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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.

心衰（HF）的症状和住院治疗主要是由充血引起的