Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure

Jozine M. ter Maaten, Veena S. Rao, Jennifer S. Hanberg, F. Perry Wilson, Lavanya Bellumkonda, Mahlet Assefa, J. Sam Broughton, Julie D'Ambrosi, W. H. Wilson Tang, Kevin Damman, Adriaan A. Voors, David Ellison, Jeffrey M. Testani

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background: 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. Methods and results: 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. Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.

Original languageEnglish (US)
JournalEuropean Journal of Heart Failure
DOIs
StateAccepted/In press - 2017

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Sodium Potassium Chloride Symporter Inhibitors
Diuretics
Heart Failure
Bumetanide
Kidney
Sodium
Urine
Pharmaceutical Preparations
Urine Specimen Collection
Urea

Keywords

  • Diuretic resistance
  • Diuretic response
  • Heart failure
  • Mechanisms

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

ter Maaten, J. M., Rao, V. S., Hanberg, J. S., Perry Wilson, F., Bellumkonda, L., Assefa, M., ... Testani, J. M. (Accepted/In press). Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. European Journal of Heart Failure. https://doi.org/10.1002/ejhf.757

Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. / ter Maaten, Jozine M.; Rao, Veena S.; Hanberg, Jennifer S.; Perry Wilson, F.; Bellumkonda, Lavanya; Assefa, Mahlet; Sam Broughton, J.; D'Ambrosi, Julie; Wilson Tang, W. H.; Damman, Kevin; Voors, Adriaan A.; Ellison, David; Testani, Jeffrey M.

In: European Journal of Heart Failure, 2017.

Research output: Contribution to journalArticle

ter Maaten, JM, Rao, VS, Hanberg, JS, Perry Wilson, F, Bellumkonda, L, Assefa, M, Sam Broughton, J, D'Ambrosi, J, Wilson Tang, WH, Damman, K, Voors, AA, Ellison, D & Testani, JM 2017, 'Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure', European Journal of Heart Failure. https://doi.org/10.1002/ejhf.757
ter Maaten, Jozine M. ; Rao, Veena S. ; Hanberg, Jennifer S. ; Perry Wilson, F. ; Bellumkonda, Lavanya ; Assefa, Mahlet ; Sam Broughton, J. ; D'Ambrosi, Julie ; Wilson Tang, W. H. ; Damman, Kevin ; Voors, Adriaan A. ; Ellison, David ; Testani, Jeffrey M. / Renal tubular resistance is the primary driver for loop diuretic resistance in acute heart failure. In: European Journal of Heart Failure. 2017.
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abstract = "Background: 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. Methods and results: 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. Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.",
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AU - ter Maaten, Jozine M.

AU - Rao, Veena S.

AU - Hanberg, Jennifer S.

AU - Perry Wilson, F.

AU - Bellumkonda, Lavanya

AU - Assefa, Mahlet

AU - Sam Broughton, J.

AU - D'Ambrosi, Julie

AU - Wilson Tang, W. H.

AU - Damman, Kevin

AU - Voors, Adriaan A.

AU - Ellison, David

AU - Testani, Jeffrey M.

PY - 2017

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N2 - Background: 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. Methods and results: 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. Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.

AB - Background: 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. Methods and results: 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. Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF.

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