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: 10600056
• 负责人: Finnian R McCausland
• 金额: $ 35.8万
• 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/10600056
• 关键词: Address; Angiotensin Receptor; Angiotensins; Biological; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Characteristics; Chronic Kidney Failure; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Creatinine; Data; Development; Diabetes Mellitus; Diameter; Double-Blind Method; Echocardiography; Event; Exclusion; 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; 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; pharmacologic; pilot trial; preservation; pressure; pro-brain natriuretic peptide (1-76); randomized placebo controlled trial; randomized placebo-controlled clinical 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.

项目摘要 每年有超过107，000名患者开始血液透析（HD）治疗晚期肾衰竭， 只有美国。死亡的风险是惊人的，在头两个月观察到死亡率高峰，大多数人 其中涉及心血管（CV）疾病。大多数HD患者都是高血容量的， 心脏结构异常的证据，与CV不良结局的风险较高相关。 此外，残余肾功能迅速丧失的患者出现不良结局的风险最高。 已知药物抑制肾素-血管紧张素系统可降低非HD患者的CV结局 并减缓2型糖尿病患者肾脏疾病的进展，但这些有益的作用并没有 在HD人群中观察到。将血管紧张素受体阻滞剂与脑啡肽酶抑制剂组合， 已被证明可降低心力衰竭患者的CV结局，同时减缓 肾功能下降。因此，有很强的生物学原理来测试这种治疗在事件中的效果。 HD患者。 因此，基于我们先前的数据，我们提出了一个试验性随机安慰剂对照平行组临床研究。 一项测试沙库巴曲/缬沙坦的安全性和耐受性的试验，并测试（与安慰剂相比） HD患者左房容积指数与残余肾功能保护的成果 研究将为更大规模的多中心结局试验的设计和开发提供信息，这是迫切需要的 以解决不可接受的高死亡率的事件HD。 总之，我们的建议是临床相关的，可行的，创新的，并得到初步数据的支持。 基于潜在的病理生理学和我们在临床试验中的经验，我们的建议 有可能改善因肾衰竭而开始HD的患者的护理。