveals unanticipated metabolic derangements in tryptophan‐kynurenine‐NAD+ and pantothenate pathways. We also show that a subgroup of children with sepsis whose genome‐wide expression profiles are characterized by repression of the PPARα signaling pathway has increased incidence of severe AKI. These findings point toward interesting associations between sepsis‐associated AKI and PPARα‐driven fatty acid metabolism that merit further investigation. [ABSTRACT FROM AUTHOR]

Children with sepsis and multisystem organ failure have downregulated leukocyte gene expression of peroxisome proliferator-activated receptor-α (PPARα), a nuclear hormone receptor transcription factor that regulates inflammation and lipid metabolism. Mouse models of sepsis have likewise demonstrated that the absence of PPARα is associated with decreased survival and organ injury, specifically of the heart. Using a clinically relevant mouse model of early sepsis, we found that heart function increases in wild-type (WT) mice over the first 24 h of sepsis, but that mice lacking PPARα (Ppara -/- ) cannot sustain the elevated heart function necessary to compensate for sepsis pathophysiology. Left ventricular shortening fraction, measured 24 h after initiation of sepsis by echocardiography, was higher in WT mice than in Ppara -/- mice. Ex vivo working heart studies demonstrated greater developed pressure, contractility, and aortic outflow in WT compared with Ppara -/- mice. Furthermore, cardiac fatty acid oxidation was increased in WT but not in Ppara -/- mice. Regulatory pathways controlling pyruvate incorporation into the citric acid cycle were inhibited by sepsis in both genotypes, but the regulatory state of enzymes controlling fatty acid oxidation appeared to be permissive in WT mice only. Mitochondrial ultrastructure was not altered in either genotype indicating that severe mitochondrial dysfunction is unlikely at this stage of sepsis. These data suggest that PPARα expression supports the hyperdynamic cardiac response early in the course of sepsis and that increased fatty acid oxidation may prevent morbidity and mortality., New & Noteworthy: In contrast to previous studies in septic shock using experimental mouse models, we are the first to demonstrate that heart function increases early in sepsis with an associated augmentation of cardiac fatty acid oxidation. Absence of peroxisome proliferator-activated receptor-α (PPARα) results in reduced cardiac performance and fatty acid oxidation in sepsis., (Copyright © 2017 the American Physiological Society.)