NAD+ biosynthetic impairment and urinary metabolomic alterations observed in hospitalized adults with COVID-19-related acute kidney injury.

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 two independent populations of adults hospitalized with COVID-19: a critically ill population in Boston, Massachusetts, and a general population in Birmingham, Alabama. Cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes criteria; controls had no AKI. Metabolites were measured by liquid chromatography - mass spectrometry. Results: Fourteen cases and 14 controls were included from Boston, and 8 cases and 10 controls from Birmingham. Increased urinary quinolinate-to-tryptophan ratio, seen with impaired NAD+ biosynthesis, was present in cases at each location and pooled across locations (median [IQR]: 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: 2/28 in Boston, 0/18 in Birmingham). Conclusion: Urinary metabolites spanning multiple biochemical pathways differentiate AKI vs. 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.