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

2018; Nature Portfolio; Volume: 24; Issue: 9 Linguagem: Inglês

10.1038/s41591-018-0138-z

1546-170X

Ali Poyan Mehr, Mei 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, Noëmie Simon, Matthew Lynch, Ravi Thadhani, Clary B. Clish, Kamal R. Khabbaz, Eugene P. Rhee, Sushrut S. Waikar, Anders H. Berg, Samir M. Parikh,

Sirtuins and Resveratrol in Medicine

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.