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

项目总结 心血管疾病是慢性肾脏疾病(CKD)患者的主要死亡原因。 肾病分期(ESRD)。肺动脉高压(PH)是一种被低估的心血管并发症 肾脏疾病的风险高达60%患有终末期肾病，在这种情况下，PH使死亡风险增加3倍。尽管它的 尽管ESRD的发病率和发病率很高，但对PH的病理生理学仍知之甚少。海流 病理生理学范式强调容量超负荷是ESRD中PH的主要原因，但容量去除 通过透析只在一小部分病例中解决了PH。埃德蒙斯顿博士的长期目标是发现新的 通过严格的前瞻性研究和探索新的治疗方法来治疗终末期肾病的PH的病理生理指标 通过有效的临床试验为这些目标量身定做。根据已发表的4772名患者的初步数据 CKD-ESRD，&GT；60%的PH患者右心导管术时肺血管阻力升高。这 肺血管阻力增加涉及容量超负荷以外的机制，从而促进 肺血管收缩和重塑。这一提议的中心假设是体积无关 肾功能减退和血液透析加重引起的血管生物学改变有助于 ESRD的PH值。循环中血管活性因子非对称性二甲基精氨酸(ADMA)和 引起肺血管重构和血管收缩的5-羟色胺可能是致病的环节。 肾功能减退与PH之间的关系。血液透析进一步引入了PH的可能危险因素： 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，清除 一氧化氮(NO)；而反复的透析中低氧血症通过频繁的缺氧促进PH- 诱导血管收缩。在一项前瞻性研究中，这项提案将调查其中每一项之间的关联 150例终末期肾病维持性血液透析患者血容量非依赖性因素与PH的关系 研究ADMA和5-羟色胺作为ESRD中PH的机制；AIM 2将建立亚临床溶血和 作为ESRD中PH的血液透析相关机制，受损的血红蛋白清除；Aim 3将量化 ESRD患者透析内和透析外低氧血症的程度及其与PH的关系。受新技术支持 重新提交的初步数据，PH将通过三尖瓣返流速度(TRV)估计 超声波心动图。一项由50名经初步评估发现患有肥厚症的患者组成的纵向亚队列将确定 这些危险因素的变化如何与6个月后的PH进展相关(目标1-3)。为了辨别 血液透析的贡献超过终末期肾病的影响，这项建议还将纳入10名终末期肾病患者 进行腹膜透析(目标1-3)。这些科学目标的实现和事业的完成 这项提议的发展活动，加上经验丰富的指导和强有力的机构支持，将 埃德蒙斯顿博士将担任未来R01拨款的首席研究员，以支持介入试验 这是ESRD和前瞻性研究的目标，这些研究确定了CKD早期阶段PH的危险因素。

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.