Observational evidence of NAD+ biosynthetic impairment and urinary metabolomic alterations in covid-related AKI

ABSTRACT

Background: Acute kidney injury (AKI) is a frequent extrapulmonary manifestation of COVID-19 and is associated with increased morbidity and mortality. We investigated alterations in the urine metabolome associated with AKI among patients with COVID-19, with the hypothesis that changes in nicotinamide adenine dinucleotide (NAD+) metabolism described in ischemic, toxic, and inflammatory AKI will be also associated with AKI in patients with COVID-19. Methods: This is a case-control study among two adult populations with COVID-19 critically ill patients hospitalized in Boston, Massachusetts, and a general hospitalized patient population in Birmingham, Alabama. Cases had AKI stages 2 or 3 by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Controls had no AKI by KDIGO criteria. Metabolites were measured by liquid chromatography -mass spectrometry. Results: 14 cases and 14 controls were included from Boston, and 8 cases and 10 controls included from Birmingham. Urinary quinolinate to tryptophan ratio, an indicator which increases with impaired NAD+ biosynthesis, was higher among cases than controls 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, unadjusted p = 0.0013;p=0.03 in analyses adjusted for age and sex). We identified alterations in tryptophan, nicotinamide, and other components of energy metabolism as well as decreases in purine metabolites which contributed to a distinct urinary metabolomic signature that could reliably differentiate patients with and without AKI (supervised random forest class error 1/14 for AKI and 1/14 for no AKI groups in Boston, 0/8 for AKI and 0/10 for no AKI groups in Birmingham). Conclusions: Conserved urinary metabolic alterations spanning multiple biochemical pathways distinguish AKI vs. non-AKI in the context of COVID-related hospitalization at two large academic medical centers. AKI is further associated with derangements in NAD+ biosynthesis that suggest impaired energy metabolism in the kidney. Augmenting renal NAD+ by administering biosynthetic precursors may present a novel therapeutic opportunity to mitigate COVID-19 associated AKI.