Enabling Technology to Prepare Ultrapure Dialysate in Dialysis Clinics

描述(由申请人提供)：透析患者因暴露于内毒素引起的慢性促炎反应的临床意义已成为肾脏病学的中心问题。欧洲肾脏协会敦促常规使用细菌和内毒素水平分别为0.1cfu/ml和0.03EU/ml的超纯透析液。在美国，水中细菌的最高允许限量为200 cfu/ml，内毒素的最高允许限量为2EU/ml。考虑到透析患者持续暴露于高水平细胞因子诱导分子的临床影响和风险，美国需要迅速采取行动，采用超纯透析液(UPD)ISO 1163：2009标准。然而，考虑到美国透析水系统的状况，如果不采用能够从透析水系统中消除生物膜的新技术，并纠正当前维护协议中的一些固有缺陷，就不可能达到这样的标准。在这一Fast Track应用中，我们建议开发一种基于我们的Cleanflow“设备的集成策略来生产UPD，该设备提供高效的两相流(TPF)流程。这一策略必须考虑将水系统的所有表面处理到透析液进入透析器的程度。在这个项目中，我们将开发方法和方案来在透析诊所测试综合策略。我们将验证我们可以降低根据这一新策略制造的透析液治疗患者的炎症标志物(IL-6和CRP)。综合策略将包括：1)用TPF工艺清洗分配回路，2)每次将透析机的连接管更换为清洁消毒的机组，3)确保透析机在透析器之前配备保持性超滤。我们将把我们的综合策略的结果与传统方法进行比较，并将评估使用或不使用超滤对结果的影响。我们还计划在超滤前后对透析液中的细菌DNA片段进行检测。这一在美国透析诊所生产UPD的综合策略的开发有望降低透析患者的慢性炎症状态，并提高对促红细胞生成素的反应性。 与公众健康相关：在这项Fast Track应用中，我们建议开发一种生产超纯透析液(UPD)的综合战略，基于我们已被证明的使用Cleanflow“设备有效去除透析水系统中的生物膜的能力，该设备提供了新型的两相流(TPF)工艺。本申请中详细介绍的策略和方法解决了诊所为了能够进行UPD而必须遵守的后勤问题，包括：1)在透析器之前使用保持式超滤器，以及2)在每次清洁期间将连接管更换到透析机。该项目旨在开发技术和协议，使美国的诊所能够达到ISO 1163：2009的UPD标准。这项研究的成功将使具有聚氯乙烯管道结构的诊所能够以合理的成本达到上述ISO标准，并将转化为降低透析患者的炎症生物标志物水平和提高对促红细胞生成素的反应性。

DESCRIPTION (provided by applicant): The clinical significance of chronic pro-inflammatory reactions in dialysis patients due to exposure to endotoxin has become a central issue in nephrology. The European Renal Association urges the routine use of ultrapure dialysate with bacteria and endotoxin levels of < 0.1 CFU/ml and < 0.03 EU/ml, respectively. In the US, the maximum allowable limit of bacteria in water is 200 cfu/ml and the maximum allowable limit for endotoxin is 2 EU/ml. Considering the clinical implications and risks of exposing dialysis patients to a high level of cytokine- inducing molecules on a continuous basis, the US needs to quickly move to adopt the ultrapure dialysate (UPD) ISO 1163:2009 Standard. However, considering the state of US dialysis water systems, meeting such standard will be impossible to achieve without adopting new technologies that can eradicate biofilm from the dialysis water systems and correcting some inherent deficiencies in current maintenance protocols. In this Fast Track application, we propose to develop an integrated strategy to produce UPD based on using our CleanFlow" device which delivers the highly effective two-phase flow (TPF) process. This strategy must consider treating all the surfaces of the water system to the point where the dialysate enters the dialyzer. In this project we will develop methods and protocols to test the integrated strategy in dialysis clinics. We will verify that we can reduce inflammation markers (IL-6 and CRP) in patients treated with dialysate made according to this new strategy. The integrated strategy will include: 1) cleaning the distribution loops with the TPF process, 2) replacing the connection tubing to dialysis machines with a cleaned and disinfected set each time, and 3) ensuring that dialysis machines are equipped with a retentive ultrafilter before the dialyzer. We will compare the results of our integrated strategy with conventional methods, and will assess the impact of using or not using the ultrafilter on the results. We plan to also include testing for bacterial DNA fragments in the dialysate before and after the ultrafilter. Development of this integrated strategy to produce UPD in US dialysis clinics is expected to decrease the chronic inflammation state in dialysis patients and increase responsiveness to erythropoietin. PUBLIC HEALTH RELEVANCE: In this Fast Track application, we propose to develop an integrated strategy to produce ultrapure dialysate (UPD) based on our proven capability of effectively removing biofilm from dialysis water systems using the CleanFlow" device which delivers the novel two-phase flow (TPF) process. The strategy and approach detailed in this application address the logistical issues that clinics must adhere to in order to be able to make UPD, including: 1) the use of a retentive ultrafilter before the dialyzer, and 2) changing the connection tubing to dialysis machines during each cleaning. The project is directed to developing the technology and protocols that will enable US clinics to meet the ISO 1163:2009 standard for UPD. Success of this development will make it possible for clinics with PVC piping construction to meet the above ISO standard at a reasonable cost, and will translate into decreasing the level of inflammatory biomarkers in dialysis patients and into increasing responsiveness to erythropoietin.