TY - JOUR
T1 - Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19–Related Acute Kidney Injury
AU - Raines, Nathan H.
AU - Cheung, Matthew D.
AU - Wilson, Landon S.
AU - Edberg, Jeffrey C.
AU - Erdmann, Nathaniel B.
AU - Schmaier, Alec A.
AU - Berryhill, Taylor F.
AU - Manickas-Hill, Zachary
AU - Li, Jonathan Z.
AU - Yu, Xu G.
AU - Agarwal, Anupam
AU - Barnes, Stephen
AU - Parikh, Samir M.
N1 - Funding Information:
Please see the Supplementary Acknowledgments for individual members of the Massachusetts General Hospital COVID-19 Collection & Processing Team, the Massachusetts Consortium on Pathogen Readiness members, and the University of Alabama at Birmingham COVID-19 Collection & Processing Team. Dr. Amar Pandit from the University of Massachusetts provided helpful insights into physiological interpretations. This work was supported by an Anderson Innovation Award (Stephen Barnes, Principal Investigator) and from the National Institutes of Health / National Institute of Diabetes, Digestive, and Kidney to the University of Alabama at Birmingham–University of California—San Diego O’Brien Center for Acute Kidney Injury (P30 DK079337, Anupam Agarwal, Principal Investigator). The mass spectrometer was purchased from a National Institutes of Health Shared Instrumentation Grant ( S10 RR220872 , Stephen Barnes, Principal Investigator). The Massachusetts General Hospital/Massachusetts Consortium on Pathogen Readiness COVID-19 biorepository was supported by a gift from Ms. Enid Schwartz, by the Mark and Lisa Schwartz Foundation, the Massachusetts Consortium for Pathogen Readiness and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard. Nathan H. Raines was supported by the National Institutes of Health / National Institute of Diabetes, Digestive, and Kidney T32 DK007199 (Pollak) and is now supported by the Doris Duke Physician Scientist Fellowship Grant 202182. Matthew Cheung is supported by the National Institutes of Health T32-GM008361 . Jeffrey C. Edberg is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR003096 (Edberg). Samir M. Parikh is supported by grants R35HL139424, R01DK095072, and R01AG027002 from the National Heart Lung Blood Institute , the National Institute of Diabetes, Digestive, and Kidney Diseases , and the National Institute on Aging .
Funding Information:
Please see the Supplementary Acknowledgments for individual members of the Massachusetts General Hospital COVID-19 Collection & Processing Team, the Massachusetts Consortium on Pathogen Readiness members, and the University of Alabama at Birmingham COVID-19 Collection & Processing Team. Dr. Amar Pandit from the University of Massachusetts provided helpful insights into physiological interpretations. This work was supported by an Anderson Innovation Award (Stephen Barnes, Principal Investigator) and from the National Institutes of Health / National Institute of Diabetes, Digestive, and Kidney to the University of Alabama at Birmingham?University of California?San Diego O'Brien Center for Acute Kidney Injury (P30 DK079337, Anupam Agarwal, Principal Investigator). The mass spectrometer was purchased from a National Institutes of Health Shared Instrumentation Grant (S10 RR220872, Stephen Barnes, Principal Investigator). The Massachusetts General Hospital/Massachusetts Consortium on Pathogen Readiness COVID-19 biorepository was supported by a gift from Ms. Enid Schwartz, by the Mark and Lisa Schwartz Foundation, the Massachusetts Consortium for Pathogen Readiness and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard. Nathan H. Raines was supported by the National Institutes of Health / National Institute of Diabetes, Digestive, and Kidney T32 DK007199 (Pollak) and is now supported by the Doris Duke Physician Scientist Fellowship Grant 202182. Matthew Cheung is supported by the National Institutes of Health T32-GM008361. Jeffrey C. Edberg is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR003096 (Edberg). Samir M. Parikh is supported by grants R35HL139424, R01DK095072, and R01AG027002 from the National Heart Lung Blood Institute, the National Institute of Diabetes, Digestive, and Kidney Diseases, and the National Institute on Aging.
Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021/12
Y1 - 2021/12
N2 - Introduction: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19–associated AKI. Methods: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography–mass spectrometry. Results: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD+ biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59–2.96] in cases, 0.31 [0.13–1.63] in controls, P = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham). Conclusion: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD+ biosynthesis, which may present a novel therapeutic target to mitigate COVID-19–associated AKI.
AB - Introduction: Acute kidney injury (AKI) is common in COVID-19 and associated with increased morbidity and mortality. We investigated alterations in the urine metabolome to test the hypothesis that impaired nicotinamide adenine dinucleotide (NAD+) biosynthesis and other deficiencies in energy metabolism in the kidney, previously characterized in ischemic, toxic, and inflammatory etiologies of AKI, will be present in COVID-19–associated AKI. Methods: This is a case-control study among the following 2 independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. The cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria; the controls had no AKI. Metabolites were measured by liquid chromatography–mass spectrometry. Results: A total of 14 cases and 14 controls were included from Boston and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio (Q/T), found with impaired NAD+ biosynthesis, was present in the cases at each location and pooled across locations (median [interquartile range]: 1.34 [0.59–2.96] in cases, 0.31 [0.13–1.63] in controls, P = 0.0013). Altered energy metabolism and purine metabolism contributed to a distinct urinary metabolomic signature that differentiated patients with and without AKI (supervised random forest class error: 2 of 28 in Boston, 0 of 18 in Birmingham). Conclusion: Urinary metabolites spanning multiple biochemical pathways differentiate AKI versus non-AKI in patients hospitalized with COVID-19 and suggest a conserved impairment in NAD+ biosynthesis, which may present a novel therapeutic target to mitigate COVID-19–associated AKI.
KW - COVID-19
KW - acute kidney injury
KW - metabolism
KW - metabolomics
KW - nicotinamide adenine dinucleotide (NAD)
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U2 - 10.1016/j.ekir.2021.09.001
DO - 10.1016/j.ekir.2021.09.001
M3 - Article
C2 - 34541422
AN - SCOPUS:85119899900
SN - 2468-0249
VL - 6
SP - 3002
EP - 3013
JO - Kidney International Reports
JF - Kidney International Reports
IS - 12
ER -