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.