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

尽管袢利尿剂是心力衰竭（HF）缓解充血治疗的基石，但矛盾的是， 是研究最少的HF药物类别之一， 上课与呋塞米相比，托拉塞米具有1）上级生物利用度和吸收，2）显著 更长的半衰期和3）潜在的广谱“抗醛固酮”作用。这些理论优势 托拉塞米，部分原因是NIH资助了6000名参与者的TRANSFORM-HF研究，该研究将最终确定 确定托拉塞米对硬结果的价值。乍一看，上述差异意味着自我- 托拉塞米的明显优势。然而，也知道严重的剂量内利尿剂抵抗发生在 健康受试者在其长半衰期期间服用托拉塞米;事实上，动物研究已经证明， 远端小管的大量不良结构重塑伴长期袢利尿剂暴露。我们有 最近证实远端肾小管代偿实际上是袢利尿剂的主要机制 人HF中的耐药性和药代动力学缺陷被降级为次要作用。此外，虽然在 可能是体外抗醛固酮作用，尚不清楚这是否转化为HF的临床相关作用 患者接受现代医学治疗。最后，呋塞米也有独特的性质，如滥交， 拮抗钠通道近端和远端的亨利环和矛盾的改善， 相对效价与进行性肾功能不全。因此，根据目前可用的数据， 托拉塞米优效性或劣效性的合理理由。本提案的总体目标是 严格描述托拉塞米可能影响结果的候选机制 TRANSFORM-HF人口。为了实现这一目标，我们提出了一个三个中心，150名患者的机制， TRANSFORM-HF的子研究，将在随机化时查询一组详细的机械参数 并在30天后再次回答以下问题：1）已知和未知的净效应是什么？ 托拉塞米和呋塞米在利尿治疗的最终目标-容量状态上的差异？我们 将通过评价金标准体液空间测量（血浆体积， 细胞外水、全身水）。2)是否存在临床相关的多效性抗醛固酮作用， 托拉塞米？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个问题; 钾排泄和醛固酮调节蛋白γENaC的尿外泌体水平。3)并 托拉塞米半衰期长，导致肾脏的不良结构重塑和肾内 肾钠处理？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。 远端肾小管转运蛋白NCC和功能，通过评估内源性锂清除率的变化， 已确立的局部肾小管钠处理的体内指标。

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.