Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19-Related Acute Kidney Injury

Nathan H Raines; Matthew D Cheung; Landon S Wilson; Jeffrey C Edberg; Nathaniel B Erdmann; Alec A Schmaier; Taylor F Berryhill; Zachary Manickas-Hill; Jonathan Z Li; Xu G Yu; Anupam Agarwal; Stephen Barnes; Samir M Parikh

doi:10.1016/j.ekir.2021.09.001

Nicotinamide Adenine Dinucleotide Biosynthetic Impairment and Urinary Metabolomic Alterations Observed in Hospitalized Adults With COVID-19-Related Acute Kidney Injury

Kidney Int Rep. 2021 Dec;6(12):3002-3013. doi: 10.1016/j.ekir.2021.09.001. Epub 2021 Sep 14.

Authors

Affiliations

¹ Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
² Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
³ Targeted Metabolomics and Proteomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁴ Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁵ Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
⁷ Ragon Institute of the Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard University, Massachusetts General Hospital, Cambridge, Massachusetts, USA.
⁸ Infectious Disease Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁹ Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁰ Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Abstract

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.

Keywords: COVID-19; acute kidney injury; metabolism; metabolomics; nicotinamide adenine dinucleotide (NAD+).

Abstract

Grants and funding