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

Nature medicine, 2018-09, Vol.24 (9), p.1351-1359 [Peer Reviewed Journal]

Copyright Nature Publishing Group Sep 2018 ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/s41591-018-0138-z ;PMID: 30127395

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Title:
De novo NAD + biosynthetic impairment in acute kidney injury in humans
Author: Poyan Mehr, Ali ; Tran, Mei T ; Ralto, Kenneth M ; Leaf, David E ; Washco, Vaughan ; Messmer, Joseph ; Lerner, Adam ; Kher, Ajay ; Kim, Steven H ; Khoury, Charbel C ; Herzig, Shoshana J ; Trovato, Mary E ; Simon-Tillaux, Noemie ; Lynch, Matthew R ; Thadhani, Ravi I ; Clish, Clary B ; Khabbaz, Kamal R ; Rhee, Eugene P ; Waikar, Sushrut S ; Berg, Anders H ; Parikh, Samir M
Subjects: Adenine ; Biosynthesis ; Kidneys ; Metabolites ; Metabolomics ; NAD ; Nicotinamide ; Nicotinamide adenine dinucleotide ; Phosphoribosyltransferase ; Quinolinate phosphoribosyltransferase ; Tryptophan
Is Part Of: Nature medicine, 2018-09, Vol.24 (9), p.1351-1359
Description: 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.
Publisher: United States: Nature Publishing Group
Language: English
Identifier: ISSN: 1078-8956
EISSN: 1546-170X
DOI: 10.1038/s41591-018-0138-z
PMID: 30127395
Source: ProQuest Central

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

Copyright Nature Publishing Group Sep 2018 ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/s41591-018-0138-z ;PMID: 30127395

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