Novel Mechanisms and Therapeutic Targets for Pulmonary Hypertension in End-Stage Renal Disease (K23)

项目摘要 心血管疾病是慢性肾病（CKD）和终末期肾病患者的主要死亡原因， 肾疾病分期（ESRD）。肺动脉高压（PH）是一种未被充分认识的心血管并发症 肾脏疾病影响高达60%的ESRD患者，其中PH使死亡风险增加3倍。尽管 尽管ESRD的患病率和发病率很高，但PH的病理生理学仍然知之甚少。当前 病理生理学范式强调容量超负荷是ESRD PH的主要原因，但容量清除 只有一小部分病例的PH值可以通过透析得到缓解。埃德蒙斯顿博士的长期目标是确定新的 通过严格的前瞻性研究，确定ESRD中PH的病理生理学靶点，并研究新疗法 通过有效的临床试验针对这些目标进行定制。基于4772例患者的已发表初步数据， CKD-ESRD，> 60%的PH患者右心导管检查肺血管阻力增高。这 肺血管阻力增加暗示了容量超负荷以外的机制， 肺血管收缩和重塑。该建议的核心假设是， 由肾功能下降引起的血管生物学变化和血液透析加剧的血管生物学变化有助于 ESRD中的PH。血管活性因子不对称二甲基精氨酸（ADMA）和 引起肺血管重塑和血管收缩的5-羟色胺可能是致病环节 血液透析进一步引入了PH的推定风险因素： 血液透析引起的亚临床溶血将游离血红蛋白（Hb）释放到循环中， 一氧化氮（NO）;和反复透析中低氧血症通过频繁的缺氧发作促进PH- 引起血管收缩。在一项前瞻性研究中，本提案将调查这些因素中每一个的关联性。 150例接受维持性血液透析的ESRD患者中PH的容量非依赖性因素：目的1将 研究ADMA和5-羟色胺作为ESRD中PH的机制;目的2将建立亚临床溶血， 血红蛋白受损作为ESRD中PH的血液透析相关机制;目的3将量化 透析中和透析外低氧血症的程度，并确定其与ESRD中PH的相关性。支持新 本次重新提交的初步数据，将通过三尖瓣返流速度（TRV）估计PH， 超声心动图在初始评估时发现患有PH的50名患者的纵向子队列将确定 6个月后这些风险因素的变化如何与PH进展相关（目的1 - 3）。辨别 血液透析的贡献高于ESRD的影响，该提案还将入组10例ESRD患者 接受腹膜透析（目标1 - 3）。这些科学目标的执行和职业生涯的完成 本提案的发展活动，沿着经验丰富的指导和强有力的机构支持，将 将Edmonston博士定位为未来R01赠款的主要研究者，以支持干预性试验 针对ESRD中PH的前瞻性研究和在CKD早期阶段确定PH风险因素的前瞻性研究。

PROJECT SUMMARY Cardiovascular disease is the leading cause of death for persons with chronic kidney disease (CKD) and end- stage renal disease (ESRD). Pulmonary hypertension (PH) is an underappreciated cardiovascular complication of kidney disease that affects up to 60% with ESRD, in whom PH increases the risk of mortality 3-fold. Despite its high prevalence and morbidity in ESRD, the pathophysiology of PH remains poorly understood. The current pathophysiologic paradigm emphasizes volume overload as the main cause of PH in ESRD, but volume removal through dialysis resolves PH in only a fraction of cases. Dr. Edmonston’s long-term goal is to identify novel pathophysiologic targets for PH in ESRD through rigorous prospective studies and investigate new therapies tailored to these targets through efficient clinical trials. Based on published preliminary data in 4772 patients with CKD-ESRD, >60% of PH cases had elevated pulmonary vascular resistance on right heart catheterization. This increased pulmonary vascular resistance implicates mechanisms beyond volume overload which promote pulmonary vasoconstriction and remodeling. The central hypothesis of this proposal is that volume-independent changes in vascular biology caused by reduced kidney function and exacerbated by hemodialysis contribute to PH in ESRD. Increased circulating levels of the vasoactive factors asymmetrical dimethylarginine (ADMA) and serotonin, which cause pulmonary vascular remodeling and vasoconstriction, may serve as pathogenic links between reduced kidney function and PH. Hemodialysis further introduces putative risk factors for PH: subclinical hemolysis caused by hemodialysis releases free hemoglobin (Hb) into circulation that scavenges nitric oxide (NO); and recurrent intradialytic hypoxemia promotes PH through frequent episodes of hypoxia- induced vasoconstriction. In a prospective study, this proposal will investigate the association of each of these volume-independent factors with PH in 150 patients with ESRD receiving maintenance hemodialysis: Aim 1 will investigate ADMA and serotonin as mechanisms of PH in ESRD; Aim 2 will establish subclinical hemolysis and impaired hemoglobin scavenge as hemodialysis-associated mechanisms of PH in ESRD; Aim 3 will quantify the extent of intra- and extradialytic hypoxemia and define its association with PH in ESRD. Supported by new preliminary data for this resubmission, PH will be estimated by tricuspid regurgitant velocity (TRV) on echocardiogram. A longitudinal subcohort of 50 patients found to have PH on initial assessment will determine how changes in these risk factors associate with PH progression after 6 months (Aims 1-3). To discern the contribution of hemodialysis above the influence of ESRD, this proposal will also enroll 10 patients with ESRD undergoing peritoneal dialysis (Aims 1-3). Execution of these scientific aims and completion of the career development activities of this proposal, along with experienced mentorship and strong institutional support, will position Dr. Edmonston to serve as the Principal Investigator on future R01 grants to support interventional trials that target PH in ESRD and prospective studies which identify risk factors for PH in earlier stages of CKD.