Advanced Kidney Health Monitoring in Persons Hospitalized with Heart Failure

项目总结 在美国，心力衰竭每年导致140万人住院治疗。 心力衰竭(ADHF)住院，肾脏的健康几乎影响到管理的方方面面， 包括利尿剂的初始剂量、治疗强化和出院计划。然而，临床依赖于 血清肌酐是一种不敏感、非特异性和经常具有误导性的肾脏生物标志物，它在很大程度上对 到次优的抗心衰治疗。尽管指南建议临床医生将患者的肾功能 作为利尿剂初始剂量的指标，肌酐实际上不能很好地预测利尿剂的反应和 临床医生必须通过“反复试验”来寻找每个患者的最佳剂量。此外，尽管 治疗期间肌酐升高通常反映出有益的效果，临床医生通常会降低 由于害怕肾脏损伤加重而产生利尿。在出院计划期间，这种恐惧也促使临床医生 口服利尿剂的剂量太低，避免有益的治疗。这些阻碍理想护理的因素 最终导致症状缓解延迟、住院时间延长、频繁再住院和高死亡风险。 鉴于肾小管在决定ADHF药理的有效性和安全性方面的核心作用 治疗，临床医生需要捕捉肾小管健康的工具，以优化利尿策略，改善 提供指南指导的药物治疗，并最大限度地减少真正肾脏损伤的风险。在门诊中 我们的团队已经证明了肾小管健康措施检测肾脏损害的非凡能力 早期，以更准确地反映肾脏对肌酐的治疗反应，并预测长期 结果。早期对ADHF中一些小管标志物的研究表明，它们与利尿剂的改善成比例 在ADHF治疗期间监测肾脏健康状况的方式具有巨大的潜力。 鉴于肾脏健康在ADHF治疗和预后中的核心作用，我们的总体目标是 从根本上改变临床医生处理肾脏健康监测和临床决策的方式 ADHF治疗。为了实现这些目标，我们将充分利用利尿剂的作用机制。 耐药(MDR)研究：一组因ADHF住院并接受过一系列生物制剂治疗的患者 在住院期间定时利尿治疗，并对关键临床进行纵向随访 结果。我们将测量一系列反映肾小管重吸收和分泌的肾脏生物标志物。 功能、损伤、合成和修复能力，以及肾小管间质炎症和纤维化。我们会 确定最有效的肾小管健康措施：1)预测对初始循环利尿剂的治疗反应 剂量和辅助利尿剂治疗(目标1)；2)鉴别假性和本质性肾损害 治疗期间肌酐升高的患者(目标2)；以及3)确定适合出院的患者 并区分它们对后续不良事件的风险(目标3)。这个项目将奠定必要的基础 为测试肾脏生物标记物引导的ADHF治疗策略的临床试验奠定基础。

PROJECT SUMMARY Heart failure leads to >1.4 million hospitalizations annually in the U.S. During these acute decompensated heart failure (ADHF) hospitalizations, the kidneys’ health influences almost every aspect of management, including initial diuretic dosing, treatment intensification, and discharge planning. However, clinical reliance on serum creatinine, an insensitive, nonspecific and often misleading kidney biomarker, substantially contributes to suboptimal ADHF treatment. Although guidelines suggest that clinicians use the patient’s kidney function as an indicator for the initial diuretic dose, the creatinine is actually a poor predictor of diuretic response and clinicians must resort to “trial and error” in searching for each patient’s optimal dose. Further, although creatinine elevations during treatment commonly reflect beneficial effects, clinicians typically de-escalate diuresis from fear of worsening kidney damage. During discharge planning, this fear also drives clinicians to prescribe an oral diuretic dose that is too low, and to avoid beneficial therapies. These obstacles to ideal care culminate in delayed symptom relief, prolonged hospitalization, frequent readmissions, and high mortality risk. Given the kidney tubules’ central role in determining the effectiveness and safety of ADHF pharmacological treatment, clinicians need tools that capture kidney tubule health to optimize diuretic strategies, improve delivery of guideline-directed medical therapy, and minimize the risk for true kidney damage. In ambulatory settings, our team has demonstrated the remarkable ability of tubule health measures to detect kidney damage early, to reflect the kidneys’ response to treatment more accurately that creatinine, and to predict long-term outcomes. Early studies of a few tubule markers in ADHF show that they improve in proportion to diuretic response and have tremendous potential to change how kidney health is monitored during ADHF treatment. Given the central role of kidney health in ADHF treatment and prognosis, our overall goals are to fundamentally change how clinicians approach kidney health monitoring and clinical decision-making during ADHF treatment. To achieve these goals, we will capitalize on the well-characterized Mechanisms of Diuretic Resistance (MDR) Study, a cohort of patients hospitalized for ADHF who have undergone serial biospecimen collections timed to diuretic treatment throughout hospitalization with longitudinal follow-up for key clinical outcomes. We will measure a broad panel of kidney biomarkers that reflect tubule reabsorptive and secretory functions, injury, synthetic and reparative capacity, and tubulointerstitial inflammation and fibrosis. We will identify which tubule health measures most effectively: 1) predict treatment response to initial loop diuretic dosing and adjunctive diuretic therapy (Aim 1); 2) discern pseudo- from intrinsic kidney damage among patients with creatinine elevations during treatment (Aim 2); and 3) identify patients appropriate for discharge and distinguish their risks for subsequent adverse events (Aim 3). This project will lay the necessary groundwork for a clinical trial to test a kidney biomarker-guided ADHF treatment strategy.