Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure

 描述(由申请人提供)：这项提案的首要目标是创建和验证实用工具，以快速检测和确定利尿剂抵抗(DR)的机制，使急性失代偿性心力衰竭(ADHF)患者能够进行个性化治疗。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。ADHF的流行主要是由液体和钠超载引起的，使得环状利尿剂成为治疗和预防ADHF最常用的药物。不幸的是，对环状利尿剂的反应丧失，称为利尿剂抵抗(DR)是常见的，并导致院外液体/钠滞留、院内不完全减充血、出院后液体/钠重新聚集和预后恶化的恶性循环。尽管它很重要，但我们诊断DR的速度和保真度是极其有限的。这可能会导致门诊患者住院，并在住院患者中没有发生有效利尿的情况下“浪费”住院日。一旦被认识到，就没有工具来确定DR的机制，从而使治疗个体化。尽管引起环状DR的机制有多种，但在治疗上存在两种截然不同的组：(1)作用于肾小管部位的作用不足，需要增加环状利尿剂的剂量或给药；(2)肾小管远端代偿性钠重吸收，这需要顺序阻断肾单位(即噻嗪利尿剂)治疗。我们无法区分这些机制，使得试验和错误成为治疗DR的唯一方法，进一步推迟了有效的利尿，并在经验性选择不正确时使患者暴露于已知毒性的药物。在这项研究中，我们将招募200名ADHF患者，并通过环状利尿剂治疗的关键转变(早期进入静脉治疗，晚期静脉治疗，转换为口服利尿剂后，以及出院后5-7天)对他们进行纵向评估。早期静脉注射治疗期间有明显DR的患者将被随机分为增加环状利尿剂剂量或加用噻嗪类利尿剂，按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、高效的工具，以可靠和及时的方式预测利尿剂的疗效；(2)了解使用内源性锂清除的治疗靶向机制的流行情况，这是一项询问体内Henle钠处理近端小管/环的“黄金标准”技术；(3)开发利用通用/廉价的实验室测试来区分DR机制的方法；以及(4)提供证据，证明量身定制的机械性利尿治疗可以改善钠尿。我们的初步数据表明，使用普遍可用的尿液/血清化学方法，DR的诊断和表型实际上可以以极高的准确性(AUC=~0.9)完成。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种可行的工具，以准确/快速地诊断和表型DR，从而允许住院和门诊心力衰竭患者进行个性化利尿治疗。

 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.