Diuretic Resistance in Heart Failure

Abstract

Purpose of review: Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF.

Recent findings: The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiological, and direct measure for diuretic responsiveness to a given loop diuretic dose. Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.

Keywords: Acute heart failure; Biomarkers; Diuretic resistance; Loop diuretics; Spot urine sodium.

Fig 1.

Diuretic secretion by the proximal tubule and diuretic action on the Loop of Henle. A. Proximal convoluted tubule: After translocation into the proximal tubule cell, the loop diuretic is then secreted across the basolateral or luminal membrane by voltage-driven organic anion transporters (OAT1 and OAT2) and at the apical membrane by multidrug resistance-associated protein 4 (MRP4) and others. B. Thick ascending limb of the loop of Henle: The primary action of loop diuretics occurs here on the luminal membrane where an electroneutral Na-K-2Cl (NKCC2) is located. This cotransporter mediates sodium and chloride movement across the apical membrane. Loop diuretics bind to the NKCC2 from the luminal surface to block the reabsorption of sodium and chloride across the apical membrane via this transporter. The tubular lumen becomes more hypertonic and the interstitium less so, diminishing the osmotic gradient required for water reabsorption.

Fig 2.

Dose-response curve for loop diuretics with sodium chloride excretion as a function of plasma loop diuretic concentration. Note a rightward shift in the curve due to diuretic resistance in a patient with chronic heart failure compared to normal subjects. In heart failure, large increases in diuretic dose are required to achieve modest increases in sodium chloride excretion.