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Nat Med. 2018 Sep;24(9):1351-1359. doi: 10.1038/s41591-018-0138-z. Epub 2018 Aug 20.

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

Author information

1
Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
2
Division of Pulmonary and Critical Care and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
3
Division of Pulmonary and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
4
Division of Renal Medicine and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
5
Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
6
Division of Nephrology and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
7
Division of General Medicine and Primary Care Medicine and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
8
Cardiovascular Institute and Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
9
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
10
Endocrine Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
11
Division of Clinical Chemistry and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
12
Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. sparikh1@bidmc.harvard.edu.

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.

PMID:
30127395
PMCID:
PMC6129212
DOI:
10.1038/s41591-018-0138-z
[Indexed for MEDLINE]
Free PMC Article

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