De novo NAD+ biosynthetic impairment in acute kidney injury in humans
医学
肾
肾脏疾病
内科学
生物
内分泌学
作者
Ali Danandeh Mehr,Mei Tran,Kenneth M. Ralto,David E. Leaf,V. Washco,Joseph Messmer,Adam Lerner,Ajay Kher,Steven B. Kim,Charbel Khoury,Shoshana J. Herzig,Mary E. Trovato,Noémie Simon-Tillaux,Matthew Lynch,Ravi Thadhani,Ramon Estruch,Kamal R. Khabbaz,Eugene P. Rhee,Sushrut S. Waikar,Anders H. Berg,Samir M. Parikh
出处
期刊:Nature Medicine [Springer Nature] 日期:2018-08-20卷期号:24 (9): 1351-1359被引量:218
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.