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

Autor: Poyan Mehr A; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Tran MT; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Ralto KM; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.; Division of Pulmonary and Critical Care and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.; Division of Pulmonary and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Leaf DE; Division of Renal Medicine and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Washco V; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Messmer J; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Lerner A; Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Kher A; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Kim SH; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Khoury CC; Division of Nephrology and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Herzig SJ; Division of General Medicine and Primary Care Medicine and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Trovato ME; Cardiovascular Institute and Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Simon-Tillaux N; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Lynch MR; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Thadhani RI; Division of Nephrology and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Clish CB; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Khabbaz KR; Cardiovascular Institute and Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Rhee EP; Division of Nephrology and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Endocrine Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Waikar SS; Division of Renal Medicine and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Berg AH; Division of Clinical Chemistry and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA., Parikh SM; Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. sparikh1@bidmc.harvard.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2018 Sep; Vol. 24 (9), pp. 1351-1359. Date of Electronic Publication: 2018 Aug 20.
DOI: 10.1038/s41591-018-0138-z
Abstrakt: 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.
Databáze: MEDLINE