Massachusetts General Hospital, 149 13th Street, 8th Floor, Boston, MA, USA.
J Am Soc Nephrol. 2010 Jun;21(6):1041-1051. doi: 10.1681/ASN.2009111132. Epub 2010 Apr 8.
ESRD is a state of small-molecule disarray. We applied liquid chromatography/tandem mass spectrometry-based metabolite profiling to survey>350 small molecules in 44 fasting subjects with ESRD, before and after hemodialysis, and in 10 age-matched, at-risk fasting control subjects. At baseline, increased levels of polar analytes and decreased levels of lipid analytes characterized uremic plasma. In addition to confirming the elevation of numerous previously identified uremic toxins, we identified several additional markers of ESRD, including dicarboxylic acids (adipate, malonate, methylmalonate, and maleate), biogenic amines, nucleotide derivatives, phenols, and sphingomyelins. The pattern of lipids was notable for a universal decrease in lower-molecular-weight triacylglycerols, and an increase in several intermediate-molecular-weight triacylglycerols in ESRD compared with controls; standard measurement of total triglycerides obscured this heterogeneity. These observations suggest disturbed triglyceride catabolism and/or beta-oxidation in ESRD. As expected, the hemodialysis procedure was associated with significant decreases in most polar analytes. Unexpected increases in several metabolites, however, indicated activation of a broad catabolic program, including glycolysis, lipolysis, ketosis, and nucleotide breakdown. In summary, this study demonstrates the application of metabolite profiling to identify markers of ESRD, provide perspective on uremic dyslipidemia, and broaden our understanding of the biochemical effects of hemodialysis.
ESRD 是一种小分子紊乱状态。我们应用基于液相色谱/串联质谱的代谢组学方法,对 44 例 ESRD 患者(透析前和透析后)和 10 例年龄匹配的、处于风险中的禁食对照者的 350 多种小分子进行了检测。在基线时,尿毒症血浆的特征是极性分析物水平升高和脂类分析物水平降低。除了证实大量先前鉴定的尿毒症毒素的升高外,我们还鉴定了 ESRD 的其他几个标志物,包括二羧酸(己二酸、丙二酸、甲基丙二酸和马来酸)、生物胺、核苷酸衍生物、酚类和神经鞘磷脂。脂质的模式以与对照组相比,ESRD 中较低分子量的三酰甘油普遍降低,而几种中分子量的三酰甘油增加为特征;总三酰甘油的标准测量掩盖了这种异质性。这些观察结果表明,在 ESRD 中,甘油三酯的分解代谢和/或β氧化受到干扰。正如预期的那样,血液透析过程与大多数极性分析物的显著降低有关。然而,一些代谢物的意外增加表明广泛的分解代谢程序的激活,包括糖酵解、脂肪分解、酮症和核苷酸分解。总之,本研究表明代谢组学可用于鉴定 ESRD 的标志物,为尿毒症脂代谢异常提供新视角,并拓宽我们对血液透析生化影响的理解。