The metabolites of de novo NAD+ synthesis are a valuable predictor of acute kidney injury


 
 
 AKI is often iatrogenic and potentially preventable. Reduced renal NAD+ is reported to increase the susceptibility of AKI. The present study explored the predictive value of urinary de novo NAD+ synthetic metabolites for AKI using two independent cohorts.
 
 
 
 The expression of de novo NAD+ synthetic enzymes in human kidney was examined by immunohistochemistry and single-cell transcriptomes. Urine samples were collected from two independent cohorts: methotrexate cohort with high-dose methotrexate treatment for lymphoma (n = 189) and liver transplantation cohort with orthotopic liver transplantation (n = 49). Urinary metabolomics study of NAD+ de novo synthesis was performed by LC-MS, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD+ synthetic enzymes expression in AKI susceptible condition.
 
 
 
 Human proximal tubule was the main structure in the kidney that expressed necessary enzymes for NAD+ de novo synthesis. In methotrexate cohort, urinary quinolinic acid (QA)/3-hydroxyanthranilic acid (3-OH AA) ratio before chemotherapy was significantly lower in those who developed AKI after chemotherapy compared with those who did not. This finding was consistent in liver transplantation cohort. The AUC of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts respectively. HAAO, the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys.
 
 
 
 The human proximal tubules were important source of NAD+ from the de novo pathway. Reduced urinary QA/3-OH AA ratio, which possibly suggested decreased HAAO activity, could be a potential AKI predictive biomarker.
