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

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 proposed elevated urinary quinolinate/tryptophan (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 dose-related increase in circulating NAD+ metabolites. Nam was well-tolerated and was associated with less AKI. Impaired NAD+ biosynthesis may therefore be a feature of high-risk hospitalizations for which NAD+ augmentation could be beneficial.