Elucidating the Biology of Cardiovascular Risk in Hemodialysis Patients Using Proteomics

项目总结 美国有500,000名终末期肾病(ESRD)血液透析(HD)患者 死亡率极高，每年约为18%，其中50%死于心血管疾病 疾病(CVD)：即动脉粥样硬化性CVD、心力衰竭和心脏性猝死。有效的方法来实现 HD人群缺乏预防、治疗和风险分层。医疗疗法是 对没有ESRD的患者有效，如他汀类药物，当在 随机临床试验。具有讽刺意味的是，传统的心血管疾病危险因素，如高胆固醇血症、肥胖和 在这些患者中，与高血压相比，高血压与心脑血管疾病的预后呈相反的相关性 普通人口。我们的提案解决了在这些领域取得进展的主要障碍，包括：1) 对血液透析患者生物学紊乱的认识不足，导致心血管疾病预后不佳；2)失败 将HD人群中的心血管疾病视为一个复杂的、潜在的异质实体，需要 使用个性化的CVD模型及其风险进行CVD风险分层的个性化方法 因素是可以修改的。循环蛋白水平可作为心血管疾病风险的可修改生物标志物 治疗并阐明致病的生物学途径和机制。我们计划利用先进的 改良适配子分析(SOMAscan)--仅从175µL血浆中测定~5000个蛋白质 敏感性和特异性。到目前为止，还没有研究利用大规模的蛋白质组学来了解结果和 终末期肾病HD患者的生物学机制。在目标1中，我们建议研究与 慢性肾功能不全队列(CRIC)中649名有慢性肾功能不全(CRIC)患者的临床心血管结局 或在HD开始后进行更多的研究访问，并在408名参与者中验证我们的发现在预测 ESRD研究中的心律失常和心血管风险。在目标2中，我们将研究蛋白质的变化 在频繁的血液透析网络中与左心室质量的进展或退化有关，以及 在CRIC中验证我们的发现。蛋白质组学将在2/3的时间间隔1-2年的两个时间点进行测量 1324名参与者，这样我们就可以研究单个时间点的蛋白质以及蛋白质的轨迹。我们将聘用 创新方法，包括支持参与者不同基线风险的分层COX分析 有和没有心血管疾病，以及风险模型的随时间变化的协变量，以适应 我们对蛋白质变化的分析。不可知性和靶向途径分析将阐明生物网络 在蛋白质预测指标中。在实现这些目标的过程中，我们将创造准确、个性化和可变的风险 血液透析患者心血管事件模型的建立。我们将确定迄今未知的蛋白质和生物途径 与CVD相关；其中一些最终可能成为ESRD介入策略的靶点 HD患者，他们非常需要新的治疗方法来改善他们糟糕的结果。

PROJECT SUMMARY The 500,000 patients in the United States with end-stage renal disease (ESRD) on hemodialysis (HD) suffer extraordinarily high rates of mortality at ~18% per year, with 50% of these deaths attributed to cardiovascular disease (CVD): namely, atherosclerotic CVD, heart failure, and sudden cardiac death. Effective approaches for prevention, treatment and risk stratification in the HD population are lacking. Medical therapies that are effective in patients without ESRD, such as statins, are not beneficial for patients with ESRD when tested in randomized clinical trials. Ironically, traditional CVD risk factors, such as hypercholesterolemia, obesity, and hypertension, have `reverse' associations with CVD outcomes among these patients as compared to the general population. Major obstacles to progress in these areas that are addressed in our proposal include: 1) poor understanding of the disturbed biology in patients on HD that leads to poor CVD outcomes; and 2) failure to consider CVD in the HD population as a complex, potentially heterogeneous entity that calls for a personalized approach to CVD risk stratification using CVD models that are individualized and whose risk factors are modifiable. Circulating protein levels can serve as modifiable biomarkers for CVD risk, guide therapy and elucidate causal biological pathways and mechanisms. We plan to take advantage of an advanced modified aptamer assay (SOMAscan) that measures ~ 5000 proteins in just 175µl of plasma with high sensitivity and specificity. To date, no studies have utilized large-scale proteomics to understand outcomes and biological mechanisms in patients with ESRD on HD. In Aim 1, we propose to study proteins associated with clinical CVD outcomes in 649 participants of the Chronic Renal Insufficiency Cohort (CRIC) who have had one or more study visits after initiation of HD, and validate our findings in 408 participants in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD study. In Aim 2, we will investigate changes in proteins that associate with progression or regression of left ventricular mass in the Frequent Hemodialysis Network, and validate our findings in CRIC. Proteomics will be measured at two time-points 1-2 years apart in 2/3 of the 1324 participants so that we may study single time-point proteins as well as protein trajectories. We will employ innovative methods, including stratified Cox analyses that support differing baseline hazards for participants with and without CVD, and time-dependent covariates for risk models, to accommodate intervening events in our analysis of protein changes. Agnostic and targeted pathway analyses will elucidate biological networks among protein predictors. In carrying out these Aims we will create accurate, personalized and mutable risk models for CVD events in HD patients. We will identify heretofore-unknown proteins and biological pathways associated with CVD; some of these may eventually become targets for interventional strategies for ESRD patients on HD, who are in great need of new therapies to improve their poor outcomes.