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Ascites is associated with significantly increased morbidity, mortality, and health care costs. Large population studies are necessary to determine the burden and impact of ascites; however, ascites ICD-10 codes perform poorly in the identification of patients.We utilized three independent retrospective cohorts at the University of Michigan (cohorts 1 and 2) and Duke University (cohort 3). Cohort 1: Child A5-6 patients followed up to 10 years (n = 150); cohort 2: Child A5-B7 patients with portal hypertension followed for up to 1 year (n = 65); cohort 3: cross-sectional cohort of patients evaluated for liver transplant (n = 100). We computed performance characteristics for ascites-related ICD-10 codes (K70.31, K70.11, K71.51, R18.8), as well as loop and/or potassium-sparing diuretics.A total of 315 patients were included across three cohorts. Algorithms including any ascites code provided better sensitivity and equivalent specificity to R18.8 alone for all cohorts. In cohort 2, we found that loop diuretics, potassium-sparing diuretics, and a combination of both with a cirrhosis code were highly sensitive (82.3% for each) and specific (89.1-93.5%). In contrast, ascites codes were insensitive. In patients with moderate-severe ascites, a combination of recorded diuretics showed high sensitivity and specificity (95.2% and 86.8%). In Cohort 3's transplant evaluation patients, we found that loop diuretics, potassium-sparing diuretics, and a combination of both with a cirrhosis code were highly sensitive (90.4%, 78.8% and 75.0%, respectively) and specific (85.0%, 90.0% and 95.0%, respectively). For moderate-severe cirrhosis, loop diuretics and R18.8 showed higher sensitivity (77.8%) and specificity (88.9%), respectively.Diuretic records with a cirrhosis code improve the identification of ascites. This method for identifying ascites should be used in future large dataset studies.

Sodium glucose cotransporter-2 (SGLT2) inhibitors and loop diuretics can cause volume depletion. However, the long-term safety of the concurrent use of both agents has not been widely evaluated. We conducted a retrospective observational cohort study to evaluate the safety of SGLT2 inhibitors with loop diuretics vs SGLT2 inhibitors alone among diabetic patients. The primary endpoint was a composite of volume-depletion adverse events at 1 month and 12 months. Of the 400 patients included, 98 received SGLT2 inhibitors with a loop diuretic and 302 received SGLT2 inhibitors alone. The concurrent use of SGLT2 inhibitors and loop diuretics was tolerated at 1 month; however, it resulted in a significant increase in volume-depletion events at 12 months (10.2% vs 1.7%; aHR = 7.03, 95% CI (1.80-27.37), P-value = 0.005). In conclusion, the long-term concurrent use of SGLT2 inhibitors and loop diuretics increases the risk of volume depletion, warranting frequent monitoring.

Hyponatraemia is very common in heart failure (HF), especially in decompensated patients. It is associated with increased mortality and morbidity and considered a marker of advanced disease. Recognition of hyponatraemia and its causes may help guide treatment strategy. Historically, therapy has primarily focused on water restriction, decongestion with loop diuretics in case of volume overload (dilutional hyponatraemia) and sodium repletion in case of depletion. In this review, we summarise the potential benefits of established and emerging HF therapies on sodium homeostasis, with a focus on dual vasopressin antagonists, angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors and hypertonic saline, and propose a potential therapeutic approach for hyponatraemia in HF.

Congestion is the primary pathophysiological lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid-filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80-kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of left versus right kidney to −30 mmHg rNPT or no rNPT. mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20–22.5 mmHg throughout the experiment. Before HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney ( P < 0.001 for all). Natriuresis, diuresis, and mGFR decreased following HF ( P < 0.001 for all) but were higher in rNPT kidney versus control ( P < 0.001 for all). RPF decreased during HF ( P < 0.001) without significant differences between rNPT treatments. During HF, the rNPT kidney had similar diuresis and natriuresis ( P > 0.5 for both) and higher fractional excretion of sodium ( P = 0.001) compared with the non-rNPT kidney in the no HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardiorenal phenotype.

BACKGROUND Drug-related adverse events associated with antihypertensive therapy may result in subsequent prescribing of other potentially harmful medications, known as prescribing cascades. The aim of this study was to assess the magnitude and characteristics of a beta-blocker–edema–loop diuretic prescribing cascade. METHODS A prescription sequence symmetry analysis was used to assess loop diuretic initiation before and after initiation of beta-blockers among patients 20 years or older without heart failure, atrial fibrillation, other arrythmias, or use of calcium channel blocker within a U.S. private insurance claims database (2005–2018). The temporality of loop diuretic initiation relative to a beta-blocker or negative control (renin-angiotensin system blocker) initiation was tabulated. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) compared the initiation of loop diuretic 90 days before and after initiation of beta-blockers. RESULTS Among 988,675 beta-blocker initiators, 9,489 patients initiated a new loop diuretic prescription 90 days after and 5,245 patients before beta-blocker initiation, resulting in an aSR of 1.78 (95% CI, 1.72–1.84). An estimated 1.72 beta-blocker initiators per 100 patient-years experienced the prescribing cascade in the first 90 days. The aSR was disproportionately higher among older adults (aSR 1.97), men (aSR 2.25), and patients who initiated metoprolol tartrate (aSR 2.48), labetalol (aSR 2.18), or metoprolol succinate (aSR 2.11). Negative control results (aSR 1.09, 95% CI, 1.05–1.13) generally corroborated our findings, but suggested modest within-person time-varying confounding. CONCLUSIONS We observed excess use of loop diuretics following beta-blocker initiation that was only partially explained by secular trends or hypertension progression.

Volume overload, defined as excess total body sodium and water with expansion of extracellular fluid volume, characterizes common disorders such as congestive heart failure, end-stage liver disease, chronic kidney disease, and nephrotic syndrome. Diuretics are the cornerstone of therapy for volume overload and comprise several classes whose mechanisms of action, pharmacokinetics, indications, and adverse effects are essential principles of nephrology. Loop diuretics are typically the first-line treatment in the management of hypervolemia, with additional drug classes indicated in cases of diuretic resistance and electrolyte or acid-base disorders. Separately, clinical trials highlight improved outcomes in some states of volume overload, such as loop diuretics and sodium/glucose cotransporter 2 inhibitors in patients with congestive heart failure. Resistance to diuretics is a frequent, multifactorial clinical challenge that requires creative and physiology-based solutions. In this installment of AJKD's Core Curriculum in Nephrology, we discuss the pharmacology and therapeutic use of diuretics in states of volume overload and strategies to overcome diuretic resistance.

Two orthologues of the gene encoding the Na+-Cl− cotransporter (NCC), termed ncca and nccb, were found in the sea lamprey genome. No gene encoding the Na+-K+-2Cl− cotransporter 2 (nkcc2) was identified. In a phylogenetic comparison among other vertebrate NCC and NKCC sequences, the sea lamprey NCCs occupied basal positions within the NCC clades. In freshwater, ncca mRNA was found only in the gill and nccb only in the intestine, whereas both were found in the kidney. Intestinal nccb mRNA levels increased during late metamorphosis coincident with salinity tolerance. Acclimation to seawater increased nccb mRNA levels in the intestine and kidney. Electrophysiological analysis of intestinal tissue ex vivo showed this tissue was anion absorptive. After seawater acclimation, the proximal intestine became less anion absorptive, whereas the distal intestine remained unchanged. Luminal application of indapamide (an NCC inhibitor) resulted in 73% and 30% inhibition of short-circuit current (Isc) in the proximal and distal intestine, respectively. Luminal application of bumetanide (an NKCC inhibitor) did not affect intestinal Isc. Indapamide also inhibited intestinal water absorption. Our results indicate that NCCb is likely the key ion cotransport protein for ion uptake by the lamprey intestine that facilitates water absorption in seawater. As such, the preparatory increases in intestinal nccb mRNA levels during metamorphosis of sea lamprey are likely critical to development of whole animal salinity tolerance.

BACKGROUND AND OBJECTIVES: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m(2) from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH

Prescribing cascades are where a drug adverse reaction is wrongly attributed to the emergence of a new condition, which leads to further drug prescribing. This promotes polypharmacy, adverse drug reactions and therapeutic burden. An example of a prescribing cascade is the co-prescribing of loop diuretics to treat the peripheral oedema caused by calcium channel blocker (CCB) drugs. Although well recognised, this is still a combination of medications taken by millions of people worldwide. CCBs have no prognostic benefit in heart failure and have an absolute risk increase for oedema of around 8-18% (number needed to harm 6-13). In the treatment of hypertension, they also increase the risk of oedema and a new diagnosis of heart failure without having any major advantages over alternative drugs. The best way to manage the oedema caused by CCBs is to switch to an alternative medication. Only where this is not possible or fails to achieve therapeutic goals would the CCB-loop diuretic combination appear to be justified. In many cases, therapeutic practice could be improved by targeting people on CCB-loop diuretic combinations for medication review. This could improve quality of life and reduce polypharmacy, adverse drug reactions, therapeutic burden and financial costs for millions of people worldwide.

Aerosol furosemide may be an option to treat refractory dyspnea, though doses, methods of delivery, and outcomes have been variable. We hypothesized that controlled delivery of high dose aerosol furosemide would reduce variability of dyspnea relief in patients with underlying pulmonary disease. Seventeen patients with chronic exertional dyspnea were recruited. Patients rated recently recalled breathing discomfort on a numerical rating scale (NRS) and the multidimensional dyspnea profile (MDP). They then performed graded exercise using an arm-ergometer. The NRS was completed following each exercise grade, and the MDP was repeated after a pre-defined dyspnea threshold was reached. During separate visits, patients received either aerosol saline or 80 mg of aerosol furosemide in a randomized, double-blind, crossover design. After treatment, graded exercise to the pre-treatment level was repeated, followed by completion of the NRS and MDP. Treatment effect was defined as the difference between pre- and post-treatment NRS at end exercise, expressed in absolute terms as % Full Scale. “Responders” were defined as those showing treatment effect ≥ 20% of full scale. Final analysis included 15 patients. Neither treatment produced a statistically significant change in NRS and there was no significant difference between treatments (p = 0.45). There were four “responders” and one patient whose dyspnea worsened with furosemide; two patients were responders with saline, of whom one also responded to furosemide. No adverse events were reported. High dose controlled delivery aerosol furosemide was not statistically different from saline placebo at reducing exercise-induced dyspnea. However, a clinically meaningful improvement was noted in some patients.

Purpose To describe methodological and reporting issues in non-randomised comparative drug safety studies pooled in meta-analyses, with focus on confounding by indication. Methods All studies included in statistically significant meta-analyses in a recent publication investigating fall risk properties of cardiovascular drugs were reviewed. Study characteristics were extracted and assessed. Results Nine studies, including between 498 and 321,995 individuals, contributed data to the significant meta-analyses in which loop diuretics and beta-blockers were associated with falls, five published in 2015. Five individual studies reported a statistically significant association. In the five cohort studies, characteristics of exposed vs unexposed individuals were either not reported (n = 3) or differed substantially regarding morbidity (n = 2). Drug treatment was determined at baseline, and data on falls were collected for up to 2 years thereafter. Out of the four case-control studies, the cases and controls in only one study were matched for morbidity. Morbidity characteristics of fallers compared with non-fallers were either not reported (n = 2) or they differed (n = 1) or were reported according to the matched-for diseases (n = 1). Confounding by indication was explicitly discussed in two studies. None of the abstract conclusions considered causality issues or the possibility of confounding by indication. Conclusions Confounding by indication is a major issue in non-randomised comparative drug safety studies, a problem which may be concealed in meta-analyses. To enhance such research, compared groups need to be balanced regarding relevant factors including morbidities and characteristics adequately reported. Confounding by indication needs to be explicitly discussed and highlighted in the abstract conclusion.

Human p.V37I mutation of GJB2 gene was strongly correlated with late-onset progressive hearing loss, especially among East Asia populations. We generated a knock-in mouse model based on human p.V37I variant (c.109G>A) that recapitulated the human phenotype. Cochlear pathology revealed no significant hair cell loss, stria vascularis atrophy or spiral ganglion neuron loss, but a significant change in the length of gap junction plaques, which may have contributed to the observed mild endocochlear potential (EP) drop in homozygous mice lasting lifetime. The cochlear amplification in homozygous mice was compromised, but outer hair cells’ function remained unchanged, indicating that the reduced amplification was EP- rather than prestin-generated. In addition to ABR threshold elevation, ABR wave I latencies were also prolonged in aged homozygous animals. We found in homozygous IHCs a significant increase in ICa but no change in Ca2+ efficiency in triggering exocytosis. Environmental insults such as noise exposure, middle ear injection of KCl solution and systemic application of furosemide all exacerbated the pathological phenotype in homozygous mice. We conclude that this Gjb2 mutation-induced hearing loss results from 1) reduced cochlear amplifier caused by lowered EP, 2) IHCs excitotoxicity associated with potassium accumulation around hair cells, and 3) progression induced by environmental insults.

Acute heart failure hospitalizations complicated by diuretic resistance are associated with worse outcomes. Yet, quantification of the frequency and accompanying risk from loop diuretic resistance is limited by the absence of a comprehensive definition with universal clinical application. Herein, we outline limitations of the current metrics used to identify and define diuretic resistance. We discuss the best available methods to identify and prognosticate outcomes in diuretic resistance. We propose a mechanism-based classification system of diuretic resistance by anatomical location as follows: pre-nephron resistance, pre-loop of Henle resistance, loop of Henle resistance, and post-loop of Henle resistance. Within this paradigm, we compare and contrast historical beliefs of resistance mechanisms with current literature specific to patients with heart failure. We recommend a treatment pathway to restore diuretic efficacy with a literature review of the various combination diuretic strategies and ongoing clinical trials that may impact current best practices.

BACKGROUND: The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure.METHODS: A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class >= II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA >= III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index.RESULTS: Sixty-one percent of patients had a Clinical Congestion Index >= 3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and >= 3 at inclusion, respectively, died (P CONCLUSIONS: The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure. (C) 2019 Elsevier Inc. All rights reserved.

Purpose of review: Chronic breathlessness is a troublesome symptom experienced by people with advanced malignant and nonmalignant disease. Disease-directed therapies are often insufficient in the management of chronic breathlessness. Therefore, pharmacological and nonpharmacological breathlessness-specific interventions should be considered for select patients. Recent findings: There is some evidence to support the use of low-dose opioids (

Actuality. The results of the EPOCH study showed that in 16 years in the Russian Federation the number of patients with chronic heart failure (CHF) of I–IV FC increased significantly. The main objectives of the treatment of CHF are the stabilization of the patient's condition and the reduction of the risks of cardiovascular mortality, decompensation and repeated hospitalizations for heart failure. But a single concept of “stable” CHF does not exist either in Russian or in foreign recommendations. Objective. To assess how ofen the subjective assessment of a doctor regarding the stability of a patient with CHF coincides with the subjective opinion of the patient with CHF regarding the stability of his condition; and to identify those parametrs that have a leading influence on the assessment of the stability of the state from the point of view of the physician and the patient. Materials and methods. Data collection was carried out in the form of interviews among general practitioners and cardiologists in outpatient clinics (OC) of Nizhny Novgorod, which were randomly selected by the method of blind envelopes. In parallel, a survey was conducted of patients with CHF who applied for outpatient medical care about this syndrome to this OC, which the doctors were not informed about, because patient interviews were conducted after the end of outpatient admission in a separate room. Answers of doctors about a patient with CHF were compared with the answers of the corresponding patient; for this, a single code was assigned to both questionnaires. The study included 211 patients with CHF of any etiology older than 18 years. The study involved 25 doctors. The study was conducted from 11/01/17 to 11/30/17. Results: Analysis of the data suggests that the doctor is more likely to consider the patient more stable in cases when the patient notes a decrease in the severity of shortness of breath, weakness and does not detect edema, while the fact of therapy with loop diuretics (LD) or an increase in them did not affect assessment of stability from the point of view of the doctor. From the point of view of the patient, the absence of the first three signs also testifies to the stability of the condition, however, unlike doctors, patients more often (p Conclusion. Reducing the severity of dyspnea, weakness and lack of edema of the lower extremities are important signs of the stability of the condition, both in the opinion of the doctor and in the opinion of the patient. Unlike the doctor, the patient is more likely to be classified as unstable in those cases when he is forced to receive therapy with loop diuretics at the outpatient stage or to increase their dose. The model for assessing the stability of a patient with CHF from the point of view of a physician more often allows one to confirm the patient’s stable condition, while the model used by patients more often allows to identify patient instability and worsening of the course of CHF.

Modulating neurohormonal imbalance is the cornerstone of successful therapy in patients with chronic heart failure with reduced ejection fraction (HFrEF). Plasma arginine vasopressin (AVP) levels are elevated in HFrEF and may contribute to disease progression by excess signaling at either the V1a or V2 receptors. The effects of V1a receptor antagonism are almost completely unexplored, but V1a signaling is closely related to that for angiotensin II and blocking that receptor deserves further study. Interfering with V2 signaling causes free water diuresis and improves congestion without worsening renal function when added to loop diuretics but alone did not improve outcomes when carried into the post-acute phase in one large study. Outcomes in chronic HFrEF are quite good while outcomes in acute HF remain poor. Therefore, further study of V2 or combined V1/V2 blockade of the effects of AVP would most likely yield positive results in patients with acute HF, perhaps especially as alternative, not adjunctive therapy to loop diuretics.

Diuretic resistance is a common issue in patients with acute decompensation of advanced chronic heart failure (ACHF). The aim of this trial was to compare boluses and continuous infusion of furosemide in a selected population of patients with ACHF and high risk for diuretic resistance. In this single-centre, double-blind, double-dummy, randomized trial, we enrolled 80 patients admitted for acute decompensation of ACHF (NYHA IV, EF ≤ 30%) with criteria of high risk for diuretic resistance (SBP ≤ 110 mmHg, wet score ≥ 12/18, and sodium ≤ 135 mMol/L). Patients were assigned in a 1:1 ratio to receive furosemide by bolus every 12 h or by continuous infusion. Diuretic treatment and dummy treatment were prepared by a nurse unassigned to patients’ care. The study treatment was continued for up to 72 h. Coprimary endpoints were total urinary output and freedom from congestion at 72 h. 80 patients were enrolled with 40 patients in each treatment arm. Mean daily furosemide was 216 mg in continuous-infusion arm and 195 mg in the bolus intermittent arm. Freedom from congestion (defined as jugular venous pressure of

A long-acting loop diuretic, azosemide, has been shown to improve long-term prognosis in patients with heart failure compared with a short-acting loop diuretic, furosemide. However, the therapeutic advantages of azosemide over furosemide have not been clearly established. In this study, we retrospectively analyzed clinical outcomes and laboratory data in patients with congestive heart failure treated with furosemide or azosemide, and the efficacy of these agents was compared. First, we screened 1900 patients and selected 124 (furosemide group: n = 40; azosemide group: n = 84) as the total study population. From these patients, we next selected 72 patients for the propensity score-matched analysis (furosemide group: n = 36; azosemide group: n = 36). The incidence of all-cause death and rehospitalization due to worsening heart failure during 24 months of follow-up was similar between the furosemide and azosemide groups in both the total study population and the propensity score-matched population. However, in the propensity score-matched analysis, the estimated glomerular filtration rate time-dependently decreased during 36 months of follow-up in the furosemide group (56.5 ± 19.5-43.2 ± 16.3 mL/min/1.73 m), whereas it did not change in the azosemide group (58.6 ± 22.0-50.3 ± 17.8 mL/min/1.73 m) (P = 0.032). Azosemide might have some potential advantage for renal protection over furosemide in patients with congestive heart failure.

ObjectiveThis study aimed to identify characteristics, spectrum of tricuspid regurgitation (TR) severity and treatment patterns in patients considered for intervention of severe TR at a tertiary centre. The population being considered for TR intervention is currently not well defined and the role of transcatheter interventions is unclear.MethodsThe study involved 87 patients with severe TR considered for intervention from 1 March 2016 to 12 November 2018 at Mayo Clinic. Patients receiving medications alone were compared with those receiving intervention to identify patterns in demographics, clinical/echocardiographic associations and survival.ResultsMean age was 80±9 (56% female), 93% had atrial fibrillation and 64% had chronic kidney disease ≥3 a. Follow-up was 331±276 days; 95% were symptomatic with 6 min walk distance of 270±110 m. Loop diuretics were used in 93%; aldosterone antagonists in 35%. Mean tricuspid annular plane systolic excursion was 15.6±3.8 mm, effective regurgitant orifice area (EROA) 82±32 mm2 and stroke volume index 39±11 mL/m2; 48% had at least moderate right ventricular (RV) dysfunction, and 75% did not undergo intervention. Patients receiving intervention showed trends towards larger EROA (93±33 vs 75±31 mm2), better right ventricular function and more severe symptoms. Overall group 30-day and 1-year survival were 100% and 76%, respectively.ConclusionsPatients with severe TR considered for intervention are commonly elderly with atrial fibrillation, advanced TR and RV dysfunction; 75% were treated with medications alone and not offered intervention. Patients with greater EROA, better RV function and more severe symptoms were more likely to receive intervention. These findings have implications for future trial design.

Introduction Signs and symptoms of congestion are the predominant reason for hospital admission with acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remains unclear. Hypothesis Acetazolamide in addition to loop diuretics increases natriuresis without further neurohumoral activation, potentially improving decongestion and outcomes in AHF. Methods This prospective, 2-center study included 34 AHF patients on loop diuretics with volume overload. All patients had a serum sodium concentration 50 and/or admission serum creatinine increased with >0.3 mg/dL compared to baseline. Patients were randomized towards acetazolamide 500 mg OD plus bumetanide 1-2 mg BID versus high-dose loop diuretics (bumetanide BID with bolus dose equal to oral maintenance dose). The primary end-point was natriuresis after 24h. Results Natriuresis after 24h was similar in the combinational treatment versus loop-diuretic only arm (264±126 versus 234±133 mmol, respectively; P-value=0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84±46 versus 52±42 mmol/mg bumetanide, respectively; P-value=0.048; Figure). More patients in the combinational treatment arm had an increase in serum creatinine levels >0.3 mg/dL (P-value=0.046). NT-proBNP reduction and peak neurohumoral activation within 72h were comparable among treatment arms. Median time to all-cause mortality or heart failure readmission was 273 versus 803 days in the group receiving high-dose loop diuretic monotherapy versus acetazolamide with low-dose loop diuretics, which favoured the latter group but was not statistically significant (P-value=0.098). Conclusion Addition of acetazolamide increases the natriuretic response to loop diuretics with similar neurohumoral responses compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance. ClinicalTrials.gov identifier: NCT01973335.

Hyperuricemia is reportedly associated with poor outcome in acute heart failure (AHF). The association between changes in Uric acid (UA) levels with renal function change, diuretic doses, and mortality in patients with AHF were studied.Consecutive patients hospitalized with AHF were reviewed (n = 535). UA levels were measured at admission and either at discharge or on approximately the seventh day of admission. Patients with an UA change in the top tertile were defined as having an increase (UA-increase) and were compared to those outside the top tertile (non-UA-increase). The endpoint was all-cause mortality, with a mean follow-up duration of 22.2 months. Patients in the UA-increase group presented with greater creatine increase (P 0.001), and were administered a higher average daily dose of loop diuretic (P = 0.016) compared with the non-UA-increase group. In-hospital UA-increase was associated with higher risk of mortality even after adjusting for confounding variables including creatine change and diuretic dosage [harzard ratio (HR) 1.53, 95% confidence interval (CI) 1.02-2.30, P = 0.042]. In patients with hyperuricemia on admission, UA-increase was associated with increased mortality (adjusted HR 2.21, 95% CI 1.38-3.52, P = 0.001). Whereas, in those without admission hyperuricemia, UA-increase had no significant association with mortality.An increase in UA during in-hospital treatment is associated with an increase in creatine levels and daily diuretic dose. Mortality associated with increased UA is restricted to patients who already have hyperuricemia at admission. A combination of UA levels at admission and UA changes on serial assessment during hospitalization may be additional value in the risk stratification of AHF patients.

Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor, was shown to improve outcome in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). There are reasons for believing that the concept that the lower the B-type natriuretic peptide (BNP) circulating level the better the prognosis may no longer be correct in patients treated with sacubitril/valsartan, since sacubitril may interfere with BNP clearance. We reported a case series of ten patients with stable chronic HF and LVEF ≤35% (mean age: 64 ± 8 years; 30% female), referred to our outpatient HF clinic, treated with sacubitril/valsartan, in whom the global amelioration of NYHA class and LVEF was coupled with a clinically significant decrease in BNP levels and a reduction of loop diuretic dose. Average sacubitril/valsartan daily dose was 220 mg. The median duration of treatment was 15 months (range: 6-21 months). Seventy percent of patients exhibited an improvement in exercise tolerance, as indicated by the change in NYHA class. There was also an improvement in LVEF from 28 ± 5% to 39 ± 7%. Clinically significant reductions in BNP levels were evident, with a median change from 181 pg/ml to 70 pg/ml. Furosemide daily dose decreased from a median of 43.3 mg to 12.5 mg. This case series suggests that BNP may still be valuable for the assessment of ambulatory HF patients, after the optimization of sacubitril/valsartan therapy.

The majority of patients with chronic heart failure (HF) receive long-term treatment with loop diuretics. The comparative effectiveness of different loop diuretics is unknown. We searched PubMed, clinicaltrials.gov , the Cochrane Central Register of Controlled Trials and the European Union Clinical Trials Register for randomised clinical trials exploring the efficacy of the loop diuretics azosemide, bumetanide, furosemide or torasemide in patients with HF. Comparators included placebo, standard medical care or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, HF-related hospitalisation and any combined endpoint thereof. Hypokalaemia and acute renal failure were defined as additional safety endpoints. Evidence was synthesised using network meta-analysis (NMA). Thirty-four trials reporting on 2647 patients were included. The overall quality of evidence was rated as moderate. NMA demonstrated no significant differences between loop diuretics with respect to all-cause mortality, cardiovascular mortality or hypokalaemia. In contrast, torasemide ranked best in terms of HF hospitalisation, and there was a trend towards benefits with torasemide with regard to occurrence of acute renal failure. Sensitivity analyses excluding trials with a follow-up

Dysregulation of cation-chloride cotransporters NKCC1 and KCC2 expression was shown to be related to drug-resistant epilepsy. Previous studies suggested that bumetanide, an inhibitor of NKCC1, might have antiepileptic effects.The aim of this study was to investigate the safety and efficacy of bumetanide add-on therapy in patients with drug-resistant epilepsy and its relation to cation-chloride cotransporters NKCC1 and KCC2.We conducted an open-label, single-arm clinical trial in drug-resistant temporal lobe epilepsy (TLE) patients. This study consisted of three phases: pretreatment (3 months), titration (3 weeks), and active treatment (6 months). During the pretreatment phase, the dose of antiepileptic drugs was stabilized, and bumetanide was then added at an initial dose of 0.5 mg/day, increasing by 0.5 mg/week until a target dose of 2 mg/day was achieved. Bumetanide treatment was then continued for 6 months. Seizure frequency and adverse events were assessed at every monthly visit. Blood samples were collected from patients and 12 healthy controls were used for polymerase chain reaction and Western blot analyses. Primary clinical outcomes were drug safety and change in seizure frequency. Changes in NKCC1 and KCC2 expression were the non-clinical endpoints.A total of 30 patients were enrolled, 27 of whom completed the study. The mean duration of epilepsy was 16.5 years. Median seizure frequency per month was 9 [interquartile range (IQR) 7-14.5] at baseline, 3.67 (IQR 1.84-6.17) at the first 3 months, and 2 (IQR 0.84-4.34) at the last 3 months (p 0.001). Five adverse events were detected in six patients. The reported adverse events were anorexia in four patients, nausea and vomiting in two patients, and agitation, headache and increased seizure frequency in one patient each. The level of NKCC1 and KCC2 gene transcripts and KCC2 protein did not change significantly following treatment (p 0.05); however, we observed a significant reduction in NKCC1 protein levels (p = 0.042).Bumetanide might be an effective and relatively tolerable drug in patients with drug-resistant TLE. Downregulation of NKCC1 protein following bumetanide treatment may be responsible for its antiepileptic effects.IRCT 201012115368N1.

Diuretic resistance (DR) is common in patients with decompensated heart failure (HF), and is associated with adverse outcomes. To determine the prevalence of DR and its impact on survival among patients with decompensated HF, we prospectively evaluated the prevalence and influence on prognosis of DR (defined as persistent congestion despite ≥ 80 mg of furosemide per day) in a cohort of elderly patients from the Spanish HF registry (RICA) admitted for an acute decompensation of HF. Patients with new-onset HF were excluded. From the global cohort of 2067 patients, 435 (21%; 95% CI 19.3%-22.7%) patients met criteria for DR. Patients with DR had more comorbidities (hypercholesterolemia, diabetes mellitus, valvular disease, chronic kidney disease, and cancer) and a worse functional status compared to patients without DR. In addition, patients with DR had a higher proportion of ischemic etiology, more advanced functional class and lower left ventricular ejection fraction values. After 1 year of follow-up, all-cause mortality was higher in patients with DR with an adjusted hazard ratio of 1.37 (95% CI 1.06-1.79; p = 0.018). The prevalence of DR in a cohort of elderly patients admitted for acute HF decompensation is 21%. DR is an independent predictor of 1-year mortality.

Loop diuretics remain the cornerstone of congestion management in contemporary chronic heart failure care. However, their use is not supported by high quality data, and there is doubt about the safety in the outpatient heart failure setting. Still, congestion is related to a worse outcome, and there is general consensus among experts that congestion should not be tolerated in heart failure patients. Recommendations in international guidelines, regarding decongestion strategies in chronic heart failure, are limited. Thus, there is an emerging need for clinical decision-making support about the best strategy for using loop diuretics and decongestion in the chronic setting. The present review provides a comprehensive overview over the evidence of chronic loop diuretic use. Strategies for the assessment of congestion in the outpatient setting and decongestion algorithm are provided to assist health care specialists in delivering high-quality heart failure care.

Purpose of review: Diuretic resistance (DR) occurs along a spectrum of relative severity and contributes to worsening of acute heart failure (AHF) during an inpatient stay. This review gives an overview of mechanisms of DR with a focus on loop diuretics and summarizes the current literature regarding the prognostic value of diuretic efficiency and predictors of natriuretic response in AHF. Recent findings: The pharmacokinetics of diuretics are impaired in chronic heart failure, but little is known about mechanisms of DR in AHF. Almost all diuresis after administration of a loop diuretic dose occurs in the first few hours after administration and within-dose DR can develop. Recent studies suggest that DR at the level of the nephron may be more important than defects in diuretic delivery to the tubule. Because loop diuretics induce natriuresis, urine sodium (UNa) concentration may serve as a functional, physiologic and direct measure for diuretic responsiveness to a given loop diuretic dose. Summary: Identifying and targeting individuals with DR for more aggressive, tailored therapy represents an important opportunity to improve outcomes. A better understanding of the mechanistic underpinnings of DR in AHF is needed to identify additional biomarkers and guide future trials and therapies.

The aim: Of the article is to conduct a comparative evaluation of the effectiveness of torasemide and furosemide in patients with heart failure.Materials and methods: Analysis of the existing clinical trials and meta-analyzes that combine the results of the completed studies aimed at the investigation of comparative efficacy of furosemide and torasemide in patients with heart failure (НF).Conclusions: There is enough convincing evidence to speak about the advantages of torasemide over furosemide both in terms of its pharmacological properties and taking into account the reduction of hospitalizations, functional progress and improvement in the quality of life of patients with НF. The safety profile of torasemide is more favorable, as it is associated with a reduced risk of hypokalemia compared to furosemide. The abovementioned facts favor the use of torasemide in patients with symptomatic НF, as well as the transition from furosemide to torasemide in patients with edema caused by НF, which remain uncontrolled despite receiving optimal doses of furosemide.

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.

Aims Intestinal oedema is one of the manifestations associated with right‐sided heart failure (HF), which is known to be associated with poorer patient outcomes. We attempted to reveal the association between intestinal oedema and diuretic resistance in hospitalized patients with acute HF. Methods and results Among 213 hospitalized patients with acute HF, abdominal ultrasonography was performed under clinically stable conditions after initial HF treatments. The association among abdominal ultrasonographic parameters, maintenance doses of loop diuretics, and responsiveness to initial loop diuretic treatment was evaluated. Higher mean colon wall thickness (CWT) independently correlated with a higher dose of loop diuretics at enrolment (adjusted β = 0.198, P = 0.0004). Increased mean CWT also correlated with poor response to oral loop diuretics as an initial treatment, whereas it did not correlate with the response to intravenous loop diuretics. Discrimination of non‐responders to initial oral loop diuretics resulted in a sensitivity of 0.772 and a specificity of 0.733 using a mean CWT cut‐off value of ≥3 mm. Conclusions In hospitalized patients with acute HF, a strong correlation was identified among the severity of intestinal oedema, required quantities as maintenance loop diuretic doses, and poor responsiveness to oral loop diuretics at admission.

PURPOSE To investigate various diuretic strategies to alleviate loop-diuretics resistance in critically ill patients. MATERIALS AND METHOD ICU adults requiring more than 1 mg/kg/day of furosemide, from the MIMIC-III database. Four diuretic strategies were investigated: incremental dose of loop diuretics, continuous infusion, combinations with a second class of diuretics and administration of intravenous albumin. A generalized estimating equation was used to investigate the associations between these strategies and endpoints. The primary outcome was the 24-h urine output and secondary endpoints included fluid balance, weight change, electrolyte and acid-base abnormalities, kidney replacement therapy initiation, and mortality. RESULTS A total of 7645 ICU stays from 6358 patients were included. After adjustment, the use of continuous loop-diuretic infusion was associated with a higher 24-h urine output (β: 732, 95% CI:669-795, p < 0.001), lower 24-h fluid balance (p < 0.001) and greater weight loss at 48-h (p < 0.001). Thiazide- and carbonic anhydrase inhibitor combinations were both associated with higher urine output (p < 0.001) and weight loss at 48-h (p < 0.01), while intravenous albumin was associated with fluid gain (p < 0.001). Risks of electrolyte and metabolic disturbances varied across diuretic strategies. CONCLUSIONS Continuous loop-diuretic infusion and thiazide- or acetazolamide-loop diuretic combinations increased urine output significantly, leading to a negative fluid balance and weight loss.

Dihydropyridine calcium channel blockers (DH CCBs) are commonly used for hypertension in older adults. However, loop diuretics can be inappropriately added to treat DH CCB-induced edema, putting individuals at increased risk for adverse events and potential decreases in quality of life.We conducted a cross-sectional analysis using United States Medical Expenditure Panel Survey (MEPS) data from 2003 to 2015. Adults aged ≥ 55 years without congestive heart failure, nephrotic syndrome, chronic kidney disease, renal failure, and cirrhosis who had consecutive rounds of DH CCB use (round 1 and 2 or round 3 and 4) and completed the self-administered questionnaire (SAQ) were included. Patients initiated on loop diuretics in round 2 or 4 were compared to those not initiated. Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were analyzed using multivariable linear regression models.Among 5,458,467 DH CCB users (weighted), 3.4% of individuals were identified with new loop diuretic use (185,130 weighted). After adjusting for covariates, DH CCB plus loop diuretic use was associated with a PCS score 3.12 units lower (95% confidence interval - 5.40 to - 0.83; p = 0.008) than DH CCB use alone. We observed no significant difference in MCS score (p = 0.160) among DH CCB plus loop diuretic users compared to DH CCB users alone.New loop diuretic use was associated with lower physical functioning among DH CCB users. These findings suggest that this potential prescribing cascade may result in both significant and clinically meaningful decreases in health-related quality of life. It is important for clinicians to avoid or intervene on this inappropriate prescribing cascade when possible.

Background: Previous literature has suggested a potential diuretic sparing effect as early as 6 months following sacubitril-valsartan initiation in patients with heart failure with reduced ejection fraction (HFrEF); however, whether this effect manifests earlier after initiation is unclear. Objective: To evaluate the acute diuretic-sparing effects of sacubitril-valsartan. Methods: This was a single-center, retrospective analysis of outpatients with HFrEF initiated on sacubitril-valsartan with follow up within 90 ± 30 days and a concomitant loop diuretic prescription. The primary outcome was the percent of patients with an increase, decrease or no change in loop diuretic total daily dose (TDD). Key secondary outcomes included change in loop diuretic TDD (mg furosemide equivalents) and hospital admissions or emergency department (ED) visits. Results: A total of 145 patients were included (overall cohort) with 120 continuing sacubitril-valsartan at follow up (on-treatment cohort). In the on-treatment cohort, 20% (n = 24) had a reduction in loop diuretic TDD and 10% had an increase (n = 12). Median change in loop diuretic TDD was unchanged from baseline to follow up (p 0.13). In patients on >80 mg TDD of furosemide at baseline (n = 9), mean change was-53 ± 44 mg (p 0.006). Hospitalizations (6.2%) and ED visits (0.7%) for heart failure were infrequent. Conclusion: Patients may require a loop diuretic dose reduction within 2-3 months following sacubitril-valsartan initiation. This diuretic-sparing effect appears larger in those on higher baseline loop diuretic doses, and closer follow up may be warranted for these patients.

The concept of multinephron segment diuretic therapy (MSDT) has been recommended in severe diuretic resistance with only expert opinion and case-level evidence. The purpose of this study was to investigate the safety and efficacy of MSDT, combining 4 diuretic classes, in acute heart failure (AHF) complicated by diuretic resistance.A retrospective analysis was conducted in patients hospitalized with AHF at a single medical center who received MSDT, including concomitant carbonic anhydrase inhibitor, loop, thiazide, and mineralocorticoid receptor antagonist diuretics. Subjects served as their own controls with efficacy evaluated as urine output and weight change before and after MSDT. Serum chemistries, renal replacement therapies, and in-hospital mortality were evaluated for safety. Patients with severe diuretic resistance before MSDT were analyzed as a subcohort. A total of 167 patients with AHF and diuretic resistance received MSDT. MSDT was associated with increased median 24-hour urine output in the first day of therapy compared with the previous day (2.16 L [0.95-4.14 L] to 3.08 L [1.74-4.86 L], P = .003) in the total cohort and in the Severe diuretic resistance cohort (0.91 L [0.43-1.43 L] to 2.08 L [1.13-3.96 L], P.001). The median cumulative weight loss at day 7 or discharge was -7.4 kg (-15.3 to -3.4 kg) (P = .02). Neither serum sodium, chloride, potassium, bicarbonate, or creatinine changed significantly relative to baseline (P.05 for all).In an AHF cohort with diuretic resistance, MSDT was associated with increased diuresis without changes in serum chemistries or kidney function. Prospective studies of MSDT in AHF and diuretic resistance are warranted.

Purpose There is an increased use in the (prescription) sequence symmetry analysis (PSSA); however, limited studies have incorporated a negative control, and no study has formally quantified and controlled for within-patient time-varying bias using a negative control. Our aim was to develop a process to incorporate the effect of negative controls into the main analysis of a PSSA. Methods Using a previously assessed dihydropyridine calcium channel blocker (DH-CCB) and loop diuretic PSSA, we directly compared the adjusted sequence ratios (aSRs) of DH-CCBs to each of the two negative control index drugs (levothyroxine and angiotensin converting enzyme [ACE] inhibitor/ angiotensin-2 receptor blocker [ARB]) using the ratio of the aSRs to estimate a relative aSR with a Z test. Further, we utilized the relative aSR in stratum-specific analyses and varying exposure windows. Results The relative aSR of DH-CCBs decreased from 1.87 to 1.72 (95% CI 1.66-1.78) using levothyroxine as a negative control index drug. ACE inhibitor/ARB negative control index drug resulted in an aSR of 1.27 thus reducing the relative aSR for DH-CBB from 1.84 to 1.45 (95% CI 1.41-1.49). When restricting the exposure window to 180 and 90 days, the relative aSR of DH-CCBs increased to 1.68 (95% CI 1.62-1.74) and 1.86 (95% CI 1.78-1.94), respectively, relative to the ACE inhibitor/ARB negative control index drug. Conclusion We illustrated how to incorporate negative control index drugs into a PSSA and generate relative aSRs. Stratum-specific assessments and varying the exposure windows while using negative control index drugs can yield more informative results.

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Kaila, Löscher and colleagues report that Phenobarbital (PHB) and Midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist Bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. Yet, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to GABAergic mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of Anti-Epileptic Drugs (AEDs) to treat this severe life-threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM attenuates efficiently Autism symptomatology notably in patients with Tuberous Sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.

Aims To study loop diuretic response and effect of loop diuretic omission in ambulatory heart failure (HF) patients on chronic low-dose loop diuretics. Methods and results Urine collections were performed on two consecutive days in 40 ambulatory HF patients with 40-80 mg furosemide (day 1 with loop diuretic; day 2 without loop diuretic). Three phases were collected each day: (i) first 6 h; (ii) rest of the day; and (iii) night. On the day of loop diuretic intake, the total natriuresis was 125.9 (86.9-155.0) mmol/24 h and urine output was 1650 (1380-2025) mL/24 h. There was a clear loop diuretic response with a natriuresis of 9.4 (6.7-15.9) mmol/h and a urine output of 117 (83-167) mL/h during the first 6 h, followed by a significant drop in natriuresis and urine output during the rest of the day [2.6 (1.8-4.8) mmol/h and 55 (33-71) mL/h] and night [2.2 (1.6-3.5) mmol/h and 44 (34-73) mL/h]. On day 2, after loop diuretic omission, the natriuresis and urine output remained similarly low the entire day, resulting in a 50% reduction in natriuresis [55.1 (33.5-77.7) mmol/24 h; P < 0.001] and a 31% reduction in urine output [1035 (875-1425) mL/24 h; P < 0.001] compared with the day of loop diuretic intake. Conclusion Patients with HF on chronic loop diuretic treatment still have a clear diuretic response phase, while loop diuretic omission leads to a significant drop in natriuresis and urine output, arguing against routine cessation of low-dose loop diuretics. Jeroen Dauw, Sebastien Deferm, Henri Gruwez and Wilfried Mullens are researchers for the Limburg Clinical Research Center (LCRC) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), province of Limburg, Flemish government, Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. Mullens, W (corresponding author), Ziekenhuis Oost Limburg, Dept Cardiol, Schiepse Bos 6, B-3600 Genk, Belgium. wilfried.mullens@zol.be