Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

血液透析开始时血管紧张素-脑啡肽酶抑制

• 批准号: 10446192
• 负责人: Finnian R McCausland
• 金额: $ 35.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446192
• 关键词: Address; Angiotensin Receptor; Angiotensins; Biological; Blood Pressure; Caliber; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Chronic Kidney Failure; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Congestive; Creatinine; Data; Development; Diabetes Mellitus; Double-Blind Method; Event; Fibrosis; Fluid overload; Frequencies; Functional disorder; Goals; Heart Atrium; Heart failure; Hemodialysis; Hypertension; Hypotension; Inferior vena cava structure; Inflammation; Kidney; Kidney Diseases; Kidney Failure; Left; Left Ventricular Mass; Left atrial structure; Maintenance; Measures; Morbidity - disease rate; Multicenter Studies; Neprilysin; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Output; Patient Care; Patients; Peptides; Performance; Perfusion; Pharmacology; Phenotype; Physiological; Pilot Projects; Placebo Control; Placebos; Population; Potassium; Predisposition; Property; Randomized; Renal function; Renin-Angiotensin System; Reporting; Residual state; Risk; Safety; Serum; Signs and Symptoms; Stress; System; Testing; Therapeutic; Time; Ultrafiltration; United States; Urea; Urine; adverse outcome; blood pressure reduction; cardiovascular risk factor; clinically relevant; design; evidence base; experience; functional decline; hemodynamics; high risk; hyperkalemia; hypertensive; improved; indexing; inhibitor; innovation; mortality; mortality risk; novel; novel therapeutic intervention; patient oriented; pilot trial; preservation; pressure; pro-brain natriuretic peptide (1-76); randomized placebo-controlled clinical trial; randomized trial; safety testing; saluretic; structural heart disease; symptomatic improvement; valsartan

PROJECT SUMMARY Each year over 107,000 patients initiate hemodialysis (HD) for the treatment of advanced kidney failure in the United States alone. The risk of death is startling, with peak mortality observed during the first two months, most of which relates to cardiovascular (CV) disease. The majority of incident HD patients are hypervolemic and have evidence of cardiac structural abnormalities, which are associated with a higher risk of adverse CV outcomes. Furthermore, patients who lose residual renal function rapidly appear to be at highest risk of adverse outcomes. Pharmacologic inhibition of the renin-angiotensin system is known to reduce CV outcomes in non-HD patients and slow the progression of kidney disease in patients with type 2 diabetes, but these beneficial effects have not been observed in the HD population. Combining an angiotensin receptor blocker with a neprilysin inhibitor has been shown to reduce CV outcomes in patients with heart failure, while at the same time slowing the rate of kidney function decline. Therefore, there is strong biologic rationale to test the effects of this therapy in incident HD patients. Thus, building on our prior data, in we propose a pilot randomized placebo-controlled parallel group clinical trial to test the safety and tolerability of sacubitril/valsartan and test the effects (vs. placebo) on the reduction of left atrial volume index and preservation of residual renal function in incident HD patients. The results of our studies will inform the design and development of a larger multi-center outcomes trial, which is urgently needed to address the unacceptably high rates of mortality in incident HD. In summary, our proposals are clinically relevant, feasible, innovative, and are supported by preliminary data. Building on the underlying pathophysiology and our experience in performance of clinical trials, our proposals have the potential to improve care for patients undergoing initiation of HD for kidney failure.

项目概要 每年有超过 107,000 名患者开始血液透析 (HD) 来治疗晚期肾衰竭 唯有美国。死亡风险令人震惊，在头两个月内观察到死亡率高峰，大多数人 其中与心血管（CV）疾病有关。大多数 HD 患者血容量过多，并且患有 心脏结构异常的证据，这与不良心血管结果的风险较高相关。 此外，迅速丧失残余肾功能的患者似乎出现不良后果的风险最高。 众所周知，药物抑制肾素-血管紧张素系统会降低非 HD 患者的心血管结局 并减缓 2 型糖尿病患者肾脏疾病的进展，但这些有益作用并没有 在 HD 人群中观察到。血管紧张素受体阻滞剂与脑啡肽酶抑制剂联合使用 已被证明可以减少心力衰竭患者的心血管结局，同时减慢心力衰竭的发生率 肾功能衰退。因此，有很强的生物学原理来测试这种疗法在事件中的效果 高清患者。 因此，根据我们之前的数据，我们提出了一项随机安慰剂对照平行组临床试验 试验测试沙库巴曲/缬沙坦的安全性和耐受性，并测试（与安慰剂相比）对减少 HD 患者的左心房容积指数和残余肾功能的保存。我们的结果 研究将为设计和开发更大规模的多中心结果试验提供信息，这是迫切需要的 解决 HD 事件中令人难以接受的高死亡率问题。 总之，我们的建议具有临床相关性、可行性、创新性，并得到初步数据的支持。 基于基本的病理生理学和我们在临床试验中的经验，我们的建议 有潜力改善因肾衰竭而接受 HD 治疗的患者的护理。