The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes.
The effect of isohydric hemodialysis on the binding and removal of uremic retention solutes.
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DOI：
10.1371/journal.pone.0192770
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Lowenstein J
中科院分区：
文献类型：
--
作者：
Etinger A;Kumar SR;Ackley W;Soiefer L;Chun J;Singh P;Grossman E;Matalon A;Holzman RS;Meijers B;Lowenstein J
越来越多的证据表明，蛋白质结合的尿毒症潴留溶质（例如硫酸吲哚酚、硫酸对甲苯酯和犬尿酸）的积累在慢性血液透析患者的心血管疾病加速中发挥作用。蛋白质结合（可能与白蛋白结合）使这些溶质的透析性较差。我们之前观察到硫酸吲哚酚的游离部分在血液透析结束时显着减少。我们假设溶质结合可能是 pH 依赖性的，并将游离溶质浓度的变化归因于标准血液透析结束时观察到的较高血清 pH 值，透析缓冲液碳酸氢盐浓度大于 35 mmol/L。我们观察到，体外将尿毒症血浆酸化至pH 6，游离IS的比例大大增加。我们通过在血液透析治疗的前一半（“等水透析”）中将透析液碳酸氢盐缓冲液浓度降低至 25 mmol/L 来检验我们的假设。 8名稳定的血液透析患者接受“等水透析”90分钟，然后改用标准缓冲液（碳酸氢盐=37mmol/L）。两天后进行第二次透析，全程使用标准缓冲液。我们发现，经过 90 分钟的“等水透析”（pH = 7.37，碳酸氢盐 = 22.4 mmol/L）和标准透析（pH = 7.49，碳酸氢盐 = 29.0 mmol/L）后，血液 pH 值和碳酸氢盐浓度明显分离。在分析的 10 种尿毒症滞留溶质中，结合亲和力差异很大。犬尿酸（0.05 游离）、对甲酚硫酸盐（0.12 游离）和硫酸吲哚酚（0.13 游离）表现出最大程度的结合。三种溶质（吲哚基葡萄糖醛酸、对甲苯基葡萄糖醛酸和苯基葡萄糖醛酸）实际上未结合。对尿毒症滞留溶质的游离和结合浓度的分析证实了我们的预测，即溶质的结合受 pH 值影响。然而，在混合模型分析中，我们发现透析过程中尿毒症总溶质浓度的降低在游离浓度变化中所占的比例更大，这可能是与白蛋白结合饱和的影响，而等水透析产生的 pH 值相对较小的变化所造成的影响更大。 pH 对结合的影响似乎仅限于那些与蛋白质结合程度最高的溶质。结合最紧密的溶质表现出最低的透析器间隙。等水透析和标准透析期间透析器清除率的增加仅对于犬尿酸具有统计学显着性。这些发现提供了尿毒症潴留溶质的结合受 pH 值影响的证据。降低缓冲液碳酸氢盐浓度（“等水透析：”）的效果虽然显着，但很小，但可能表明，进一步修改透析技术，使血液的pH值进一步降低，将导致溶质的游离分数更大程度地增加，并增强血液透析去除高度蛋白质结合的尿毒症潴留溶质的功效。
There is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable. We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS. We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment (“isohydric dialysis”). Eight stable hemodialysis patients underwent “isohydric dialysis” for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout. We found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of “isohydric dialysis” (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound. The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid. These findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration (“isohydric dialysis:”), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.
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