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De novo NAD+ biosynthetic impairment in acute kidney injury in humans.

ABSTRACT: Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD+ fell, quinolinate rose, and QPRT declined. QPRT+/- mice exhibited higher quinolinate, lower NAD+, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD+ metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD+ biosynthesis may be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.

SUBMITTER: Poyan Mehr A

PROVIDER: S-EPMC6129212 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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De novo NAD+ biosynthetic impairment in acute kidney injury in humans.

Poyan Mehr Ali A Tran Mei T MT Ralto Kenneth M KM Leaf David E DE Washco Vaughan V Messmer Joseph J Lerner Adam A Kher Ajay A Kim Steven H SH Khoury Charbel C CC Herzig Shoshana J SJ Trovato Mary E ME Simon-Tillaux Noemie N Lynch Matthew R MR Thadhani Ravi I RI Clish Clary B CB Khabbaz Kamal R KR Rhee Eugene P EP Waikar Sushrut S SS Berg Anders H AH Parikh Samir M SM

Nature medicine 20180820 9

Nicotinamide adenine dinucleotide (NAD+) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD+ biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD+ and mediates resistance to acute kidney injury ...[more]

PMID: 30127395

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Project description:ObjectivesEvaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors.DesignProspectively cohort study of children with cerebral malaria, severe malarial anemia, or community children.SettingMulago National Referral Hospital in Kampala, Uganda.SubjectsChildren 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months.InterventionsNone.Measurements and main resultsChildren underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β -0.42, 95% CI, -0.69 to -0.15, p = 0.002; children ≥ 5, β -0.39, 95% CI, -0.67 to -0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau).ConclusionsThese data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.

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De novo NAD+ biosynthetic impairment in acute kidney injury in humans.

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De novo NAD<sup>+</sup> biosynthetic impairment in acute kidney injury in humans.

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