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In nondiabetic rats, the Na+-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin increased vasopressin-related stimulation of fluid intake and free water reabsorption and maintained fluid balance and serum creatinine, whereas the loop diuretic furosemide reduced vasopressin and induced a negative fluid balance followed by a subsequent increase in serum creatinine. This study suggests that differences in vasopressin secretion in response to a SGLT2 inhibitor or loop diuretic may contribute to differences in body fluid status and subsequent renal function.

Among patients with acute decompensated heart failure (HF), national and international loop diuretic therapy recommendations may not be followed in the emergency department (ED).To examine if loop diuretic treatment and patient disposition from the ED differed after implementing a clinical pathway based on national HF guidelines.Using an observational, pre- and post-intervention design, after clinical pathway implementation, loop diuretic medications and clinical outcomes were retrieved from medical records. Analyses included Pearson's Chi-square or Fisher's exact test, 2-sample T-test or Wilcoxon rank sum test.Of 182 pre- and 122 post-intervention patients, mean (SD) patient age was 67.9 (13.4) years and 44.2% were Caucasian. There were no between-group differences in pre-ED visit loop diuretic prescription or dosages. More post-intervention ED patients received at least one dose of loop diuretic (94.3% vs. 81.9%, p = 0.010); however, the overall dose (mg) across groups was lower than the home dose and was not based on national guideline expectations. Doses from home to ED decreased less in the post-intervention group for patients who received doses at both time points and for all patients: p = 0.047 and p = 0.048, respectively. There was no between-group differences in short-stay unit (SSU) admissions, p = 0.33. Post-intervention patients were hospitalized from the ED (p = 0.050) and SSU (p = 0.005) less often than pre-intervention patients. Discharge to home from the ED or SSU increased in the post-intervention period; 16.4% vs. 4.9%, p = 0.009.Among ED patients treated for HF, diuretic dosing was non-optimized. New interventions are needed to enhance adherence to national guidelines.

Progressive intravascular, interstitial, and alveolar fluid overload underlies the transition from compensated to acutely decompensated heart failure and loop diuretics are the mainstay of treatment. Adverse effects and resistance to loop diuretics received much attention while the contribution of a depressed cardiac output to diuretic resistance was downplayed.Analysis of experience with positive inotropic agents, especially dobutamine, indicates that enhancement of cardiac output is not consistently associated with increased renal blood flow. However, urinary output and renal sodium excretion increase likely due to dobutamine-mediated decrease in renal and systemic reduced activation of sympathetic nervous- and renin-angiotensin-aldosterone system. Mechanical circulatory support with left ventricular assist devices ascertained the contribution of low cardiac output to diuretic resistance and the pathogenesis and progression of kidney disease in acutely decompensated heart failure. Diuretic resistance commonly occurs in acutely decompensated heart failure. However, failure to resolve fluid overload despite high doses of loop diuretics should alert to the presence of a low cardiac output state.

Background: Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear. Methods: In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Results: Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6]; P =0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6–27.7]; P =0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²; P =0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P =0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P =0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (−1861 versus −727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI, 0.83–0.95]; P Conclusions: Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04049045.

Existing guidelines offer little direction about the use of thiazide and loop diuretics in patients with chronic kidney disease (CKD). This review summarizes recent studies impacting indications and safety considerations for these agents in patients with CKD.Chlorthalidone reduces blood pressure compared to placebo in patients with advanced CKD, challenging the belief that thiazide diuretics lose efficacy at lower glomerular filtration rates (GFR). Existing studies show no clear impact of thiazide or loop diuretic use on kidney or cardiovascular outcomes in patients with CKD. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have diuretic effects, but concomitant use of a diuretic does not diminish the preventive benefits of these agents against acute kidney injury (AKI). Despite theoretical concerns, thiazide diuretics likely do not worsen circulating vasopressin levels or cyst progression in polycystic kidney disease and may be useful for alleviating polyuria from tolvaptan. Diuretics cause multiple adverse effects, including electrolyte abnormalities, hemodynamic-mediated decrease in estimated GFR, and AKI.Recent evidence supports expanded indications for diuretics in patients with kidney disease, including chlorthalidone for hypertension in advanced CKD. Monitoring electrolytes and estimated GFR is critical to ensure patient safety when prescribing these agents for patients with CKD.

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are used to prevent cardiovascular complications in type 2 diabetes mellitus (T2DM) and newly indicated to treat heart failure (HF). Loop diuretics are commonly prescribed to manage volume overload in HF and may increase the risk of volume depletion in real-world practice. This study evaluated the risk of volume depletion following concomitant use of SGLT2is and loop diuretics in veterans.Veterans with T2DM were included if they received concomitant loop diuretics and SGLT2is and experienced at least one volume depletion event between December 2012 and December 2019, utilizing a self-controlled case series design. Concomitant prescribing periods were divided into focal windows of 1 to 14 days, 14 to 28 days, and greater than 28 days. Incidence rate ratios (IRR) were estimated using multivariable Poisson regressions adjusted for age and renal function.3352 patients experienced at least one volume depletion event and were concomitantly prescribed SGLT2is and loop diuretics at least once. The risk of volume depletion increased in the treatment versus control windows during the 1 to 14-day window (IRR = 1.82, 95% CI 1.63-2.02) the 15-to-28-day window (IRR = 1.46, 95% CI 1.28-1.67), and the greater than 28-day window (IRR = 1.22, 95% CI 1.21-1.34).Concomitant prescribing of SGLT2is and loop diuretics is associated with an increased risk of volume depletion, an effect that attenuates with longer therapy durations. Prescribers need to closely monitor fluid status in patients receiving concomitant therapy, especially those with advancing age or with eGFR below 60.

Furosemide, a short-acting loop diuretic (SD), is the dominant agent prescribed for heart failure (HF) in clinical practice. However, accumulating data suggests that long-acting loop diuretics (LD), such as torsemide or azosemide, might have more favourable pharmacological profiles. This study aimed to investigate the relationship between the type of loop diuretics and long-term outcomes among patients hospitalized for acute HF enrolled in a contemporary multicentre registry.Within the West Tokyo Heart Failure Registry from 2006 to 2017, a total of 2680 patients (60.1% men with a median age of 77 years) were analysed. The patients were characterized by the type of diuretics used at the time of discharge; 2073 (77.4%) used SD, and 607 (22.6%) used LD. The primary endpoint was composite of all-cause death or HF re-admission after discharge, and the secondary endpoints were all-cause death and HF re-admission, respectively. During the median follow-up period of 2.1 years, 639 patients died [n = 519 (25.0%) in the SD group; n = 120 (19.8%) in the LD group], and 868 patients were readmitted for HF [n = 697 (33.6%) in the SD group; n = 171 (28.2%) in the LD group]. After multivariable adjustment, the LD group had lower risk for the composite outcome [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.66-0.96; P = 0.017], including all-cause death (HR; 0.73; 95% CI; 0.54-0.99; P = 0.044) and HF re-admission (HR, 0.81; 95% CI, 0.66-0.99; P = 0.038), than the SD group. Propensity score matching yielded estimates that were consistent with those of the multivariable analyses, with sub-group analyses demonstrating that use of LD was associated with favourable outcomes predominantly in younger patients with reduced ejection fraction.LD was associated with lower risk of long-term outcomes in patients with HF and a recent episode of acute decompensation.

A recent Phase II randomized, controlled trial of bumetanide as an adjunctive treatment for neonatal seizures showed a robust efficacy signal and no evidence of toxicity. Concerns regarding bumetanide as an adjunctive anticonvulsant are addressed here. An adequately powered multi-institutional trial is needed to accurately determine efficacy.

Background: Chronic kidney disease (CKD) has been associated with adverse clinical outcomes. Hyponatremia, a marker of illness severity and poor prognosis, is commonly exhibited in patients with CKD. Methods: This cross-sectional study included patients hospitalized due to heart failure (HF). We used stepwise logistic regression to investigate the independent association of cardiovascular drugs, markers of HF severity, and baseline clinical characteristics with hyponatremia in three subgroups ; normal renal function, mild-to-moderate CKD, and severe CKD. Results: Of the 1232 patients, 38.6% were hyponatremic. Patients with severe CKD, compared to those with normal renal function and mild-to- moderate CKD, were more likely to be hyponatremic (47.1%, 34.4% and 36.6%, respectively ; p

Aims: One of the bothersome symptoms that heart failure (HF) patients can experience is thirst. There are limited data on the association between thirst and fluid intake and clinical variables. Therefore, the aim of this study was to describe severe thirst in stable HF patients and assess factors related to severe thirst, including actual fluid intake and sodium intake. Methods and results: The study had a cross-sectional design. Stable HF patients from two HF clinics in the Netherlands were included and assessed thirst by a visual analogue scale ranging from 0 to 100. They also completed questionnaires on thirst distress, self-care behaviour, and HF symptoms. A 3 day food diary was completed to assess actual fluid intake and sodium intake. Finally, patients collected urine for 24 h. Patients were divided into severe and low thirst based on thirst score and thirst distress. T-tests, Mann-Whitney tests, and chi(2) tests were conducted to assess differences between both groups. Multivariable logistic regression analysis was performed to assess factors associated with severe thirst. A total of 100 patients were included (40% female, mean age 72 +/- 12) of which 68 completed the food diary. The mean thirst score was 28 +/- 25, and 25% experienced severe thirst. The majority of patients (94%) were prescribed a fluid restriction, 37% had a restriction between 1500 and 2000 mL, and 32% a restriction of 1500 mL. Severe thirst in the total group with 100 patients was associated with a higher dose of loop diuretics [odds ratio (OR) 3.25; 95% confidence interval (CI) 1.01-10.45; P = 0.048] and a higher urine output over 24 h (OR 1.002; 95% CI 1.00-1.003; P = 0.010). In the group of patients who completed the food diary (N = 68), severe thirst was associated with a higher sodium intake (OR 1.002; 95% CI 1.001-1.003; P = 0.003), a higher dose of loop diuretics (OR 22.69; 95% CI 2.78-185.04; P = 0.004), and more fatigue (OR 11.2; 95% CI 1.54-82.12; P = 0.017). Conclusions: A quarter of all stable HF patients experienced severe thirst. A higher dose of loop diuretics was associated with more thirst; therefore, it might be important to review the dose of loop diuretics critically and try to decrease it in order to relieve severe thirst. Because all patients were prescribed a fluid restriction, a reconsideration of this restriction is also suggested.

We aimed to assess the effectiveness and nephrotoxicity of polymyxin B in critically ill patients with nosocomial pneumonia and to evaluate the utility of its therapeutic drug monitoring (TDM).We retrospectively analyzed patients who received polymyxin B treatment for ≥48 h since the establishment of polymyxin B TDM in a 26-bed tertiary referral intensive care unit. Univariate and multivariate analyses were conducted to assess the variables associated with polymyxin B effectiveness and nephrotoxicity.A total of 62 patients were enrolled. Most (56.5%) of the patients performed TDM, 54.3% of them reached the therapeutic target of area under curve across 24 h at steady state (AUCOur findings show that TDM of polymyxin B is a valuable intervention, and the achievement of its optimal pharmacodynamic target can improve treatment outcome. Renal insufficiency and concomitant treatment with loop diuretics were found to be associated with the risk of nephrotoxicity.

Background: Loop diuretics help to manage the patients with edema associated with congestive heart failure, liver cirrhosis, and renal disease and hypertension. The patients taking loop diuretics may receive other medications to treat comorbidities leading to drug interactions. Methods: The literature was searched in databases such as Medline/PMC/PubMed, Google Scholar, Cochrane Library, Science Direct, EMBASE, Web of science, Ebsco, Directory of open access journals (DOAJ) and reference lists were used to spot relevant articles using keywords Drug interactions, Pharmacodynamic interactions, Loop diuretics, Bumetanide, Ethacrynic acid, Furosemide, and Torsemide. Results: Loop diuretics are associated with hypokalemia, ototoxicity and other adverse effects. The drugs affected by hypokalemia and having the potential of inducing ototoxicity could interact with loop diuretics pharmacodynamically. Loop diuretics can interact with drugs such as amphotericin B, digoxin, angiotensin-converting enzyme inhibitors (ACE inhibitors), antidiabetic drugs, antifungal agents, dobutamine, gossypoland sotalol due to diuretic associated hypokalemia. In addition, the risk of ototoxicity could be enhanced by the concomitant use of loop diuretics and cisplatin, aminoglycoside antibiotics or phosphodiesterase 5 (PDE 5) inhibitors. Loop diuretics may also interact pharmacodynamically with drugs like cephalosporins, ceritinib, levothyroxine, pixantrone, probenecid, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), sulfonylureas and herbal drugs. Conclusion: Clinicians, pharmacists and other health care providers should take responsibility for the safe use of medications. In addition, they are required to be aware of the drugs interacting with loop diuretics to prevent adverse drug interactions.

Given the concern that beta-blocker use may be associated with an increased risk for heart failure (HF) in populations with normal left ventricular systolic function, we evaluated the association between beta-blocker use and incident HF events, as well as loop diuretic initiation in the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT demonstrated that a blood pressure target of120 mm Hg reduced cardiovascular outcomes compared with140 mm Hg in adults with at least one cardiovascular risk factor and without HF. The lower rate of the composite primary outcome in the 120 mm Hg group was primarily driven by a reduction in HF events. Subjects on a beta blocker for the entire trial duration were compared with subjects who never received a beta blocker after 1:1 propensity score matching. A competing risk survival analysis by beta-blocker status was performed to estimate the effect of the drug on incident HF and was then repeated for a secondary end point of cardiovascular disease death. Among the 3,284 propensity score-matched subjects, beta-blocker exposure was associated with an increased HF risk (hazard ratio 5.86; 95% confidence interval 2.73 to 13.04; p0.001). A sensitivity analysis of propensity score-matched cohorts with a history of coronary artery disease or atrial fibrillation revealed the same association (hazard ratio 3.49; 95% confidence interval 1.15 to 10.06; p = 0.028). In conclusion, beta-blocker exposure in this secondary analysis was associated with increased incident HF in subjects with hypertension without HF at baseline.

Background Post-transplantation diabetes mellitus (PTDM) is a major clinical problem in kidney transplant recipients (KTRs). Diuretic-induced hyperglycaemia and diabetes have been described in the general population. We aimed to investigate whether diuretics also increase PTDM risk in KTRs. Methods We included 486 stable outpatient KTRs (with a functioning graft ≥1 year) without diabetes from a prospective cohort study. Participants were classified as diuretic users and non-users based on their medication use verified by medical records. Results At the baseline study, 168 (35%) KTRs used a diuretic (thiazide, n = 74; loop diuretic, n = 76; others, n = 18) and 318 KTRs did not use a diuretic. After 5.2 years [interquartile range (IQR) 4.0‒5.9] of follow up, 54 (11%) KTRs developed PTDM. In Cox regression analyses, diuretic use was associated with incident PTDM, independent of age, sex, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) {hazard ratio [HR] 3.28 [95% confidence interval (CI) 1.84–5.83]; P Conclusions This study demonstrates that diuretics overall are associated with an increased risk of developing PTDM in KTRs, independent of established risk factors for PTDM development. The association was present for both thiazide and loop diuretics.

To analyze therapy in patients with arterial hypertension (AH) in 20102020.Data of hypertensive patients observed in primary health care, entered into the base of hypertension registry for 20102020 years in the whole group (n=44 653) and in a separate subgroup of hypertensive patients in the absence of: ischemic heart disease, a history of myocardial infarction, chronic heart failure (n=20 569).About 80% of hypertensive patients are patients of high and very high risks (from 2010 to 2020, the proportion of very high cardiovascular risk (CVR) increased from 18.1 to 57.3%). The number of hypertensive patients with a history of myocardial infarction increased in 5 times, in 3 times with ischemic heart disease and with chronic heart failure. The number of prescribed drugs increased: mineralocorticoid receptor antagonist (in 5.8 times), loop diuretics (in 7.2) angiotensin receptor blockers (in 3 times), b-adrenoblockers, calcium channel blockers of the dihydropyridine series, thiazide-like diuretics in 2 times. Patients at high and very high risk are more likely reached target blood pressure values. Angiotensin-converting enzyme inhibitors were prescribed in more than 70% of patients with hypertension and the absence of coronary heart disease, chronic heart failure, history of myocardial infarction; the prescription of b-adrenoblockers, angiotension receptor blockers, thiazide-like and loop diuretics increased.The proportion of more severe and comorbid patients has increased in observed in primary health care patients with AH over a 10-year period (20102020). This was probably the main factor of increasing antihypertensive therapy and prescribing drugs with additional indications and improving the achievement of target blood pressure in patients with high and very high cardiovascular risk.Цель. Анализ лечения больных артериальной гипертонией (АГ) в 20102020 гг. Материалы и методы. Проведен анализ медицинских данных 44 653 больных АГ, наблюдавшихся в первичном звене здравоохранения, аккумулированных в регистре АГ за период 20102020 гг. и в подгруппе, включившей 20 569 больных АГ без диагностированных сердечно-сосудистых заболеваний (ССЗ) ишемической болезни сердца, инфаркта миокарда в анамнезе, хронической сердечной недостаточности. Результаты. За 10-летний период среди больных АГ, наблюдаемых в условиях первичного звена здравоохранения, 80% больных были высокого и очень высокого сердечно-сосудистого риска (ССР); с 2010 по 2020 г. регистрируется увеличение доли больных очень высокого ССР с 18,1 до 57,3%. В 5 раз увеличилось число больных АГ, перенесших инфаркт миокарда; в 3 раза ишемическую болезнь сердца и хроническую сердечную недостаточность. Отмечено увеличение назначаемых препаратов: антагонистов минералокортикоидных рецепторов в 5,8 раза, петлевого диуретика в 7,2, блокаторов рецепторов ангиотензина в 3 раза, -адреноблокаторов, дигидропиридиновых блокаторов кальциевых каналов и тиазидоподобных диуретиков в 2 раза. У больных высокого и очень высокого риска чаще достигался целевой уровень артериального давления. У больных АГ без ССЗ (ишемическая болезнь сердца, хроническая сердечная недостаточность, перенесенный инфаркт миокарда) ингибиторы ангиотензинпревращающего фермента назначались более чем 70% больных; чаще стали назначаться -адреноблокаторы, блокаторы рецепторов ангиотензина, тиазидоподобный диуретик, петлевой диуретик. Заключение. В структуре больных АГ, наблюдаемых в первичном звене здравоохранения за 10-летний период, увеличилась доля более тяжелых больных АГ, у которых диагностированы ССЗ. Это, вероятно, явилось основным фактором усиления антигипертензивной терапии и назначения препаратов с учетом дополнительных показаний, что, по-видимому, улучшило достижение целевого артериального давления у больных высокого и очень высокого ССР.

Mullens W, Dauw J, Martens P, et al.

Addressing volume expansion may improve the management of hypertension across the pregnancy continuum. We conducted a systematic review to summarize the evidence on the use of loop diuretics in the context of hypertensive disorders during pregnancy and the postpartum period.Medline, Embase, Cochrane library, ClinicalTrials.gov, and Google Scholar were searched for original research articles published up to 29 June 2021. Of the 2801 results screened, 15 studies were included: eight randomized controlled trials, six before-after studies, and one cohort study. Based on random effects meta-analysis of before-after studies, antepartum use of loop diuretics was associated with lower DBP [mean difference -17.73 mmHg, (95% confidence intervals -34.50 to -0.96); I2 = 94%] and lower cardiac output [mean difference -0.75 l/min, (-1.11 to -0.39); I2 = 0%], with no difference in SBP, mean arterial pressure, heart rate, or total peripheral resistance. Meta-analysis of randomized controlled trials revealed that postpartum use of loop diuretics was associated with decreased need for additional antihypertensive patients [relative risk 0.69, (0.50-0.97); I2 = 14%], and an increased duration of hospitalization [mean difference 8.80 h, (4.46-13.14); I2 = 83%], with no difference in the need for antihypertensive therapy at hospital discharge, or persistent postpartum hypertension.Antepartum use of loop diuretics lowered DBP and cardiac output, while their postpartum use reduced the need for additional antihypertensive medications. There was insufficient evidence to suggest a clear benefit. Future studies focusing on women with hypertensive pregnancy disorders who may most likely benefit from loop diuretics are required.

Purpose To identify the incidence of continuation of newly initiated loop diuretics upon intensive care unit (ICU) and hospital discharge and identify factors associated with continuation. Methods This was a single-center retrospective study using electronic health records in the setting of adult ICUs at a quaternary care academic medical center. It involved patients with sepsis admitted to the ICU from January 1, 2014, to June 30, 2019, who received intravenous fluid resuscitation. The endpoints of interest were (1) the incidence of loop diuretic use during an ICU stay following fluid resuscitation, (2) continuation of loop diuretics following transition of care, and (3) potential factors associated with loop diuretic continuation after transition from the ICU. Results Of 3,591 patients who received intravenous fluid resuscitation for sepsis, 39.4% (n = 1,415) were newly started on loop diuretics during their ICU stay. Among patients who transitioned to the hospital ward from the ICU, loop diuretics were continued in 33% (388/1,193) of patients. At hospital discharge, 13.4% (52/388) of these patients were prescribed a loop diuretic to be used in the outpatient setting. History of liver disease, development of acute kidney injury, being on vasopressors while in the ICU, receiving blood products, and receiving greater than 90 mL/kg of bolus fluids were significant potential factors associated with loop diuretic continuation after transition from the ICU. Conclusion New initiation of loop diuretics following intravenous fluid resuscitation in patients with sepsis during an ICU stay is a common occurrence. Studies are needed to assess the effect of this practice on patient outcomes and resource utilization.

In heart failure (HF) patients, current European Society of Cardiology (ESC) guidelines recommend the use of three loop diuretics (furosemide, torasemide, bumetanide) in order to not only reduce HF hospitalizations but also improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion. In addition, for the first time in hypertensive patients, European Society of Hypertension (ESH) guidelines recommend the use of torasemide. This review aimed to summarize the mode of action of loop diuretics, to present their pharmacokinetic characteristics, and to discuss their place in the management of arterial hypertension and heart failure, with special emphasis however on torasemide.

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a diagnosis of EGPA, which was later confirmed by a consultant in rheumatology. The patient was commenced on prednisone at a dose of 0.5 mg per kg of body weight daily and mycophenolate mofetil at a daily dose of 2 g. The antihypertensive therapy was modified, and torasemide was replaced by spironolactone 25 mg per day. The treatment resulted in a gradual regression of skin lesions within a few weeks. The first report of EGPA dates back to 1951. Its authors were Jacob Churg and Lotte Strauss. They described a case series of 13 patients who had severe asthma, fever, peripheral blood eosinophilia, and granulomatous vasculitis in microscopic evaluation of the skin. Three histopathological criteria were then proposed, and Churg-Strauss syndrome was recognized when eosinophilic infiltrates in the tissues, necrotizing inflammation of small and medium vessels, and the presence of extravascular granulomas were observed together in a patient (1). Only 17.4% of patients met all three histopathological criteria, and the diagnosis of the disease was frequently delayed despite of its overt clinical picture (2). In 1984, Lanham et al. proposed new diagnostic criteria which included the presence of bronchial asthma, eosinophilia in a peripheral blood smear1.5 thousand per mm3, and signs of vasculitis involving at least two organs other than the lungs (3). Lanham's criteria could also delay the recognition of the syndrome before involvement of internal organs, and the American College of Rheumatology therefore established classification criteria in 1990. These included the presence of bronchial asthma, migratory infiltrates in the lungs as assessed by radiographs, the presence of abnormalities in the paranasal sinuses (polyps, allergic rhinitis, chronic inflammation), mono- or polyneuropathy, peripheral blood eosinophilia (10% of leukocytes must be eosinophils), and extravascular eosinophilic infiltrates in a histopathological examination. Patients who met 4 out of 6 criteria were classified as having Churg-Strauss syndrome (4). The term EGPA was recommended to define patients with Churg-Strauss syndrome in 2012 (5). EGPA is a condition with low incidence (0.11-2.66 cases per million) and morbidity. It usually occurs in the fifth decade of life (6,7), although 65 cases reports of EGPA in people under 18 years of age could be found in the PubMed and Ovid Medline Database at the end of 2020 (8). The etiopathogenesis of the disease has not been fully explained so far. Approximately 40-60% of patients are positive to pANCA (9), but the role of these antibodies in the pathogenesis of EGPA remains unclear. They are suspected to mediate binding of the Fc receptor to MPO exposed on the surface of neutrophils. Subsequently, this may active neutrophils and contribute to a damage of the vascular endothelium (9,10). Glomerulonephritis, neuropathy, and vasculitis are more common in patients with EGPA who have detectable pANCA when compared with seronegative patients. There are at least several drugs which potentially may EGPA. The strongest association with the occurrence of EGPA was found with the use of leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast), although they are commonly used in the treatment of asthma, which is paradoxically one of the complications of the syndrome (13). Although no relationship has been demonstrated so far between the occurrence of EGPA and the intake of drugs from the groups used by the presented patient, a clear time relationship can be observed between the commencement of torasemide and the onset of symptoms in our patient. To date, only three cases of leukocytoclastic vasculitis have been reported after the administration of torasemide. Both of them developed cutaneous symptoms of the disease within 24 hours of the administration of torasemide in patients with no previous history of drug hypersensitivity, but they disappeared quickly within 8-15 days after drug discontinuation (14,15). The chemical structure of torasemide is similar to the molecule of sulfonamides which were previously found to be a triggering factors for EGPA (12). This drug belongs to the group of loop diuretics classified as sulfonamide derivatives. A comparison of the chemical structure of torasemide and sulphanilamide molecules is presented in Figure 1. The clear time relationship between starting the administration of torasemide and the occurrence of purpura-like lesions suggests that it was an aggravating factor for EGPA in our patient. A coexistence of several disorders (asthma, nasal polyps, symptoms of peripheral neuropathy) in our patient suggest EGPA could have developed in her years before oral intake of torasemide. The sudden onset of skin symptoms shows torasemide to be possible inducing factor for the development of vascular purpura in patients suffering from EGPA but without previous cutaneous involvement.

Pulmonary hypertension (PH) is common in end-stage renal disease (ESRD) patients and is associated with increased all-cause and cardiovascular mortality in this group. There is scarce data on the long-term effect of arteriovenous fistula (AVF) creation on pulmonary hypertension (PH) and the reflected changes in echocardiographic measurements.This is a retrospective study of 54 patients who underwent AVF creation between 2009 and 2014 and with echocardiographic evaluations before and after surgery. We analyzed pairwise changes in right ventricular systolic pressure (RVSP), right atrial pressure (RAP) during systole, left ventricular mass (LVM), tricuspid regurgitation (TR), mitral E/E' ratio, and ejection fraction (EF), as well as the factors that predicted change in RVSP after surgery.The median time for the preoperative echocardiogram was 0.3 years (interquartile range (IQR) 0.2 - 0.7 years) prior to AVF creation, while the follow-up echo was done 1.3 (0.6 - 2.1) years after surgery. 67% of the patients had RVSP gt; 37 mmHg at baseline. There was a significant reduction in RVSP after AVF creation compared to baseline (median 33 (IQR 26 - 43) vs. 46 mmHg, p = 0.0015), with 59% of the patients experiencing a decrease and 19% remaining stable. There were also significant decreases in LVM (201 (143 - 256) vs. 215 (163 - 276), p = 0.045) and RAP systole (10 (10 - 15) vs. 3 (3 - 8); p lt; 0.001) after surgery. Higher preoperative weight (p = 0.038) and RVSP (p = 0.006), and use of loop diuretics (p = 0.015) were significantly associated with improvement in RVSP after AVF creation.Our results suggest that AVF creation is associated with a significant reduction or stable measurements of RVSP in the ESRD population, likely due to an improvement in volume status.

Background The co-administration of loop diuretics with thiazide diuretics is a therapeutic strategy in patients with hypertension and volume overload. The aim of this study was to assess the efficacy and safety of treatment with bumetanide plus chlorthalidone in patients with chronic kidney disease (CKD) stage 4–5 KDIGO. Methods A double-blind randomized study was conducted. Patients were randomized into two groups: bumetanide plus chlorthalidone group (intervention) and the bumetanide plus placebo group (control) to evaluate differences in TBW, ECW and ECW/TBW between baseline and 30 Days of follow-up. Volume overload was defined as ‘bioelectrical impedance analysis as fluid volume above the 90th percentile of a presumed healthy reference population. The study’s registration number was NCT03923933. Results Thirty-two patients with a mean age of 57.2 ± 9.34 years and a median estimated glomerular filtration rate (eGFR) of 16.7 ml/min/1.73 m2 (2.2–29) were included. There was decreased volume overload in the liters of total body water (TBW) on Day 7 (intervention: -2.5 vs. control: -0.59, p = 0.003) and Day 30 (intervention: -5.3 vs. control: -0.07, p = 0.016); and in liters of extracellular water (ECW) on Day 7 (intervention: -1.58 vs. control: -0.43, p p p = 0.073) and Day 30 (intervention: -26.1 vs. control: -10, p = 0.028) and in diastolic blood pressure on Day 7 (intervention: -8.5 vs. control: -2.25, p = 0.059) and Day 30 (intervention: -13.5 vs. control: -3.4, p = 0.018). Conclusion In CKD stage 4–5 KDIGO without renal replacement therapy, bumetanide in combination with chlorthalidone is more effective in treating volume overload and hypertension than bumetanide with placebo.

ObjectiveDiuretics reduce congestion in patients with heart failure with preserved ejection fraction (HFpEF). However, comparison of clinical effects across diuretic classes or combinations of diuretics in patients with HFpEF are not well described. Therefore, we sought to conduct a scoping review to map trial data of diuretic efficacy and safety in patients with HFpEF.Review methods and resultsWe searched multiple bibliometric databases for published literature and ClinicalTrials.gov, and hand searched unpublished studies comparing different classes of diuretics to usual care or placebo in patients with HFpEF. We included randomised controlled trials or quasi-experimental studies. Two authors independently screened and extracted key data using a structured form. We identified 13 published studies on diuretics in HFpEF, with 1 evaluating thiazide use, 7 on mineralocorticoid receptor antagonists (MRAs) and 5 on sodium-glucose co-transporter 2 inhibitors (SGLT2i). There remain 17 ongoing trials evaluating loop diuretics (n=1), MRAs (n=5), SGLT2i (n=10) and a polydiuretic (n=1), including 2 well-powered trials of SGLT2i that will be completed in 2021.ConclusionsThe limited number of published trials evaluating different classes of diuretics in patients with HFpEF have been generally small and short term. Ongoing and emerging trials of single or combination diuretics with greater power will be useful to better define their safety and efficacy.Scoping review registrationdoi:10.18131/g3-dejv-tm77.

The effect of loop diuretics on clinical outcomes in heart failure has not been evaluated in randomized controlled trials. In hospitalized patients with heart failure, a discharge loop diuretic prescription has been shown to be associated with improved 30-day outcomes, which appears to be more pronounced in subgroups with congestion. In the current study, we examined these associations and association modifications during longer follow-up.We assembled a propensity score-matched cohort of 2191 pairs of hospitalized heart failure patients discharged with, vs without, a prescription for loop diuretics, balanced on 74 baseline characteristics (mean age 78 years; 54% women; 11% African American).Hazard ratio (HR) and 95% confidence interval (CI) for 6-year combined endpoint of heart failure readmission or all-cause mortality was 1.02 (0.96-1.09). HRs and 95% CIs for this combined endpoint in patients with no, mild-to-moderate, and severe pulmonary rales were 1.19 (1.07-1.33), 0.95 (0.86-1.04), and 0.77 (0.63-0.94), respectively (P for interaction,.001). Respective HRs (95% CIs) for no, mild-to-moderate, and severe lower extremity edema were 1.16 (1.06-1.28), 0.94 (0.85-1.04), and 0.71 (0.56-0.89; interaction P.001).The association between a discharge loop diuretic prescription and long-term clinical outcomes in hospitalized patients with heart failure is modified by admission congestion with worse, neutral, and better outcomes in patients with no, mild-to-moderate, and severe congestion, respectively. If these findings can be replicated, congestion may be used to risk-stratify patients with heart failure for potential optimization of loop diuretic prescription and outcomes.

Contains fulltext : 238842.pdf (Publisher’s version ) (Closed access) A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT(1)) receptors in the kidney, stimulating Na(+) reabsorption. AT(1) receptors in tubular epithelia control expression and stimulation of Na(+) transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT(1) receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na(+) excretion in SMKO mice, we considered whether alterations in Na(+) transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na(+) transporters and associated proteins. Here, we show that levels of Na(+)-K(+)-2Cl(-) cotransporter isoform 2 (NKCC2) and Na(+)/H(+) exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser(71)), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na(+) channel. However, the increases in α- and γ-epithelial Na(+) channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na(+) excretion observed after cell-specific deletion of AT(1) receptors from smooth muscle cells is associated with altered Na(+) transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na(+) transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear.METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed.RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; PCONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

The misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade. The aim of this systematic review is to identify published prescribing cascades in community-dwelling adults. A systematic review was reported in line with the PRISMA guidelines and pre-registered with PROSPERO. Electronic databases (Medline [Ovid], EMBASE, PsycINFO, CINAHL, Cochrane Library) and grey literature sources were searched. Inclusion criteria: community-dwelling adults; risk-prescription medication; outcomes-initiation of new medicine to "treat" or reduce ADR risk; study type-cohort, cross-sectional, case-control, and case-series studies. Title/abstract screening, full-text screening, data extraction, and methodological quality assessment were conducted independently in duplicate. A narrative synthesis was conducted. A total of 101 studies (reported in 103 publications) were included. Study sample sizes ranged from 126 to 11 593 989 participants and 15 studies examined older adults specifically (≥60 years). Seventy-eight of 101 studies reported a potential prescribing cascade including calcium channel blockers to loop diuretic (n = 5), amiodarone to levothyroxine (n = 5), inhaled corticosteroid to topical antifungal (n = 4), antipsychotic to anti-Parkinson drug (n = 4), and acetylcholinesterase inhibitor to urinary incontinence drugs (n = 4). Identified prescribing cascades occurred within three months to one year following initial medication. Methodological quality varied across included studies. Prescribing cascades occur for a broad range of medications. ADRs should be included in the differential diagnosis for patients presenting with new symptoms, particularly older adults and those who started a new medication in the preceding 12 months.

Aim: Intrinsic renal sodium avidity (IRSA) is a hallmark feature of acute heart failure (AHF) and can be measured by evaluating the urinary sodium (UNa) concentration. The aim of this study is to assess the role of measuring IRSA through a random Una-sample and its association with decongestive response. Methods and results: A post-hoc analysis of the ROSE-AHF trial was performed in all patients with a random UNa spot sample before randomization (n = 339/360). Patients were categorized according to tertiles of UNa as high (range 19–40 mmol/L), intermediate (range 41–68 mmol/L), or low (range 69–139 mmol/L) IRSA. Linear mixed effect models and ANCOVA were used to assess the relation with decongestive effectiveness measured by: (i) weight change, (ii) visual analogue scale (VAS) improvement, (iii) N-terminal pro-B-type natriuretic peptide (NT-proBNP) change, (iv) natriuretic response (UNa in mmol/L), (v) 72 h natriuresis (mmol), (vi) oedema resolution, and (vii) length of stay. High IRSA patients had less improvement in decongestive metrics, including weight loss (p = 0.028), VAS improvement, NT-proBNP decrease, natriuretic response (p-time interaction 24 h, resulted in an increase in natriuretic response in the high IRSA group, however cumulative natriuresis still remained lower at 72 h (p < 0.001). Longitudinal UNa profiling of patients with low IRSA showed physiologic breaking in the UNa pattern, associated with attaining decongestion and slight increase in creatinine and cystatin C, forming a potential signal of complete decongestion. Conclusions: A simple random UNa sample at the time of AHF, gives insight into IRSA which is consistently associated with decongestive effectiveness across multiple metrics, offering an opportunity for early AHF care improvement.

Background Fluid overload and venous congestion are associated with morbi-mortality in the ICU (intensive care unit). Administration of diuretics to correct the fluid balance is common, although there is no strong relationship between the consequent fluid loss and clinical improvement. The aim of the study was to evaluate the ability of the portal pulsatility index, the renal venous impedance index, and the VEXUS score (venous ultrasound congestion score) to predict appropriate diuretic-induced fluid depletion. Methods The study had a prospective, observational, single-center observational design and was conducted in a university-affiliated medico-surgical ICU. Adult patients for whom the clinician decided to introduce loop diuretic treatment were included. Hemodynamic and ultrasound measurements (including the portal pulsatility index, renal venous impedance index and VEXUS score) were performed at inclusion and 2 hours after the initiation of the diuretics. The patients’ characteristics were noted at inclusion, 24 h later, and at ICU discharge. The appropriate diuretic-induced fluid depletion was defined by a congestive score lower than 3 after diuretic fluid depletion. The congestive score included clinical and biological parameters of congestion. Results Eighty-one patients were included, and 43 (53%) patients presented with clinically significant congestion score at inclusion. Thirty-four patients (42%) had an appropriate response to diuretic-induced fluid depletion. None of the left- and right-sided echocardiographic parameters differed between the two groups. The baseline portal pulsatility index was the best predictor of appropriate response to diuretic-induced fluid depletion (AUC = 0.80, CI95%:0.70–0.92, p = 0.001), followed by the renal venous impedance index (AUC = 0.72, CI95% 0.61–0.84, p = 0.001). The baseline VEXUS score (AUC of 0.66 CI95% 0.53–0.79, p = 0.012) was poorly predictive of appropriate response to diuretic-induced fluid depletion. Conclusion The portal pulsatility index and the renal venous impedance index were predictive of the appropriate response to diuretic-induced fluid depletion in ICU patients. The portal pulsatility index should be evaluated in future randomized studies.

Background and Objectives: The aim of this paper is to evaluate the impact of humoral substance mid-regional pro-adrenomedullin (MR-proADM) on the two-year survival of patients with chronic heart failure and relate it to the dosage of furosemide. Materials and Methods: The data is taken from the stable systolic heart failure (EF < 50%) FAR NHL registry (FARmacology and NeuroHumoraL activation). The primary endpoint at two-year follow-up was death, heart transplantation, or LVAD implantation. Results: A total of 1088 patients were enrolled in the FAR NHL registry; MR-proADM levels were available for 569 of them. The mean age was 65 years, and 81% were male. The aetiology of HF was ischemic heart disease in 53% and dilated cardiomyopathy in 41% of patients. The mean EF was 31 ± 9%. Statistically significant differences (p < 0.001) were obtained in several parameters: patients with higher MR-proADM levels were older, rated higher in NYHA class, suffered more often from lower limb oedema, and had more comorbidities such as hypertension, atrial fibrillation, diabetes, and renal impairment. MR-proADM level was related to furosemide dose. Patients taking higher doses of diuretics had higher MR-proADM levels. The mean MR-proADM level without furosemide (n = 122) was 0.62 (±0.55) nmol/L, with low dose (n = 113) 1–39 mg/day was 0.67 (±0.30) nmol/L, with mid dose (n = 202) 40–79 mg/day was 0.72 (±0.34) nmol/L, with high dose (n = 58) 80–119 mg/day was 0.85 (±0.40) nmol/L, and with maximum dose (n = 74) ≥120 mg/day was 1.07 (±0.76) nmol/L, p < 0.001. Patients with higher MR-proADM levels were more likely to achieve the primary endpoint at a two-year follow-up (p < 0.001) according to multivariant analysis. Conclusions: Elevated plasma MR-proADM levels in patients with chronic heart failure are associated with an increased risk of death and hospitalization. Higher MR-proADM levels in combination with increased use of loop diuretics reflect residual congestion and are associated with a higher risk of severe disease progression.

Aims There is paucity of clinical data comparing continuous infusion (CI) with bolus injection (BI) of intravenous loop diuretics in patients with acute decompensated heart failure (ADHF) and chronic renal dysfunction. This study aimed to compare the efficacy and safety of CI versus BI intravenous furosemide administration in patients with ADHF and moderate chronic renal insufficiency. Methods and results Acute decompensated heart failure and moderate chronic renal insufficiency [with estimated glomerular filtration rate (eGFR) 15.0–44.9 mL/min/1.73 m2] were randomized to start intravenous furosemide by BI or by a 6 h CI. End points included freedom from congestion at 72 h, the degree of dyspnoea assessed using the 0–10 Borg's category ratio scale, net daily urine output, weight loss during the study, length of hospital stay, total urinary sodium excretion, and development of acute kidney injury or electrolyte disturbance. After 72 h of treatment, the rate of the primary endpoint of freedom from congestion in the CI group was significantly higher than that in the BI group (69.05% vs. 43.59%, P = 0.02). The modified Borg scale indicated patients in the CI group had lower dyspnoea score than those in the BI group at 48 h (4.29 ± 1.23 vs. 5.97 ± 1.56; P = 0.02) and 72 h (1.15 ± 0.35 vs. 2.66 ± 0.83; P = 0.003). There were other significant differences favouring the CI group with regard to net urine output at 72 h (5145.98 ± 621.37 mL vs. 3755.95 ± 456.93 mL; P = 0.007), the mean body weight loss (4.72 ± 1.01 kg vs. 3.53 ± 0.73 kg; P = 0.02) and the total urinary sodium excretion (385.05 ± 38.15 vs. 320.33 ± 37.67; P = 0.02). The length of hospitalization in the CI group was significantly shorter than that in the BI group (10.36 ± 4.20 days vs. 15.68 ± 6.15 days; P = 0.02). No significant differences were observed between groups in the frequency of acute kidney injury, tinnitus, electrolyte disturbance or mortality. Conclusions Continuous intravenous infusion of furosemide resulted in significantly greater diuresis than bolus administration of an equal dose in patients with moderate chronic renal insufficiency and ADHF, while no differences emerged in terms of side effects or mortality.

BACKGROUND: Loop diuretics are the main treatment for patients with acute heart failure, but are associated with neurohormonal stimulation and worsening renal function and do not improve long-term outcomes. Antagonists to arginine vasopressin may provide an alternative strategy to avoid these effects. The AVANTI study will investigate the efficacy and safety of pecavaptan, a novel, balanced dual-acting V1a/V2 vasopressin antagonist, both as adjunctive therapy to loop diuretics after admission for acute heart failure, and later as monotherapy.METHODS AND RESULTS: AVANTI is a double-blind, randomized phase II study in 571 patients hospitalized with acute heart failure and signs of persistent congestion before discharge. In part A, patients will receive either pecavaptan 30 mg/d or placebo with standard of care for 30 days. In part B, eligible patients will continue treatment or receive pecavaptan or diuretics as monotherapy for another 30 days. The primary end points for part A are changes in body weight and serum creatinine; for part B, changes in body weight and blood urea nitrogen/creatinine ratio.CONCLUSIONS: This study will provide the first evidence that a balanced V1a/V2 antagonist may safely enhance decongestion, both as an adjunct to loop diuretics and as an alternative strategy.TRIAL REGISTRATION NUMBER: NCT03901729.

Background Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces cardiovascular death and worsening heart failure in patients with chronic heart failure and reduced ejection fraction. Early initiation during an acute heart failure (AHF) hospitalization may facilitate decongestion, improve natriuresis, and facilitate safe transition to a beneficial outpatient therapy for both diabetes and heart failure. Objective The objective is to assess the efficacy and safety of initiating dapagliflozin within the first 24 hours of hospitalization in patients with AHF compared to usual care. Methods DICTATE-AHF is a prospective, multicenter, open-label, randomized trial enrolling a planned 240 patients in the United States. Patients with type 2 diabetes hospitalized with hypervolemic AHF and an estimated glomerular filtration rate of at least 30 mL/min/1.73m2 are eligible for participation. Patients are randomly assigned 1:1 to dapagliflozin 10 mg once daily or structured usual care until day 5 or hospital discharge. Both treatment arms receive protocolized diuretic and insulin therapies. The primary endpoint is diuretic response expressed as the cumulative change in weight per cumulative loop diuretic dose in 40 mg intravenous furosemide equivalents. Secondary and exploratory endpoints include inpatient worsening AHF, 30-day hospital readmission for AHF or diabetic reasons, change in NT-proBNP, and measures of natriuresis. Safety endpoints include the incidence of hyper/hypoglycemia, ketoacidosis, worsening kidney function, hypovolemic hypotension, and inpatient mortality. Conclusions The DICTATE-AHF trial will establish the efficacy and safety of early initiation of dapagliflozin during AHF across both AHF and diabetic outcomes in patients with diabetes.

Background: Although diuretics are one of the most widely used drugs by nephrologists, their antiproteinuric properties are not generally taken into consideration. Summary: Thiazide diuretics have been shown to reduce proteinuria by >35% in several prospective controlled studies, and these values are markedly increased when combined with a low-salt diet. Thiazide-like diuretics (indapamide and chlorthalidone) have shown similar effectiveness. The antiproteinuric effect of mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) has been clearly established through prospective and controlled studies, and treatment with finerenone reduces the risk of chronic kidney disease progression in type-2 diabetic patients. The efficacy of other diuretics such as amiloride, triamterene, acetazolamide, or loop diuretics has been less explored, but different investigations suggest that they might share the same antiproteinuric properties of other diuretics that should be evaluated through controlled studies. Although the inclusion of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among diuretics is a controversial issue, their renoprotective and cardioprotective properties, confirmed in various landmark trials, constitute a true revolution in the treatment of patients with kidney disease. Recent subanalyses of these trials have shown that the early antiproteinuric effect induced by SGLT2i predicts long-term preservation of kidney function. Key Message: Whether the early reduction in proteinuria induced by diuretics other than finerenone and SGLT2i, as summarized in this review, also translates into long-term renoprotection requires further prospective and observational studies. In any case, it is important for the clinician to be aware of the antiproteinuric properties of drugs so often used in daily clinical practice.

Purpose We aimed to investigate the prevalence, risk factors and outcome of hypo- and hypernatremia in emergency patients with acute kidney injury (AKI). Methods In this cross-sectional analysis all emergency patients between January 1st 2017 and December 31st 2018 with measurements of creatinine and sodium were included. Baseline characteristics, medication and laboratory data were gathered. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract baseline creatinine. For all other patients the ADQI backformula was used to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of dysnatremias and outcome. Results AKI was found in 8% of patients. 392 patients (23.16%) had hyponatremia, 24 (1.4%) had hypernatremia. Use of potassium sparing diuretics, a medical cause for emergency referral, use of thiazide diuretics and AKI stage were the strongest risk factors for hyponatremia. Loop diuretics, a medical cause for emergency referral and AKI stage were risk factors for hypernatremia. In patients with all classes of hyponatremia, length of hospital stay was significantly longer compared to patients with a normal serum sodium. In the binary logistic regression analysis with death as outcome, hyponatremia as well as severe hypernatremia were independent risk factors for mortality. Conclusions Dysnatremias are common in emergency patients with AKI. Diuretic medication is a major risk factor for hypo- and hypernatremia. Both hyponatremia and severe hypernatremia were independent risk factors for adverse outcome.

To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark.This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs.Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years.We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries.

To assess whether more severe urinary symptoms and poorer quality of life among patients on diuretic therapy are associated with decreased adherence to the diuretic regimen.Participants were recruited via ResearchMatch.org and sent a REDCap survey. The Overactive Bladder Questionnaire-Short Form (OAB-q SF) was used to assess urinary symptom bother and health-related quality of life (HRQL). Participants were asked if they skip diuretic doses due to urinary symptoms with a bivariate (yes or no) outcome. Subgroup analyses of loop vs non-loop diuretic and those taking the diuretic for a cardiovascular indication (hypertension or heart failure) were performed.A total of 4029 surveys were sent, 285 were returned (7.1% response rate), and 279 were included in the study. Fifty-three participants admitted to skipping diuretic doses due to urinary symptoms. Lower HRQL scores were significantly associated with poorer adherence scores among all participants (P .001), among participants taking a loop diuretic (P .001), and among participants with hypertension and heart failure (P .039). Association between symptoms and adherence remained significant after adjustment in the multivariate model for the whole cohort and loop diuretic subgroup but lost significance in the hypertension and heart failure subgroup.Worsening quality of life due to urinary symptoms may be associated with poorer adherence to diuretics, particularly loop diuretics.

Serum chloride plays an important role in fluid homeostasis and is associated with impaired diuretic responsiveness and mortality in adults with heart failure (HF). We sought to characterize the relationship of serum chloride and diuretic efficiency (DE) and to determine its prognostic importance in children hospitalized with acute decompensated HF (ADHF). We studied DE, defined as net fluid output/kg+constant per mg of loop diuretic/kg, in 200 children hospitalized with ADHF. Median serum chloride at admission was 102 mmol/L (interquartile range 99 to 105 mmol/L), and hypochloremia (chloride ≤96 mmol/L) was present in 16% of the population at admission. Serum chloride correlated with serum sodium (r = 0.66; p0.001) and bicarbonate (r = -0.39; p0.001). In the adjusted analysis, lower chloride was associated with reduced DE (p0.001). Serum sodium was associated with DE on the unadjusted analysis; however, the association was eliminated when added to the model with chloride (p = 0.442). Lower chloride was also associated with features of inadequate decongestion during hospitalization: a positive fluid balance (p = 0.003), greater cumulative loop diuretic dose per weight (p = 0.001), addition of a thiazide diuretic during hospitalization (p0.001), less weight loss (p = 0.025), and longer length of stay (p = 0.003). Chloride concentration was independently associated with death or transplant 1 year after admission (hazard ratio 0.94; p0.001). As a dichotomous variable, hypochloremia was independently associated with reduced DE (p0.001) and decreased 1-year transplant-free survival (hazard ratio 2.3, p0.001). Lower serum chloride at hospital admission is strongly and independently associated with impaired DE and reduced transplant-free survival in children hospitalized with ADHF.

Heart failure can lead to renal impairment, an interaction now termed "cardiorenal syndrome." The prevalent physiological explanation for the renal impairment that accompanies heart failure centers around the forward failure hypothesis, which emphasizes the role of left ventricular dysfunction in causing edema, and the backward failure hypothesis, which singles out venous congestion as the dominant mechanism of edema and reduced glomerular filtration rate. In this review, we provide an appraisal on venous congestion, an extremely important contributor that has received little attention. We also summarize the pharmacology of loop diuretics, explain current understanding of diuretic resistance, and address controversies regarding decongestive treatments.

In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect-even a transient one-on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na-K-2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain-permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of gamma-aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures.

Supplemental Digital Content is available in the text., Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure–associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics. Methods: The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6. Results: Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133–936]; P=0.005) and week 6 (mean difference, 545 mL [95% CI, 136–954]; P=0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, −7.85 mmol/L [95% CI, −2.43 to 6.73]; P=0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, −0.03 to 0.63]; P=0.09; week 6, 0.11% [95% CI, −0.22 to 0.44]; P>0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26–598]; P=0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6. Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.

Objectives This study sought to characterize in-hospital treatment patterns and associated patient outcomes among patients hospitalized for heart failure (HF) in U.S. clinical practice. Background Hospitalizations for HF are common and associated with poor patient outcomes. Real-world patterns of in-hospital treatment, including diuretic therapy, in contemporary U.S. practice are unknown. Methods Using Optum de-identified Electronic Health Record data from 2007 through 2018, patients hospitalized for a primary diagnosis of HF (ejection fraction ≤40%) and who were hemodynamically stable at admission, without concurrent acute coronary syndrome or end-stage renal disease, and treated with intravenous (IV) diuretic agents within 48 h of admission were identified. Patients were categorized into 1 of 4 mutually exclusive hierarchical treatment groups defined by complexity of treatment during hospitalization (intensified treatment with mechanical support or IV vasoactive therapy, IV diuretic therapy reinitiated after discontinuation for ≥1 day without intensified treatment, IV diuretic dose increase/combination diuretic treatment without intensified treatment or IV diuretic reinitiation, or uncomplicated). Results Of 22,677 patients hospitalized for HF with reduced ejection fraction (HFrEF), 66% had uncomplicated hospitalizations without escalation of treatment beyond initial IV diuretic therapy. Among 7,809 remaining patients, the highest level of therapy received was IV diuretic dose increase/combination diuretic treatment in 25%, IV diuretic reinitiation in 36%, and intensified therapy in 39%. Overall, 19% of all patients had reinitiation of IV diuretic agents (26% of such patients had multiple instances), 12% were simultaneously treated with multiple diuretics, and 61% were transitioned to oral diuretic agents before discharge. Compared with uncomplicated treatment, IV diuretic reinitiation and intensified treatment were associated with significantly longer median length of stay (uncomplicated: 4 days; IV diuretic reinitiation: 8 days; intensified: 10 days) and higher rates of in-hospital (uncomplicated: 1.6%; IV diuretic reinitiation: 4.2%; intensified: 13.2%) and 30-day post-discharge mortality (uncomplicated: 5.2%; IV diuretic reinitiation: 9.7%; intensified: 12.7%). Conclusions In this contemporary real-world population of U.S. patients hospitalized for HFrEF, one-third of patients had in-hospital treatment escalated beyond initial IV diuretic therapy. These more complex treatment patterns were associated with highly variable patterns of diuretic use, longer hospital lengths of stay, and higher mortality. Standardized and evidence-based approaches are needed to improve the efficiency and effectiveness of in-hospital HFrEF care.

Background Our objective was to characterize cases of hospitalized heart failure (HHF) focusing on in-hospital resource utilization (particularly furosemide doses) and worsening heart failure (WHF), and identify which factors are associated with the length of stay (LOS). Methods Cases of HHF (≥20 years), excluding those undergoing surgical procedures and in-hospital deaths, were retrieved from the Japanese Diagnosis Procedure Combination database (April 2012 to March 2016). WHF was defined using eight components, including up-titration of intravenous drugs and non-pharmacological management. Results The mean age of 78,953 cases of HHF was 79 years and 51% were male. The median LOS was 17 days. The maximum daily dose and cumulative dose of furosemide (mean ± standard deviation) were 43.3 ± 56.0 mg and 215.6 ± 450.6 mg, respectively, for intravenous furosemide, and 44.0 ± 37.3 mg and 523.3 ± 675.4 mg, respectively, for oral furosemide. The incidence of WHF was 36.1% during hospitalization and 19.3% from 6th hospital day to discharge. The mean number of WHF components was 1.4 ± 0.7 during hospitalization and 1.3 ± 0.6 from 6th hospital day. Regression analyses showed that the number of WHF components from 6th hospital day, pneumonia, and hyponatremia were strongly associated with longer LOS. Conclusions These findings in patients with HHF could be vital to focus future efforts to improve the therapeutic strategies for heart failure.

Background Digoxin reduces the risk of heart failure hospitalization in patients with heart failure with reduced ejection fraction. Less is known about this association in patients with heart failure with preserved ejection fraction (HFpEF), the examination of which was the objective of the current study. Methods In the Medicare-linked OPTIMIZE-HF registry, 7374 patients hospitalized for HF had ejection fraction ≥50% and were not receiving digoxin prior to admission. Of these, 5675 had a heart rate ≥50 beats per minute, an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or did not receive inpatient dialysis, and digoxin was initiated in 524 of these patients. Using propensity scores for digoxin initiation, calculated for each of the 5675 patients, we assembled a matched cohort of 513 pairs of patients initiated and not initiated on digoxin, balanced on 58 baseline characteristics (mean age, 80 years; 66% women; 8% African American). Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes associated with digoxin initiation were estimated in the matched cohort. Results Among the 1026 matched patients with HFpEF, 30-day heart failure readmission occurred in 6% and 9% of patients initiated and not initiated on digoxin, respectively (HR 0.70; 95% CI, 0.45-1.10; P = .124). HRs (95% CIs) for 30-day all-cause readmission and all-cause mortality associated with digoxin initiation were 0.95 (0.73-1.23; P = .689) and 0.93 (0.55-1.56; P = .773), respectively. Digoxin initiation had no association with 6-year outcomes. Conclusion Digoxin initiation prior to hospital discharge was not associated with 30-day or 6-year outcomes in older hospitalized patients with HFpEF.

Despite evidence highlighting harms of fluid overload, minimal guidance exists on counteraction via utilization of diuretics in the de-resuscitation phase. While diuretics have been shown to decrease net volume and improve clinical outcomes in the critically ill, a lack of standardization surrounding selection of diuretic regimen or monitoring of de-resuscitation exists. Current monitoring parameters of de-resuscitation often rely on clinical signs of fluid overload, end organ recovery and other biochemical surrogate markers which are often deemed unreliable. The majority of evidence suggests that achieving a net-negative fluid balance within 72 h after shock resolution may be of benefit; however, approaches to such goal are uncertain. Loop diuretics are a widely available type of diuretic for removal of volume in patients with sufficient kidney function, with the potential for adjunct diuretics in special circumstances. At present, administration of diuretics within the broad critically ill population fails to find uniformity and often efficacy. Given the lack of randomized controlled trials in this susceptible population, we aim to provide a thorough therapeutic understanding of diuretic pharmacotherapy which is necessary in order to achieve desired goal of fluid balance and improve overall outcomes.