title: Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure.
abstract: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF.
  
  
  
  Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR.
  
  
  
  Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.|Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Jozine M
authors.initials: JM
authors.lastname: Ter Maaten
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.|Department of Pharmacy Services, Yale-New Haven Hospital, New Haven, CT, USA.
authors.forename: Veena S
authors.initials: VS
authors.lastname: Rao
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Hanberg
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.|Department of Internal Medicine, Yale University, New Haven, CT, USA.
authors.forename: F
authors.initials: F
authors.lastname: Perry Wilson
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT, USA.
authors.forename: Lavanya
authors.initials: L
authors.lastname: Bellumkonda
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.
authors.forename: Mahlet
authors.initials: M
authors.lastname: Assefa
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sam Broughton
authors.affiliation: Department of Pharmacy Services, Yale-New Haven Hospital, New Haven, CT, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: D'Ambrosi
authors.affiliation: Section of Heart Failure and Cardiac Transplantation, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Wilson Tang
authors.affiliation: Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Kevin
authors.initials: K
authors.lastname: Damman
authors.affiliation: Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
authors.affiliation: Program of Applied Translational Research, Yale University, New Haven, CT, USA.|Department of Internal Medicine, Yale University, New Haven, CT, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Testani
mesh_terms: D000208:Acute Disease; D061605:Administration, Intravenous; D015415:Biomarkers / Q000652:urine; D002034:Bumetanide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000188:drug therapy* / Q000652:urine; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012964:Sodium / Q000652:urine*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D015415:Biomarkers; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D012964:Sodium
keywords: Diuretic resistance; Diuretic response; Heart failure; Mechanisms