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Nature Medicine Oct 2023Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute... (Randomized Controlled Trial)
Randomized Controlled Trial
Measurement of natriuresis has been suggested as a reliable, easily obtainable biomarker for assessment of the response to diuretic treatment in patients with acute heart failure (AHF). Here, to assess whether natriuresis-guided diuretic therapy in patients with AHF improves natriuresis and clinical outcomes, we conducted the pragmatic, open-label Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure trial, in which 310 patients (45% female) with AHF requiring treatment with intravenous loop diuretics were randomly assigned to natriuresis-guided therapy or standard of care (SOC). In the natriuresis-guided arm, natriuresis was determined at set timepoints, prompting treatment intensification if spot urinary sodium levels were <70 mmol l. The dual primary endpoints were 24 h urinary sodium excretion and a combined endpoint of time to all-cause mortality or adjudicated heart failure rehospitalization at 180 days. The first primary endpoint was met, as natriuresis in the natriuresis-guided and SOC arms was 409 ± 178 mmol arm versus 345 ± 202 mmol, respectively (P = 0.0061). However, there were no significant differences between the two arms for the combined endpoint of time to all-cause mortality or first heart failure rehospitalization, which occurred in 46 (31%) and 50 (31%) of patients in the natriuresis-guided and SOC arms, respectively (hazard ratio 0.92 [95% confidence interval 0.62-1.38], P = 0.6980). These findings suggest that natriuresis-guided therapy could be a first step towards personalized treatment of AHF. ClinicalTrials.gov registration: NCT04606927 .
Topics: Female; Humans; Male; Acute Disease; Diuretics; Heart Failure; Natriuresis; Sodium; Sodium Potassium Chloride Symporter Inhibitors
PubMed: 37640861
DOI: 10.1038/s41591-023-02532-z -
European Journal of Heart Failure Nov 2019To investigate the effects of acetazolamide on natriuresis, decongestion, kidney function and neurohumoral activation in acute heart failure (AHF). (Comparative Study)
Comparative Study Randomized Controlled Trial
AIMS
To investigate the effects of acetazolamide on natriuresis, decongestion, kidney function and neurohumoral activation in acute heart failure (AHF).
METHODS AND RESULTS
This prospective, two-centre study included 34 AHF patients on loop diuretics with volume overload. All had a serum sodium concentration < 135 mmol/L and/or serum urea/creatinine ratio > 50 and/or an admission serum creatinine increase of > 0.3 mg/dL compared to baseline. Patients were randomised towards acetazolamide 250-500 mg daily plus bumetanide 1-2 mg bid vs. high-dose loop diuretics (bumetanide bid with daily dose twice the oral maintenance dose). The primary endpoint was natriuresis after 24 h. Natriuresis after 24 h was similar in the combinational treatment vs. loop diuretic only arm (264 ± 126 vs. 234 ± 133 mmol; P = 0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84 ± 46 vs. 52 ± 42 mmol/mg bumetanide; P = 0.048). More patients in the combinational treatment arm had an increase in serum creatinine levels > 0.3 mg/dL (P = 0.046). N-terminal pro-B-type natriuretic peptide reduction and peak neurohumoral activation within 72 h were comparable among treatment arms. There was a non-significant trend towards lower all-cause mortality or heart failure readmissions in the group receiving acetazolamide with low-dose loop diuretics vs. high-dose loop diuretic monotherapy (P = 0.098).
CONCLUSION
Addition of acetazolamide increases the natriuretic response to loop diuretics compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01973335.
Topics: Acetazolamide; Adult; Aged; Bumetanide; Dose-Response Relationship, Drug; Drug Resistance; Drug Therapy, Combination; Female; Heart Failure; Humans; Kidney Function Tests; Male; Middle Aged; Natriuresis; Prospective Studies; Risk Factors; Sodium Potassium Chloride Symporter Inhibitors; Survival Analysis
PubMed: 31074184
DOI: 10.1002/ejhf.1478 -
Circulation Jul 2023SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and... (Review)
Review
SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Chlorides; Sodium-Glucose Transporter 2; Sodium; Water; Homeostasis; Diuretics; Heart Failure; Glucose
PubMed: 37486998
DOI: 10.1161/CIRCULATIONAHA.123.064346 -
Electrolyte & Blood Pressure : E & BP Jun 2023Metabolic alkalosis is a common acid-base imbalance frequently observed in intensive care unit (ICU) patients and is associated with increased mortality.... (Review)
Review
Metabolic alkalosis is a common acid-base imbalance frequently observed in intensive care unit (ICU) patients and is associated with increased mortality. Post-hypercarbia alkalosis (PHA) is a type of metabolic alkalosis caused by sustained high serum bicarbonate levels following a rapid resolution of hypoventilation in patients with chronic hypercapnia due to prolonged respiratory disturbance. Common causes of chronic hypercapnia include chronic obstructive pulmonary disease (COPD), central nervous system disorders, neuromuscular disorders, and narcotic abuse. Rapid correction of hypercapnia through hyperventilation leads to a swift normalization of pCO, which lacks renal compensation, consequently causing an increase in plasma HCO levels and severe metabolic alkalosis. Most of PHA occurs in the ICU setting requiring mechanical ventilation and can progress severe alkalemia due to secondary mineralocorticoid excess from volume depletion or decreased HCO excretion from decreased glomerular filtration rate and increased proximal tubular reabsorption. PHA is associated with increased ICU stay, ventilator dependency, and mortality. Acetazolamide, a carbonic anhydrase inhibitor, has been utilized for managing PHA by inducing alkaline diuresis and reducing tubular reabsorption of bicarbonate. While acetazolamide effectively improves alkalemia, its impact on hard outcomes may be limited by factors such as patient complexity, co-administered medications, and underlying conditions contributing to alkalosis.
PubMed: 37434801
DOI: 10.5049/EBP.2023.21.1.18 -
Neuropharmacology Mar 2022The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation... (Review)
Review
The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl cotransporter KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation and consequent effects on GABAergic signaling have been implicated in numerous CNS disorders. While KCC2 modulators are not yet clinically available, the loop diuretic bumetanide has been used in clinical studies to treat brain disorders and as a tool for NKCC1 inhibition in preclinical models. Bumetanide is known to have anticonvulsant and neuroprotective effects under some pathophysiological conditions. However, as shown in several species from neonates to adults (mice, rats, dogs, and by extrapolation in humans), at the low clinical doses of bumetanide approved for diuresis, this drug has negligible access into the CNS, reaching levels that are much lower than what is needed to inhibit NKCC1 in cells within the brain parenchyma. Several drug discovery strategies have been used over the last ∼15 years to develop brain-permeant compounds that, ideally, should be selective for NKCC1 to eliminate the diuresis mediated by inhibition of renal NKCC2. The strategies employed to improve the pharmacokinetic and pharmacodynamic properties of NKCC1 blockers include evaluation of other clinically approved loop diuretics; development of lipophilic prodrugs of bumetanide; development of side-chain derivatives of bumetanide; and unbiased high-throughput screening approaches of drug discovery based on large chemical compound libraries. The main outcomes are that (1), non-acidic loop diuretics such as azosemide and torasemide may have advantages as NKCC1 inhibitors vs. bumetanide; (2), bumetanide prodrugs achieve significantly higher brain levels of the parent drug and have lower diuretic activity; (3), the novel bumetanide side-chain derivatives do not exhibit any functionally relevant improvement of CNS accessibility or NKCC1 selectivity vs. bumetanide; (4) novel compounds discovered by high-throughput screening may resolve some of the inherent problems of bumetanide, but as yet this has not been achieved. Thus, further research is needed to optimize the design of brain-permeant NKCC1 inhibitors. Another major challenge is to identify the mechanisms whereby various NKCC1-expressing cellular targets of these drug within (e.g., neurons, oligodendrocytes or astrocytes) and outside the brain parenchyma (e.g., blood-brain barrier, choroid plexus, endocrine and immune system), as well as molecular off-target effects, might contribute to their reported therapeutic and adverse effects.
Topics: Animals; Bumetanide; Central Nervous System; Humans; Sodium Potassium Chloride Symporter Inhibitors; Solute Carrier Family 12, Member 2
PubMed: 34883135
DOI: 10.1016/j.neuropharm.2021.108910 -
Therapeutic Advances in Endocrinology... 2022Hyponatraemia is the most common electrolyte abnormality encountered in clinical practice; despite this, the work-up and management of hyponatraemia remain suboptimal... (Review)
Review
Hyponatraemia is the most common electrolyte abnormality encountered in clinical practice; despite this, the work-up and management of hyponatraemia remain suboptimal and varies among different specialist groups. The majority of data comparing hyponatraemia treatments have been observational, up until recently. The past two years have seen the publication of several randomised control trials investigating hyponatraemia treatments, both for chronic and acute hyponatraemia. In this article, we aim to provide a background to the physiology, cause and impact of hyponatraemia and summarise the most recent data on treatments for acute and chronic hyponatraemia, highlighting their efficacy, tolerability and adverse effects.
PubMed: 35586730
DOI: 10.1177/20420188221097343