【摘要】急性肾损伤是表现为肾功能急剧下降的成人心脏外科术后的严重并发症之一。代谢组学是通过对生物体液或组织中所有内源性小分子代谢物进行高通量检测，分析代谢物与机体病理生理关系的一门学科。近年来，将代谢组学技术应用于心脏术后急性肾损伤的研究，对明确其发病机制、寻找简单无创的预后标志物等具有重要价值。本文拟对代谢组学在心脏外科术后急性肾损伤的预警作用做简要综述。
【关键词】心脏外科；急性肾损伤；代谢组学
【中图分类号】R654.2 【文献标识码】A 【文章编号】2095-1752（2019）18-0005-02
Progress in metabolomics research of diabetes acute renal injury after cardiac surgery
Shi Ning,Zhang Song,Ma Gaoxiang,Ma Shiping(Corresponding author)
School of Traditional Chinese Medicine,China Pharmaceutical University,Nanjing,Jiangsu 210000,China
【Abstract】Acute kidney injury is a serious postoperative complication after cardiac surgery in adults with abrupt decline in renal function. Metabolomics is a discipline using a high throughput detection to analyze all low-molecular endogenous metabolites in biological fluid or tissues, with the purpose of illustrating the relationship between metabolite changes and pathophysiology of organisms. In recent years, metabolomics has showed great value in clarifying pathogenesis and finding non-invasive prognostic markers in the studies of acute kidney injury after cardiac surgery. This article reviews the contribution of metabolomics in warning of acute kidney injury after cardiac surgery research.
【Key words】Cardiac surgery;Acute kidney injury;Metabolomics
急性肾损伤（Acute kidney injury，AKI）是一种多病因引起的肾功能快速下降的复杂的临床综合征，是成人心脏外科术后常见的严重并发症[1]。心脏外科术后发生急性肾损伤不仅会延长患者的住院时间，还会增加患者术后的死亡风险[2-5]。在所有接受心脏手术的患者中，约18%的患者术后发生AKI事件，最终约有2%-6%的患者需要接受肾脏替代治疗（Renal replacement therapy，RRT）[6]。
心脏手术相关AKI的发病机制复杂，包括多种损伤途径：缺血再灌注、外源性和内源性毒素、炎症、氧化应激和血流动力学因素等[7]。临床工作中，血清肌酐和尿量作为常用的AKI的诊断标准已超过50年[8]，然而血清肌酐易受循环容量状态、药物等非肾脏因素影响，对AKI检测的特异性较低，限制了AKI的检出率[9-10]。因此，找到一种能够辅助早期预测AKI的生物标志物成为了肾脏领域的研究热点。
1.代谢组学研究概况
代谢组学是系统生物学领域一门迅速发展起来的学科，是除了基因组学、转录组学和蛋白质组学之外的高通量“组学”技术之一[11]。代谢组学利用具有高通量、高准确性和高灵敏度的现代分析技术[12]，通过对机体体液中内源性代谢物进行检测与分析，灵敏且迅速地反映生物体内代谢物的变化，衡量机体的代谢改变，同时借助多变量统计方法，探究内源性代谢物的变化与机体生理病理的关系[13]。
根据研究目的可将代谢组学分为非靶向代谢组学和靶向代谢组学。非靶向代谢组学针对生物样品中可检测到的所有或大部分内源性代谢物进行无差别的定性或定量分析，可从整体上阐明疾病发展过程中的代谢紊乱情况[14]。靶向代谢组学是指针对某一个或几个或特定类别的内源性代谢物进行定量分析，通常为相似理化性质的一类代谢物（如脂质、氨基酸等）或相关代谢途径所涉及的代谢物[15]。
代谢组学研究过程主要包括样品收集、样品制备、数据采集、数据处理与统计、代谢物鉴定和代谢标志物筛选等。血液、尿液、组织是代谢组学生物标志物研究中最常用的标本，其中的内源性代谢物包含多类型化合物，且浓度范围跨度较广，因此，高灵敏度、高准确性、高通量的仪器分析技术是代谢组学研究的基础[16-18]。核磁共振波谱法（Nuclear Magnetic Resonance Spectroscopy，NMR）和质谱法（Mass Spectrometry，MS）分析是当前代谢组学领域应用最广泛的两种核心技术[19-20]，前者具有无偏向性、所需样品量少、非破坏性检测、可提供代谢物精确结构信息的优点[21]，而后者则具有较高的灵敏度和专属性，检测动态范围更为广泛[16]。
代谢组学具有无损伤、可量化的特点及高通量、低成本的优势，应用于多种疾病模型中以进行代谢产物的轮廓分析[22-25]，为临床心脏术后AKI的研究提供了新的思路。
2.代谢组学在心脏术后急性肾损伤中的研究进展
代谢组学技术能够从代谢网络终端表象反映生物体的功能水平，因此其在疾病预测和诊断等方面的作用备受关注。内源性代谢标志物不仅可以作为疾病发生的诊断标志物在疾病早期判断疾病的发生，而且可以通过研究其代谢途径的扰动找到相关通路以及确定关键的代谢酶，从而为疾病机制的探索及治疗提供证据。
2.1 代谢组学描绘心脏术后急性肾损伤代谢特征及代谢标志物的发现
Wei[26]等通过对缺血再灌注造模的急性肾损伤小鼠的血浆、肾皮质和髓质进行代谢组学分析，采用气相色谱-质谱技术、液相色谱-质谱联用的技术手段，检测到11种代谢物在肾损伤早期于肾脏和血浆中变化显著升高，包括氨基酸类及一些脂肪酸分解的代谢产物，包括2-甲基丁甘氨酸、3-甲基巴豆酰甘氨酸、3-吲哚基硫酸盐、苯酚硫酸盐等。在临床研究中，Martin[27]等采用核磁共振（NMR）与液相色谱-质谱法（LC-MS/MS）结合的方法对心脏术后发生AKI的患者的尿液样本进行检测，证明AKI患者尿液中的代谢物发生了显著变化，N-乙酰神经氨酸、磷酸乙醇胺和丝氨酸的水平升高，而2-羟基丁酸、泛酸和马尿酸水平显著降低，有显著性差异，其中马尿酸、磷酸乙醇胺和丝氨酸在肾前性AKI患者中的变化程度高于肾性AKI患者。已有研究[10]采用核磁共振波谱技术对85例成人心脏手术患者进行前瞻性研究，探究血浆样本的代谢特征谱对体外循环心脏手术后AKI预后的判断潜力，Mg2+、乳酸及葡萄糖苷酸缀合物可作为鉴别是否发生AKI的差异代谢物，但仍缺乏更为严谨、广泛的多中心临床研究。曾有学者[28]针对主动脉瓣膜置换术后发生AKI的患者的血浆代谢物进行代谢组学分析，发现5-腺苷同型半胱氨酸与肌酐升高和患者死亡率显著相关。
2.2 代谢组学探究心脏术后AKI 发生相关的分子代谢路径
研究者们[26]通过研究代谢产物的变化来推断心脏术后急性肾损伤分子代谢路径的扰动。动物实验中，AKI发生之后，葡萄糖、丙酮酸、乳酸及三羧酸循环中间产物包括琥珀酸、苹果酸等含量降低，表明糖代谢受抑制，三羧酸循环氧化供能受阻；血浆中乙酰肉碱、乙酰乙酸、3-羟基丁酸的增加，表明游离脂肪酸及其分解增加，提示脂质成为代偿供能物质。一项17例AKI患者与肾功能正常者的血清代谢谱进行比较的临床试验中[29]，研究人员观察到酰基肉碱和氨基酸（蛋氨酸、同型半胱氨酸、焦谷氨酸、非对称二甲基精氨酸和苯丙氨酸）的增加及血清精氨酸和几种溶血磷脂酰胆碱的降低，参与氧化应激途径化合物显著增加提示氧化应激反映增强。近期研究表明[30]，小鼠缺血再灌注造成的急性肾损伤模型中AKI后肾组织中NAD+（烟酰胺腺嘌呤二核苷酸）下降，喹诺酮类升高，QPRT（喹啉磷酸核糖转移酶）下降，随后研究者在QPRT+/-小鼠中验证这一现象，小鼠模型表现出更多的喹诺酮类累积、更低的NAD+水平和更高的AKI敏感性。在术后AKI患者的临床前瞻队列研究中，证实了NAD+的从头合成通路的抑制是AKI高危患者的代谢特征。
3.总结与展望
综上所述，代谢组学结果能够直观地反映出心脏术后急性肾损伤造成的内源性代谢物的扰动，发现潜在的早期诊断生物标志物及代谢紊乱途径，为临床心脏术后AKI的诊断研究提供了新的思路。但在现阶段的研究中，仍存在较多不足之处，需在检测技术、临床样本数量、多组学结合等方面不断突破。因此, 在心脏术后AKI研究中应用代谢组学应积极总结自身优势, 建立更可靠的临床队列样本，探索疾病进展过程中的代谢差异与病理机制，促进心脏术后AKI研究更好发展，为临床诊断、治疗及预后提供新的科学证据与思路。
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论文作者:石宁,张松,马高祥,马世平（通讯作者）
论文发表刊物:《医药前沿》2019年18期
论文发表时间:2019/8/16
标签：代谢物论文; 术后论文; 损伤论文; 患者论文; 心脏论文; 心脏外科论文; 通量论文; 《医药前沿》2019年18期论文;