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.
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This randomized clinical trial was funded by an Innovation Grant from the BIDMC awarded to A.P.M. and K.R.K. K.M.R., V.W., A.K., and M.R.L. were supported by T32DK007199; D.E.L. by K23DK106448; C.C.K. and R.I.T. by T32DK007540; S.J.H. by K23AG042459; N.S.-T. by a grant from Assistance Publique—Hôpitaux de Paris; and A.H.B. by K08HL121801 and R56HL133399. Work in S.M.P.’s laboratory was supported by R35HL139424, R01HL125275, and R01DK095072.
S.M.P. is listed as an inventor on disclosures filed by BIDMC pertaining to NAD+.
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Poyan Mehr, A., Tran, M.T., Ralto, K.M. et al. De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat Med 24, 1351–1359 (2018). https://doi.org/10.1038/s41591-018-0138-z
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