Itoh Yoshiharu, Ezawa Atsuko, Kikuchi Kaori, Tsuruta Yoshinari, Niwa Toshimitsu
Biomedical Research Laboratories, Kureha Corporation.
Meiyo Clinic.
Mass Spectrom (Tokyo). 2013;2(Spec Iss):S0017. doi: 10.5702/massspectrometry.S0017. Epub 2013 Apr 15.
Uremic toxins are involved in a variety of symptoms in advanced chronic kidney disease. Especially, the accumulation of protein-bound uremic toxins in the blood of dialysis patients might play an important role in the development of cardiovascular disease. Serum concentration of protein-bound uremic toxins such as indoxyl sulfate, indoxyl glucuronide, indoleacetic acid, p-cresyl sulfate, p-cresyl glucuronide, phenyl sulfate, phenyl glucuronide, phenylacetic acid, phenylacetylglutamine, hippuric acid, 4-ethylphenyl sulfate, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) in hemodialysis patients were simultaneously measured by liquid chromatography/tandem mass spectrometry. Serum levels of these protein-bound uremic toxins were increased in hemodialysis patients. Indoxyl sulfate, p-cresyl sulfate, and CMPF could not be removed efficiently by hemodialysis due to their high protein-binding ratios. Serum level of total indoxyl sulfate did not show any significant correlation with total p-cresyl sulfate. However, free indoxyl sulfate correlated with free p-cresyl sulfate, and reduction rate by hemodialysis of indoxyl sulfate correlated with that of p-cresyl sulfate. Serum levels of total and free indoxyl sulfate showed significantly positive correlation with those of indoxyl glucuronide, phenyl sulfate, and phenyl glucuronide. Serum levels of total and free p-cresyl sulfate showed significantly positive correlation with those of p-cresyl glucuronide, phenylacetylglutamine, and phenylacetic acid. Indoxyl sulfate and indoxyl glucuronide are produced from indole which is produced in the intestine from tryptophan by intestinal bacteria. p-Cresyl sulfate and p-cresyl glucuronide are produced from p-cresol which is produced in the intestine from tyrosine by intestinal bacteria. Thus, intestinal bacteria play an important role in the metabolism of protein-bound uremic toxins.
尿毒症毒素与晚期慢性肾脏病的多种症状有关。特别是，透析患者血液中蛋白结合型尿毒症毒素的蓄积可能在心血管疾病的发生发展中起重要作用。采用液相色谱/串联质谱法同时测定血液透析患者血清中硫酸吲哚酚、吲哚酚葡萄糖醛酸苷、吲哚乙酸、对甲酚硫酸盐、对甲酚葡萄糖醛酸苷、苯硫酸盐、苯葡萄糖醛酸苷、苯乙酸、苯乙酰谷氨酰胺、马尿酸、4-乙基苯硫酸盐和3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）等蛋白结合型尿毒症毒素的浓度。血液透析患者这些蛋白结合型尿毒症毒素的血清水平升高。由于硫酸吲哚酚、对甲酚硫酸盐和CMPF的蛋白结合率高，血液透析不能有效清除它们。总硫酸吲哚酚的血清水平与总对甲酚硫酸盐无显著相关性。然而，游离硫酸吲哚酚与游离对甲酚硫酸盐相关，硫酸吲哚酚的血液透析清除率与对甲酚硫酸盐的清除率相关。总硫酸吲哚酚和游离硫酸吲哚酚的血清水平与吲哚酚葡萄糖醛酸苷、苯硫酸盐和苯葡萄糖醛酸苷的血清水平呈显著正相关。总对甲酚硫酸盐和游离对甲酚硫酸盐的血清水平与对甲酚葡萄糖醛酸苷、苯乙酰谷氨酰胺和苯乙酸的血清水平呈显著正相关。硫酸吲哚酚和吲哚酚葡萄糖醛酸苷由吲哚产生，吲哚是肠道细菌在肠道内由色氨酸产生的。对甲酚硫酸盐和对甲酚葡萄糖醛酸苷由对甲酚产生，对甲酚是肠道细菌在肠道内由酪氨酸产生的。因此，肠道细菌在蛋白结合型尿毒症毒素的代谢中起重要作用。
