Determinants of Uremic Symptoms in CKD and Associations to Clinical Outcomes

CKD 尿毒症症状的决定因素及其与临床结果的关联

• 批准号: 10724236
• 负责人: Kendra Elizabeth Wulczyn
• 金额: $ 4.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10724236
• 关键词: Acceleration; Adult; Anorexia; Award; Biological; Biometry; Biostatistical Methods; Cessation of life; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Investigator; Cohort Studies; Complex; Cross-Sectional Studies; Data; Data Analyses; Data Set; Development; Dialysis procedure; Epidemiologic Methods; Fatigue; Fostering; Functional disorder; Glomerular Filtration Rate; Goals; Individual; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Laboratory Markers; Lead; Learning; Link; Longitudinal trends; Master of Science; Mentors; Metabolic; Metabolic Pathway; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Nausea; Outcome; Paresthesia; Participant; Pathogenesis; Patients; Pattern; Performance; Pharmaceutical Preparations; Plasma; Play; Process; Prognosis; Provider; Proxy; Pruritus; Psyche structure; Public Health; Quality of life; Questionnaires; Renal function; Reporting; Research; Research Methodology; Research Personnel; Research Proposals; Risk; Risk Factors; Role; Severities; Socioeconomic Factors; Specimen; Survival Analysis; Symptoms; Technology; Testing; Time; Time trend; Toxin; Training; Update; Uremia; Visit; Waste Products; adjudication; adverse outcome; associated symptom; clinical care; clinical decision-making; clinical practice; cohort; comorbidity; economic determinant; experience; health related quality of life; improved; innovation; insight; machine learning algorithm; metabolomics; modifiable risk; mortality; novel; novel therapeutic intervention; novel therapeutics; patient oriented research; patient population; patient prognosis; poor sleep; predictive modeling; psychosocial; rate of change; secondary analysis; skills; socioeconomics; solute; symptom science; symptom treatment; symptomatic improvement

Uremic symptoms, including fatigue, nausea, anorexia, pruritus, decreased mental acuity, poor sleep, and paresthesia, represent a significant burden on the quality of life for millions of US adults living with chronic kidney disease (CKD). The observation that many uremic symptoms improve following kidney transplantation suggests that retained solutes play a causal role in their pathogenesis. However, cross-sectional studies do not show a consistent association between kidney function and uremic symptoms, suggesting that other determinants must also be present. In order to guide management strategies, research is needed to evaluate the association between kidney function and uremic symptoms and identify any modifiable factors that additionally influence this relationship. Furthermore, the distinct disrupted metabolic pathways that contribute to the development of uremic symptoms are unknown. Metabolomics technology, which involves the comprehensive analysis of metabolites in a biological specimen, has the potential to rapidly accelerate the identification of uremic retention solutes that drive symptoms, leading to novel therapeutic strategies. The Chronic Renal Insufficiency Cohort (CRIC), an NIDDK-sponsored study of 3,939 individuals with CKD that has over 14 years of longitudinal assessments of kidney function and uremic symptoms, creates the ideal opportunity to complete our overall objective: to identify determinants of and outcomes associated with longitudinal trends in uremic symptoms and gain insight into their metabolic causes. Our central hypothesis is that beyond metrics of kidney function (e.g. estimated glomerular filtration rate [eGFR]), novel modifiable factors, both clinical and metabolite, will be associated with uremic symptoms, and that symptom trends over time can identify patients at increased risk of adverse outcomes. In Aim 1 of the study, we will quantify the association between changes in eGFR and changes in uremic symptoms and the association of uremic symptoms with dialysis initiation. In Aim 2 we will utilize the available plasma metabolomics data for a subset of CRIC participants (N=1,800) to identify metabolites associated with uremic symptoms and will evaluate whether metabolite markers of symptoms are also associated with the risk of dialysis initiation. These studies will result in a comprehensive picture of the prognosis for patients with uremic symptoms and provide insight into associations between disrupted metabolic pathways and symptom development. Such information stands to influence clinical practice as well as lead to novel therapeutics aimed at directly improving the quality of life for this patient population. The research aims are integrated into a comprehensive training plan that includes practical mentored experiences and a Master’s Degree in Public Health and will provide Dr. Wulczyn the opportunity to 1) learn advanced principals of biostatistical and epidemiological methods, including mixed effects modelling and survival analysis, 2) apply machine learning algorithms to predictive modelling, and 3) advance towards independence as a clinical investigator.

尿毒症症状，包括疲劳、恶心、厌食、瘙痒、精神敏锐度下降、睡眠不佳和 感觉异常对数百万患有慢性病的美国成年人的生活质量造成了重大负担 肾脏疾病（CKD）。肾移植后许多尿毒症症状改善的观察 表明保留的溶质在其发病机制中发挥因果作用。然而，横断面研究并没有 显示肾功能和尿毒症症状之间存在一致的关联，这表明其他 决定因素也必须存在。为了指导管理策略，需要进行研究来评估 肾功能与尿毒症症状之间的关联，并确定任何可改变的因素 也影响这种关系。此外，独特的代谢途径被破坏，导致 尿毒症症状的发展尚不清楚。代谢组学技术，涉及 全面分析生物样本中的代谢物，有可能迅速加速 识别引起症状的尿毒症潴留溶质，从而产生新的治疗策略。这 慢性肾功能不全队列 (CRIC)，这是一项由 NIDDK 赞助的研究，对 3,939 名 CKD 患者进行了研究， 对肾功能和尿毒症症状进行超过 14 年的纵向评估，创造了理想的 完成我们总体目标的机会：确定与相关的决定因素和结果 尿毒症症状的纵向趋势并深入了解其代谢原因。我们的中心假设是 除了肾功能指标（例如估计肾小球滤过率 [eGFR]）之外，新颖的可修改 临床和代谢因素都与尿毒症症状相关，并且症状趋势超过 时间可以识别出不良结果风险增加的患者。在本研究的目标 1 中，我们将量化 eGFR 变化与尿毒症症状变化之间的关联以及尿毒症症状的关联 开始透析时出现的症状。在目标 2 中，我们将利用可用的血浆代谢组学数据来研究一部分 CRIC 参与者 (N=1,800) 确定与尿毒症症状相关的代谢物并评估 症状的代谢标志物是否也与透析开始的风险相关。这些研究 将全面了解尿毒症症状患者的预后并提供见解 代谢途径破坏与症状发展之间的关联。此类信息站 影响临床实践并开发旨在直接改善生活质量的新疗法 对于这个患者群体。研究目标被纳入综合培训计划中，其中包括 实践指导经验和公共卫生硕士学位将为 Wulczyn 博士提供 有机会 1) 学习生物统计和流行病学方法的高级原理，包括混合方法 效果建模和生存分析，2) 将机器学习算法应用于预测建模，以及 3) 作为一名临床研究者，迈向独立。

项目成果

One-Year Pruritus Trends Among Patients Receiving Hemodialysis and Associated Outcomes.

接受血液透析的患者一年瘙痒趋势及相关结果。

• DOI: 10.1053/j.ajkd.2023.08.004
• 发表时间: 2023
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Wulczyn,KendraE;Steele,DavidJR
• 通讯作者: Steele,DavidJR