BACKGROUND Loop diuretics have well-described toxicities, and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Nonrenal removal of sodium directly across the peritoneal membrane (direct sodium removal [DSR]) with a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal. METHODS This article describes the preclinical development and first-in-human proof of concept for DSR. Sodium-free 10% dextrose was used as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, and scalability and to determine the effect of experimental heart failure. In the human study, participants with end-stage renal disease on peritoneal dialysis (PD) underwent randomization and crossover to either a 2-hour dwell with 1 L DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary end point was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary end point was difference in sodium removal between DSR and standard PD solution. RESULTS Porcine experiments revealed that 1 L DSR solution removed 4.1±0.4 g sodium in 2 hours with negligible off-target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (P=0.005). In the setting of experimental heart failure with elevated right atrial pressure, sodium removal was ≈4 times greater than in healthy animals (P<0.001). In the human proof-of-concept study, DSR solution was well tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable, and off-target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 g) compared with standard PD solution (1.0±0.3 g; P<0.0001). CONCLUSIONS DSR was well tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in heart failure is warranted. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03801226.

中文翻译：

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使用零钠溶液腹膜直接除钠的人类首次体验：容量过载的新候选疗法。

背景环利尿剂具有充分描述的毒性，并且对这些药剂失去反应是常见的。需要替代策略来维持心力衰竭 (HF) 中的血容量。使用无钠渗透溶液直接通过腹膜非肾性去除钠（直接去除钠 [DSR]）应该会导致大量钠的提取，而脱靶溶质去除有限。方法 本文描述了 DSR 的临床前开发和首次人体概念验证。无钠的 10% 葡萄糖用作 DSR 溶液。进行猪实验以研究最佳停留时间、安全性和可扩展性，并确定实验性心力衰竭的影响。在人体研究中，接受腹膜透析 (PD) 的终末期肾病参与者进行随机化和交叉，以使用 1 L DSR 溶液或标准 PD 溶液（Dianeal 4.25% 葡萄糖，Baxter）停留 2 小时。主要终点是在没有明显不适或不良事件的情况下完成 2 小时的停留，次要终点是 DSR 和标准 PD 溶液之间的钠去除差异。结果 猪实验表明，1 L DSR 溶液在 2 小时内去除 4.1±0.4 g 钠，脱靶溶质去除可忽略不计，血清电解质总体稳定。增加通过腹膜循环的 DSR 溶液的体积会增加钠的去除并显着降低血浆体积 (P=0.005)。在右心房压力升高的实验性心力衰竭的情况下，钠去除率是健康动物的 ≈4 倍（P<0.001）。在人体概念验证研究中，DSR 解决方案具有良好的耐受性，并且与显着的不适或不良事件无关。血浆电解质浓度稳定，脱靶溶质去除可以忽略不计。与标准 PD 溶液 (1.0±0.3 g; P<0.0001) 相比，DSR (4.5±0.4 g) 的钠去除率显着更高。结论 DSR 在动物和人类受试者中均具有良好的耐受性，并且比标准 PD 溶液产生更大的钠去除。需要进一步研究评估使用 DSR 作为预防和治疗心力衰竭高血容量的方法。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。DSR 溶液具有良好的耐受性，并且与显着的不适或不良事件无关。血浆电解质浓度稳定，脱靶溶质去除可以忽略不计。与标准 PD 溶液 (1.0±0.3 g; P<0.0001) 相比，DSR (4.5±0.4 g) 的钠去除率显着更高。结论 DSR 在动物和人类受试者中均具有良好的耐受性，并且比标准 PD 溶液产生更大的钠去除。需要进一步研究评估使用 DSR 作为预防和治疗心力衰竭高血容量的方法。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。DSR 溶液具有良好的耐受性，并且与显着的不适或不良事件无关。血浆电解质浓度稳定，脱靶溶质去除可以忽略不计。与标准 PD 溶液 (1.0±0.3 g; P<0.0001) 相比，DSR (4.5±0.4 g) 的钠去除率显着更高。结论 DSR 在动物和人类受试者中均具有良好的耐受性，并且比标准 PD 溶液产生更大的钠去除。需要进一步研究评估使用 DSR 作为预防和治疗心力衰竭高血容量的方法。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。与标准 PD 溶液 (1.0±0.3 g; P<0.0001) 相比，DSR (4.5±0.4 g) 的钠去除率显着更高。结论 DSR 在动物和人类受试者中均具有良好的耐受性，并且比标准 PD 溶液产生更大的钠去除。需要进一步研究评估使用 DSR 作为预防和治疗心力衰竭高血容量的方法。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。与标准 PD 溶液 (1.0±0.3 g; P<0.0001) 相比，DSR (4.5±0.4 g) 的钠去除率显着更高。结论 DSR 在动物和人类受试者中均具有良好的耐受性，并且比标准 PD 溶液产生更大的钠去除。需要进一步研究评估使用 DSR 作为预防和治疗心力衰竭高血容量的方法。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT03801226。