Retained Organic Solutes and Clinical Outcomes in Hemodialysis

描述(由申请人提供)：血液透析治疗终末期肾病(ESRD)是最常见的肾脏替代疗法，目前的目标是清除尿素。血液透析患者的发病率和死亡率继续居高不下，远远超过一般人群。最近的HEMO临床试验显示，增强尿素清除并不会导致死亡率的提高。除尿素外，ESRD中还保留了大量的有机溶质。其中许多溶质具有某些特性，例如蛋白质结合或在某些身体隔室中的隔离，这使得它们不能通过目前的透析方法有效地清除。目前尚不清楚这些溶质是否与透析患者的不良结局有关。这项应用的总体目标是确定血液透析患者中与不良结局相关的滞留溶质。研究设计将是一项队列研究，其中已获得并存储了生物标本。这些储存的标本将被取回，分析推定的毒素水平，并与重要的患者预后相关。我们建议利用CHOICE和HEMO研究中可用的大样本储存库，以及先前的工作来仔细描述患者及其结果，以检验特定的肾功能衰竭溶液(如对甲酚硫酸盐、吲哚硫酸盐、甲胺)与不良透析结果相关的假说。CHOICE是对1995-1998年招募的767名血液透析患者进行的前瞻性队列研究，HEMO是一项前瞻性、多中心、随机临床试验，在1995-2000年间招募了1846名参与者。这两项研究都有标本库，其中包含基线和年度随访的冰冻标本，我们建议对这些标本进行有机溶质检测。我们将把这些有机溶质的水平与全因死亡率、心血管事件、食欲不振、低白蛋白水平、不宁腿症状和自我报告的认知问题联系起来。该应用程序将建立临床和实验室科学方面经验丰富的项目的合作，以解决肾衰竭及其治疗科学中的一个基本问题。这项研究将对了解终末期肾病患者发病率和死亡率显著的原因以及未来针对这些原因的干预措施的发展具有重要意义，从而寻求改善终末期肾病患者的生活质量和寿命。该应用程序将建立临床和实验室科学方面经验丰富的项目的合作，以解决肾衰竭及其治疗科学中的一个基本问题。这项研究将对了解慢性肾脏病患者大量发病率和死亡率的原因以及未来针对这些原因的干预措施的发展具有重要意义，从而寻求改善慢性肾脏病患者的生活质量和寿命。该提案将建立临床和实验室科学方面经验丰富的项目的合作，以 阐述肾衰竭及其治疗科学中的一个基本问题。这项研究将具有重要的意义 了解慢性肾脏疾病致残率和死亡率的原因 患者和未来干预措施的发展，以解决这些原因，从而寻求改善 慢性肾脏疾病患者的生活质量和生存时间。

DESCRIPTION (provided by applicant): Treatment for end-stage renal disease (ESRD) with hemodialysis, the most common renal replacement modality, is currently aimed at clearing urea. Hemodialysis patients continue to experience high rates of morbidity and mortality far in excess of the general population. The recent HEMO clinical trial revealed that enhanced urea clearance did not lead to improved mortality. There are a large number of organic solutes, other than urea, that are retained in ESRD. Many of these solutes have characteristics, such as protein-binding or sequestration in certain body compartments, which do not allow them to be cleared efficiently through current dialysis methods. It is currently unknown whether these solutes are associated with the poor outcomes experienced by dialysis patients. The overall goal of this application is to identify retained solutes which are associated with poor outcomes in hemodialysis patients. The study design will be a cohort study in which biological specimens have been obtained and stored. These stored specimens will be retrieved, analyzed for levels of putative toxins and correlated with important patient outcomes. We propose to take advantage of the large specimen repositories available in the CHOICE and HEMO studies, as well as the prior work to carefully characterize patients and their outcomes, to test hypotheses that particular kidney failure solutes (e.g. p-cresol sulfate, indoxyl sulfate, methylamine) are associated with poor dialysis outcomes. CHOICE is a prospective cohort study of 767 incident hemodialysis patients recruited from 1995-1998 and HEMO is a prospective, multicenter, randomized clinical trial in which 1846 participants were recruited between 1995 and 2000. Both these studies have specimen banks containing frozen specimens from baseline and annual follow-ups which we propose to assay for organic solutes. We will relate levels of these organic solutes to all-cause mortality, cardiovascular events, loss of appetite, low albumin levels, restless leg symptoms and self reported problems with cognition. The application will build a collaboration of experienced programs in the clinical and laboratory sciences to address a fundamental issue in the science of kidney failure and its treatment. This study will have important implications for understanding the cause of the substantial morbidity and mortality in ESRD patients and the development of future interventions to address these causes, thereby seeking to improve the quality and length of life for ESRD patients. The application will build a collaboration of experienced programs in the clinical and laboratory sciences to address a fundamental issue in the science of kidney failure and its treatment. This study will have important implications for understanding the cause of the substantial morbidity and mortality in chronic kidney disease patients and the development of future interventions to address these causes, thereby seeking to improve the quality and length of life for persons with chronic kidney disease. The proposal will build a collaboration of experienced programs in the clinical and laboratory sciences to address a fundamental issue in the science of kidney failure and its treatment. This study will have important implications for understanding the cause of the substantial morbidity and mortality in chronic kidney disease patients and the development of future interventions to address these causes, thereby seeking to improve the quality and length of life for persons with chronic kidney disease.