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.

Public Health Relevance

Loop diuretics are the most commonly used medications to relieve and prevent fluid and sodium overload in patients with heart failure. Unfortunately, the development of resistance to these agents is common. This study will seek to gain a better understanding of the mechanisms underlying this diuretic resistance and develop tools for more rapid and accurate diagnosis allowing personalized therapy for these patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128973-04
Application #
9475873
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2015-08-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ter Maaten, Jozine M; Rao, Veena S; Hanberg, Jennifer S et al. (2017) Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. Eur J Heart Fail 19:1014-1022
Grodin, Justin L; Sun, Jie-Lena; Anstrom, Kevin J et al. (2017) Implications of Serum Chloride Homeostasis in Acute Heart Failure (from ROSE-AHF). Am J Cardiol 119:78-83
Hanberg, Jennifer S; Rao, Veena S; Ahmad, Tariq et al. (2017) Inflammation and cardio-renal interactions in heart failure: a potential role for interleukin-6. Eur J Heart Fail :
Hanberg, Jennifer S; Rao, Veena; Ter Maaten, Jozine M et al. (2016) Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights. Circ Heart Fail 9:
Brisco, Meredith A; Zile, Michael R; Hanberg, Jennifer S et al. (2016) Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial. J Card Fail 22:753-60