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

Ali Poyan Mehr, Mei T. Tran, Kenneth M. Ralto, David E. Leaf, Vaughan Washco, Joseph Messmer, Adam Lerner, Ajay Kher, Steven H. Kim, Charbel C. Khoury, Shoshana J. Herzig, Mary E. Trovato, Noemie Simon-Tillaux, Matthew R. Lynch, Ravi I. Thadhani, Clary B. Clish, Kamal R. Khabbaz, Eugene P. Rhee, Sushrut S. Waikar, Anders H. BergSamir M. Parikh

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1351-1359
Number of pages9
JournalNature medicine
Volume24
Issue number9
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'De novo NAD<sup>+</sup> biosynthetic impairment in acute kidney injury in humans'. Together they form a unique fingerprint.

Cite this