Metabolomics of Uremic Symptoms in Dialysis Patients

透析患者尿毒症症状的代谢组学

• 批准号: 10604245
• 负责人: EUGENE P. RHEE
• 金额: $ 53.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604245
• 关键词: Address; Advanced Development; Affect; Anorexia; Biochemical Pathway; Blood; Canada; Cessation of life; Chemicals; Clinical; Clinical Trials; Computational Biology; Data; Desire for food; Development; Dialysis patients; Dialysis procedure; Disease; Dose; Drowsiness; End stage renal failure; Ensure; Epidemiology; Excessive Daytime Sleepiness; Fatigue; Funding; Goals; Health Policy; Hemodialysis; Individual; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Link; Measurement; Measures; Membrane; Metabolic; Metabolism; N,N-dimethylarginine; National Center for Complementary and Integrative Health; National Institute of Nursing Research; Nausea; Pain; Participant; Patients; Persons; Phase; Physicians; Prevalence; Prospective, cohort study; Pruritus; Publishing; Quality of life; Randomized; Randomized, Controlled Trials; Research Design; Research Priority; Sampling; Sampling Studies; Symptoms; System; Technology; Testing; Time; Toxic effect; Toxin; United States National Institutes of Health; Uremia; Validation; Work; acylcarnitine; biomarker discovery; biomarker driven; cohort; common symptom; design; epidemiology study; experience; follow-up; health related quality of life; improved; insight; instrument; interdisciplinary approach; interest; metabolomics; microbiome; mitochondrial dysfunction; new technology; novel; patient oriented; persistent symptom; prevent; primary outcome; secondary outcome; solute; symptom science; symptomatic improvement; tool

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.

摘要 在美国，需要血液透析（HD）的终末期肾病（ESRD）影响了超过40万例患者， 未来十年将有一百万人开始透析。虽然HD可以预防尿毒症导致的立即死亡， 患者继续经历衰弱性尿毒症症状，包括疲劳、瘙痒和厌食， 他人这些症状很常见，每种症状的患病率均> 30%，>90%的患者有两种或两种以上的症状。 是导致健康相关生活质量（HRQOL）差的主要因素。因此，管理尿毒症 症状被认为是患者和医生的首要研究重点。然而， 尿毒症症状不明。 我们的中心假设是，残留的尿毒症代谢物，由肾脏清除的物质， 肾功能衰竭的原因有哪些？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， 不带偏见的时尚在这里，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， 用于症状评估的通用、有效工具。我们的共同主要结果将是 三种最常见的和使人衰弱的尿毒症性疾病-疲劳、瘙痒和乏力-每种都被认为是 因为它们的机制可能不同。次要结局将是：a）其他尿毒症患者的症状评分 症状（恶心、难以集中注意力、白天过度嗜睡和疼痛）和B）HRQOL。为 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 进入纵向美国/加拿大事件透析研究（LUCID），一项正在进行的多中心前瞻性研究 HD患者队列研究（N=700）。我们将单独考虑代谢物， 比较，以及使用基于系统的方法来解释代谢物的相互关系， 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 (Aim 2）在1- 10岁的LUCID随机子队列（N=300）中，代谢物与症状和HRQOL的相关性 年的后续。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）血液透析（HEMO）研究，一项NIH资助的HD剂量多中心随机对照试验 (Kt/Vurea）和透析膜。 该提案汇集了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HRQOL不佳的代谢紊乱我们的发现也将 刺激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，下游影响患者管理和卫生政策。

项目成果

A metabolomics approach identified toxins associated with uremic symptoms in advanced chronic kidney disease.

• DOI: 10.1016/j.kint.2021.10.035
• 发表时间: 2022-03
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Hu JR;Myint L;Levey AS;Coresh J;Inker LA;Grams ME;Guallar E;Hansen KD;Rhee EP;Shafi T
• 通讯作者: Shafi T

Kidney Disease Symptoms before and after Kidney Transplantation.

肾移植前后的肾脏疾病症状。

• DOI: 10.2215/cjn.19031220
• 发表时间: 2021
• 期刊: Clinical journal of the American Society of Nephrology : CJASN
• 作者: Taylor,Kathryn;Chu,NadiaM;Chen,Xiaomeng;Shi,Zhan;Rosello,Eileen;Kunwar,Sneha;Butz,Paul;Norman,SilasP;Crews,DeidraC;Greenberg,KeikoI;Mathur,Aarti;Segev,DorryL;Shafi,Tariq;McAdams-DeMarco,MaraA
• 通讯作者: McAdams-DeMarco,MaraA

Fibroblast Growth Factor 23 Regulation and Acute Kidney Injury.

• DOI: 10.1159/000517734
• 发表时间: 2022
• 期刊: Nephron
• 影响因子: 2.5
• 作者: Zhou W;Simic P;Rhee EP
• 通讯作者: Rhee EP