Sterzel R B, Semar M, Lonergan E T, Treser G, Lange K
J Clin Invest. 1971 Nov;50(11):2295-304. doi: 10.1172/JCI106727.
Patients with chronic uremia develop neurologic defects which are similar to the demyelinating lesions seen in thiamine deficiency. The present study describes inhibitory effects of uremic material on nervous tissue transketolase, a thiamine-dependent enzyme of the pentose phosphate pathway which has been reported to have functional importance in the metabolism of myelinated nervous structures. Transketolase activity (TKA) of normal human brain and spinal cord was measured by the conversion of ribose-5-phosphate (R5P) to sedoheptulose-7-phosphate (S7P). TKA was significantly inhibited by plasma, cerebrospinal fluid and low molecular weight dialysate fractions obtained from patients with uremic neuropathy, but not by samples from normal subjects. The specific effect on transketolase by uremic material was established by showing suppressed formation of S7P from R5P also in the presence of excess cofactor thiamine pyrophosphate and of the other substrate xylulose-5-phosphate. Uremic plasma likewise inhibited a partially purified transketolase preparation from bakers' yeast.31 of 35 chronic uremic patients with inhibition values between 10 and 84% before or during the early phase of intermittent hemodialysis had evidence of neuropathy. Data of clinical grading of the neurologic deficits and values of motor nerve conduction velocity revealed a correlation between the extent of uremic neuropathy and the degree of nervous tissue transketolase inhibition. Hemodialysis markedly reduced the inhibitory effects of the patients' plasma and the data indicate that uremic patients who received effective long-term dialysis treatment show a parallel decline of transketolase inhibition and uremic neuropathy.The findings demonstrate that in patients with chronic renal failure, low molecular weight factors accumulate and inhibit nervous tissue transketolase. This biochemical defect-uncorrectable by thiamine but reversible by dialysis-may interfere with the metabolism of myelin-supporting cells, and/or of the axonal metabolism of medullated structures, and may thus contribute to the degeneration of myelinated nerves seen with uremic neuropathy.
慢性尿毒症患者会出现神经功能缺陷，这些缺陷与硫胺素缺乏时所见的脱髓鞘病变相似。本研究描述了尿毒症物质对神经组织转酮醇酶的抑制作用，转酮醇酶是戊糖磷酸途径中一种依赖硫胺素的酶，据报道该酶在有髓神经结构的代谢中具有重要功能。通过测量核糖-5-磷酸（R5P）向景天庚酮糖-7-磷酸（S7P）的转化来测定正常人脑和脊髓的转酮醇酶活性（TKA）。尿毒症神经病变患者的血浆、脑脊液和低分子量透析液组分可显著抑制TKA，但正常受试者的样本则无此作用。在存在过量辅因子焦磷酸硫胺素和另一种底物木酮糖-5-磷酸的情况下，尿毒症物质对转酮醇酶的特异性作用也通过R5P生成S7P的过程受到抑制得以证实。尿毒症血浆同样抑制了从面包酵母中部分纯化的转酮醇酶制剂。35例慢性尿毒症患者中有31例在间歇性血液透析前或早期阶段抑制值在10%至84%之间，有神经病变的证据。神经功能缺损的临床分级数据和运动神经传导速度值显示，尿毒症神经病变的程度与神经组织转酮醇酶抑制程度之间存在相关性。血液透析显著降低了患者血浆的抑制作用，数据表明接受有效长期透析治疗的尿毒症患者转酮醇酶抑制作用和尿毒症神经病变呈平行下降。研究结果表明，在慢性肾衰竭患者中，低分子量因子会蓄积并抑制神经组织转酮醇酶。这种生化缺陷不能通过硫胺素纠正，但可通过透析逆转，可能会干扰髓鞘支持细胞的代谢和/或有髓结构的轴突代谢，从而可能导致尿毒症神经病变中所见的有髓神经变性。
