Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients.
Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients.
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DOI：
10.1371/journal.pone.0143731
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hostetter TH
中科院分区：
文献类型：
--
作者：
Hai X;Landeras V;Dobre MA;DeOreo P;Meyer TW;Hostetter TH
众所周知，大尺寸、蛋白质结合和细胞内隔离限制了化合物的透析去除。在研究氧化三甲胺（TMAO）（一种与普通人群心血管疾病相关的分子）的正常肾脏和透析处理过程中，我们发现了慢性血液透析持续减少溶质的两个基本未被认识到的额外限制。我们测量了长期血液透析受试者（ESRD，n = 7）的溶质水平和处理，并将其与正常对照组（NLS，n = 6）的水平和清除率进行了比较。终末期肾病患者透析前血浆TMAO峰值水平明显高于非透析患者（77 ± 26 vs 2 ± 1 μ M，均值±标准差，p <0.05）。相比之下，ESRD受试者的透析前BUN水平为45 ± 11 mg/dl，NLS为15 ± 3 mg/dl。因此，ESRD中的TMAO水平平均约为NLS中的40倍，而BUN是NLS的3倍。然而，在透析期间TMAO浓度的分数降低实际上大于尿素的分数降低（86 ± 3%对74 ± 6%，TMAO对尿素，p <0.05），并且其透析清除率虽然略低于尿素的透析清除率，但与肌酐的透析清除率相当。此外，生产率相似（533 ± 272 vs 606 ± 220 μ mol/天，ESRD vs NLS，p> 0.05）。然而，TMAO的分布体积约为尿素的一半。此外，在NLS中，TMAO的尿清除率（219 ± 78 ml/min）高于尿尿素和肌酐清除率（分别为55 ± 14和119 ± 21 ml/min）。因此，TMAO水平达到比尿素水平高得多的正常倍数，主要是由于1）TMAO相对于尿素被正常肾脏的高清除率和2）其较小的分布体积。模型表明，只有更频繁的透析才能降低水平。因此，应探索其他策略，如减少产量。此外，使用尿素作为透析充分性的唯一标志物可能会产生误导，因为透析后的分子TMAO很容易积累到基于尿素的透析处方正常值的更高倍数。
Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine’s. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO’s high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.