Determinants of Uremic Symptoms in CKD and Associations to Clinical Outcomes

尿毒症症状，包括疲倦、恶心、食欲不振、瘙痒、精神敏锐度下降、睡眠不佳，以及 感觉异常是数百万患有慢性阻塞性肺病的美国成年人的生活质量的沉重负担 肾病(CKD)。肾移植术后尿毒症多项症状改善的观察 说明滞留的溶质在其发病机制中起着因果作用。然而，横断面研究并没有 表明肾功能和尿毒症症状之间存在一致的联系，这表明其他 决定因素也必须存在。为了指导管理战略，需要进行研究以评估 肾功能与尿毒症症状之间的关系，并找出任何可修改的因素 此外，还会影响这段关系。此外，不同的被破坏的代谢途径有助于 尿毒症症状的发展尚不清楚。代谢组学技术，它涉及 对生物样本中代谢物的全面分析，有可能迅速加速 识别导致症状的尿毒症滞留溶液，导致新的治疗策略。这个 慢性肾功能不全队列(CRIC)，一项由NIDDK赞助的针对3939名慢性肾功能不全患者的研究 对肾功能和尿毒症症状进行了14年的纵向评估，创造了理想的 有机会完成我们的总体目标：确定与以下方面相关的决定因素和结果 尿毒症症状的纵向趋势，并洞察其代谢原因。我们的中心假设是 超越肾功能指标(例如，估计的肾小球滤过率[EGFR])，新颖可修改 临床因素和代谢物因素都与尿毒症症状有关，症状的趋势是 时间可以识别出不良结果风险增加的患者。在研究的目标1中，我们将量化 表皮生长因子受体变化与尿毒症症状变化的相关性及其与尿毒症的关系 开始透析时的症状。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=1800)确定与尿毒症症状相关的代谢物，并将评估 症状的代谢物标记物是否也与开始透析的风险有关。这些研究 将为有尿毒症症状的患者提供一个全面的预后图景，并提供洞察力 代谢途径紊乱与症状发展之间的关联。这样的信息是成立的 影响临床实践，并导致旨在直接改善生活质量的新疗法 对于这群病人来说。研究目标被整合到一个全面的培训计划中，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)学习生物统计学和流行病学方法的高级原理，包括混合方法 效应建模和生存分析，2)将机器学习算法应用于预测建模，以及3) 作为一名临床研究人员走向独立。

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.