A combined clinical and biomarker approach to predict diuretic response in acute heart failure

Background: Poor diuretic response in acute heart failure is related to poor clinical outcome. The underlying mechanisms and pathophysiology behind diuretic resistance are incompletely understood. We evaluated a combined approach using clinical characteristics and biomarkers to predict diuretic response in acute heart failure (AHF). Methods and results: We investigated explanatory and predictive models for diuretic response—weight loss at day 4 per 40 mg of furosemide—in 974 patients with AHF included in the PROTECT trial. Biomarkers, addressing multiple pathophysiological pathways, were determined at baseline and after 24 h. An explanatory baseline biomarker model of a poor diuretic response included low potassium, chloride, hemoglobin, myeloperoxidase, and high blood urea nitrogen, albumin, triglycerides, ST2 and neutrophil gelatinase-associated lipocalin (r2 = 0.086). Diuretic response after 24 h (early diuretic response) was a strong predictor of diuretic response (β = 0.467, P < 0.001; r2 = 0.523). Addition of diuretic response after 24 h to biomarkers and clinical characteristics significantly improved the predictive model (r2 = 0.586, P < 0.001). Conclusions: Biomarkers indicate that diuretic unresponsiveness is associated with an atherosclerotic profile with abnormal renal function and electrolytes. However, predicting diuretic response is difficult and biomarkers have limited additive value. Patients at risk of poor diuretic response can be identified by measuring early diuretic response after 24 h

CAPA neuropeptides and their receptor form an anti-diuretic hormone signalling system in the human disease vector, Aedes aegypti

Insect CAPA neuropeptides are homologs of mammalian neuromedin U and are known to influence ion and water balance by regulating the activity of the Malpighian ‘renal’ tubules (MTs). Several diuretic hormones are known to increase primary fluid and ion secretion by insect MTs and, in adult female mosquitoes, a calcitonin-related peptide (DH31) called mosquito natriuretic peptide, increases sodium secretion to compensate for the excess salt load acquired during blood-feeding. An endogenous mosquito anti-diuretic hormone was recently described, having potent inhibitory activity against select diuretic hormones, including DH31. Herein, we functionally deorphanized, both in vitro and in vivo, a mosquito anti-diuretic hormone receptor (AedaeADHr) with expression analysis indicating highest enrichment in the MTs where it is localized within principal cells. Characterization using a heterologous in vitro system demonstrated the receptor was highly sensitive to mosquito CAPA neuropeptides while in vivo, AedaeADHr knockdown abolished CAPA-induced anti-diuretic control of DH31-stimulated MTs. CAPA neuropeptides are produced within a pair of neurosecretory cells in each of the abdominal ganglia, whose axonal projections innervate the abdominal neurohaemal organs, where these neurohormones are released into circulation. Lastly, pharmacological inhibition of nitric oxide synthase (NOS) and protein kinase G (PKG) signaling eliminated anti-diuretic activity of CAPA, highlighting the role of the second messenger cGMP and NOS/PKG in this anti-diuretic signaling pathway.York University Librarie

Rationale and study design of intravenous loop diuretic administration in acute heart failure. DIUR-AHF

Aims: Although loop diuretics are the most commonly used drugs in acute heart failure (AHF) treatment, their short-term and long-term effects are relatively unknown. The significance of worsening renal function occurrence during intravenous treatment is not clear enough. This trial aims to clarify all these features and contemplate whether continuous infusion is better than an intermittent strategy in terms of decongestion efficacy, diuretic efficiency, renal function, and long-term prognosis. Methods and results: This is a prospective, multicentre, randomized study that compares continuous infusion to intermittent infusion and a low vs. high diuretic dose of furosemide in patients with a diagnosis of acute heart failure, BNP ≥ 100 pg/mL, and specific chest X-ray signs. Randomization criteria have been established at a 1:1 ratio using a computer-generated scheme of either twice-daily bolus injection or continuous infusion for a time period ranging from 72 to 120 h. The initial dose will be 80 mg/day of intravenous furosemide and, in the case of poor response, will be doubled using an escalation algorithm. A high diuretic dose is defined as a furosemide daily amount >120 mg/day respectively. Conclusions: Continuous and high dose groups could reveal a more intensive diuresis and a greater decongestion with respect to intermittent and low dose groups; high dose and poor loop diuretic efficiency should be related to increased diuretic resistance, renal dysfunction occurrence, and greater congestion status. Poor diuretic response will be associated with less decongestion and an adverse prognosis

Uji Efektivitas Diuretik Ekstrak Etanol Biji Salak (Salacca Zalacca Varietas Zalacca (Gaert.) Voss) Pada Tikus Putih Jantan Galur Wistar (Rattus Norvegicus)

This research has purpose to examine the diuretic effects of Salak seed\u27s ethanol extract and to analyze the relationship of dose concentration of Salak seed\u27s ethanol extract upon diuretic effect on Wistar white male mice (Rattus norvegicus). 15 mice were divided into five different treatment groups, namely: negative control (0.5% CMC suspension), positive control (5.04 mg/kg furosemide suspension), suspension of Salak seed\u27s ethanol extract 0.07 g/KgBB, suspension of Salak seed\u27s ethanol extract 0.14 g/KgBB, and suspensions of ethanol extract of salak seeds 0.28 g/KgBB. The Tests of diuretic effect were conducted by calculate the urine volume which was excreted urine during 6 hours of treatment. The data were analyzed by SPSS ver.20, one way ANOVA test to find out the average difference in each treatment group, if there is significant difference, it is continued with LSD test. The result of LSD test showed that the treatment group of Salak seed\u27s ethanol extract 0.07 g/KgBB didn\u27t give any significant results with CMC 0.5% (negative control) as compared with the treatment group of Salak seed\u27s ethanol extract 0.14 g/KgBB and 0.028 g/KgBB that gave significant results, this means that the higher concentration of Salak seed\u27s ethanol extract is set, the bigger diuretic effect is created

Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than other diuretic classes, results in greater electrolyte-free water clearance, and ultimately in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling, and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects administered either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2-fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling due to low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion

Medical treatment of ascites in cirrhosis

Medical treatment of cirrhotic ascites is essentially supportive, dictated by the patient's discomfort, impaired cardiovascular or respiratory function and potential for infection. Treatment of ‘simple’ ascites (moderate fluid accumulation, serum albumin > 3.5 g/dl, serum creatinine < 1.5 mg/dl, no electrolyte disturbance) is implemented sequentially. Only 10% of patients respond to dietary sodium restriction and bed rest; most require pharmacotherapy consisting of spironolactone, which increases the proportion of responding patients to 65% and loop diuretics, which may produce clinical improvement in an additional 20% (85% in all); in the remaining 15% of refractory patients, use of novel adjunctive therapies may be attempted. Patients with tense ascites, impaired renal function and electrolyte disturbances merit special consideration before diuretics are introduced. Spironolactone has long been a standard for the treatment of cirrhotic ascites because it directly antagonizes aldosterone. The loop diuretic most frequently added to spironolactone has been furosemide. However, there is preliminary evidence that torasemide may be more effective in some patients. Other investigational agents that may play a role in treatment of patients resistant to conventional drugs include ornipressin (a vasopressin analogue) and atrial natriuretic factor

Effects of empagliflozin on cardiorespiratory fitness and significant interaction of loop diuretics

The effects of empagliflozin on cardiorespiratory fitness in patients with type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) are unknown. In this pilot study we determined the effects of empagliflozin 10 mg/d for 4 weeks on peak oxygen consumption (VO2 ) in 15 patients with T2DM and HFrEF. As an exploratory analysis, we assessed whether there was an interaction of the effects of empagliflozin on peak VO2 of loop diuretics. Empagliflozin reduced body weight (-1.7 kg; P = .031), but did not change peak VO2 (from 14.5 mL kg-1 min-1 [12.6-17.8] to 15.8 [12.5-17.4] mL kg-1 min-1 ; P = .95). However, patients using loop diuretics (N = 9) demonstrated an improvement, whereas those without loop diuretics (N = 6) experienced a decrease in peak VO2 (+0.9 [0.1-1.4] vs -0.9 [-2.1 to -0.3] mL kg-1 min-1 ; P = .001), and peak VO2 changes correlated with the baseline daily dose of diuretics (R = +0.83; P &lt; .001). Empagliflozin did not improve peak VO2 in patients with T2DM and HFrEF. However, as a result of exploratory analysis, patients concomitantly treated with loop diuretics experienced a significant improvement in peak VO2

The synthesis of an analogue of the locust CRF-like diuretic peptide, and the biological activities of this and some C-terminal fragments.

The synthesis is described of an analogue of the locust CRF-like diuretic peptide in which methionine in positions 1,3, and 13 is replaced by isosteric methyl-homoserine residues. This analogue has been tested for biological activity on Malpighian tubules in vitro, and feeding behavior in vivo. It is highly active in stimulating fluid secretion and accumulation of cAMP in tubules, and on increasing the latency to feed and reducing meal duration. A 15 residue fragment from the C-terminus of the CRF-like peptide, Locmi-DP32–46, is fully active in the feeding assay, but has only weak ability to stimulate the accumulation of cAMP in tubules. Two smaller fragments, Locmi-DP32–37 and Locmi-DP41–46, were tested but neither had consistent biological activity in any of the assays used here. None of the peptides tested have any substantive activity in increasing cGMP in tubules

secCl is a cys-loop ion channel necessary for the chloride conductance that mediates hormone-induced fluid secretion in Drosophila

Organisms use circulating diuretic hormones to control water balance (osmolarity), thereby avoiding dehydration and managing excretion of waste products. The hormones act through G-protein-coupled receptors to activate second messenger systems that in turn control the permeability of secretory epithelia to ions like chloride. In insects, the chloride channel mediating the effects of diuretic hormones was unknown. Surprisingly, we find a pentameric, cys-loop chloride channel, a type of channel normally associated with neurotransmission, mediating hormone-induced transepithelial chloride conductance. This discovery is important because: 1) it describes an unexpected role for pentameric receptors in the membrane permeability of secretory epithelial cells, and 2) it suggests that neurotransmitter-gated ion channels may have evolved from channels involved in secretion

Serum potassium levels and outcome in acute heart failure (data from the PROTECT and COACH trials)

Serum potassium is routinely measured at admission for acute heart failure (AHF), but information on association with clinical variables and prognosis is limited. Potassium measurements at admission were available in 1,867 patients with AHF in the original cohort of 2,033 patients included in the Patients Hospitalized with acute heart failure and Volume Overload to Assess Treatment Effect on Congestion and Renal FuncTion trial. Patients were grouped according to low potassium (&lt;3.5 mEq/l), normal potassium (3.5 to 5.0 mEq/l), and high potassium (&gt;5.0 mEq/l) levels. Results were verified in a validation cohort of 1,023 patients. Mean age of patients was 71 – 11 years, and 66% were men. Low potassium was present in 115 patients (6%), normal potassium in 1,576 (84%), and high potassium in 176 (9%). Potassium levels increased during hospitalization (0.18 – 0.69 mEq/l). Patients with high potassium more often used angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists before admission, had impaired baseline renal function and a better diuretic response (p [ 0.005), independent of mineralocorticoid receptor antagonist usage. During 180-day follow-up, a total of 330 patients (18%) died. Potassium levels at admission showed a univariate linear association with mortality (hazard ratio [log] 2.36, 95% confidence interval 1.07 to 5.23; p [ 0.034) but not after multivariate adjustment. Changes of potassium levels during hospitalization or potassium levels at discharge were not associated with outcome after multivariate analysis. Results in the validation cohort were similar to the index cohort. In conclusion, high potassium levels at admission are associated with an impaired renal function but a better diuretic response. Changes in potassium levels are common, and overall levels increase during hospitalization. In conclusion, potassium levels at admission or its change during hospitalization are not associated with mortality after multivariate adjustment