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

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

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / urine
  • Aged
  • Animals
  • Biosynthetic Pathways*
  • Cardiac Surgical Procedures
  • Humans
  • Ischemia / urine
  • Mice
  • Middle Aged
  • NAD / biosynthesis*
  • Niacinamide / administration & dosage
  • Niacinamide / therapeutic use
  • Pentosyltransferases / metabolism
  • Pilot Projects
  • Quinolinic Acid / metabolism
  • Quinolinic Acid / urine
  • Treatment Outcome
  • Tryptophan / urine

Substances

  • NAD
  • Niacinamide
  • Tryptophan
  • Pentosyltransferases
  • nicotinate-nucleotide diphosphorylase (carboxylating)
  • Quinolinic Acid