First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload.
First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload.
复制标题
使用零钠溶液进行腹膜直接钠去除的人体首次经验：容量超负荷的新候选疗法。
DOI：
10.1161/circulationaha.119.043062
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发表时间：
2020
期刊：
影响因子：
37.8
通讯作者：
Testani,JeffreyM
中科院分区：
文献类型：
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作者：
Rao,VeenaS;Turner,JeffreyM;Griffin,Matthew;Mahoney,Devin;Asher,Jennifer;Jeon,Sangchoon;Yoo,PeterS;Boutagy,Nabil;Feher,Attila;Sinusas,Albert;Wilson,FPerry;Finkelstein,Fredric;Testani,JeffreyM
髓袢利尿剂有明确的毒性，对这些药物的反应丧失是常见的。需要替代策略来维持心力衰竭（HF）患者的正常血容量。非肾去除钠直接穿过腹膜（直接钠去除[DSR]）与无钠渗透溶液应导致大量的钠与有限的脱靶soluterremove.MethodsThis文章介绍了临床前的发展和第一次在人类的概念证明DSR的提取。使用无钠的10%葡萄糖作为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接受随机化并交叉至使用1 L DSR溶液或标准PD溶液（Dianeal 4.25%葡萄糖，巴克斯特）停留2小时。主要终点是完成2小时的停留没有显着的不适或不良事件，和次要终点是在DSR和标准PD solution.ResultsPorcine实验中的钠去除之间的差异显示，1 L DSR溶液去除4.1±0.4克钠在2小时内与可忽略不计的脱靶溶质去除和整体稳定的血清电解质。增加穿过腹膜循环的DSR溶液的体积增加了钠的清除，并显著降低了血浆体积（P=0.005）。在实验性心力衰竭伴右心房压力升高的情况下，钠清除量是健康动物的2.4倍（P<0.001）。在人体概念验证研究中，DSR溶液耐受性良好，与显著不适或不良事件无关。血浆电解质浓度稳定，脱靶溶质清除可忽略不计。与标准PD溶液（1.0±0.3 g;P<0.0001）相比，DSR的钠清除率显著更高（4.5±0.4 g）。需要进行额外的研究来评估DSR作为预防和治疗心力衰竭高血容量症的方法。RegistrationURL：https://www.clinicaltrials.gov;唯一标识符：NCT 03801226。
BackgroundLoop 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.MethodsThis 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.ResultsPorcine 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).ConclusionsDSR 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.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03801226.