Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure

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.

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Diuretic Resistance and Chronic Heart Failure

Cardiorenal Syndrome in Heart Failure ◽

10.1007/978-3-030-21033-5_9 ◽

2019 ◽

pp. 121-135

Author(s):

Alice Ravera ◽

Jozine M. ter Maaten ◽

Marco Metra

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Diuretic Resistance

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45 Ultrafiltration in decompensated chronic heart failure patients with diuretic resistance

10.1136/heartjnl-2018-bcs.45 ◽

2018 ◽

Author(s):

Keenan Saleh ◽

Mayooran Shanmuganathan ◽

Dahlia Abdulrahman ◽

Noemi Findlay ◽

Laura Greswell ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Diuretic Resistance ◽

Heart Failure Patients

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Assessment and Management of Volume Overload and Congestion in Chronic Heart Failure: Can Measuring Blood Volume Provide New Insights?

Kidney Diseases ◽

10.1159/000450526 ◽

2016 ◽

Vol 2 (4) ◽

pp. 164-169 ◽

Cited By ~ 3

Author(s):

Wayne L. Miller

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Blood Volume ◽

Volume Overload

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Study of the Functional State of the Proximal Renal Tubules in Patients with Asymptomatic Chronic Heart Failure in Dyslipidemia and its Correction with Simvastatin Treatment

Rational Pharmacotherapy in Cardiology ◽

10.20996/1819-6446-2020-11-01 ◽

2020 ◽

Vol 16 (6) ◽

pp. 925-930

Author(s):

V. Yu. Kopylov

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Heart Failure ◽

Functional State ◽

Renal Tubules ◽

Healthy Individuals ◽

Organ Specific

Aim. To study indicators of epithelial dysfunction in the proximal renal tubules by determining the activity of organ-specific enzymes neutral α-glucosidase (NAG) and L-alanine aminopeptidase (LAAP), in patients with the initial stage of chronic heart failure in dyslipidemia, and the possibility of reducing with simvastatin.Material and methods. The study involved 90 subjects, who were divided into control and main groups. The control group consisted of 30 practically healthy individuals, the main group was divided into 2 subgroups: patients with stage I chronic heart failure (CHF) without type 2 diabetes mellitus (DM2) and patients with CHF with DM2. Patients of each of the main subgroups received simvastatin 20-40 mg/day in addition to treatment of the main pathology. The main group included patients with a total serum cholesterol level of more than 6.0 mmol/l, a BMI level of more than 30 kg/m2, and who had not previously taken statins. The exclusion criterion was a violation of the filtration capacity of the kidneys and the presence of gross dysfunction of organs and systems of the body. The functional state of the proximal renal tubules was assessed by the concentration of NAG and LAAP in dialized urine.Results. Initially, the level of activity of renal enzymes in representatives of both major subgroups is higher than the group of practically healthy individuals. Taking simvastatin in the CHF without DM2 subgroup does not cause an increase in enzyme activity throughout the entire observation period, either at a daily dosage of 20 mg (NAG - 12.36±2.65 ncat/1 14.1±5.23 ncat/1 and after 3 and 6 months, LAAP - 9.4±1.62 and 11.2±2.99 ncat/1 after 3 and 6 months), or at a dosage of 40 mg/day (NAG - 30.47±3.85 and 26.2±6.75 ncat/1 after 3 and 6 months; LAAP -17.3±3.56 and 19.58±3.83 ncat/1 after 3 and 6 months). Taking simvastatin 20 mg/day in patients with CHF with DM 2 causes an increase in the NAG activity: 26.68±6.03 and 34.57±9.73 ncat/1 after 3 and 6 months). Taking simvastatin 40 mg/day increase both enzyme activity: NAG -34.3±8.7 and 46.94±9.02 ncat/1 after 3 and 6 months, LAAP - 17.08±5.81 and 22.41±4.89 ncat/1 after 3 and 6 months).Conclusion. The appointment of simvastatin in patients with dyslipidemia on the background of obesity is permissible in order to normalize lipid metabolism. Safe for the functional state of the proximal renal tubules, long-term administration of simvastatin, within the limits of medium-therapeutic dosages, is possible for patients without type 2 diabetes. Long-term use of simvastatin in patients with dyslipidemia on the background of type 2 diabetes mellitus has a negative effect on the epithelium of the proximal renal tubules, in the form of an increase in the activity of renal organ-specific enzymes, which indicates an increased dystrophy of the epithelium.

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Editor’s Choice-Diuretic resistance in acute heart failure

European Heart Journal Acute Cardiovascular Care ◽

10.1177/2048872618768488 ◽

2018 ◽

Vol 7 (4) ◽

pp. 379-389 ◽

Cited By ~ 17

Author(s):

Frederik H Verbrugge

Keyword(s):

Heart Failure ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Acute Heart Failure ◽

Filtration Rate ◽

Loop Diuretic ◽

Volume Overload ◽

Renal Perfusion ◽

Loop Diuretics ◽

Diuretic Resistance

Diuretic resistance is a powerful predictor of adverse outcome in acute heart failure (AHF), irrespectively of underlying glomerular filtration rate. Metrics of diuretic efficacy such as natriuresis, urine output, weight loss, net fluid balance, or fractional sodium excretion, differ in their risk for measurement error, convenience, and biological plausibility, which should be taken into account when interpreting their results. Loop diuretic resistance in AHF has multiple causes including altered drug pharmacokinetics, impaired renal perfusion and effective circulatory volume, neurohumoral activation, post-diuretic sodium retention, the braking phenomenon and functional as well as structural adaptations in the nephron. Ideally, these mechanisms should guide specific treatment decisions with the goal of achieving complete decongestion. Therefore, volume overload needs to be identified correctly to avoid poor diuretic response due to electrolyte depletion or dehydration. Next, renal perfusion should be optimised if possible and loop diuretics should be prescribed above their threshold dose. Addition of thiazide-type diuretics should be considered when a progressive decrease in loop diuretic efficacy is observed with prolonged use (i.e., the braking phenomenon). Furthermore, thiazide-type diuretics are a useful addition in patients with low glomerular filtration rate. However, they limit free water excretion and are relatively contraindicated in cases of hypotonic hyponatremia, where acetazolamide is the better option. Finally, ultrafiltration should be considered in patients with refractory diuretic resistance as persistent volume overload after decongestive treatment is associated with worse outcomes. Whether more upfront use of any of these individually tailored decongestion strategies is superior to monotherapy with loop diuretics remains to be shown by adequately powered randomised clinical trials.

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Renal denervation improves sodium excretion in rats with chronic heart failure: effects on expression of renal ENaC and AQP2

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00299.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. H958-H968 ◽

Cited By ~ 5

Author(s):

Hong Zheng ◽

Xuefei Liu ◽

Kenichi Katsurada ◽

Kaushik P. Patel

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Sodium Channels ◽

Renal Denervation ◽

Water Retention ◽

Renal Cortex ◽

Renal Nerves ◽

Coronary Artery Ligation ◽

Epithelial Sodium Channels ◽

Aquaporin 2

Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changed the expressions of renal sodium transporters ENaC, sodium-hydrogen exchanger-3 proteins (NHE3), and water channel aquaporin 2 (AQP2) in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, surgical bilateral RDN was performed. The expression of ENaC, NHE3, and AQP2 in both renal cortex and medulla were measured. As a functional test for ENaC activation, diuretic and natriuretic responses to ENaC inhibitor benzamil were monitored in four groups of rats (Sham, Sham+RDN, CHF, CHF+RDN). Western blot analysis indicated that RDN (1 wk later) significantly reduced protein levels of α-ENaC, β-ENaC, γ-ENaC, and AQP2 in the renal cortex of CHF rats. RDN had no significant effects on the protein expression of kidney NHE3 in both Sham and CHF rats. Immunofluorescence studies of kidney sections confirmed the reduced signaling of ENaC and AQP2 in the CHF+RDN rats compared with the CHF rats. There were increases in diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. RDN reduced the diuretic and natriuretic responses to benzamil in CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of ENaC and AQP2 and subsequent pathophysiology of renal sodium and water retention associated with CHF. NEW & NOTEWORTHY This is the first study to show in a comprehensive way that renal denervation initiated after a period of chronic heart failure reduces the expression of epithelial sodium channels and aquaporin 2 leading to reduced epithelial sodium channel function and sodium retention.

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