Determinants of Uremic Symptoms in CKD and Associations to Clinical Outcomes

尿毒症症状，包括疲劳、恶心、厌食、瘙痒、精神敏锐度下降、睡眠不良和 感觉异常是数百万美国成年人生活质量的重大负担， 肾病（CKD）。肾移植术后多种尿毒症症状改善的观察 表明保留的溶质在其发病机制中起因果作用。然而，横截面研究并不 显示肾功能和尿毒症症状之间的一致关联，表明其他 决定因素也必须存在。为了指导管理战略，需要进行研究， 肾功能和尿毒症症状之间的联系，并确定任何可改变的因素， 也影响了这种关系。此外，不同的破坏代谢途径，有助于 尿毒症症状的发展是未知的。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 确定尿毒症滞留溶质驱动症状，导致新的治疗策略。的 慢性肾功能不全队列（CRIC），一项NIDDK申办的3，939例CKD患者的研究， 超过14年的肾功能和尿毒症症状的纵向评估， 完成我们总体目标的机会：确定与下列方面有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。我们的核心假设是 除了肾功能指标（例如估计的肾小球滤过率[eGFR]），新的可修改的 临床因素和代谢物因素都与尿毒症症状相关， 时间可以识别出不良后果风险增加的患者。在研究的目标1中，我们将量化 eGFR变化与尿毒症症状变化之间的相关性以及尿毒症 透析开始时的症状。在目标2中，我们将利用现有的血浆代谢组学数据， CRIC参与者（N= 1，800），以确定与尿毒症症状相关的代谢物，并将评估 症状的代谢物标志物是否也与透析开始的风险相关。这些研究 将对尿毒症症状患者的预后进行全面了解， 代谢途径紊乱和症状发展之间的联系。这些信息表明， 影响临床实践，并导致旨在直接改善生活质量的新疗法 对于这个病人群体。研究目标被纳入一个全面的培训计划，其中包括 实践指导经验和公共卫生硕士学位，并将为Wulczyn博士提供 有机会1）学习生物统计学和流行病学方法的先进原理，包括混合 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） 作为临床研究者走向独立。

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.