Metabolomics of Uremic Symptoms in Dialysis Patients

摘要 终末期肾病(ESRD)需要血液透析(HD)，影响美国40多万患者 在接下来的十年里，将有100万人开始透析。虽然HD可以防止尿毒症导致的直接死亡， 患者继续经历衰弱的尿毒症症状，包括疲倦、瘙痒和厌食症 其他。这些症状是常见的--每种症状的患病率为30%，90%的患者有两种或两种或两种以上的症状 更多-并且是与健康相关的生活质量差(HRQOL)的主要因素。因此，管理尿毒症 症状被患者和医生视为研究的重中之重。然而，其根本原因是 尿毒症症状尚不清楚。 我们的中心假设是残留的尿毒症代谢物，即被肾脏清除的物质 积聚在肾衰竭中，是尿毒症症状的起因。新兴的代谢组学技术提供了 这是一个前所未有的机会，可以同时评估数千种血液代谢物 不偏不倚的时尚。在这里，我们寻求使用领先的非靶向代谢组学平台来发现和验证 两个大型血液透析队列中与尿毒症症状相关的尿毒症毒素 常见的、经过验证的症状评估工具。我们的共同初选结果将是 三种最常见和最令人衰弱的尿毒症症状--疲劳、瘙痒和厌食症--每一种都被认为 因为它们的机制可能不同。次要结果将是：a)其他尿毒症的症状评分 症状(恶心、注意力不集中、白天嗜睡和疼痛)和b)HRQOL。对于 发现阶段(目标1)，我们将在研究中确定与症状和HRQOL相关的新代谢物 正在进行的多中心前瞻性美国/加拿大事件透析纵向研究(LUID)的条目 血液透析患者队列研究(N=700)。我们将单独考虑代谢物，根据多个因素进行调整 比较，以及使用基于系统的方法来解释代谢物之间的相互关系并 在已建立的生化途径的背景下评估结果。接下来，我们将进行内部验证 (目标2)在随机亚群组(N=300)中，1-2岁的Lucid代谢物与症状和HRQOL的相关性。 一年的随访。对于外部验证(目标3)，我们将在随机子队列中确认这些关联 (n=300)美国国立卫生研究院资助的HD剂量多中心随机对照试验的血液透析(HEMO)研究 (KT/V尿素)和透析膜。 这项建议汇集了ESRD流行病学、代谢组学、计算 生物学、尿毒症毒性和症状科学。如果成功，我们的集体努力将提供宝贵的见解 导致尿毒症症状和低HRQOL的代谢紊乱。我们的发现也将 促进尿毒症毒性的机制研究，促进新治疗方法的开发，并为设计提供信息 以患者为中心的临床试验，对患者管理和卫生政策的下游影响。

ABSTRACT End stage renal disease (ESRD) requiring hemodialysis (HD) affects >400,000 patients in the US, and over one million people will start dialysis in the next decade. While HD prevents immediate death due to uremia, patients continue to experience debilitating uremic symptoms including fatigue, pruritus, and anorexia among others. These symptoms are common—the prevalence of each is >30%, and >90% of patients have two or more—and are a major contributor to poor health-related quality of life (HRQOL). Thus, managing uremic symptoms is considered a top research priority by patients and physicians. However, the underlying cause of uremic symptoms is unknown. Our central hypothesis is that retained uremic metabolites, substances cleared by the kidney that accumulate in kidney failure, are the cause of uremic symptoms. Emerging metabolomics technologies provide an unprecedented opportunity to simultaneously assess thousands of blood metabolites in an efficient and unbiased fashion. Here, we seek to use a leading untargeted metabolomics platform to discover and validate the uremic toxins associated with uremic symptoms across two large hemodialysis cohorts that utilized a common, validated tool for symptom assessment. Our co-primary outcomes will be symptom scores for the three most common and debilitating uremic symptoms—fatigue, pruritus, and anorexia—each considered separately as their mechanisms may differ. Secondary outcomes will be: a) symptom scores for other uremic symptoms (nausea, difficulty concentrating, excessive daytime sleepiness, and pain) and b) HRQOL. For the discovery phase (Aim 1), we will identify novel metabolites associated with symptoms and HRQOL at study entry in the Longitudinal US/Canada Incident Dialysis Study (LUCID), an ongoing multicenter prospective cohort study of HD patients (N=700). We will consider metabolites individually, adjusting for multiple comparisons, as well as use systems-based approaches to account for metabolite inter-correlations and to assess results in the context of established biochemical pathways. Next, we will conduct internal validation (Aim 2) of metabolite associations with symptoms and HRQOL in a random sub-cohort (N=300) of LUCID at 1- year follow-up. For external validation (Aim 3), we will confirm these associations in a random sub-cohort (N=300) of the Hemodialysis (HEMO) Study, an NIH-funded multicenter randomized controlled trial of HD dose (Kt/Vurea) and dialysis membranes. This proposal brings together leading expertise in ESRD epidemiology, metabolomics, computational biology, uremic toxicity, and symptom science. If successful, our collective effort will provide valuable insight into the metabolic derangements responsible for uremic symptoms and poor HRQOL. Our findings will also spur mechanistic studies of uremic toxicity, advance the development of new treatments, and inform the design of patient-centered clinical trials, with downstream implications for patient management and health policy.