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. 2017 Aug;19(8):1014-1022.
doi: 10.1002/ejhf.757. Epub 2017 Jan 19.

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

Jozine M Ter Maaten  1   2 , Veena S Rao  1   3 , Jennifer S Hanberg  1 , F Perry Wilson  1   4 , Lavanya Bellumkonda  4 , Mahlet Assefa  1 , J Sam Broughton  1 , Julie D'Ambrosi  3 , W H Wilson Tang  5 , Kevin Damman  2 , Adriaan A Voors  2 , David H Ellison  6 , Jeffrey M Testani  1   4
Affiliations

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

Jozine M Ter Maaten et al. Eur J Heart Fail. 2017 Aug.

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.

Keywords: Diuretic resistance; Diuretic response; Heart failure; Mechanisms.

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Conflict of interest statement

Conflict of interest: none declared.

Figures

Figure 1
Figure 1
Relationship between the quantity of intravenously (IV) administered bumetanide and the quantity excreted unchanged in the urine in patients with and without renal dys-function. The red line represents the median relative renal bumetanide clearance of 52% of the administered dose. Renal dysfunction defined as estimated glomerular filtration rate <60 mL/min/1.73 m2.
Figure 2
Figure 2
Relative strength of factors associated with diuretic response in acute heart failure.
Figure 3
Figure 3
Scatter plots relation between estimated glomerular filtration rate (eGFR) and metrics of response to diuretic treatment after 6 h. DR, diuretic response; FENa, fractional excretion of sodium.
Figure 4
Figure 4
Tubular fractional excretion of sodium diuretic response (FENa DR) over 6 h in patients with and without significant renal dysfunction. eGFR, estimated glomerular filtration rate.
See this image and copyright information in PMC

Comment in

  • The complexity of diuretic resistance.
    Aronson D. Aronson D. Eur J Heart Fail. 2017 Aug;19(8):1023-1026. doi: 10.1002/ejhf.815. Epub 2017 Mar 31. Eur J Heart Fail. 2017. PMID: 28370822 No abstract available.

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