The Proximal Tubule Is a Source of De Novo NAD<sup>+</sup> Synthesis, the Metabolites of Which Are a Valuable Predictor of AKI
October 22, 2020 | 10:00 AM - 12:00 PM
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The Proximal Tubule Is a Source of De Novo NAD+ Synthesis, the Metabolites of Which Are a Valuable Predictor of AKI
- AKI Mechanisms - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Wang, Yujia, Huashan Hospital Fudan University, Shanghai, Shanghai, China
- Hao, Chuan-Ming, Huashan Hospital Fudan University, Shanghai, Shanghai, China
Reduced NAD+ is reported to increase the susceptibility of AKI. De novo synthesis pathway from tryptophan is an important source of NAD+ in the liver and probably kidney. In the present study, we characterized the expression of the enzymes of de novo NAD+ synthesis pathway in the human kidney. We then examined the association of the urine metabolites in this pathway and AKI development in patients who received high-dose methotrexate(HDMTX) chemotherapy or liver transplantation(LT) and analyzed their predictive value for AKI.
The expression of the enzymes of de novo NAD+ synthesis pathway was examined by immunohistochemistry. To examine the predictive value of urine tryptophan metabolites in AKI, 71 patients who received a total of 191 HDMTX treatments were prospectively enrolled as a discovery cohort and 49 patients receiving LT were enrolled as a validation cohort. Urine samples were collected within 72 hours before chemotherapy/surgery. AKI was defined by KDIGO criteria. Urine tryptophan metabolites were measured by LC-MS and adjusted by creatinine. The performance of these metabolites to predict AKI after HDMTX/LT was analyzed.
Enzymes of de novo NAD+ synthesis pathway including KMO, KYNU, HAAO, QPRT, and ACMSD were detected in renal tubules that were positive for LTL, but not labeled by AQP2, NCCT, nor THP, consistent with proximal tubule expression.
A total of 191 HDMTX treatments were included in the discovery cohort and AKI developed after 35 HDMTX treatments (18.3%). In those who developed AKI, the urine level of 3-hydroxyanthranilic acid (3-OH AA) was significantly higher while the level of quinolinic acid (QA) was significantly lower compared with those who did not develop AKI (3-OH AA: 4.42[2.74-9.52] vs 3.57[1.86-5.73], p=0.023; QA: 13.43[9.69-22.34] vs 20.64[14.80-32.05], p=0.004). The area under the receiver operating characteristic curve (AUC) of urine QA/3-OH AA for AKI prediction was 0.748. The discrimination ability of the urine QA/3-OH AA on AKI susceptibility was validated in LT cohort, with the AUC as 0.729.
The proximal tubules are an important source of de novo NAD synthesis. Reduced urine QA / 3-OH AA ratio is associated with development of AKI. The present study suggests that urine QA / 3-OH AA ratio is a potential biomarker to predict AKI and NAD+ synthesis pathway is a potential therapeutic target.