Mechanism and Effects of Manipulating Chloride Homeostasis in Heart Failure

控制心力衰竭氯离子稳态的机制和作用

• 批准号: 10371886
• 负责人: JEFFREY M TESTANI
• 金额: $ 83.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371886
• 关键词: Address; Alanine; Avidity; Blood Volume; Chlorides; Consumption; Data; Dietary Sodium; Distal; Diuretics; Dose; Down-Regulation; Effectiveness; Electrolyte Balance; Environment; Epidemiology; Equilibrium; Excretory function; Family; Feedback; Goals; Gold; Heart failure; Homeostasis; Inpatients; Kidney; Lesion; Literature; Lithium; Lysine; Manuscripts; Molecular; Nephrons; Outcome; Oxidative Stress; Participant; Patients; Pattern; Phosphorylation; Phosphotransferases; Physiology; Pilot Projects; Placebo Control; Placebos; Population; Proline; Protein-Serine-Threonine Kinases; Proteins; Randomized; Renal function; Renin; Research; Resistance; SLC12A3 gene; Series; Signal Transduction; Sodium; Sodium Chloride; Supplementation; Techniques; Therapeutic; Translations; Tubular formation; Urine; efficacy study; exosome; improved; in vivo; innovation; mortality; prevent; response; salt intake; sensor; solute; therapeutic candidate; therapeutic target; thiazide; treatment as usual; treatment comparison; urinary

Perturbations in sodium homeostasis are, unarguably, a central pathophysiologic lesion in heart failure (HF). Unfortunately, attempts to prevent or treat volume overload with salt restriction can further worsen the sodium avid state. Recent literature, spanning experimental to epidemiologic, has highlighted the double edged sword of salt restriction, finding that neurohormonal activation, volume status and even outcomes can sometimes improve with higher salt intake. While it is clear that sodium drives volume overload, a significant body of literature has confirmed renal salt sensing relies on chloride rather than sodium. It has been known for decades that renal responses such as tubuloglomerular feedback and renin release are governed by chloride. Recently, a family of serine-threonine kinases (With-No-Lysine (K), WNK) have been identified as the molecular sensor for chloride and master regulator of sodium transporters in the kidney. The above observations led us to hypothesize that chloride may be an important target in HF and over a series of 7 manuscripts we have demonstrated that chloride, rather than sodium, is primarily associated with diuretic resistance, neurohormonal activation and mortality in HF. Moreover, in a pilot study we demonstrated that administration of three days of 115 mmol/day of sodium-free chloride (as lysine chloride) caused a substantial downregulation in renal sodium transporters and multiple signals supporting improvement in volume status. The overarching goal of the current proposal is to address the fundamental gaps in our understanding of chloride homeostasis in HF, facilitating the translation of a large body of promising experimental and observational literature into a potentially viable therapeutic approach in HF. To achieve this goal, we propose a classic and rigorous placebo controlled crossover inpatient “GCRC” balance study (n=20 participants), a placebo controlled “real world” efficacy study in decompensated HF patients receiving aggressive IV diuretics (n=100 patients) and innovative interrogation of renal structural (quantitation of renal tubular solute transporters using urinary exosomes) and functional changes (using lithium clearance, the “gold standard” technique to query in vivo proximal tubular sodium handling). Our aims are to 1) To understand the quantitative effects of sodium free chloride supplementation on electrolyte balance, volume status, and sodium avidity in stable HF patients in a highly controlled inpatient environment. 2) To determine if sodium free chloride supplementation will improve volume status in the real world setting of decompensated HF treated with aggressive use of IV loop diuretics. 3) To determine if sodium free chloride supplementation induces an intra-renal pattern of change consistent with suppression of WNK including deactivation of downstream kinases, reduction of the quantity of WNK regulated sodium cotransporters, and a redistribution of intra-renal sodium reabsorption.

无可争议，钠稳态紊乱是心力衰竭的中心病理生理损害。 (Hf)。不幸的是，试图通过限制盐分来预防或治疗容量超载会进一步恶化 钠盐饥渴状态。最近的文献，从实验到流行病学，都强调了双刃剑 盐限制之剑，发现神经激素的激活、容量状态甚至结果都可以 有时，摄入更多的盐分会有所改善。虽然很明显钠会导致容量过载，但一个重要的 大量文献证实，肾脏对盐的感知依赖于氯化物而不是钠。它因 几十年来，肾脏的反应，如肾小球反馈和肾素释放，都是由氯化物控制的。 最近，一个丝氨酸苏氨酸激酶家族(带有-NO-赖氨酸，WNK)被鉴定为 氯离子分子传感器和肾脏钠转运蛋白的主控调节器。以上内容 观察结果使我们假设氯可能是HF的一个重要目标，并在一系列 我们已经证明氯化物，而不是钠，主要与利尿剂有关 心衰患者的抵抗力、神经激素激活和死亡率。此外，在一项初步研究中，我们证明了 每天服用115毫摩尔的无钠氯化物(以赖氨酸氯化物的形式)三天会引起大量的 肾脏钠转运体的下调和多个信号支持容量状态的改善。 当前提案的总体目标是解决我们的 了解氯离子在HF中的动态平衡，有助于翻译一大堆有希望的 一种潜在可行的心衰治疗方法的实验和观察文献。至 为了实现这一目标，我们提出了一个经典而严格的安慰剂控制的交叉住院患者“GCRC”平衡 研究(n=20名参与者)：失代偿性心衰患者的安慰剂对照“真实世界”疗效研究 接受积极的静脉利尿剂(n=100名患者)和创新的肾脏结构询问(量化 使用尿外切体的肾小管溶质转运体的变化)和功能变化(使用锂清除， 询问活体近端肾小管钠离子的“黄金标准”技术)。我们的目标是：1) 了解补充无氯化钠对电解质平衡、容量的定量影响 在高度受控的住院环境中，稳定的心衰患者的状态和钠的亲和力。2)确定是否 补充无氯化钠将改善失代偿现实世界中的容量状况 积极使用静脉循环利尿剂治疗心衰。3)确定无氯化钠补充剂是否 诱导肾内与抑制WNK一致的变化模式，包括失活 下游激酶，WNK调节的钠协同转运体数量的减少，以及 肾内钠重吸收。

项目成果

Association of Urine Galectin-3 With Cardiorenal Outcomes in Patients With Heart Failure.

尿半乳糖凝集素 3 与心力衰竭患者心肾结局的关系。

• DOI: 10.1016/j.cardfail.2023.05.018
• 发表时间: 2024
• 期刊: Journal of cardiac failure
• 影响因子: 6
• 作者: Rao,VeenaS;Ivey-Miranda,JuanB;Cox,ZacharyL;Moreno-Villagomez,Julieta;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM

Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease.

• DOI: 10.1161/circulationaha.121.052792
• 发表时间: 2022-03
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Beldhuis, Iris E.;Lam, Carolyn S. P.;Testani, Jeffrey M.;Voors, Adriaan A.;Van Spall, Harriette G. C.;ter Maaten, Jozine M.;Damman, Kevin
• 通讯作者: Damman, Kevin

Congestion and Decongestion Assessment in Heart Failure: Pressure, Volume, or Both?

心力衰竭的充血和减充血评估：压力、容量或两者兼而有之？

• DOI: 10.1016/j.jchf.2023.05.034
• 发表时间: 2023
• 期刊: JACC. Heart failure
• 作者: Biegus,Jan;Borlaug,BarryA;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM

Improvement in Renal Function During the Treatment of Acute Decompensated Heart Failure: Relationship With Markers of Renal Tubular Injury and Prognostic Importance.

急性失代偿性心力衰竭治疗期间肾功能的改善：与肾小管损伤标志物和预后重要性的关系。

• DOI: 10.1161/circheartfailure.122.009776
• 发表时间: 2023
• 期刊: Circulation. Heart failure
• 作者: Natov,PeterS;Ivey-Miranda,JuanB;Cox,ZacharyL;Moreno-Villagomez,Julieta;Maulion,Christopher;Bellumkonda,Lavanya;Shlipak,MichaelG;Estrella,MichelleM;Borlaug,BarryA;Rao,VeenaS;Testani,JeffreyM
• 通讯作者: Testani,JeffreyM

First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload.

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
• 发表时间: 2020
• 期刊: Circulation
• 影响因子: 37.8
• 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
• 通讯作者: Testani,JeffreyM