Wang Jiayi, Yan Wenzhe, Zhou Xiang, Liu Yu, Tang Chengyuan, Peng Youming, Liu Hong, Sun Lin, Xiao Li, He Liyu
Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, China.
Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China.
PeerJ. 2020 May 14;8:e9111. doi: 10.7717/peerj.9111. eCollection 2020.
Metabolomics has emerged as a valuable tool to discover novel biomarkers and study the pathophysiology of diabetic nephropathy (DN). However, the effect of postoperative acute kidney injury (AKI) on diabetes mellitus (DM) to chronic DN progression has not been evaluated from the perspective of metabolomics.
A group of type 2 diabetes mellitus (T2DM) inpatients, who underwent off-pump coronary artery bypass grafting (CABG), were enrolled in our study. According to whether postoperative AKI occurred, patients were grouped in either the AKI group (AKI, = 44) or the non-AKI group (NAKI, = 44). Urine samples were collected from these patients before and 24 h after operation. Six patients from the AKI group and six patients from the NAKI group were chosen as the pilot cohort for untargeted metabolomics analysis, with the goal of identifying postoperative AKI-related metabolites. To understand the possible role of these metabolites in the chronic development of renal injury among T2DM patients, trans-4-hydroxy-L-proline and azelaic acid were quantified by targeted metabolomics analysis among 38 NAKI patients, 38 AKI patients, 46 early DN patients (DN-micro group), and 34 overt DN patients (DN-macro group).
Untargeted metabolomics screened 61 statistically distinguishable metabolites in postoperative urine samples, compared with preoperative urine samples. Via Venn diagram analysis, nine of 61 were postoperative AKI-related metabolites, including trans-4-hydroxy-L-proline, uridine triphosphate, p-aminobenzoate, caffeic acid, adrenochrome, δ-valerolactam, L-norleucine, 5'-deoxy-5'-(methylthio) adenosine, and azelaic acid. By targeted metabolomics analysis, the level of trans-4-hydroxy-L-proline increased gradually from the NAKI group to the AKI, DN-micro, and DN-macro groups. For azelaic acid, the highest level was found in the NAKI and DN-micro groups, followed by the DN-macro group. The AKI group exhibited the lowest level of azelaic acid.
The detection of urinary trans-4-hydroxy-L-proline after AKI could be treated as an early warning of chronic DN progression and might be linked to renal fibrosis. Urinary azelaic acid can be used to monitor renal function noninvasively in DM and DN patients. Our results identified markers of AKI on DM and the chronic progression of DN. In addition, the progression of DN was associated with AKI-like episodes occurring in DM.
代谢组学已成为发现新型生物标志物和研究糖尿病肾病（DN）病理生理学的重要工具。然而，术后急性肾损伤（AKI）对糖尿病（DM）向慢性DN进展的影响尚未从代谢组学角度进行评估。
选取一组接受非体外循环冠状动脉搭桥术（CABG）的2型糖尿病（T2DM）住院患者纳入本研究。根据术后是否发生AKI，将患者分为AKI组（AKI，n = 44）和非AKI组（NAKI，n = 44）。在术前及术后24小时采集这些患者的尿液样本。从AKI组和NAKI组中各选取6例患者作为非靶向代谢组学分析的先导队列，旨在鉴定术后与AKI相关的代谢物。为了解这些代谢物在T2DM患者肾损伤慢性发展中的可能作用，通过靶向代谢组学分析对38例NAKI患者、38例AKI患者、46例早期DN患者（DN-微小组）和34例显性DN患者（DN-宏小组）的反式-4-羟基-L-脯氨酸和壬二酸进行定量分析。
非靶向代谢组学在术后尿液样本中筛选出61种与术前尿液样本相比具有统计学差异的代谢物。通过维恩图分析，61种代谢物中有9种是术后与AKI相关的代谢物，包括反式-4-羟基-L-脯氨酸、三磷酸尿苷、对氨基苯甲酸、咖啡酸、肾上腺素色素、δ-戊内酰胺、L-正亮氨酸、5'-脱氧-5'-（甲硫基）腺苷和壬二酸。通过靶向代谢组学分析，反式-4-羟基-L-脯氨酸水平从NAKI组到AKI组、DN-微小组和DN-宏小组逐渐升高。对于壬二酸，NAKI组和DN-微小组中水平最高，其次是DN-宏小组。AKI组中壬二酸水平最低。
AKI后尿液中反式-4-羟基-L-脯氨酸的检测可作为慢性DN进展的早期预警，可能与肾纤维化有关。尿液壬二酸可用于DM和DN患者肾功能的无创监测。我们的结果确定了AKI对DM和DN慢性进展的标志物。此外，DN的进展与DM中发生的类似AKI发作有关。
