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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:BackgroundStudies have shown that more than half of patients with heart failure (HF) with acute kidney injury (AKI) have newonset AKI, and renal function evaluation markers such as estimated glomerular filtration rate are usually not repeatedly tested during the hospitalization. As an independent risk factor, delayed AKI recognition has been shown to be associated with the adverse events of patients with HF, such as chronic kidney disease and death.ObjectiveThe aim of this study is to develop and assess of an unsupervised machine learning model that identifies patients with HF and normal renal function but who are susceptible to de novo AKI.MethodsWe analyzed an electronic health record data set that included 5075 patients admitted for HF with normal renal function, from which 2 phenogroups were categorized using an unsupervised machine learning algorithm called K-means clustering. We then determined whether the inferred phenogroup index had the potential to be an essential risk indicator by conducting survival analysis, AKI prediction, and the hazard ratio test.ResultsThe AKI incidence rate in the generated phenogroup 2 was significantly higher than that in phenogroup 1 (group 1: 106/2823, 3.75%; group 2: 259/2252, 11.50%; P<.001). The survival rate of phenogroup 2 was consistently lower than that of phenogroup 1 (P<.005). According to logistic regression, the univariate model using the phenogroup index achieved promising performance in AKI prediction (sensitivity 0.710). The generated phenogroup index was also significant in serving as a risk indicator for AKI (hazard ratio 3.20, 95% CI 2.55-4.01). Consistent results were yielded by applying the proposed model on an external validation data set extracted from Medical Information Mart for Intensive Care (MIMIC) III pertaining to 1006 patients with HF and normal renal function.ConclusionsAccording to a machine learning analysis on electronic health record data, patients with HF who had normal renal function were clustered into separate phenogroups associated with different risk levels of de novo AKI. Our investigation suggests that using machine learning can facilitate patient phengrouping and stratification in clinical settings where the identification of high-risk patients has been challenging.

Dataset Information

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

Publications

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

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