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

Ali Poyan Mehr; Mei T. Tran; Kenneth M. Ralto; David E. Leaf; Vaughan Washco; Joseph Messmer; Adam Lerner; Ajay Kher; Steven H. Kim; Charbel C. Khoury; Shoshana J. Herzig; Mary E. Trovato; Noemie Simon-Tillaux; Matthew R. Lynch; Ravi I. Thadhani; Clary B. Clish; Kamal R. Khabbaz; Eugene P. Rhee; Sushrut S. Waikar; Anders H. Berg; Samir M. Parikh

doi:10.1038/s41591-018-0138-z

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

Ali Poyan Mehr, Mei T. Tran, Kenneth M. Ralto, David E. Leaf, Vaughan Washco, Joseph Messmer, Adam Lerner, Ajay Kher, Steven H. Kim, Charbel C. Khoury, Shoshana J. Herzig, Mary E. Trovato, Noemie Simon-Tillaux, Matthew R. Lynch, Ravi I. Thadhani, Clary B. Clish, Kamal R. Khabbaz, Eugene P. Rhee, Sushrut S. Waikar, Anders H. BergSamir M. Parikh

Research output: Contribution to journal › Article › peer-review

231 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1351-1359
Number of pages	9
Journal	Nature medicine
Volume	24
Issue number	9
DOIs	https://doi.org/10.1038/s41591-018-0138-z
State	Published - Sep 1 2018
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/s41591-018-0138-z

Cite this

Poyan Mehr, A., Tran, M. T., Ralto, K. M., Leaf, D. E., Washco, V., Messmer, J., Lerner, A., Kher, A., Kim, S. H., Khoury, C. C., Herzig, S. J., Trovato, M. E., Simon-Tillaux, N., Lynch, M. R., Thadhani, R. I., Clish, C. B., Khabbaz, K. R., Rhee, E. P., Waikar, S. S., ... Parikh, S. M. (2018). De novo NAD⁺ biosynthetic impairment in acute kidney injury in humans. Nature medicine, 24(9), 1351-1359. https://doi.org/10.1038/s41591-018-0138-z

Poyan Mehr, A, Tran, MT, Ralto, KM, Leaf, DE, Washco, V, Messmer, J, Lerner, A, Kher, A, Kim, SH, Khoury, CC, Herzig, SJ, Trovato, ME, Simon-Tillaux, N, Lynch, MR, Thadhani, RI, Clish, CB, Khabbaz, KR, Rhee, EP, Waikar, SS, Berg, AH & Parikh, SM 2018, 'De novo NAD⁺ biosynthetic impairment in acute kidney injury in humans', Nature medicine, vol. 24, no. 9, pp. 1351-1359. https://doi.org/10.1038/s41591-018-0138-z

@article{c5a24eee31894469b1c3829b37f6c2ba,

title = "De novo NAD+ biosynthetic impairment in acute kidney injury in humans",

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.",

author = "{Poyan Mehr}, Ali and Tran, {Mei T.} and Ralto, {Kenneth M.} and Leaf, {David E.} and Vaughan Washco and Joseph Messmer and Adam Lerner and Ajay Kher and Kim, {Steven H.} and Khoury, {Charbel C.} and Herzig, {Shoshana J.} and Trovato, {Mary E.} and Noemie Simon-Tillaux and Lynch, {Matthew R.} and Thadhani, {Ravi I.} and Clish, {Clary B.} and Khabbaz, {Kamal R.} and Rhee, {Eugene P.} and Waikar, {Sushrut S.} and Berg, {Anders H.} and Parikh, {Samir M.}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = sep,

day = "1",

doi = "10.1038/s41591-018-0138-z",

language = "English (US)",

volume = "24",

pages = "1351--1359",

journal = "Nature medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - De novo NAD+ biosynthetic impairment in acute kidney injury in humans

AU - Poyan Mehr, Ali

AU - Tran, Mei T.

AU - Ralto, Kenneth M.

AU - Leaf, David E.

AU - Washco, Vaughan

AU - Messmer, Joseph

AU - Lerner, Adam

AU - Kher, Ajay

AU - Kim, Steven H.

AU - Khoury, Charbel C.

AU - Herzig, Shoshana J.

AU - Trovato, Mary E.

AU - Simon-Tillaux, Noemie

AU - Lynch, Matthew R.

AU - Thadhani, Ravi I.

AU - Clish, Clary B.

AU - Khabbaz, Kamal R.

AU - Rhee, Eugene P.

AU - Waikar, Sushrut S.

AU - Berg, Anders H.

AU - Parikh, Samir M.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052304181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052304181&partnerID=8YFLogxK

U2 - 10.1038/s41591-018-0138-z

DO - 10.1038/s41591-018-0138-z

M3 - Article

C2 - 30127395

AN - SCOPUS:85052304181

SN - 1078-8956

VL - 24

SP - 1351

EP - 1359

JO - Nature medicine

JF - Nature medicine

IS - 9

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this