Roumelioti Maria Eleni, Nolin Thomas, Unruh Mark L, Argyropoulos Christos
Division of Nephrology, Department of Internal Medicine, University of New Mexico Health Sciences Center, School of Medicine, Albuquerque, NM, United States of America.
Department of Pharmacy and Therapeutics, and Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, PA, United States of America.
PLoS One. 2016 Apr 7;11(4):e0153157. doi: 10.1371/journal.pone.0153157. eCollection 2016.
Beta-2 Microglobulin (β2M) is a prototypical "middle molecule" uremic toxin that has been associated with a higher risk of death in hemodialysis patients. A quantitative description of the relative importance of factors determining β2M concentrations among patients with impaired kidney function is currently lacking.
Herein we undertook a systematic review of existing studies reporting patient level data concerning generation, elimination and distribution of β2M in order to develop a population model of β2M kinetics. We used this model and previously determined relationships between predialysis β2M concentration and survival, to simulate the population distribution of predialysis β2M and the associated relative risk (RR) of death in patients receiving conventional thrice-weekly hemodialysis with low flux (LF) and high flux (HF) dialyzers, short (SD) and long daily (LD) HF hemodialysis sessions and on-line hemodiafiltration at different levels of residual renal function (RRF).
We identified 9 studies of 106 individuals and 156 evaluations of or more compartmental kinetic parameters of β2M. These studies used a variety of experimental methods to determine β2M kinetics ranging from isotopic dilution to profiling of intra/inter dialytic concentration changes. Most of the patients (74/106) were on dialysis with minimal RRF, thus facilitating the estimation of non-renal elimination kinetics of β2M. In large scale (N = 10,000) simulations of individuals drawn from the population of β2M kinetic parameters, we found that, higher dialytic removal materially affects β2M exposures only when RRF (renal clearance of β2M) was below 2 ml/min. In patients initiating conventional HF hemodialysis, total loss of RRF was predicted to be associated with a RR of death of more than 20%. Hemodiafiltration and daily dialysis may decrease the high risk of death of anuric patients by 10% relative to conventional, thrice weekly HF dialysis. Only daily long sessions of hemodialysis consistently reduced mortality risk between 7-19% across the range of β2M generation rate.
Preservation of RRF should be considered one of the therapeutic goals of hemodialysis practice. Randomized controlled trials of novel dialysis modalities may require large sample sizes to detect an effect on clinical outcomes even if they enroll anuric patients. The developed population model for β2M may allow personalization of hemodialysis prescription and/or facilitate the design of such studies by identifying patients with higher β2M generation rate.
β2微球蛋白（β2M）是一种典型的“中分子”尿毒症毒素，与血液透析患者较高的死亡风险相关。目前缺乏对肾功能受损患者中决定β2M浓度的因素相对重要性的定量描述。
在此，我们对现有报告β2M生成、清除和分布的患者水平数据的研究进行了系统综述，以建立β2M动力学的人群模型。我们使用该模型以及先前确定的透析前β2M浓度与生存率之间的关系，来模拟接受传统每周三次低通量（LF）和高通量（HF）透析器、短程（SD）和长程每日（LD）HF血液透析以及不同残余肾功能（RRF）水平的在线血液透析滤过的患者透析前β2M的人群分布及其相关的相对死亡风险（RR）。
我们确定了9项涉及106名个体的研究以及对β2M的156次或更多房室动力学参数评估。这些研究使用了多种实验方法来确定β2M动力学，范围从同位素稀释到透析内/透析间浓度变化分析。大多数患者（74/106）处于透析状态且RRF极低，从而便于估计β2M的非肾清除动力学。在从β2M动力学参数人群中抽取个体的大规模（N = 10,000）模拟中，我们发现，仅当RRF（β2M的肾清除率）低于2 ml/分钟时，更高的透析清除率才会对β2M暴露产生实质性影响。在开始传统HF血液透析的患者中，预计RRF完全丧失与超过20%的死亡RR相关。与传统的每周三次HF透析相比，血液透析滤过和每日透析可能会使无尿患者的高死亡风险降低10%。只有每日长时间的血液透析在β2M生成率范围内始终将死亡风险降低7 - 19%。
应将保留RRF视为血液透析实践的治疗目标之一。新型透析方式的随机对照试验可能需要大样本量才能检测到对临床结局的影响，即使纳入了无尿患者。所建立的β2M人群模型可能允许血液透析处方个性化和/或通过识别β2M生成率较高的患者来促进此类研究设计。
