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De novo NAD+ biosynthetic impairment in acute kidney injury in humans
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De novo NAD+ biosynthetic impairment in acute kidney injury in humans
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Journal Article
De novo NAD+ biosynthetic impairment in acute kidney injury in humans
2018
Overview
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.
Impaired NAD
+
biosynthesis may be a common feature of high-risk hospitalizations for which NAD
+
augmentation could improve therapeutic outcome.
Publisher
Nature Publishing Group US,Nature Publishing Group
