Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

项目总结 每年有超过107,000名患者开始血液透析(HD)以治疗晚期肾功能衰竭 单单是美国。死亡的风险是惊人的，在头两个月观察到了死亡率的峰值，大多数 其中一些与心血管疾病有关。大多数发生的HD患者都是高容量血症患者 心脏结构异常的证据，这与心血管不良结局的风险较高有关。 此外，快速丧失残余肾功能的患者似乎具有最高的不良结局风险。 已知对肾素-血管紧张素系统的药物抑制可降低非HD患者的心血管结局 并延缓2型糖尿病患者肾脏疾病的进展，但这些有益效果并没有 已在HD人群中观察到。血管紧张素受体阻滞剂和奈普利辛抑制剂联合使用有 已被证明可以减少心力衰竭患者的心血管结局，同时减缓 肾功能下降。因此，有很强的生物学基础来检验这种疗法在突发事件中的效果。 HD患者。 因此，在我们先前数据的基础上，我们提出了一个试点的随机安慰剂对照的平行组临床 试验测试萨舒比利/valsartan的安全性和耐受性，并测试它们(与安慰剂相比)对减少 急性血液透析患者左房容量指数与残存肾功能的保存我们的结果是 研究将为设计和开发一个更大的多中心结果试验提供信息，这是迫切需要的 以解决HD事件死亡率高得令人无法接受的问题。 总而言之，我们的建议具有临床相关性、可行性、创新性，并得到了初步数据的支持。 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 有潜力改善对肾衰竭患者开始透析的护理。

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.