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而发生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< 0.1 CFU/ml和< 0.03 EU/ml的超纯透析液。在美国，水中细菌的最大允许限值为200 cfu/ml，内毒素的最大允许限值为2 EU/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方案中的一些固有缺陷，则不可能达到该标准。在此快速通道应用中，我们建议开发一种集成策略，以使用我们的CleanFlow设备生产UPD，该设备提供高效的两相流（TPF）工艺。该策略必须考虑处理水系统的所有表面，直至透析液进入透析器。在这个项目中，我们将开发方法和协议，以测试在透析诊所的综合战略。我们将验证我们可以降低根据这种新策略制备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）使用TPF工艺清洁分配回路，2）每次使用清洁和消毒的套件更换透析机的连接管，以及3）确保透析机在透析器之前配备截留超滤器。我们将比较我们的综合策略与传统方法的结果，并评估使用或不使用超滤器对结果的影响。我们还计划在超滤器前后对透析液中的细菌DNA片段进行检测。在美国透析诊所开发这种生产UPD的综合策略，预计将减少透析患者的慢性炎症状态，并增加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.