Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

心力衰竭利尿抵抗的诊断和靶向机制

• 批准号: 9115702
• 负责人: JEFFREY M TESTANI
• 金额: $ 73.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115702
• 关键词: Accounting; Acute; Algorithms; Body Weight decreased; Chemistry; Data; Diagnosis; Distal; Diuresis; Diuretics; Dose; Early treatment; Enrollment; Epidemic; Expenditure; Failure; Fluid overload; Freedom; Funding; Goals; Gold; Health; Heart failure; Henle' s loop; Hospitalization; Hospitals; Hour; Inpatients; Investigation; Kidney; Laboratories; Left; Length of Stay; Liquid substance; Lithium; Low Cardiac Output; Measures; Medicare; Methodology; Methods; Natriuresis; Nephrons; Oral; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Phenotype; Prevalence; Randomized; Research; Research Personnel; Resistance; Resistance development; Sampling; Serum; Site; Sodium; Speed; Spottings; Symptoms; Techniques; Testing; Thiazide Diuretics; Toxic effect; Tubular formation; United States National Institutes of Health; Urine; Weight Gain; accurate diagnosis; beneficiary; improved; in vivo; individualized medicine; personalized medicine; prevent; rapid diagnosis; resistance mechanism; response; saluretic; therapy resistant; tool; treatment strategy; wasting

 DESCRIPTION (provided by applicant): The overarching goal of this proposal is to create and validate pragmatic tools to rapidly detect and define the mechanism of diuretic resistance (DR), allowing individualized therapy in patients with acute decompensated heart failure (ADHF). ADHF is the most common hospital discharge diagnosis among Medicare beneficiaries and accounts for more than half of all heart failure (HF) related expenditures. This epidemic of ADHF is primarily driven by fluid and sodium overload, leaving the loop diuretics as the most commonly used medications to treat and prevent ADHF. Unfortunately, a loss of response to loop diuretics, termed diuretic resistance (DR), is common and contributes to a vicious cycle of out of hospital fluid/sodium retention, incomplete in-hospital decongestion, followed by post-discharge re-accumulation of fluid/sodium and worsened outcomes. Despite its importance, the speed and fidelity with which we can diagnose DR is extremely limited. This results in potentially avoidable hospitalization of outpatients and "wasted" hospital days where effective diuresis does not occur in inpatients. Once recognized, tools to determine the mechanism for DR and thus individualize treatment are nonexistent. Although multiple mechanisms contribute to loop DR, two therapeutically distinct groups exist: (1) inadequate effect at the tubular site of action, whih requires treatment with increased dose or delivery of loop diuretic and (2) compensatory distal tubular sodium reabsorption, which requires treatment with sequential nephron blockade (i.e., thiazide diuretics). Our inability to differentiate these mechanisms leaves trial and error as the only method to treat DR, further delaying effective diuresis and exposing patients to medications with known toxicities when the empiric choice is incorrect. In the present study, we will enroll 200 ADHF patients and evaluate them longitudinally through key transitions in loop diuretic therapy (early into IV therapy, late IV therapy, after conversion to oral diuretics, and 5-7 days post discharge). Patients with significant DR during early IV therapy will be randomized to increased loop diuretic dose or add on thiazide diuretic stratified by the DR mechanism. The data generated through the above investigation will allow us to: (1) develop inexpensive and efficient tools to predict diuretic response in a reliable and timely manner; (2) understand the prevalence of therapeutically targetable mechanisms of DR using endogenous lithium clearance, a "gold standard" technique to query in vivo proximal tubular/loop of Henle sodium handling; (3) develop methodology to differentiate DR mechanisms using common/inexpensive laboratory tests; and (4) provide proof of concept that mechanistically tailored diuretic therapy can improve natriuresis. Our preliminary data suggests that diagnosis and phenotyping of DR can in fact be done with excellent accuracy (AUC =~0.9) using universally available urine/serum chemistries. At the conclusion of this research, our goal is to provide clinicians and researchers with a workable tool to accurately/rapidly diagnose and phenotype DR allowing individualized diuretic therapy for both inpatients and outpatients with heart failure.

 描述（由申请人提供）：该提案的总体目标是创建和验证实用工具，以快速检测和定义利尿剂抵抗（DR）机制，从而允许对急性失代偿性心力衰竭（ADHF）患者进行个体化治疗。 ADHF 是 Medicare 受益人中最常见的出院诊断，占所有心力​​衰竭 (HF) 相关支出的一半以上。这种 ADHF 的流行主要是由液体和钠超载引起的，因此袢利尿剂成为治疗和预防 ADHF 的最常用药物。不幸的是，对袢利尿剂失去反应，称为利尿抵抗（DR），是很常见的，会导致院外液体/钠潴留、院内充血不完全、出院后液体/钠重新积累和结局恶化的恶性循环。尽管它很重要，但我们诊断 DR 的速度和保真度却极其有限。这可能会导致门诊患者住院治疗，以及住院患者无法进行有效利尿的“浪费”住院时间。一旦认识到，确定 DR 机制并由此进行个体化治疗的工具就不存在了。尽管导致袢 DR 的机制有多种，但存在两种治疗上不同的组：(1) 肾小管作用部位效果不足，需要增加袢利尿剂的剂量或给药；(2) 补偿性远端肾小管钠重吸收，需要序贯肾单位阻断（即噻嗪类利尿剂）治疗。我们无法区分这些机制，使得反复试验成为治疗 DR 的唯一方法，当经验选择不正确时，进一步延迟有效的利尿并使患者接触具有已知毒性的药物。 在本研究中，我们将招募 200 名 ADHF 患者，并通过袢利尿治疗的关键转变（早期进入静脉注射治疗、晚期静脉注射治疗、转为口服利尿剂后以及出院后 5-7 天）对他们进行纵向评估。在早期静脉注射治疗期间出现显着 DR 的患者将被随机分配至增加袢利尿剂剂量或根据 DR 机制分层添加噻嗪类利尿剂。通过上述调查产生的数据将使我们能够：（1）开发廉价且有效的工具来可靠且及时地预测利尿反应； (2) 使用内源性锂清除率了解 DR 治疗靶向机制的流行情况，内源性锂清除率是查询体内近端肾小管/袢处理 Henle 钠的“金标准”技术； (3) 开发使用普通/廉价实验室测试来区分 DR 机制的方法； (4) 提供机械定制利尿疗法可以改善尿钠排泄的概念证明。我们的初步数据表明，事实上，使用普遍可用的尿液/血清化学物质可以非常准确地进行 DR 的诊断和表型分析 (AUC =~0.9)。在这项研究的结论中，我们的目标是为临床医生和研究人员提供一个可行的工具来准确/快速地诊断 DR 和表型 DR，从而为心力衰竭住院患者和门诊患者提供个体化利尿治疗。