急性肾损伤（AKI）通常是医源性的，潜在可预防的。减少肾脏尼克酰胺腺嘌呤二核苷酸（NAD+）被报道增加了AKI的易感性。本研究探讨了利用两个独立队列的尿路新合成的NAD+代谢产物对AKI预测价值。通过免疫组织化学和单细胞转录组研究了人肾脏中新合成NAD+的酶的表达。从两个独立队列（高剂量MTX治疗淋巴瘤的MTX队列和肝移植队列）中收集了尿样。通过液相色谱-质谱法进行尿液代谢组学研究，筛选AKI预测生物标志物。使用Nephroseq数据库和免疫组织化学分析了AKI易感情况下肾脏新合成NAD+酶的表达。人近曲小管是肾脏中表达新合成NAD+必要酶的主要结构。在MTX队列中，化疗前尿液鬼臼烷酸（QA）/ 3-羟基蒽醌酸（3-OH AA）比值在化疗后发生AKI的人群中显著低于未发生AKI的人群。这一发现在肝移植队列中也得到了验证。尿液QA / 3-OH AA的受试者工作特征曲线下面积（AUC）分别为0.749和0.729。3-羟基蒽醌酸双氧酶（HAAO），催化QA合成从3-OH AA，在易感患有糖尿病的肾脏中明显下降。人近曲小管是肾脏从新合成途径获得NAD+的重要来源。减少的QA/3-OH AA比值，可能暗示HAAO活性下降，是潜在的AKI预测生物标志物。 ©作者2022年。由牛津大学出版社代表ERA发表。

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.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.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.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.© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.