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

终末期肾病肺动脉高压的新机制和治疗靶点（K23）

• 批准号: 10666408
• 负责人: Daniel Edmonston
• 金额: $ 18.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666408
• 关键词: Adverse effects; Affect; Binding; Biology; Blood Vessels; Cardiac Catheterization Procedures; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic Kidney Failure; Circulation; Clinical Investigator; Clinical Trials; Complication; Data; Dialysis procedure; Dose; Echocardiography; End stage renal failure; Enrollment; Excision; Functional disorder; Future; Genotype; Goals; Grant; Haptoglobins; Hemodialysis; Hemoglobin; Hemolysis; High Prevalence; Hour; Hypoxemia; Hypoxia; Impairment; Institution; Intervention Studies; Intervention Trial; Kidney Diseases; Kidney Failure; Lead; Link; Maintenance; Mentorship; Morbidity - disease rate; N,N-dimethylarginine; Nitric Oxide; Observational Study; Outcome; Oxygen; Pathogenicity; Patient-Focused Outcomes; Patients; Peripheral; Peritoneal Dialysis; Persons; Positioning Attribute; Preparation; Prevalence; Principal Investigator; Proliferating; Prospective Studies; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulse Oximetry; Recurrence; Renal function; Research; Respiratory Disease; Risk; Risk Factors; Serotonin; Severities; Sleep Disorders; Smooth Muscle; Testing; Therapeutic; career development; cohort; comorbidity; experience; high risk; improved; improved outcome; individualized medicine; mortality risk; novel; novel strategies; novel therapeutics; prevent; pulmonary vascular remodeling; pulmonary vasoconstriction; skills; therapeutic target; vasoconstriction

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.

项目概要 心血管疾病是慢性肾病 (CKD) 和终末期患者死亡的主要原因 阶段性肾病 (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，尽管 PH 会导致死亡风险增加 3 倍。 ESRD 的患病率和发病率较高，但目前对 PH 的病理生理学仍知之甚少。 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 埃德蒙斯顿博士的长期目标是通过透析解决一小部分病例。 通过严格的前瞻性研究和研究新疗法来确定 ESRD 中 PH 的病理生理学目标 根据已发表的 4772 名患者的初步数据，通过有效的临床试验针对这些目标进行定制。 CKD-ESRD，> 60% 的 PH 病例在右心导管检查时肺血管阻力升高。 肺血管阻力增加涉及容量超负荷以外的机制，从而促进 该提议的中心假设是与容量无关。 肾功能下降引起的血管生物学变化以及血液透析加剧导致 ESRD 中的 PH 值升高，血管活性因子不对称二甲基精氨酸 (ADMA) 和 导致肺血管重塑和血管收缩的血清素可能是致病环节 肾功能下降和 PH 之间的关系进一步引入了 PH 的假定危险因素： 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，从而清除血红蛋白 一氧化氮 (NO)；反复透析中低氧血症通过频繁发生的缺氧促进 PH 在一项前瞻性研究中，该提案将调查其中每一项的关联。 150 名接受维持性血液透析的 ESRD 患者中与 PH 相关的容量独立因素：目标 1 将 研究 ADMA 和血清素作为 ESRD 中 PH 的机制；目标 2 将建立亚临床溶血和 血红蛋白清除受损是 ESRD 中血液透析相关 PH 的机制；目标 3 将量化 透析内和透析外低氧血症的程度，并确定其与 ESRD 中 PH 的关系，得到新的支持。 本次重新提交的初步数据，PH 将通过三尖瓣反流速度 (TRV) 估算 超声心动图由 50 名在初步评估中发现患有 PH 的患者组成的纵向亚组将进行确定。 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）。 血液透析的贡献高于 ESRD 的影响，该提案还将招募 10 名 ESRD 患者 接受腹膜透析（目标 1-3）。执行这些科学目标并完成职业生涯。 该提案的制定活动，加上经验丰富的指导和强有力的机构支持，将 让 Edmonston 博士担任未来 R01 拨款的首席研究员，以支持介入试验 针对 ESRD 中 PH 的前瞻性研究以及确定 CKD 早期阶段 PH 危险因素的前瞻性研究。

项目成果

Noninvasive Risk Score to Screen for Pulmonary Hypertension With Elevated Pulmonary Vascular Resistance in Diseases of Chronic Volume Overload.

• DOI: 10.1016/j.amjcard.2021.08.016
• 发表时间: 2021-11-15
• 期刊: AMERICAN JOURNAL OF CARDIOLOGY
• 影响因子: 2.8
• 作者: Edmonston, Daniel L.;Matsouaka, Roland;Shah, Svati H.;Rajagopal, Sudarshan;Wolf, Myles
• 通讯作者: Wolf, Myles