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Journal of the American College of... Mar 2020Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling... (Review)
Review
Expansion of extracellular fluid volume is central to the pathophysiology of heart failure. Increased extracellular fluid leads to elevated intracardiac filling pressures, resulting in a constellation of signs and symptoms of heart failure referred to as congestion. Loop diuretics are one of the cornerstones of treatments for heart failure, but in contrast to other therapies, robust clinical trial evidence to guide the use of diuretics is sparse. A nuanced understanding of renal physiology and diuretic pharmacokinetics is essential for skillful use of diuretics in the management of heart failure in both the inpatient and outpatient settings. Diuretic resistance, defined as an inadequate quantity of natriuresis despite an adequate diuretic regimen, is a major clinical challenge that generally portends a poor prognosis. In this review, the authors discuss the fundamental mechanisms and physiological principles that underlie the use of diuretic therapy and the available data on the optimal use of diuretics.
Topics: Diuretics; Gastrointestinal Absorption; Heart Failure; Humans; Kidney; Review Literature as Topic; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 32164892
DOI: 10.1016/j.jacc.2019.12.059 -
Current Heart Failure Reports Apr 2019Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review... (Review)
Review
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.
Topics: Diuretics; Drug Resistance; Heart Failure; Humans; Nephrons; Prognosis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 30762178
DOI: 10.1007/s11897-019-0424-1 -
Clinical Journal of the American... Aug 2019
Review
Topics: Diuretics; Edema; Extracellular Fluid; Gastrointestinal Absorption; Humans
PubMed: 30936153
DOI: 10.2215/CJN.09630818 -
Seminars in Nephrology Nov 2011All diuretics except spironolactone exert their effects from the lumen of the nephron. Thus, to exert an effect, they must reach the urine. Pharmacokinetics (PK)... (Review)
Review
All diuretics except spironolactone exert their effects from the lumen of the nephron. Thus, to exert an effect, they must reach the urine. Pharmacokinetics (PK) describes this access. Different edematous disorders can affect access to this site of action and therein affect response to a diuretic. In addition, once a diuretic reaches the site of action, a response ensues. The characteristics of this response that can be affected by a patient's clinical condition are described by the pharmacodynamics (PD) of a diuretic. To understand the mechanisms of abnormal response to a diuretic one must dissect its PK and PD in different edematous disorders. For example, in patients with renal insufficiency, the mechanism of poor diuretic response is PK. In contrast, in patients with cirrhosis or in those with congestive heart failure, it is PD. In patients with nephrotic syndrome, both PK and PD are operative. These different mechanisms mandate differences in therapeutic strategy, as explained in this article.
Topics: Diuretics; Edema; Heart Failure; Humans; Liver Cirrhosis; Nephrotic Syndrome; Renal Insufficiency; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 22099505
DOI: 10.1016/j.semnephrol.2011.09.003 -
Hypertension (Dallas, Tex. : 1979) Oct 2020Diuretic resistance implies a failure to increase fluid and sodium (Na) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of... (Review)
Review
Diuretic resistance implies a failure to increase fluid and sodium (Na) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level (80 mg of furosemide once or twice daily or greater in those with reduced glomerular filtration rate or heart failure). It is a major cause of recurrent hospitalizations in patients with chronic heart failure and predicts death but is difficult to diagnose unequivocally. Pharmacokinetic mechanisms include the low and variable bioavailability of furosemide and the short duration of all loop diuretics that provides time for the kidneys to restore diuretic-induced Na losses between doses. Pathophysiological mechanisms of diuretic resistance include an inappropriately high daily salt intake that exceeds the acute diuretic-induced salt loss, hyponatremia or hypokalemic, hypochloremic metabolic alkalosis, and reflex activation of the renal nerves. Nephron mechanisms include tubular tolerance that can develop even during the time that the renal tubules are exposed to a single dose of diuretic, or enhanced reabsorption in the proximal tubule that limits delivery to the loop, or an adaptive increase in reabsorption in the downstream distal tubule and collecting ducts that offsets ongoing blockade of Na reabsorption in the loop of Henle. These provide rationales for novel strategies including the concurrent use of diuretics that block these nephron segments and even sequential nephron blockade with multiple diuretics and aquaretics combined in severely diuretic-resistant patients with heart failure.
Topics: Diuretics; Drug Resistance; Heart Failure; Humans; Kidney Tubules; Treatment Failure
PubMed: 32829662
DOI: 10.1161/HYPERTENSIONAHA.120.15205 -
Revista Portuguesa de Cardiologia :... Sep 2023Acute heart failure (HF) decompensation generally manifests with signs and symptoms of congestion that strongly predict poor poor patient outcome. Loop diuretics are the... (Review)
Review
Acute heart failure (HF) decompensation generally manifests with signs and symptoms of congestion that strongly predict poor poor patient outcome. Loop diuretics are the cornerstone of therapy to counteract fluid overload and are widely used for acute management and chronic stabilization of HF. However, a diminished response to loop diuretics is a common problem, affecting the patient's clinical course and potentially prolonging hospitalization. Diuretic resistance is defined as failure to decongest despite appropriate and escalating loop diuretic therapy. We propose a protocol for the management of diuretic resistance. The initial approach should include an assessment of causes of pseudo-diuretic resistance. Adjustments to loop diuretic therapy, such as increasing doses and frequency of administration and sequential nephron blockade, may be successful. For hospitalized patients with progressive disease there are more invasive methods for fluid removal. Switching from oral to intravenous loop diuretics is essential to avoid variable absorption and for symptomatic relief. Extracorporeal ultrafiltration is also an option since this technique is highly effective at removing plasma fluid from blood. While extracorporeal ultrafiltration is an invasive solution, peritoneal dialysis is a home-based, intermittent therapeutic option that can enable efficient management of fluid overload, preventing HF-related hospital admission, and improving quality of life. As a last resort for fluid removal, a peritoneal dialysis regimen should fully exploit its decongestive properties and should be tailored to the patient's characteristics and clinical needs.
Topics: Humans; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Ultrafiltration; Quality of Life; Heart Failure
PubMed: 36948455
DOI: 10.1016/j.repc.2022.05.012 -
Clinical Journal of the American... Oct 2023In contrast to significant advances in the management of patients with chronic heart failure over the past few years, there has been little change in how patients with... (Review)
Review
In contrast to significant advances in the management of patients with chronic heart failure over the past few years, there has been little change in how patients with acute heart failure are treated. Symptoms and signs of fluid overload are the primary reason for hospitalization of patients who experience acute decompensation of heart failure. Intravenous loop diuretics remain the mainstay of therapy in this patient population, with a significant subset of them showing suboptimal response to these agents leading to incomplete decongestion at the time of discharge. Combination diuretic therapy, that is, using loop diuretics along with an add-on agent, is a widely applied strategy to counter renal sodium avidity through sequential blockade of sodium absorption within renal tubules. The choice of the second diuretic is affected by several factors, including the site of action, the anticipated secondary effects, and the available evidence on their efficacy and safety. While the current guidelines recommend combination diuretic therapy as a viable option to overcome suboptimal response to loop diuretics, it is also acknowledged that this strategy is not supported by strong evidence and remains an area of uncertainty. The recent publication of landmark studies has regenerated the interest in sequential nephron blockade. In this article, we provide an overview of the results of the key studies on combination diuretic therapy in the setting of acute heart failure and discuss their findings primarily with regard to the effect on renal sodium avidity and cardiorenal outcomes.
Topics: Humans; Diuretics; Heart Failure; Kidney; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 37102974
DOI: 10.2215/CJN.0000000000000188 -
European Heart Journal Aug 2023Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection...
AIMS
Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated.
METHODS AND RESULTS
In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001).
CONCLUSION
In patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.
Topics: Humans; Diuretics; Heart Failure; Furosemide; Benzhydryl Compounds; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Ventricular Function, Left
PubMed: 37220093
DOI: 10.1093/eurheartj/ehad283 -
American Journal of Nephrology 1999Diuretics are one of the most common causes of severe hyponatremia. Yet, despite several relevant studies and years of clinical experience, the mechanism and optimal... (Review)
Review
Diuretics are one of the most common causes of severe hyponatremia. Yet, despite several relevant studies and years of clinical experience, the mechanism and optimal treatment of diuretic-induced hyponatremia remain unclear. What is clear is that most cases are caused by thiazide rather than loop diuretics and that severe hyponatremia can develop very rapidly in susceptible patients. In this review, I will discuss the pathogenesis, clinical features, prevention, and treatment of diuretic-induced hyponatremia in the hope that increased awareness and understanding will reduce the incidence and complications of this potentially life-threatening syndrome.
Topics: Benzothiadiazines; Diuretics; Female; Humans; Hypertension; Hyponatremia; Male; Sodium Chloride Symporter Inhibitors; Water-Electrolyte Balance
PubMed: 10460932
DOI: 10.1159/000013496 -
Kidney & Blood Pressure Research 2019Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital... (Review)
Review
BACKGROUND
Diuretic resistance is among the most challenging problems that the cardio-nephrologist must address in daily clinical practice, with a considerable burden on hospital admissions and health care costs. Indeed, loop diuretics are the first-line therapy to overcome fluid overload in heart failure patients. The pathophysiological mechanisms of fluid and sodium retention are complex and depend on several neuro-hormonal signals mainly acting on sodium reabsorption along the renal tubule. Consequently, doses and administration modalities of diuretics must be carefully tailored to patients in order to overcome under- or overtreatment. The frequent and tricky development of diuretic resistance depends in part on post-diuretic sodium retention, reduced tubular secretion of the drug, and reduced sodium/chloride sensing. Sodium and chloride depletions have been recently shown to be major factors mediating these processes. Aquaretics and high-saline infusions have been recently suggested in cases of hyponatremic conditions. This review discusses the limitations and strengths of these approaches.
SUMMARY
Long-term diuretic use may lead to diuretic resistance in cardio-renal syndromes. To overcome this complication intravenous administration of loop diuretics and a combination of different diuretic classes have been proposed. In the presence of hyponatremia, high-saline solutions in addition to loop diuretics might be beneficial, whereas aquaretics require caution to avoid overcorrection. Key Messages: Diuretic resistance is a central theme for cardio-renal syndromes. Hyponatremia and hypochloremia may be part of the mechanisms for diuretic resistance. Aquaretics and high-saline solutions have been proposed as possible new therapeutic solutions.
Topics: Cardio-Renal Syndrome; Diuretics; Heart Failure; Humans; Kidney; Nephrology
PubMed: 31437845
DOI: 10.1159/000502648