Compensatory distal reabsorption drives diuretic resistance in human heart failure

Veena S. Rao, Noah Planavsky, Jennifer S. Hanberg, Tariq Ahmad, Meredith A. Brisco-Bacik, Francis P. Wilson, Daniel Jacoby, Michael Chen, W. H.Wilson Tang, David Z.I. Cherney, David Ellison, Jeffrey M. Testani

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Abstract

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean6SD prediuretic FELi was 16.2%69.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%69.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%610.8% (P,0.001) but increased FENa by only 4.8%6 3.3%. Thus, only 34%(interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodiumrelease did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

Original languageEnglish (US)
Pages (from-to)3414-3424
Number of pages11
JournalJournal of the American Society of Nephrology
Volume28
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

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ASJC Scopus subject areas

  • Nephrology

Cite this

Rao, V. S., Planavsky, N., Hanberg, J. S., Ahmad, T., Brisco-Bacik, M. A., Wilson, F. P., ... Testani, J. M. (2017). Compensatory distal reabsorption drives diuretic resistance in human heart failure. Journal of the American Society of Nephrology, 28(11), 3414-3424. https://doi.org/10.1681/ASN.2016111178