Mechanism of impaired natriuretic response to furosemide during prolonged therapy

Loon, Nicholas R.; Wilcox, Christopher S.; Unwin, Robert J.

doi:10.1038/ki.1989.246

Cited by 189 publications

(128 citation statements)

References 14 publications

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“…Continuous infusion of furosemide results in a substantial increase in the size of distal cells (43). The same adaptation of distal convoluted tubule has been demonstrated in humans during long-term use of furosemide (96). As a compensatory process, Na ϩ that escapes from the loop of Henle could, therefore, be partially reabsorbed at more distal sites, decreasing overall Increase in distal delivery (C-Li), ml/min Increase in distal delivery (C-Li), ml/min Decrease in GFR (C-In), ml/min Decrease in GFR (C-In), ml/min C D Fig.…”

Section: What Determines the Braking Phenomenon And Is There A Fundammentioning

confidence: 56%

“…Although a potential mechanism explaining rebound sodium retention is that furosemide could induce hyperaldosteronism, increases in aldosterone similar after 1 and 3 days of furosemide administration and 4 wk administration furosemide with or without spironolactone had similar effects on sodium balance (96). Moreover, neither ACEi nor ARB treatment could prevent acute diuretic resistance, suggesting that activation of RAAS is not responsible (81,90).…”

Section: What Determines the Braking Phenomenon And Is There A Fundammentioning

confidence: 92%

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Everything we always wanted to know about furosemide but were afraid to ask

Huang

Mees

Vos

et al. 2016

American Journal of Physiology-Renal Physiology

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Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol 310: F958 -F971, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00476.2015.-Furosemide is a widely used, potent natriuretic drug, which inhibits the Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion. extracellular fluid volume; natriuresis; renal function; chronic kidney disease; heart failure DIURETICS BLOCKING THE Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC) have an important place in the treatment of fluid overload, specifically in the context of kidney disease and heart failure (64). Of the drugs that inhibit the NKCC2 in the loop of Henle (furosemide, bumetanide, torsemide, ethacrynic acid), furosemide is most commonly applied (66) and Ͼ40 million prescriptions are dispensed every year in the USA (66a). However, many uncertainties remain about intrarenal and systemic actions of furosemide, including its two main targets NKCC1 and NKCC2.Clinically, there are a number of undesirable consequences of the use of furosemide, of which the pathophysiological mechanisms have not been sufficiently investigated. Furosemide has been associated with worsening of kidney function in patients treated for volume overload admitted for acute heart failure (104) and even glomerular filtration rate (GFR) ...

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Section: What Determines the Braking Phenomenon And Is There A Fundammentioning

confidence: 56%

Section: What Determines the Braking Phenomenon And Is There A Fundammentioning

confidence: 92%

Everything we always wanted to know about furosemide but were afraid to ask

Huang

Mees

Vos

et al. 2016

American Journal of Physiology-Renal Physiology

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“…We conclude that there is no significant additive natriuresis with dapagliflozin and bumetanide on first administration. However, there is an adaptive natriuresis over 1 week that is reminiscent of the synergy between loop and thiazide diuretics in subjects adapted to loop diuretics 13, 24. Interestingly, despite rather modest natriuresis, administration of dapagliflozin to patients with T2DM reduced the blood volume, whereas treatment with a thiazide was not effective.…”

Section: Discussionmentioning

confidence: 99%

“…This “diuretic braking phenomenon”14 ultimately leaves many patients with CHF with an expanded blood volume that predicts adverse outcomes 15. Thus, new strategies for treatment of Na + retention are needed 13, 16, 17, 18, 19…”

mentioning

confidence: 99%

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Wilcox

Shen

Boulton

et al. 2018

JAHA

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112

105

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BackgroundDapagliflozin inhibits the sodium‐glucose–linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium‐glucose–linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide.Methods and ResultsHealthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d−1 of Na+ were randomized to bumetanide (1 mg·d−1), dapagliflozin (10 mg·d−1), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na+ excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d−1; P<0.005) but by more (P<0.005) with the first dose of bumetanide (74±7 mmol·d−1; P<0.005), which was not significantly different from both diuretics together (80±5 mmol·d−1; P<0.005). However, Na+ excretion with dapagliflozin was 190% greater (P<0.005) when added after 1 week of bumetanide (64±6 mmol·d−1), and Na+ excretion with bumetanide was 36% greater (P<0.005) when added after 1 week of dapagliflozin (101±8 mmol·d−1). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (P<0.05).ConclusionsFirst‐dose Na+ excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na+ excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide‐induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865.

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“…Studies in rats have shown that chronic administration of a loop diuretic induces hypertrophy and hyperplasia in epithelial cells of the distal convoluted tubule, leading to an increased reabsorption of sodium in this segment, thereby blunting the natriuretic effect. These adaptations also occur in humans 5,6,7 . Management of diuretic resistance (A) Rule out non-compliance Non-compliance with either salt restriction (sodium intake <100 mmol/day) or medication intake should first be excluded.…”

mentioning

confidence: 90%

Mechanism and management of diuretic resistance in congestive heart failure

Nag

Murshed

Chakrabortty

et al. 2012

J. Dhaka Natl. Med. Coll. Hosp.

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Diuretic drugs are used almost universally in patients with congestive heart failure, most frequently the potent loop diuretics. Despite their unproven effect on survival, their indisputable efficacy in relieving congestive symptoms makes them first line therapy for most patients. In the treatment of more advanced stages of heart failure diuretics may fail to control salt and water retention despite the use of appropriate doses. Diuretic resistance may be caused by decreased renal function and reduced and delayed peak concentrations of loop diuretics in the tubular fluid, but it can also be observed in the absence of these pharmacokinetic abnormalities. When the effect of a short acting diuretic has worn off, postdiuretic salt retention will occur during the rest of the day. Chronic treatment with a loop diuretic results in compensatory hypertrophy of epithelial cells downstream from the thick ascending limb and consequently its diuretic effect will be blunted. Strategies to overcome diuretic resistance include restriction of sodium intake, changes in dose, changes in timing, and combination diuretic therapy.

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Mechanism of impaired natriuretic response to furosemide during prolonged therapy

Cited by 189 publications

References 14 publications

Everything we always wanted to know about furosemide but were afraid to ask

Everything we always wanted to know about furosemide but were afraid to ask

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

Mechanism and management of diuretic resistance in congestive heart failure

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