Mechanisms of diuretic resistance in heart failure

心力衰竭的利尿抵抗机制

基本信息

批准号：
10342535
负责人：
JEFFREY M TESTANI
金额：
$ 75.8万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10342535
关键词：
Acute Adult Affect Affinity Amiloride Bumetanide Cause of Death Chloride-Bicarbonate Antiporters Chlorides Clinical Trials Collection Congestive Consensus Defect Distal Diuretics Dose Excretory function FDA approved Furosemide Goals Heart failure Henle&apos s loop Hospitalization Human Infrastructure Ions Kidney Knock-out Knowledge Liquid substance Lithium Location Membrane Proteins Molecular Natriuresis Nephrons Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Placebos Population Prevention RNA Splicing Regulation Regulatory Pathway Research Resistance Resistance development SLC12A3 gene Site Sodium Sodium Chloride Structure Symptoms System Therapeutic Titrations Translating Translations Tubular formation Urine Variant antagonist attenuation carbonate dehydratase cost druggable target epithelial Na+ channel extracellular vesicles improved insight prevent resistance mechanism response solute targeted treatment thiazide tool urinary wasting

项目摘要

Symptoms and hospitalizations for heart failure (HF) are primarily driven by congestion, making loop diuretics a cornerstone therapy in HF. This is problematic since loop diuretic resistance (DR) is common and a driver of persistent congestion and the poor outcomes that follow. We have recently confirmed that: 1) The dominant driver of DR in human HF is at the renal tubular level, rather than poor diuretic delivery. 2) Proximal tubular sodium reabsorption is not a substantial contributor, rather 3) reduced response at the site of action in the loop of Henle and compensatory distal tubular sodium reabsorption drive DR. 4) Resistance at the loop of Henle appears to be addressable with diuretic doses traditionally considered above the ceiling dose. Despite progress in defining the general locations for DR, the culprit transporters and thus specific druggable targets remain undefined. There is consensus on the existence of three stoichiometrically relevant distal sodium (Na) transport pathways. The central components to these three pathways are the sodium chloride cotransporter (NCC), the epithelial sodium channel (ENaC), and the chloride bicarbonate exchanger, pendrin. Importantly, these targets can be manipulated in humans with FDA approved drugs; NCC can be selectively inhibited by bendroflumethiazide (a thiazide with minimal carbonic anhydrase inhibition), ENaC by amiloride, and pendrin downregulated by NH4Cl loading. We have also learned that sodium reabsorption in the loop of Henle is dynamic with substantial regulation and plasticity of NKCC2. Importantly, NKCC2 splice variants have been identified that have dramatically different ion affinities, transport capacity, and diuretic sensitivities. The primary goal of this proposal is to translate the above knowledge into therapeutically actionable approaches to human DR. To accomplish this, we will conduct 3 mechanistically focused clinical trials using pharmacologic manipulation of different transport pathways, endogenous lithium clearance to understand regional nephron sodium handling, and urinary extracellular vesicles to investigate differences in tubular solute transporter levels and splice variants. Specifically, Aim 1 will investigate the mechanism underlying the substantial shift in the loop diuretic dose response curve to the right in human HF. Here we will serially titrate the highly selective NKCC2 antagonist bumetanide to 10mg (400mg furosemide equivalents) in stable DR and diuretic responsive HF patients. In Aim 2 we seek to understand the effect of acute antagonism of amiloride sensitive, thiazide sensitive, or combined amiloride & thiazide sensitive transport pathways on loop diuretic response in stable DR HF patients. We will accomplish this by administration of the combinations of placebo, amiloride, and/or bendroflumethiazide, in conjunction with bumetanide, to stable DR HF patients. In Aim 3 we will determine if NH4CL loading, known to downregulate pendrin, can reduce non-amiloride/non- thiazide sensitive distal sodium reabsorption. Through the completion of these aims we will gain substantial understanding of the specific mechanisms underlying DR in HF allowing targeted therapeutic strategies.

心力衰竭的症状和住院治疗主要由拥塞驱动，使循环循环利尿剂在HF中是基石疗法。这是有问题的，因为循环利尿剂耐药性（DR）很常见，并且持续交通拥堵的驾驶员和随后的不良结果。我们最近确认：1）人类HF中DR的主要驱动力是肾小管水平，而不是利尿剂递送不良。 2）近端肾小管钠的吸收不是重要的贡献者，而是3）在作用部位的反应减少 Henle的环和代偿性远端管状钠摄入驱动DR。 4）阻力在循环中 Henle似乎可以通过在天花板剂量上方考虑利尿剂剂量来解决。尽管定义DR的一般位置的进展目标仍然不确定。关于存在三个静态相关的远端存在共识钠（NA）传输途径。这三个途径的中心成分是氯化钠共转运蛋白（NCC），上皮钠通道（ENAC）和氯化碳酸氢盐交换剂Pendrin。重要的是，可以在使用FDA批准的药物的人类中操纵这些靶标。 NCC可以选择性地被弯曲的甲氮化氮化物抑制（具有最小碳酸酐酶抑制的噻嗪类），由Amiloride ENAC，Amiloride，并由NH4CL加载下调Pendrin。我们还了解到，钠在 Henle具有动态性，具有NKCC2的大量调节和可塑性。重要的是，NKCC2剪接变体具有被鉴定出具有截然不同的离子亲和力，运输能力和利尿敏感性的明显不同。该提案的主要目标是将上述知识转化为治疗人类DR的可行方法。为此，我们将进行3种机械集中的临床使用不同运输途径的药理学操纵，内源性锂清除到了解区域肾脏钠处理和尿液外囊泡的研究管状溶质转运蛋白水平和剪接变体。具体而言，AIM 1将研究机制循环利尿剂剂量响应曲线的实质转移是在人类HF中的右侧。我们会在这里在高度选择性的NKCC2拮抗剂bumetanide中串行滴定至10mg（400mg速尿等同）稳定的DR和利尿反应型HF患者。在AIM 2中，我们试图了解急性拮抗作用在循环时敏感，噻嗪类敏感或联合噻嗪类敏感的传输途径稳定的HF患者的利尿剂反应。我们将通过管理的组合来实现安慰剂，阿米洛利和/或弯曲氟甲氮化氮化物与Bumetanide结合使用，以稳定的HF患者。在 AIM 3我们将确定NH4CL加载是否已知pendrin已知，是否可以减少非氨基甲甲化物/非 - 非 - 非 - 噻嗪类敏感的远端钠重吸收。通过完成这些目标，我们将获得大量了解HF中DR的具体机制，从而允许有针对性的治疗策略。