Urea for chronic hyponatremia: a pilot study

项目总结/摘要 低钠血症是临床上最常见的电解质紊乱。急性和/或重度 低钠血症通常与显著的症状、较轻的和更慢性的形式相关， 低钠血症在临床上仍然不明显，因为大脑有效地适应低的细胞外渗透压。 然而，最近的证据表明，即使是轻微的低钠血症也与微妙的神经认知有关。 缺陷、步态障碍、福尔斯、骨折和骨质疏松症，以及死亡率增加。当前治疗 低钠血症的干预措施，包括液体限制和袢利尿剂，缺乏临床试验数据来支持其 疗效差，通常与依从性差有关。血管加压素拮抗剂（vaptans）的发现 提供了一种靶向低钠血症最常见机制的新药，即，加压素升高 尽管在临床试验中证明了vaptans的功效，但它们的使用受到高成本以及 与肝损伤风险和快速纠正低钠血症的可能性相关的安全性问题。因此，尽管 慢性非重度低钠血症相关的显著发病率和死亡率， 明确有效、安全、耐受性良好且价格合理的治疗。 欧洲的小型病例系列表明，口服尿素治疗 低钠血症然而，在美国，尿素还不能用于治疗低钠血症， 就在最近我们的小组最近发表了第一个也是唯一一个研究，描述了 美国一种新的口服尿素制剂用于低钠血症住院患者。然而，我们的是一个 回顾性研究仅限于住院患者。关于尿素治疗糖尿病的疗效的大型临床试验数据 在慢性低钠血症患者中缺乏以患者为中心的结局预防。现时的建议 是一项试点研究，旨在确定招募慢性低钠血症门诊患者的可行性 进入尿素的研究，确定尿素对患者的可接受性，并探讨该试剂对血浆的影响 钠水平、神经认知功能和姿势稳定性。我们将招募30名患有慢性 非重度低钠血症，并将其随机分配至口服尿素或无药物治疗，持续42天。 在该初始阶段之后，所有患者将有10天的洗脱期，随后是42天的阶段，其中 最初随机分配至无药物治疗组的受试者将接受尿素治疗，最初接受尿素治疗的受试者将接受 没有药物治疗。我们将收集关于招募难易程度、患者对尿素的依从性和不良反应的数据。 与其使用有关的事件。我们将监测患者的血浆钠、神经认知功能和姿势稳定性 在研究过程中。本初步研究的可行性、可接受性和概念验证/有效性数据 将确认我们小组的能力，并将告知一个大型临床试验的设计，将评估 尿素预防慢性非重度低钠血症严重临床结局的有效性。

PROJECT SUMMARY/ABSTRACT Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous as the brain effectively adapts to the low extracellular osmolality. However, recent evidence suggests that even mild hyponatremia is associated with subtle neurocognitive deficits, gait disturbances, falls, fractures, and osteoporosis, as well as increased mortality. Current therapeutic interventions for hyponatremia, including fluid restriction and loop diuretics lack clinical trial data to support their efficacy and are commonly associated with poor adherence. The discovery of vasopressin antagonists (vaptans) provided a new drug class targeting the most common mechanism of hyponatremia, i.e., elevated vasopressin. Despite the demonstrated efficacy of vaptans in clinical trials, their use has been limited by high cost as well as safety concerns related to risk of liver injury and the potential for rapid correction of hyponatremia. Thus, despite the significant morbidity and mortality associated with chronic non-severe hyponatremia, there is a paucity of definitively effective, safe, well-tolerated, and reasonably priced treatments. Small European case series have suggested that oral urea is safe and effective for the treatment of hyponatremia. However, urea has not been available for the treatment of hyponatremia in the United States until very recently. Our group recently published the first and only study describing the effectiveness and safety of a new American formulation of oral urea among hospitalized patients with hyponatremia. However, ours was a retrospective study limited to hospitalized patients. Data from large clinical trials on the efficacy of urea for the prevention of patient-centered outcomes in those with chronic hyponatremia are lacking. The current proposal is a pilot study that seeks to establish the feasibility of recruiting ambulatory patients with chronic hyponatremia into a study of urea, determine the acceptability of urea to patients, and explore the effect of this agent on plasma sodium level, neurocognitive function, and postural stability. We will recruit 30 ambulatory patients with chronic non-severe hyponatremia and randomize them to oral urea or no drug treatment for a period of 42 days. Following this initial phase, all patients will have a 10-day washout period, followed by a 42 day period in which subjects initially randomized to no drug therapy will receive urea and those initially treated with urea will receive no drug therapy. We will collect data regarding the ease of recruitment, patient adherence to urea, and adverse events related to its use. We will monitor patients’ plasma sodium, neurocognitive function, and postural stability over the course of the study. The feasibility, acceptability, and proof of concept/efficacy data from this pilot study will confirm our group’s capacity to conduct, and will inform the design of a large clinical trial that will assess the efficacy of urea for the prevention of serious clinical outcomes of chronic non-severe hyponatremia.