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

Background Acute kidney injury (AKI) is often iatrogenic and potentially preventable. Reduced renal nicotinamide adenine dinucleotide (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. Methods 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: the methotrexate (MTX) cohort with high-dose MTX treatment for lymphoma (n = 189) and the liver transplantation cohort with orthotopic liver transplantation (n = 49). Urinary metabolomics study of NAD(+)de novo synthesis was performed by liquid chromatography with mass spectrometry, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD(+) synthetic enzymes expression in AKI-susceptible conditions. Results Human proximal tubule was the main structure in the kidney that expressed the necessary enzymes for NAD(+)de novo synthesis. In the MTX cohort, the 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 the liver transplantation cohort. The area under the receiver-operating characteristic curve (AUC) of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts, respectively. 3-Hydroxyanthranilic acid dioxygenase (HAAO), the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys. Conclusions 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. Lay Summary Acute kidney injury (AKI) is a great threat to public health with a very high mortality in the intensive care unit setting. Strong evidence indicates that susceptibility to AKI differs significantly following an acute insult, and aging is a risk factor for AKI. However, the biological mechanism underlying this AKI susceptibility remains poorly understood, which hinders the development of biomarkers and interventional targets for AKI prevention. The present study characterized the de novo nicotinamide adenine dinucleotide (NAD(+)) metabolism in human kidney and explored the potential of using their metabolites in the urine to predict the development of AKI using two independent patient cohorts. We found that the urinary quinolinic acid/3-hydroxyanthranilic acid ratio had an ability to predict AKI with an AUC of 0.749 and 0.729 in these two cohorts, respectively. The present study provides valuable information not only on potential biomarkers that predict AKI but also potential intervention target to prevent AKI.