Conventional Diuretics Research Articles

Abstract 10772: Could Tolvaptan Protect Renal Function in the Early Postoperative Period After Cardiac Surgery?

Introduction: Tolvaptan (TV), a vasopressin V2 inhibitor, has a strong diuretic effect, which is beneficial for body fluid management in patients with acute heart failure (AHF). Several studies have reported that TV significantly reduces worsening renal function (WRF), which has recently been highlighted as an exacerbation factor in the treatment of AHF. We hypothesized that concomitant administration of TV with conventional diuretic treatment is beneficial for perioperative body fluid management in patients who have undergone cardiac surgery. In this study, we prospectively randomized the patients into the TV group, in which TV was administered in addition to conventional diuretics, and the control group, in which the patients received conventional diuretics only. Methods: A total of 176 patients who underwent cardiac surgery were divided into 2 groups, which were the TV group (TV + furosemide, 90 patients) and conventional diuretic treatment group (Control [C], furosemide with or without spironolactone, 86 patients). We compared urine output for 3 days after surgery, the time required to restore the preoperative body weight, and the incidence of WRF between the 2 groups. In the TV group, patients received TV 7.5mg/day orally starting on POD1 and continued to take TV up to POD 5. WRF was defined as a rise in the serum creatinine level (Cr) of ≥0.3 mg/dL. Results: The mean daily urine output from POD1 to POD 3 of the TV group (2672 ± 769 mL/day) was higher than that of the C group (2240 ± 529 mL/day) (p = 0.001). The time required to restore preoperative body weight was shorter in the TV group (3.8 ± 1.4 days) than in the C group (4.8 ± 2.0 days) (p=0.003). While the highest postoperative Cr of the TV group (1.01 ± 0.50 mg/dL) was the same as that of the C group (1.16 ± 0.91 mg/dL) (p=0.25), the incidence of WRF in the TV group (9 patients, 10%) was significantly lower than in the C group (24 patients, 28%) (p=0.007), which might indicate the protective effect of TV against WRF in the patients undergoing cardiac surgery. Conclusions: Administration of TV with conventional diuretics in the early postoperative period after cardiac surgery could be beneficial in maintaining urine output without affecting renal function, which may help to avoid WRF after cardiac surgery.

Effects of tolvaptan in the early postoperative stage after heart valve surgery: results of the STAR (Study of Tolvaptan for fluid retention AfteR valve surgery) trial.

The purpose of this study was to assess the efficacy of tolvaptan, a vasopressin V2 receptor antagonist, for the management of postoperative surgical fluid retention after heart valve surgery. This was a prospective observational study of 64 patients with heart valve disease who underwent valve surgery between 2013 and 2014. Those in the tolvaptan group received tolvaptan in addition to conventional diuretic therapy. The results were compared to the results of 55 patients who underwent heart valve surgery between 2007 and 2010 and received conventional postoperative diuretics alone. The time to return to the preoperative BW was significantly shorter in the patients who received tolvaptan (6.1 ± 3.8 vs. 8.7 ± 6.7 days, p < 0.05), while the level of sodium was significantly decreased in the patients who received conventional diuretics. The degree of increase in the creatinine level tended to be smaller in the tolvaptan group. The response to tolvaptan was related to the postoperative degree of BW increase and the preoperative creatinine level. Tolvaptan was effective in treating fluid retention during the early postoperative stage in cardiac surgery patients, without increased renal failure or abnormal electrolyte levels. This new type of diuretic therapy may be a suitable option for postoperative fluid management in patients undergoing cardiac surgery.

The treatment of vasopressin V2-receptor antagonists in cirrhosis patients with ascites: a meta-analysis of randomized controlled trials

BackgroundAscites is the most common complication of cirrhosis. It may lead to the consequence of poor prognosis and the deterioration of quality of life. Asopressin V2 receptor antagonists is a kind of vaptans, and it has been proved to be effective in hyponatremia patients. We conducted a meta-analysis about treatment of vaptans in cirrhosis patients with ascites.MethodsFollowing our selection criteria, we collected a total of 14 studies containing 16 randomized controlled trials (2620 patients) from a series of database about the treatment with vaptans for cirrhosis with ascites patients. The included studies compared the treatment effect of lixivaptan (VPA 985), or RMJ-351647, or satavaptan, or tolvaptan with placebo.ResultsThe included vaptans (asopressin V2 receptor antagonists) showed significant effect of increasing the serum sodium concentration for cirrhosis patients (WMD = 2.11 mmol/L, p < 0.00001). Patients also could acquire significant improvement of ascites, as this kind of aquaretics can significantly reduce ascites patients’ weight (WMD = −1.53, p < 0.00001), abdominal girth (WMD = −2.04, p < 0.00001), and the ratio of worsening ascites (RR = 0.51, p = 0.001). Though the drug did not produce more total adverse events (RR = 1.04, p = 0.09) and the total serious events (RR = 1.04, p = 0.42), the emergence of excessive correction of serum sodium concentrations (>145 mmol/L) was more frequently noted in patients under the employment of vaptans (RR = 2.14, 95 % CI [1.45, 3.16], p = 0.0001). Whether with the administration of vaptans for short-term or long-term, no survival benefit was detected from the selected studies.ConclusionsAsopressin V2 receptor antagonists could play an effective and safe role in symptomatic treatment for cirrhosis patients with ascites, especially for refractory ascites patients who presented insufficient response to conventional diuretics.

Echocardiographic characteristics of patients with acute heart failure requiring tolvaptan: a retrospective study

BackgroundNo study has investigated the admission echocardiographic characteristics of acute heart failure (AHF) patients who are resistant to conventional diuretics and require tolvaptan.MethodsWe retrospectively analyzed the echocardiographic characteristics of AHF patients who were resistant to conventional diuretics and took tolvaptan (tolvaptan group: 26 patients), and compared them to those who were sensitive to conventional diuretics (conventional group: 180 patients).ResultsThe tolvaptan group had a higher left atrial volume index (96.0 ± 85.0 mL/m2 vs. 45.8 ± 25.9 mL/m2, p < 0.0001), maximum inferior vena cava diameter (20.7 ± 6.9 mm vs. 18.1 ± 4.2 mm, p < 0.01), and higher tricuspid regurgitation grade (1.1 ± 0.8 vs. 0.8 ± 0.6, p < 0.05) than the conventional group. However, the left ventricular ejection fraction and end diastolic diameter were similar between the groups. Responders of tolvaptan had no significant echocardiographic differences compared to the non-responders.ConclusionsThe admission echocardiographic characteristics of AHF patients requiring tolvaptan included a larger left atrium, inferior vena cava, and more severe tricuspid regurgitation. Echocardiography may provide useful information for the early and appropriate initiation of tolvaptan.

Can serum albumin level affect the pharmacological action of tolvaptan in patients with liver cirrhosis? A post hoc analysis of previous clinical trials in Japan.

BackgroundPatients with hypoalbuminemia often fail to respond to increased doses of loop diuretics. We therefore performed a post hoc analysis to investigate the pharmacological action of tolvaptan and whether it is dependent on the serum albumin level.MethodsThis analysis was based on four previous clinical trials of tolvaptan in patients with liver cirrhosis who exhibited insufficient response to conventional diuretics. We analyzed the correlation between the change in the initial 24-h cumulative urine volume from baseline and the serum albumin level at baseline, and assessed potential predictive factors of response to tolvaptan.ResultsThe correlation coefficient was 0.029 in the placebo group and −0.112 in the 7.5 mg tolvaptan group of patients with liver cirrhosis. Administration of tolvaptan provoked a stable response regardless of the serum albumin level. Tolvaptan use was identified as a significant predictor of pharmacological action, and was shown to change the initial urine volume by 885 mL (P < 0.0001) in liver cirrhosis patients.ConclusionsIn this post hoc analysis, tolvaptan increased the initial urine volume from baseline regardless of serum albumin levels. Use of tolvaptan as an add-on therapy to loop diuretics can be considered an optimal therapeutic option in patients with insufficient response to loop diuretics.

Continuous ultrafiltration in acute decompensated heart failure: current issues and future directions.

Most patients hospitalized for acutely decompensated heart failure (ADHF) present with symptoms and signs of volume overload, which are also associated with high rates of death and re-hospitalization. Several studies have investigated the possible use of extracorporeal ultrafiltration in the management of ADHF, evaluating potential clinical benefits in terms of hospitalization and survival rates versus those of conventional diuretic therapy. Though ultrafiltration remains an extremely appealing therapeutic option for patients with AHDF, some of the most recent studies have reported conflicting results. Differences in the selection of study population, heterogeneity of the indications for the use of ultrafiltration, disparity in the ultrafiltration protocols, and high variability in the pharmacologic therapies used for the control group could explain some of these contradictory findings. The purpose of the present review is to provide an overview and an update on the mechanisms and clinical effects of ultrafiltration and on currently available evidence supporting its use in ADHF.

Therapeutic effects of short- and intermediate-term tolvaptan administration for refractory ascites in patients with advanced liver cirrhosis.

Tolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites. Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, five) after adding tolvaptan (3.75-11.25 mg/day) to conventional diuretics. Bodyweights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 days (range, 28-56). In the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P < 0.004). The numbers of good responders (≥3 kg reduction in 4 days), responders (<3 kg weight reduction) and non-responders (no weight reduction) were seven (46.7%), six (40.0%) and two of the 15 (13.3%), respectively. The two non-responders had concomitant chylous pleural effusion or spontaneous bacterial peritonitis. All patients continued tolvaptan for 2 weeks or longer and six (40%, three good responders and three responders) were treated for a median of 42 days without additional intervention. During this intermediate-term administration of tolvaptan, the median weight reduction was statistically significant (65.4, 61.9 and 56.9 kg on days 0, 7 and 42, respectively; P < 0.030) and there was no serum sodium imbalance or renal dysfunction; but two of these six developed hepatic coma. Tolvaptan safely alleviated fluid retention caused by hepatic cirrhosis. Intermediate-term administration of tolvaptan apparently helped maintain weight reduction achieved during the introduction phase.

Efficacy And Safety of Coadministration of Tolvaptan And Carperitide for Acute Decompensated Heart Failure Patients

For acute decompensated heart failure (ADHF) therapy, combination of carperitide, a human atrial natriuretic peptide, and tolvaptan, a novel vasopressin type 2 receptor antagonists, has not been used. Tolvaptan is a drug newly developed to treat volume overload in ADHF patients. Of 102 consecutive cases treated upon admission for ADHF between April and October 2012, we analyzed 51 patients treated with carperitide plus tolvaptan (tolvaptan+carperitide group) and 51 patients treated with carperitide plus conventional diuretics (carperitide group). On comparison between both groups, total dose of carperitide and loop diuretic doses during 48 h in tolvaptan +carperitide group were lower than those in the carperitide group (both p<0.001). Urine output at 24 h and 48 h after admission in the tolvaptan+carperitide group were significantly higher than those in carperitide group (p=0.02 and p<0.001, respectively). Changes in NT-pro brain-type natriuretic peptide levels in tolvaptan+carperitide group were significantly higher than those in carperitide group (p=0.01). No significant differences were detected in worsening renal function. On conclusion, in ADHF therapy, coadministration of tolvaptan and carperitide was more effective and safe compared with conventional therapy.

Urea transporter proteins as targets for small-molecule diuretics.

Conventional diuretics such as furosemide and thiazides target salt transporters in kidney tubules, but urea transporters (UTs) have emerged as alternative targets. UTs are a family of transmembrane channels expressed in a variety of mammalian tissues, in particular the kidney. UT knockout mice and humans with UT mutations exhibit reduced maximal urinary osmolality, demonstrating that UTs are necessary for the concentration of urine. Small-molecule screening has identified potent and selective inhibitors of UT-A, the UT protein expressed in renal tubule epithelial cells, and UT-B, the UT protein expressed in vasa recta endothelial cells. Data from UT knockout mice and from rodents administered UT inhibitors support the diuretic action of UT inhibition. The kidney-specific expression of UT-A1, together with high selectivity of the small-molecule inhibitors, means that off-target effects of such small-molecule drugs should be minimal. This Review summarizes the structure, expression and function of UTs, and looks at the evidence supporting the validity of UTs as targets for the development of salt-sparing diuretics with a unique mechanism of action. UT-targeted inhibitors may be useful alone or in combination with conventional diuretics for therapy of various oedemas and hyponatraemias, potentially including those refractory to treatment with current diuretics.

Serum sodium concentration is associated with increased risk of mortality in patients with compensated liver cirrhosis

Although hyponatremia is associated with a poor prognosis in liver cirrhosis, little is known about the clinical significance of serum sodium concentration in cirrhosis in Japan. This study investigated associations of mortality in Japanese cirrhosis patients taking conventional diuretics with serum sodium concentration and other clinical characteristics. A total of 171 consecutive patients with cirrhosis who were taking diuretic medication were enrolled retrospectively. We determined the prevalence of low serum sodium concentration and searched for associations with age, sex, etiology, complications of cirrhosis, liver function tests and Model for End-Stage Liver Disease (MELD) and MELD-Na scores. The predictive ability of sodium level on mortality was also investigated. Median serum sodium concentration was 139 mEq/L (interquartile range, 137-141). Only eight of 171 (4.7%) patients had low serum sodium (<130 mEq/L). Median MELD-Na score was 10.5 (interquartile range, 8.0-14.3). Cumulative survival rates were significantly lower in patients with Na of less than 139 mEq/L or MELD-Na score of 10.5 or more (log-rank test, P = 0.017 and P = 0.0002, respectively). Several liver function tests, MELD and MELD-Na scores, and the incidence of ascites were all significantly associated with patients having Na of less than 139 mEq/L. Serum sodium concentration below 139 mEq/L and MELD-Na score above 10.5 may be predictive markers for mortality in patients with cirrhosis despite being within normal ranges. These markers may help to better assess and manage the prognosis of patients with cirrhosis in Japan.

OUTCOMES OF ULTRAFILTRATION IN ADVANCED HEART FAILURE PATIENTS RESISTANT TO DIURETIC THERAPY

Over the last 2 decades, the treatment of advanced HF has seen the introduction of several novel medications and devices. Ultrafiltration (UF) is a strategy that has been used for treatment of refractory edema for many years. In 2012, the CARRESS-HF trial compared UF as a first line alternative to diuretic therapy in patients with acute decompensated HF. In our study, we examined the impact of UF in advanced decompensated HF patients resistant to diuretic therapy. This is a single-centered prospective analysis of 18 patients between 2010 to 2012 with advanced HF receiving UF after failing conventional diuretic therapy. The mean age of our patients was 67 ± 9 years, with 88% male patients. On enrollment, 66% of patients had NYHA Class III symptoms, 13 patients had 3+ pitting edema and mean LVEF was 35.8 ± 16%. Eight patients had ≥ 1 admission in the previous year, related to HF. UF fluid removal rate was performed at an average of 116.8 ± 61 mL per hour. We measured serum creatinine, pre and post-UF, weight change, need for inotropes, need for loop diuretics at discharge, and final outcomes. UF in our patient population demonstrated 55% survival rate at 1 year. The average length of time of UF was 3.98 ± 3.45 days, with 1 patient requiring 16 days of UF. The mean change in creatinine level at 96 hours was -5.86 ± 17.7 μmol per liter. The mean weight change post-UF was -6.7 ± 4.8 kg. There were no bleeding complications noted. Other complications included seizures secondary to hyponatremia in 1 patient, rise in creatinine in 8 patients. Eight patients required inotropes while on UF, with 1 requiring post-UF pressor support after acute decompensation (due to H1N1 infection). Five patients were taken off UF due to success (1 at 17 hours, 2 at 48 hours, 1 at 72 hours, and 1 at 168 hours), assessed by improvement in NYHA class and volume status. Complications resulting in discontinuation of UF included line infection (1), death due to VF (1), worsening creatinine (5), VT (1), hypotension (1), received VAD (1), filter clot (2), seizure (1) and line infection (1). In conclusion, UF can be used with careful consideration in a selected population of advanced HF patients resistant to diuretic therapy. Future larger studies are required in these subsets of patients to determine the efficacy and full extent of adverse effects of UF.

Sensitivity to Aldosterone

See related article, p 1212–1218 In this issue, Tu et al1 show clear differences in sensitivity of blood pressure (BP) to aldosterone between blacks and those of predominantly white ancestry, in both children and adults. It has long been known that blacks are more salt sensitive than whites: this contribution thus complements the previous findings and has ramifications for the role of aldosterone across the board. The article reports the unusual combination of a long-term (>20 years) observational study on children aged 5 to 17 years starting in 1986 and an acute intervention study comparing the effects of fludrocortisone administration for 2 weeks on BP, weight, and hormonal parameters in black and white adults. The long-term study enrolled 580 children (266 blacks, 314 whites). Age, height, weight, systolic and diastolic BP (DBP), concentrations of plasma electrolytes (Na+ K+), plasma aldosterone (PAC), and renin activity (PRA) were measured, plus urinary excretion of Na+, K+, and creatinine. At baseline, black children were on average 18 months older, with a higher body mass index and slightly but significantly higher BP (103/43 versus 100/41 mm Hg). They also showed significantly lower PAC (9 versus 14 ng/dL) and PRA levels (2.8 versus 3.3 ng/mL per hour), with indistinguishable plasma [K+] and overnight urinary excretion levels of K+ and Na+. In the subsequently re-enrolled adult subcohort, the blacks were 17 months younger, with higher body mass index (31 versus 28) but identical systolic and DBP (116/74 mm Hg). They had lower levels of PRA (1.0 versus 1.5 ng/mL per hour) and PAC (5 versus 9 ng/dL), with levels of plasma K+ and BP indistinguishable from those in whites. Urinary Na+ excretion was similar (78 versus 81 nmol/mg creatinine), but K+ excretion …

Discovery of thienoquinolin urea transporter inhibitors acts as a potential diuretic (LB587)

The motivation for this study was the need for novel diuretics in order to circumvent the side effects associated with long‐term use of conventional diuretics. Urea transporters (UTs) are a family of membrane channel proteins that are specifically permeable to urea and play an important role in intrarenal urea recycling and in urine concentration. Using an erythrocyte osmotic lysis assay, we screened a small‐molecule library for inhibitors of urea transport. A novel class of thienoquinolin UT‐B inhibitors were identified, of which PU‐14 had potent inhibition activity on human, rabbit, rat, and mouse UT‐B. The half‐maximal inhibitory concentration of PU‐14 on rat UT‐B‐mediated urea transport was ~0.8 μmol/l, and it did not affect urea transport in mouse blood cell lacking UT‐B but inhibited UT‐A‐type urea transporters. PU‐14 showed no significant cellular toxicity at concentrations up to its solubility limit of 80 μmol/l. Subcutaneous delivery of PU‐14 (at 12.5, 50, and 100 mg/kg) to rats caused an increase of urine output and a decrease of the urine urea concentration and subsequent osmolality without electrolyte disturbances and liver or renal damages. This suggests that PU‐14 has a diuretic effect by urea‐selective diuresis. Thus, PU‐14 or its analogs might be developed as a new diuretic in diseases associated with water retention without causing electrolyte imbalance. PU‐14 may establish ‘chemical knockout’ animal models to study the physiological functions of UTs. Further studies will be focused on the structural modification and characterization of pharmacokinetics and the absorption, distribution, metabolism, excretion, and toxicity properties of PU‐14.

Alternativas al tratamiento diurético convencional en insuficiencia cardíaca

Although treatment of acute heart failure is based primarily on the administration of intravenous loop diuretics, evidence supporting this practice is still scarce and there is uncertainty about the optimal dose. The existence of a considerable percentage of patients refractory to diuretic therapy and worsening of renal failure associated with the use of these drugs, with possible implications for medium-term mortality, have prompted the search for more effective and safer alternatives. Extracorporeal purification techniques, such as ultrafiltration, have demonstrated efficacy, although their superiority is unclear, due to the possible adverse effects associated with the procedure. The use of low-dose dopamine is not superior to conventional diuretic therapy after the first few hours of treatment. Moreover, combination with furosemide and hypertonic saline could be a valid alternative for patients with refractory congestion and depressed ejection fraction and serum creatinine ≤ 2.5mg/dL, but further studies are needed before its widespread use. The use of tolvaptan may be an effective alternative in the short-term but its use may be limited by its price. There is still controversy about whether treatment with loop diuretics is associated with higher mortality in all groups of patients with HF exacerbations. These controversies should be clarified by future clinical trials.

Assessment of quality of life during long-term treatment of tolvaptan in refractory heart failure: design and rationale of the AQUA-TLV study.

The vasopressin type 2 receptor antagonist tolvaptan (TLV) has recently become available to treat congestion in in-hospital patients with heart failure (HF). However, there is no evidence confirming the long-term efficacy of TLV. The Assessment of Quality of life during long-term treatment of TLV in refractory heart failure (AQUA-TLV) study is a multicenter, open-labeled, randomized, controlled clinical trial that will enroll 100 patients from 18 hospitals in Japan. Patients with HF assigned to New York Heart Association class III or IV, who had a previous history of hospitalization due to congestive HF during the past 1 year and ongoing symptomatic congestion with baseline urine osmolality > 350 mOsm/L regardless of being prescribed daily furosemide ≥ 60 mg are randomized to the conventional diuretics group (50 patients) and TLV add-on group (50 patients), and their quality of life will be assessed using the Minnesota Living with Heart Failure Questionnaire after 6 months of treatment. This study is the first multicenter prospective randomized study in Japan to evaluate the long-term clinical effectiveness of TLV compared with conventional treatment in patients with congestive HF (UMIN Clinical Trial Registry Number: UMIN 000009604).

Urea Transporter Inhibitors: En Route to New Diuretics

A selective urea transporter UT-A1 inhibitor would be a novel type of diuretic, likely with less undesirable side effects than conventional diuretics, because it acts on the last portion of the nephron. In this issue of Chemistry & Biology, Esteva-Font and colleagues develop such an inhibitor by using a clever high-throughput screening assay and document its selectivity.

A Small Molecule Screen Identifies Selective Inhibitors of Urea Transporter UT-A

Urea transporter (UT) proteins, including UT-A in kidney tubule epithelia and UT-B in vasa recta microvessels, facilitate urinary concentrating function. A screen for UT-A inhibitors was developed in MDCK cells expressing UT-A1, water channel aquaporin-1, and YFP-H148Q/V163S. An inwardly directed urea gradient produces cell shrinking followed by UT-A1-dependent swelling, which was monitored by YFP-H148Q/V163S fluorescence. Screening of ~90,000 synthetic small molecules yielded four classes of UT-A1 inhibitors with low micromolar half-maximal inhibitory concentration that fully and reversibly inhibited urea transport by a noncompetitive mechanism. Structure-activity analysis of >400 analogs revealed UT-A1-selective and UT-A1/UT-B nonselective inhibitors. Docking computations based on homology models of UT-A1 suggested inhibitor binding sites. UT-A inhibitors may be useful as diuretics ("urearetics") with a mechanism of action that may be effective in fluid-retaining conditions in which conventional salt transport-blocking diuretics have limited efficacy.

The vasopressin V2-receptor antagonist, tolvaptan, can not only induce aquaresis but also enhance natriuresis in heart failure patients refractory to loop diuretics

Purpose: Although experimental studies have demonstrated that tolvaptan (TLV), a selective vasopressin V2-receptor antagonist, induces free water clearance without increasing urine sodium, there are only few reports on its clinical efficacy concerning urodynamics in acute decompensated heart failure (ADHF) patients concomitant with conventional diuretic use in usual practice. Methods: 22 consecutive ADHF patients with volume overload despite using loop diuretics were treated with TLV for 7 days. We divided these patients into two groups, responder (R, ≥+42%) or non-responder (N, <+42%), depending on the median value of urine volume (UV) increase in the first 24h compared with the baseline. Results: UV during the next 24h after TLV treatment was significantly higher than that just before induction of TLV (1701±871ml/day vs. 1137±341 ml/day; P<0.05). Although there was no significant difference in the baseline characteristics including serum creatinine and sodium together with TLV dose (8.8±3.0mg/day vs. 9.5±3.5mg/day, NS) between the groups, the first 24h UV increased and the body weight reduced by Day 7 more in R than in N (108±57% vs. -2±35%, P<0.001; -1.1±1.7kg vs. -0.4±1.1kg, P<0.05, respectively). Despite the decrease in loop diuretics with administration of TLV in both the groups (furosemide equivalent dose: 58±23 to 25±16mg/day in R, 67±63 to 33±22mg/day in N), sodium and potassium excretion in urine in the first 24h was maintained in R but decreased in N (1±34% vs. -47±21%, P<0.001; 8±34 vs. -18±21%, P<0.05, respectively) (Figure). ![Figure][1] Sodium and potassium excretion in urine Conclusions: In some ADHF patients responsive to adjunctive TLV, urinary sodium and potassium excretion is enhanced presumably by the improved efficacy of concomitant use of loop diuretics. [1]: pending:yes

Ultrafiltration versus Intravenous Diuretic Therapy to Treat Acute Heart Failure: A Systematic Review

Patients with decompensated heart failure frequently present with volume overload, which is conventionally treated with diuretics. These drugs have been associated with several adverse effects, including increased mortality, leading some clinicians to propose ultrafiltration as a safe alternative to remove sodium and water. The objective of our study was to compare the safety and efficacy of ultrafiltration and conventional intravenous diuretic therapy for patients with acute heart failure and volume overload. We searched the following databases through November 2012: Cochrane Library (1993-), PubMed (1988-), OVID (1984-), EBSCO (1984-), CBM (1978-), VIP (1989-), and CNKI (1979-). In addition, we manually searched relevant references and review articles. Randomized controlled trials comparing the efficacy of ultrafiltration and intravenous diuretics in patients diagnosed with hypervolemic acute heart failure were included. Five trials were found to satisfy all the inclusion criteria. Two reviewers independently determined study eligibility, assessed methodological quality and extracted the data. We analyzed the data and pooled them, when appropriate, using Revman 5.0. We assessed the risk of bias in the included studies using guidelines in the Cochrane Handbook 5.0 for Systematic Reviews of Interventions, taking into account sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. Data from the initial phase of five trials involving 477 participants were included. Meta-analysis of the pooled data showed that ultrafiltration was significantly better than diuretic drugs based on 48-h weight loss (Z = 3.72; P < 0.001, weighted mean difference [WMD] = 1.25 kg, 95 % CI 0.59-1.91) and based on 48-h fluid removal (Z = 4.23; P < 0.001, WMD = 1.06 L, 95 % CI 0.57-1.56). Adverse events did not differ significantly between the ultrafiltration and intravenous diuretic treatment groups. There are several limitations to our review, including publication bias and selection bias. Our review included only a few studies involving relatively few participants. The available evidence suggests that early ultrafiltration is safe and effective for patients with hypervolemic acute heart failure. It allows greater fluid removal and weight loss by 48 h than do intravenous diuretics, with no significant increase in adverse effects.

Vaptans: a novel class of drugs causing free water diuresis

>> We read with interest the recent review on diuretics. 1 The author comprehensively discussed types of diuretics, their physiological basis and their clinical use as well as side-effects associated with them. We would also wish to mention vaptans, which have recently been incorporated in the management of hyponatremia. Vaptans are competitive antagonists of vasopressin receptors without detectable agonist activity. The various types of vaptans are mozavaptan, conivaptan, tolvaptan, satavaptan and lixivaptan. Their specificity for the various vasopressin receptors (V1A ,V 1B and V2) differs between the various types. 2 The vaptans result in a water diuresis (aquaresis) that, if not offset by increased fluid intake, reduces body water content and raises plasma sodium concentration. These drugs are helpful in the treatment of hypervolaemic hyponatraemia associated with severe congestive heart failure or chronic liver failure, where the only other treatments currently available (i.e. fluid restriction and conventional diuretics) are slow-acting and less effective. Vaptans have also been successfully used in the management of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, a common cause of euvolaemic hyponatraemia. The most important contraindication to vaptan use is hypovolaemic hyponatraemia. Thus, before vaptans are used hypovolaemia needs to be ruled out clinically as well as with other laboratory investigations. 3