Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

 描述（由申请人提供）：本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）的机制，从而实现急性失代偿性心力衰竭（ADHF）患者的个体化治疗。ADHF是医疗保险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负荷驱动的，使得袢利尿剂成为治疗和预防ADHF最常用的药物。不幸的是，对袢利尿剂的反应丧失（称为利尿剂抵抗（DR））是常见的，并导致医院外液体/钠潴留，医院内不完全缓解充血，随后是出院后液体/钠重新积聚和结局恶化的恶性循环。尽管它很重要，但我们诊断DR的速度和准确性非常有限。这导致门诊病人住院治疗，住院病人不能进行有效的利尿，从而“浪费”了住院日。一旦认识到，工具来确定DR的机制，从而个性化治疗是不存在的。虽然多种机制导致袢DR，但存在两种治疗上不同的组：（1）在肾小管作用部位的作用不足，其需要用增加剂量或递送袢利尿剂进行治疗，和（2）代偿性远端肾小管钠重吸收，其需要用顺序肾单位阻断进行治疗（即，噻嗪类利尿剂）。我们无法区分这些机制，使得试错法成为治疗DR的唯一方法，进一步延迟了有效的利尿，并在经验性选择不正确时使患者暴露于已知毒性的药物。 在本研究中，我们将入组200例ADHF患者，并通过袢利尿剂治疗的关键转换（早期进入IV治疗，晚期IV治疗，转换为口服利尿剂后，以及出院后5-7天）对其进行纵向评价。在早期IV治疗期间发生显著DR的患者将被随机分配至增加袢利尿剂剂量或添加噻嗪类利尿剂组，根据DR机制分层。通过上述研究产生的数据将使我们能够：（1）开发廉价和有效的工具，以可靠和及时的方式预测利尿反应;（2）了解使用内源性锂清除率的DR治疗靶向机制的流行率，这是一种查询体内近端肾小管/Henle钠处理环的“金标准”技术;（3）开发使用常见/廉价实验室检查区分DR机制的方法;（4）提供机械定制利尿剂治疗可以改善尿钠排泄的概念证据。我们的初步数据表明，DR的诊断和表型分型实际上可以使用普遍可用的尿液/血清化学进行，具有极好的准确性（AUC =~0.9）。在这项研究的结论，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，以准确/快速诊断和表型DR允许个性化利尿治疗的住院患者和门诊患者的心力衰竭。

 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.