# Mechanisms of diuretic resistance in heart failure

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $757,951

## Abstract

Symptoms and hospitalizations for heart failure (HF) are primarily driven by congestion, making loop
diuretics a cornerstone therapy in HF. This is problematic since loop diuretic resistance (DR) is common and a
driver of persistent congestion and the poor outcomes that follow. We have recently confirmed that: 1) The
dominant driver of DR in human HF is at the renal tubular level, rather than poor diuretic delivery. 2) Proximal
tubular sodium reabsorption is not a substantial contributor, rather 3) reduced response at the site of action in
the loop of Henle and compensatory distal tubular sodium reabsorption drive DR. 4) Resistance at the loop of
Henle appears to be addressable with diuretic doses traditionally considered above the ceiling dose. Despite
progress in defining the general locations for DR, the culprit transporters and thus specific druggable
targets remain undefined. There is consensus on the existence of three stoichiometrically relevant distal
sodium (Na) transport pathways. The central components to these three pathways are the sodium chloride
cotransporter (NCC), the epithelial sodium channel (ENaC), and the chloride bicarbonate exchanger, pendrin.
Importantly, these targets can be manipulated in humans with FDA approved drugs; NCC can be selectively
inhibited by bendroflumethiazide (a thiazide with minimal carbonic anhydrase inhibition), ENaC by amiloride,
and pendrin downregulated by NH4Cl loading. We have also learned that sodium reabsorption in the loop of
Henle is dynamic with substantial regulation and plasticity of NKCC2. Importantly, NKCC2 splice variants have
been identified that have dramatically different ion affinities, transport capacity, and diuretic sensitivities.
 The primary goal of this proposal is to translate the above knowledge into therapeutically
actionable approaches to human DR. To accomplish this, we will conduct 3 mechanistically focused clinical
trials using pharmacologic manipulation of different transport pathways, endogenous lithium clearance to
understand regional nephron sodium handling, and urinary extracellular vesicles to investigate differences in
tubular solute transporter levels and splice variants. Specifically, Aim 1 will investigate the mechanism
underlying the substantial shift in the loop diuretic dose response curve to the right in human HF. Here we will
serially titrate the highly selective NKCC2 antagonist bumetanide to 10mg (400mg furosemide equivalents) in
stable DR and diuretic responsive HF patients. In Aim 2 we seek to understand the effect of acute antagonism
of amiloride sensitive, thiazide sensitive, or combined amiloride & thiazide sensitive transport pathways on loop
diuretic response in stable DR HF patients. We will accomplish this by administration of the combinations of
placebo, amiloride, and/or bendroflumethiazide, in conjunction with bumetanide, to stable DR HF patients. In
Aim 3 we will determine if NH4CL loading, known to downregulate pendrin, can reduce non-amilo...

## Key facts

- **NIH application ID:** 10342535
- **Project number:** 1R01DK130997-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JEFFREY M TESTANI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $757,951
- **Award type:** 1
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10342535

## Citation

> US National Institutes of Health, RePORTER application 10342535, Mechanisms of diuretic resistance in heart failure (1R01DK130997-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10342535. Licensed CC0.

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