Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic Sub-Study

托塞米与呋塞米的心肾效应：TRANSFORM-HF 机制子研究

基本信息

批准号：
10444981
负责人：
JEFFREY M TESTANI
金额：
$ 83.08万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10444981
关键词：
Acute Address Albumins Aldosterone Animals Applications Grants Binding Biological Assay Biological Availability Blood Plasma Volume Body Fluids Body Water Bolus Infusion Cessation of life Clinical Congestive Continuous Infusion Controlled Environment Data Defect Deuterium Oxide Diet Distal Diuresis Diuretics Dose Drug Kinetics Excretory function Financial compensation Funding Furosemide Goals Gold Half-Life Heart failure Henle&apos s loop Heterogeneity Hospitalization Human Hypertrophy I131 isotope In Vitro Inferior Infusion procedures Inpatients Iothalamate Kidney Kinetics Liquid substance Lithium Low Cardiac Output Measurement Measures Medical Minor Nephrons Outcome Participant Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Population Potassium Property Proteins Proxy Randomized Research Technics Resistance Role SLC12A3 gene Signal Transduction Sodium Sodium Channel Symptoms Tissues Translating Tubular formation United States National Institutes of Health Up-Regulation Water absorption antagonist clinical practice clinically relevant design extracellular improved in vivo insight kidney dysfunction member pharmacokinetics and pharmacodynamics prevent receptor standard measure urinary

项目摘要

Despite being the cornerstone of decongestive therapy in heart failure (HF), loop diuretics are paradoxically one of the least well-studied classes of HF medications and substantial differences exist between members of the class. Compared to furosemide, torsemide has 1) superior bioavailability and absorption, 2) significantly longer half-life and 3) potential broad spectrum “anti-aldosterone” effects. These theoretical advantages of torsemide, in part, motivated the NIH funded 6000 participant TRANSFORM-HF study, which will definitively establish the value of torsemide on hard outcomes. At first glance, the above differences would imply a self- evident superiority of torsemide. However, it is also known that severe within-dose diuretic resistance occurs in healthy subjects administered torsemide during its long half-life; indeed, animal studies have demonstrated massive adverse structural remodeling of the distal tubule with prolonged loop diuretic exposure. We have recently demonstrated that distal tubular compensation is in fact the dominant mechanism of loop diuretic resistance in human HF and pharmacokinetic defects are relegated to a minor role. Additionally, while there may be in vitro anti-aldosterone effects, it is unclear if this translates into clinically relevant effects in HF patients on contemporary medical therapy. Lastly, furosemide also has unique properties such as promiscuous antagonism of sodium channels proximal and distal to the loop of Henle and a paradoxical improvement in relative potency with progressive renal dysfunction. As such, with currently available data, a biologically plausible case for superiority or inferiority of torsemide can be made. The overarching goal of this proposal is to rigorously characterize candidate mechanisms by which torsemide may influence outcome within the TRANSFORM-HF population. To achieve this goal, we propose a three center, 150 patient mechanistic sub study of TRANSFORM-HF which will query a detailed set of mechanistic parameters both at randomization and again at 30 days to answer the following questions: 1) What are the net effects of known and unknown differences between torsemide and furosemide on the ultimate target of diuretic therapy- volume status? We will address this by evaluating changes in gold standard body fluid space measurements (plasma volume, extra cellular water, total body water). 2) Are there clinically relevant pleiotropic anti-aldosterone effects of torsemide? We will address this with functional and structural readouts of tissue level aldosterone activity; potassium excretion and urinary exosomal levels of the aldosterone regulated protein γENaC. 3) Does torsemide, with its long half-life, result in adverse structural remodeling of the kidney and redistribution of intra- renal sodium handling? We will address this by evaluating structural changes with urinary exosomal levels of the distal tubular transporter NCC and functionally by evaluating changes in endogenous lithium clearance, a well-established in vivo metric of regional tubular sodium handling.

尽管是心力衰竭（HF）中充血治疗的基石，但循环利尿剂是矛盾的在班级。与速尿相比，扭矩具有1）优越的生物利用度和滥用，2）显着更长的半衰期和3）潜在的广泛范围“抗醛固酮”效应。这些理论优势托塞米部分部分成熟了NIH资助的6000名参与者Transform-HF研究，这将一定会对确定托西利层对硬性结果的价值。乍一看，上述差异将暗示一个自我扭转的证据优势。但是，还知道严重的剂量内利尿剂发生在健康的受试者在其长期寿命期间给予了扭转局。确实，动物研究表明远端小管的大规模不良结构重塑，并长时间循环利尿剂暴露。我们有最近证明，远端管状补偿实际上是循环利尿剂的主要机制人HF和药代动力学缺陷的耐药性与次要作用有关。另外，在那里可能是体外抗醛固酮的作用，目前尚不清楚这是否转化为HF的临床相关作用当代药物治疗的患者。最后，速尿还具有独特的特性，例如混杂钠通道的拮抗作用近端和远端的亨尔环和远端进行性肾功能障碍的相对效力。因此，对于当前可用的数据，一个生物学上可以制造出可行的扭曲或自卑感的合理案例。该提议的总体目标是要严格地表征候选机制，候选机制可能会影响内部的结果转型-HF人口。为了实现这一目标，我们提出了一个三个中心，150个患者机械转换-HF的子研究将在随机化时查询一组详细的机械参数再次在30天回答以下问题：1）已知和未知的净影响是什么扭转和速尿对利尿治疗体积状态的最终靶标之间的差异？我们将通过评估黄金标准体流体空间测量的变化来解决此问题（等离子体体积，额外的蜂窝水，全身水）。 2）是否存在临床上相关的多效性抗醛固酮的作用扭转？我们将通过组织水平醛固酮活性的功能和结构读数来解决这一问题。醛固酮调节的蛋白γENAC的钾排泄和尿外泌体水平。 3）做托塞德层具有长期的半衰期，导致肾脏的结构重塑和内部重新分布肾脏钠处理？我们将通过评估尿外泌体水平的结构变化来解决这一问题远端管状转运蛋白NCC，并通过评估内源性锂清除率的变化，A 良好的区域管状钠处理的体内指标。