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

Nature Medicine volume 24, pages 1351–1359 (2018)Cite this article

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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.

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Fig. 1: Renal and urinary quinolinate elevation in ischemic AKI.
Fig. 2: QPRT mediates resistance to experimental AKI.
Fig. 3: Elevation of the uQ/T ratio in human AKI.
Fig. 4: Participants and outcomes of oral NAM phase 1 pilot study in cardiac surgery patients.

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Acknowledgements

This randomized clinical trial was funded by an Innovation Grant from the BIDMC awarded to A.P.M. and K.R.K. K.M.R., V.W., A.K., and M.R.L. were supported by T32DK007199; D.E.L. by K23DK106448; C.C.K. and R.I.T. by T32DK007540; S.J.H. by K23AG042459; N.S.-T. by a grant from Assistance Publique—Hôpitaux de Paris; and A.H.B. by K08HL121801 and R56HL133399. Work in S.M.P.’s laboratory was supported by R35HL139424, R01HL125275, and R01DK095072.

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Author notes

  1. These authors contributed equally: Ali Poyan Mehr, Mei T. Tran, Kenneth M. Ralto.

  2. These authors jointly supervised: Kamal R. Khabbaz, Anders H. Berg, Samir M. Parikh.

Authors and Affiliations

  1. Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Ali Poyan Mehr, Mei T. Tran, Kenneth M. Ralto, Vaughan Washco, Joseph Messmer, Ajay Kher, Steven H. Kim, Noemie Simon-Tillaux, Matthew R. Lynch & Samir M. Parikh

  2. Division of Pulmonary and Critical Care and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Kenneth M. Ralto

  3. Division of Pulmonary and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Kenneth M. Ralto

  4. Division of Renal Medicine and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    David E. Leaf & Sushrut S. Waikar

  5. Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Adam Lerner

  6. Division of Nephrology and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Charbel C. Khoury, Ravi I. Thadhani & Eugene P. Rhee

  7. Division of General Medicine and Primary Care Medicine and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Shoshana J. Herzig

  8. Cardiovascular Institute and Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Mary E. Trovato & Kamal R. Khabbaz

  9. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Clary B. Clish & Eugene P. Rhee

  10. Endocrine Unit and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Eugene P. Rhee

  11. Division of Clinical Chemistry and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Anders H. Berg

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Contributions

A.P.M. and K.R.K. were co-principal investigators on the phase 1 pilot study of oral NAM in cardiac surgery patients for which V.W., J.M., A.L., and M.E.T. were coinvestigators. S.J.H. served as the independent medical monitor for this trial. K.M.R., N.S.-T., and A.H.B. analyzed samples and data from all human studies. A.H.B. developed targeted metabolic assays and conducted all related measurements. M.T.T. conducted the mouse studies and analyzed the results with assistance from N.S.-T. and M.R.L. D.E.L. and S.S.W. enrolled the ICU cohort, created that repository, and performed statistical analyses of the uQ/T results in the ICU cohort. A.K. and S.H.K. enrolled the discovery cohort of cardiac surgery patients and created that repository with guidance from S.M.P. C.C.K., E.P.R., and R.I.T. developed and conducted the trial of oral NAM in healthy volunteers. E.P.R. also conducted metabolomic screening of mouse samples on the platform developed in C.B.C.’s laboratory with input from C.B.C. A.P.M., M.T.T., K.M.R., and S.M.P. assumed primary responsibility for writing the manuscript. All authors reviewed, provided substantive input, and approved of the final manuscript.

Corresponding author

Correspondence to Samir M. Parikh.

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S.M.P. is listed as an inventor on disclosures filed by BIDMC pertaining to NAD+.

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Poyan Mehr, A., Tran, M.T., Ralto, K.M. et al. De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat Med 24, 1351–1359 (2018). https://doi.org/10.1038/s41591-018-0138-z

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