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Nicotinamide adenine dinucleotide (NAD+) levels decline in experimental models of acute kidney injury (AKI). Attenuated enzymatic conversion of tryptophan to NAD+ in tubular epithelium may contribute to adverse cellular and physiological outcomes. Mechanisms underlying defense of tryptophan-dependent NAD+ production are incompletely understood. Here we show that regulation of a bottleneck enzyme in this pathway, quinolinate phosphoribosyltransferase (QPRT) may contribute to kidney resilience. Expression of QPRT declined in two unrelated models of AKI. Haploinsufficient mice developed worse outcomes compared to littermate controls whereas novel, conditional gain-of-function mice were protected from injury. Applying these findings, we then identified hepatocyte nuclear factor 4 alpha (HNF4α) as a candidate transcription factor regulating QPRT expression downstream of the mitochondrial biogenesis regulator and NAD+ biosynthesis inducer PPARgamma coactivator-1-alpha (PGC1α). This was verified by chromatin immunoprecipitation. A PGC1α - HNF4α -QPRT axis controlled NAD+ levels across cellular compartments and modulated cellular ATP. These results propose that tryptophan-dependent NAD+ biosynthesis via QPRT and induced by HNF4α may be a critical determinant of kidney resilience to noxious stressors., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Lipoprotein modification by reactive dicarbonyls, including isolevuglandin (IsoLG), produces dysfunctional particles. Kidneys participate in lipoprotein metabolism, including tubular uptake. However, the process beyond the proximal tubule is unclear, as is the effect of kidney injury on this pathway. We found that patients and animals with proteinuric injury have increased urinary apolipoprotein AI (apoAI), IsoLG, and IsoLG adduct enrichment of the urinary apoAI fraction compared with other proteins. Proteinuric mice, induced by podocyte-specific injury, showed more tubular absorption of IsoLG-apoAI and increased expression of lipoprotein transporters in proximal tubular cells compared with uninjured animals. Renal lymph reflects composition of the interstitial compartment and showed increased apoAI and IsoLG in proteinuric animals, supporting a tubular cell-interstitium-lymph pathway for renal handling of lipoproteins. IsoLG-modified apoAI was not only a marker of renal injury but also directly damaged renal cells. IsoLG-apoAI increased inflammatory cytokines in cultured tubular epithelial cells (TECs), activated lymphatic endothelial cells (LECs), and caused greater contractility of renal lymphatic vessels than unmodified apoAI. In vivo, inhibition of IsoLG by a dicarbonyl scavenger reduced both albuminuria and urinary apoAI and decreased TEC and LEC injury, lymphangiogenesis, and interstitial fibrosis. Our results indicate that IsoLG-modified apoAI is, to our knowledge, a novel pathogenic mediator and therapeutic target in kidney disease.

Acute kidney injury (AKI) is a serious and highly prevalent disease, yet only supportive treatment is available. Nicotinamide adenine dinucleotide (NAD+) is a cofactor necessary for adenosine triphosphate (ATP) production and cell survival. Changes in renal NAD+ biosynthesis and energy utilization are features of AKI. Targeting NAD+ as an AKI therapy shows promising potential. However, the pursuit of NAD+-based treatments requires deeper understanding of the unique drivers and effects of the NAD+ biosynthesis derangements that arise in AKI. This article summarizes the NAD+ biosynthesis alterations in the kidney in AKI, chronic disease, and aging. To enhance this understanding, we explore instances of NAD+ biosynthesis alterations outside the kidney in inflammation, pregnancy, and cancer. In doing so, we seek to highlight that the different NAD+ biosynthesis pathways are not interconvertible and propose that the way in which NAD+ is synthesized may be just as important as the NAD+ produced., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: AUTHOR DISCLOSURE:Drs Clark, Hernanz-Schulman, Mason, and Hunley have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

The kidney has extraordinary metabolic demands to sustain the active transport of solutes that is critical to renal filtration and clearance. Mitochondrial health is vital to meet those demands and maintain renal fitness. Decades of studies have linked poor mitochondrial health to kidney disease. Key regulators of mitochondrial health-adenosine monophosphate kinase, sirtuins, and peroxisome proliferator-activated receptor γ coactivator-1α-have all been shown to play significant roles in renal resilience against disease. This review will summarize the latest research into the activities of those regulators and evaluate the roles and therapeutic potential of targeting those regulators in acute kidney injury, glomerular kidney disease, and renal fibrosis., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The kidney is a highly metabolic organ that requires substantial adenosine triphosphate for the active transport required to maintain water and solute reabsorption. Aberrations in energy availability and energy utilization can lead to cellular dysfunction and death. Mitochondria are essential for efficient energy production. The pathogenesis of acute kidney injury is complex and varies with different types of injury. However, multiple distinct acute kidney injury syndromes share a common dysregulation of energy metabolism. Pathways of energy metabolism and mitochondrial dysfunction are emerging as critical drivers of acute kidney injury and represent new potential targets for treatment. This review shows the basic metabolic pathways that all cells depend on for life; describes how the kidney optimizes those pathways to meet its anatomic, physiologic, and metabolic needs; summarizes the importance of metabolic and mitochondrial dysfunction in acute kidney injury; and analyzes the mitochondrial processes that become dysregulated in acute kidney injury including mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and changes in mitochondrial energy metabolism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Although high-density lipoprotein (HDL) modulates many cell types in the cardiovascular system, little is known about HDL in the kidney. We assessed urinary excretion of apolipoprotein AI (apoAI), the main protein in HDL., Methods: We enrolled 228 children with various kidney disorders and 40 controls. Urinary apoAI, albumin, and other markers of kidney damage were measured using ELISA, apoAI isoforms with Western blot, and renal biopsies stained for apoAI., Results: Patients followed in nephrology clinic had elevated urinary apoAI vs. controls (median 0.074 μg/mg; interquartile range (IQR) 0.0160-0.560, vs. 0.019 μg/mg; IQR 0.004-0.118, p < 0.001). Patients with tubulopathies, renal dysplasia/congenital anomalies of the kidney and urogenital tract, glomerulonephritis, and nephrotic syndrome (NS) in relapse had the greatest elevations (p ≤ 0.01). Patients with NS in remission, nephrolithiasis, polycystic kidney disease, transplant, or hypertension were not different from controls. Although all NS in relapse had higher apoAI excretion than in remission (0.159 vs. 0.0355 μg/mg, p = 0.01), this was largely driven by patients with focal segmental glomerulosclerosis (FSGS). Many patients, especially with FSGS, had increased urinary apoAI isoforms. Biopsies from FSGS patients showed increased apoAI staining at proximal tubule brush border, compared to diffuse cytoplasmic distribution in minimal change disease., Conclusions: Children with kidney disease have variably increased urinary apoAI depending on underlying disease. Urine apoAI is particularly elevated in diseases affecting proximal tubules. Kidney disease is also associated with high molecular weight (HMW) apoAI isoforms in urine, especially FSGS. Whether abnormal urinary apoAI is a marker or contributor to renal disease awaits further study.

Objectives: Bronchiolitis, the leading cause of infant hospitalizations in the United States, is associated with increased risk of childhood asthma. We hypothesized that factors during a bronchiolitis hospitalization were associated with subsequent asthma., Methods: This is a retrospective cohort study at an urban, tertiary-care children's hospital of infants <12 months old, hospitalized for bronchiolitis. The primary outcome measure was an asthma diagnosis, defined as a billing code for an asthma visit or a prescription for controller medication, within 5 years of discharge from the bronchiolitis hospitalization., Results: There were 534 infants hospitalized for bronchiolitis, of which 294 (55.1%) were diagnosed with asthma, and 102 (19.1%) were hospitalized for asthma within 5 years of discharge. There was significant interaction between age and family history. In both models, female sex was protective (odds ratio [OR] 0.46). Age and race were only associated with asthma in infants without a family history of asthma: age (OR 1.19; 95% confidence interval 1.08-1.32) and race (OR 4.06; 95% confidence interval 1.56-10.58). Hospitalization length, ICU stay, albuterol treatments received, supplemental oxygen, respiratory support, highest respiratory rate, and respiratory syncytial virus infection were not associated with asthma diagnosis., Conclusions: More than 55% of infants hospitalized for bronchiolitis developed asthma within 5 years of discharge. Demographic and family history variables were independently associated with asthma. However, hospital-based variables during the bronchiolitis hospitalization were not independently associated with asthma. These results can direct further research and differentiate anticipatory guidance for infants with bronchiolitis at risk for asthma., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objective: The Multiple Errands Test (MET) was designed to measure the effect of executive dysfunction on everyday life activities, but little is known about the cognitive requirements for successful performance. This study's objective was to investigate cognitive functions associated with successful MET performance, specifically, the Baycrest-MET., Method: Correlation analysis examined relationships between Baycrest-MET performance and neuropsychological functioning in participants with acquired brain injury (ABI; N = 27)., Results: The association of tasks omitted with executive function (EF) accounted for 15.2%-42.3% of the variance; the association of tasks omitted with attention and processing speed, for 16.8%-24.0%; and the association of tasks omitted and total rule breaks with visuospatial memory, for 18.5%-31.4%., Conclusion: Poor performance on the Baycrest-MET in people with ABI is associated with impairments of EF, attention, memory, and processing speed. Different patterns of performance may arise from different constellations of impairments., (Copyright © 2018 by the American Occupational Therapy Association, Inc.)

Objectives: Acute kidney injury frequently complicates critical illness and is associated with high morbidity and mortality. Frailty is common in critical illness survivors, but little is known about the impact of acute kidney injury. We examined the association of acute kidney injury and frailty within a year of hospital discharge in survivors of critical illness., Design: Secondary analysis of a prospective cohort study., Setting: Medical/surgical ICU of a U.S. tertiary care medical center., Patients: Three hundred seventeen participants with respiratory failure and/or shock., Interventions: None., Measurements and Main Results: Acute kidney injury was determined using Kidney Disease Improving Global Outcomes stages. Clinical frailty status was determined using the Clinical Frailty Scale at 3 and 12 months following discharge. Covariates included mean ICU Sequential Organ Failure Assessment score and Acute Physiology and Chronic Health Evaluation II score as well as baseline comorbidity (i.e., Charlson Comorbidity Index), kidney function, and Clinical Frailty Scale score. Of 317 patients, 243 (77%) had acute kidney injury and one in four patients with acute kidney injury was frail at baseline. In adjusted models, acute kidney injury stages 1, 2, and 3 were associated with higher frailty scores at 3 months (odds ratio, 1.92; 95% CI, 1.14-3.24; odds ratio, 2.40; 95% CI, 1.31-4.42; and odds ratio, 4.41; 95% CI, 2.20-8.82, respectively). At 12 months, a similar association of acute kidney injury stages 1, 2, and 3 and higher Clinical Frailty Scale score was noted (odds ratio, 1.87; 95% CI, 1.11-3.14; odds ratio, 1.81; 95% CI, 0.94-3.48; and odds ratio, 2.76; 95% CI, 1.34-5.66, respectively). In supplemental and sensitivity analyses, analogous patterns of association were observed., Conclusions: Acute kidney injury in survivors of critical illness predicted worse frailty status 3 and 12 months postdischarge. These findings have important implications on clinical decision making among acute kidney injury survivors and underscore the need to understand the drivers of frailty to improve patient-centered outcomes.

Surprisingly few ecologically-valid assessments of executive function exist, but the Baycrest Multiple Errands Test (BMET) shows promise in identifying executive impairment. The goal of the present study was to develop both a revised version of the assessment (BMET-R), to improve the test's ability to discriminate between patients and healthy participants, and an alternate form of the BMET-R to permit repeat testing. Sixteen individuals with acquired brain injury (ABI) due to stroke or trauma and 16 healthy participants completed a series of neuropsychological assessments, questionnaires, the BMET-R and its alternate form (in counterbalanced order). The results of the study indicated that participants with ABI omitted more tasks, broke more rules, and were less efficient than healthy participants on both the revised BMET-R and its alternate form. Moreover, significant correlations were found between the two versions of the BMET-R for task completions, omissions, errors, rule breaks and inefficiencies but few significant correlations were observed between the BMET-R versions and measures of executive dysfunction in everyday life. These results indicate that the two versions of the BMET-R are able to dissociate the performance of participants with ABI from that of healthy participants. However, despite overlaps in performance and correlations between the two versions of the BMET-R, they did not identically assess executive deficits. This suggests that caution should be used when constructing and validating alternate versions of performance-based assessments.

This study examined the clinical utility of the Multiple Errands Test (MET) from the perspective of clinicians. Employing a qualitative descriptive design, in-depth semi-structured interviews were conducted with eight occupational therapists. Participants had an average of 12 years clinical experience and their experience using the MET varied. Interviews were transcribed and analysed using framework analysis. Three dominant themes emerged from the data. Theme 1 was that clinicians value the MET because it reflects real-life functioning. Clinicians perceived the MET to be a unique assessment collecting data on functional performance, and sensitive to higher level cognitive deficits. Theme 2 was that the MET could be used flexibly depending on one's rehabilitation goals. Clinicians employed the MET as an assessment to inform the direction of treatment and as a component of their intervention. Theme 3 was that the MET is a challenging assessment requiring buy in and commitment from therapists. This study is the first to report clinicians' perspectives of the clinical utility of the MET. It reinforces the importance of ecologically valid tests, and augments existing research evaluating psychometric properties of the MET by describing how the MET has been employed in rehabilitation settings to improve health outcomes for adults with neurological conditions.

Rationale: Acute kidney injury may contribute to distant organ dysfunction. Few studies have examined kidney injury as a risk factor for delirium and coma., Objectives: To examine whether acute kidney injury is associated with delirium and coma in critically ill adults., Methods: In a prospective cohort study of intensive care unit patients with respiratory failure and/or shock, we examined the association between acute kidney injury and daily mental status using multinomial transition models adjusting for demographics, nonrenal organ failure, sepsis, prior mental status, and sedative exposure. Acute kidney injury was characterized daily using the difference between baseline and peak serum creatinine and staged according to Kidney Disease Improving Global Outcomes criteria. Mental status (normal vs. delirium vs. coma) was assessed daily with the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale., Measurements and Main Results: Among 466 patients, stage 2 acute kidney injury was a risk factor for delirium (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.07-2.26) and coma (OR, 2.04; 95% CI, 1.25-3.34) as was stage 3 injury (OR for delirium, 2.56; 95% CI, 1.57-4.16) (OR for coma, 3.34; 95% CI, 1.85-6.03). Daily peak serum creatinine (adjusted for baseline) values were also associated with delirium (OR, 1.35; 95% CI, 1.18-1.55) and coma (OR, 1.44; 95% CI, 1.20-1.74). Renal replacement therapy modified the association between stage 3 acute kidney injury and daily peak serum creatinine and both delirium and coma., Conclusions: Acute kidney injury is a risk factor for delirium and coma during critical illness.

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

Separate bodies of literature indicate that a history of a traumatic brain injury (TBI) and natural aging may result in overlapping cognitive profiles, yet little is known about their combined effect. We predicted that a remote TBI would compound normal age-related cognitive decline, particularly affecting executive function. Neuropsychological task performance was compared between a group of older adults who sustained a TBI in their distant past (N = 9) and a group of older adults with no history of head injury (N = 15). While all participants scored in the normal range on the Mini-Mental State Examination, the TBI group scored lower than the non-TBI group. Also, in line with predictions, the TBI group made more errors on measures of executive functioning compared to the non-TBI group (the Trail Making B test and the incongruent condition of the Stroop Test), but performed similarly on all tasks with little executive requirements. Findings from this exploratory study indicate that a past TBI may put older adults at a higher risk for exacerbated age-related cognitive decline compared to older adults with no history of TBI.

Regardless of age, education, or social status, we all experience moments where we ask ourselves, "what was I thinking?!?" Typically, we experience errors of this sort, or slips of action, during routine tasks that require a whole sequence of movements. However, most action slip research has focused on creating response conflict within single movements. The Slip Induction Task (SIT) is a step toward creating response conflict within truer to life action routines. As such, the SIT attempts to induce action slips in a well-learned movement routine through the occasional presentation of unexpected cues. We find that the SIT is able to reliably induce action slips, especially when the unexpected cue necessitates a movement to an unexpected target location. Furthermore, when participants are able to avoid an action slip, these changes in movement routine are accompanied by a cost in speed.

Background: Plasma amino acid (PAA) levels can be largely normalized during parenteral nutrition (PN) in infants and children using a pediatric-specific amino acid (AA) formulation. However, these previous results were based on individual clinical studies of small populations of neonates and infants., Objective: We have now examined AA levels in 108 children (0-7 years of age) receiving a pediatric-specific AA formulation in PN using a single analytical methodology., Methods: Infants and children were enrolled in specific protocols and parents/caregivers gave informed consent. Patients were stable and receiving age-appropriate intakes of AA and non-protein calories. Samples were obtained between 8 and10 am, processed immediately, deproteinized, and AA concentrations (μmol/L) were determined on a Beckman 6300 analyzer. Means and SD were calculated for sub-populations stratified by age: 0-1 month (48 patients, n=139), 1-6 months (36 patients, n=124), 7-12 months (11 patients, n=41), and 1-7 years (13 patients, n=51). Z scores were calculated for each amino acid [(observed mean - normal control mean)/normal control SD]., Results: When compared to the neonatal reference range, nonessential AA had Z scores that ranged from -1.84 (asparagine) to +1.48 (threonine). Only plasma free cystine, free tyrosine, and phenylalanine had Z scores outside the -2.0 to +2.0 range (95% confidence limits). Plasma free cystine values were low in all groups except neonates. Free tyrosine levels were low in all groups despite the presence of N-acetyl-L-tyrosine in the pediatric AA formulation. Phenylalanine levels were elevated only in neonates. When children 1 to 7 years old were compared with an age-matched reference range, plasma free cystine values were low (Z score -2.47), as were plasma glutamine values (-3.11), but elevations were found in the dicarboxylic amino acids aspartic acid (+2.5) and glutamic acid (+4.27). Regardless of reference range used for comparison, all essential amino acids, except phenylalanine in neonates, were within range (-2 to +2 of the 95% confidence limits)., Conclusions: While most AAs were within the normal range, formulation modifications are needed to normalize free cystine in infants and young children, free tyrosine in all children, and phenylalanine in neonates. The decrease in glutamine concentrations in older children has been noted by our group before, and may imply limited ability to convert glutamic acid to glutamine, or increased consumption of glutamine. In either case, increased concentrations of glutamine in older children, especially those receiving home parenteral nutrition, should be considered.