The blunted loop diuretic response in acute heart failure is driven by reduced tubular responsiveness rather than insufficient tubular delivery. The role of furosemide urine excretion on diuretic and natriuretic response in acute heart failure

Abstract

AimsDiuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness.Methods and resultsWe conducted a prospective, observational study of 50 patients with acute heart failure patients divided into two groups based on previous furosemide use (furosemide naïve: n = 28 [56%] and chronic furosemide users: n = 22 [44%]). Each patient received a protocol‐derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints (all p < 0.05). Urine furosemide delivery was similar in furosemide naïve versus chronic users after accounting for differences in estimated glomerular filtration rate (28.02 [21.03–35.89] vs. 29.70 [18.19–34.71] mg, p = 0.87). However, the tubular response to delivered diuretic was dramatically higher in naïve versus chronic users, that is the urine volume per 1 μg/ml of urine furosemide at 2 h was 148.6 ± 136.1 versus 50.6 ± 56.1 ml (p = 0.005).ConclusionsPatients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery.

Design and baseline characteristics of SALT‐HF trial: hypertonic saline therapy in ambulatory heart failure

“…The rationale of this approach is the osmotic capacity of HSS, which leads to fluid mobilization from the interstitial space into the intravascular compartment, increasing intravascular volume and renal blood flow and facilitating the delivery of the diuretic agents to the nephron. 28 Although some research suggests that the blunted diuretic response observed in chronic furosemide users is primarily due to decreased tubular responsiveness rather than insufficient furosemide tubular delivery, 29 we speculate that the volume expansion and the action of IV furosemide will lead to a more efficient diuretic response in a cohort of patients with data of diuretic resistance. Notably, the administration of chloride together with sodium may also play a role in the potential benefits of this therapy in HF patients.…”

August 2023 at a glance: Focus on epidemiology and medical therapy

“…However, the tubular response to delivered diuretic was higher in diuretic naïve versus chronic users showing the central role of the tubule in diuretic resistance. 26…”

Beyond loop diuretics: Unlocking the potential of co‐diuretics in heart failure management

“…In this issue of the Journal, Biegus and colleagues present a mechanistic study that adds valuable insights to our understanding of loop diuretics' effects. 2 The study included 50 patients admitted within 36 h of acute HF, comprising 28 furosemide-naïve individuals and 22 chronic furosemide users. The authors meticulously examined the association between previous furosemide use, diuretic response, and urine furosemide concentrations.…”

“…In this issue of the Journal, Biegus and colleagues present a mechanistic study that adds valuable insights to our understanding of loop diuretics' effects 2 . The study included 50 patients admitted within 36 h of acute HF, comprising 28 furosemide‐naïve individuals and 22 chronic furosemide users.…”