Mechanisms of diuretic resistance in heart failure

心力衰竭的利尿抵抗机制

• 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
• 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' 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

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 (HF) 的症状和住院治疗主要是由充血引起的，使循环 利尿剂是心力衰竭的基础治疗。这是有问题的，因为袢利尿阻力 (DR) 很常见，而且 持续拥堵和随之而来的不良后果的驱动因素。我们最近确认：1） 人类心衰中 DR 的主要驱动因素是肾小管水平，而不是利尿剂输送不良。 2) 近端 肾小管钠重吸收不是一个重要因素，而是 3) 作用部位的反应降低 Henle 袢和代偿性远端肾小管钠重吸收驱动 DR。 4）环路电阻 亨利似乎可以通过传统上认为高于上限剂量的利尿剂量来解决。尽管 在确定 DR 的一般位置、罪魁祸首转运蛋白以及特定可成药药物方面取得了进展 目标仍未确定。人们一致认为存在三种化学计量相关的远端 钠 (Na) 运输途径。这三个途径的核心成分是氯化钠 协同转运蛋白 (NCC)、上皮钠通道 (ENaC) 和氯化物碳酸氢盐交换器 pendrin。 重要的是，这些靶标可以通过 FDA 批准的药物在人体中进行操纵。 NCC可以选择性地 受苯氟噻嗪（一种对碳酸酐酶抑制最小的噻嗪类药物）抑制，ENaC 受阿米洛利抑制， 和 pendrin 通过 NH4Cl 负载下调。我们还了解到，循环中的钠重吸收 Henle 具有动态性，对 NKCC2 具有显着的调节作用和可塑性。重要的是，NKCC2 剪接变体具有 已确定具有显着不同的离子亲和力、转运能力和利尿敏感性。 该提案的主要目标是将上述知识转化为治疗方法 人类灾难恢复的可行方法。为了实现这一目标，我们将进行 3 次机械重点临床 使用不同转运途径的药理操作、内源性锂清除率的试验 了解区域肾单位钠处理和尿液细胞外囊泡，以研究差异 管状溶质转运蛋白水平和剪接变体。具体来说，目标 1 将研究其机制 人类心力衰竭中袢利尿剂剂量反应曲线向右大幅移动的潜在原因。在这里我们将 连续滴定高选择性 NKCC2 拮抗剂布美他尼至 10mg（相当于 400mg 呋塞米） 稳定的 DR 和利尿反应性心力衰竭患者。在目标 2 中，我们试图了解急性拮抗作用的影响 环上阿米洛利敏感、噻嗪类敏感或阿米洛利和噻嗪类联合敏感转运途径 稳定 DR HF 患者的利尿反应。我们将通过组合管理来实现这一目标 安慰剂、阿米洛利和/或苯氟噻嗪与布美他尼联合治疗稳定的 DR HF 患者。在 目标 3 我们将确定已知可下调 pendrin 的 NH4CL 负载是否可以减少非阿米洛利/非阿米洛利 噻嗪类药物对远端钠重吸收敏感。通过完成这些目标，我们将获得丰厚的回报 了解心力衰竭 DR 的具体机制，从而制定有针对性的治疗策略。