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

Yujia Wang; Yi Guan; Qionghong Xie; Weiyuan Gong; Jianhua Li; Tong Chen; Yanfang Xu; Ning Xu; Shaohao Chen; Mo Chen; Zhengxin Wang; Chuan-Ming Hao

doi:10.1093/ckj/sfac262

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

Clin Kidney J. 2022 Dec 8;16(4):711-721. doi: 10.1093/ckj/sfac262. eCollection 2023 Apr.

Authors

Yujia Wang¹, Yi Guan¹, Qionghong Xie¹, Weiyuan Gong¹, Jianhua Li², Tong Chen³, Yanfang Xu⁴, Ning Xu⁵, Shaohao Chen⁵, Mo Chen⁶, Zhengxin Wang², Chuan-Ming Hao¹

Affiliations

¹ Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
² Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
³ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
⁴ Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁵ Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁶ Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.

Abstract

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.

Keywords: acute kidney injury, 3-hydroxyanthranilic acid; nicotinamide adenine dinucleotide; quinolinic acid; renal tubules.