Impact of Tolvaptan Combined with Low-Dose Dopamine in Heart Failure Patients with Acute Kidney Injury.

The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 µg/kg・minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.

A population pharmacokinetics model of balovaptan to support dose selection in adult and pediatric populations.

Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.

Peak Lag Between Plasma Vasopressin and Urine Aquaporin-2 Following Cardiac Surgery.

Tolvaptan, a vasopressin type-2 receptor antagonist, is utilized to ameliorate fluid retention following cardiac surgery. However, the optimal timing of tolvaptan administration considering novel biomarkers remains unknown. We prospectively included patients who underwent cardiac surgery between 2016 and 2020. We measured perioperative trends of free water reabsorption mediators including plasma arginine vasopressin and urine aquaporin-2. A total of 20 patients (68 [60, 75] years old, 18 men) were included. Urine volume decreased gradually after the initial 3 hours following cardiac surgery. The plasma arginine vasopressin level increased significantly with a peak at postoperative 6 hours, whereas the urine aquaporin-2 level increased later with a delayed peak at postoperative 12 hours. As a result, urine aquaporin-2 relative to the plasma arginine vasopressin level, which represents the activity of the collecting ducts and indicates predicted responses to tolvaptan, was a minimum at postoperative 6 hours. Tolvaptan administration immediately after cardiac surgery might not be recommended given the transient refractoriness to tolvaptan probably due to the stunning of kidney collecting ducts.

Pharmacological Dilutional Therapy Using the Vasopressin Antagonist Tolvaptan for Young Patients With Cystinuria: A Pilot Investigation.

OBJECTIVE: To perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water) among adolescents and young adults with cystinuria. MATERIALS AND METHODS: We enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvaptan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg). Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target capacity > 0). Secondary outcomes included other urinary/serum parameters, tolerability, and thirst response. RESULTS: Two females (17, 23 years) and 2 males (13, 24 years) were enrolled. Cystine capacity respectively went from baseline of -312, -82, -353, and -628 mg/L to 97, 111, 75, and -3 mg/L on high dose (Figure 1). Twenty-four-hour volume went from 1.96, 3.0, 2.1, and 0.91 L to 11.74, 6.5, 9.9, and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver enzymes. Subjects did experience extreme thirst (9/10 on visual scale), but none discontinued treatment or reduced dose. CONCLUSION: Dilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treatment approach has the potential to reduce recurrence of stones in this population. Further investigation should study longer term effects and safety, and determine optimal dosing to improve tolerability.

Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: a case report.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by the presence of renal cysts. Over time the expanding cysts lead to progressive renal failure. The use of tolvaptan, a V2-receptor antagonist, was recently approved in ADPKD patients. It was demonstrated that tolvaptan get slower decline in Kidney function compared with placebo. Idiosyncratic hepatic toxicity was described in patients receiving tolvaptan, with elevations in aminotransferases levels. We describe the first case reported in the literature in which hepatic toxicity is caused by the association of amoxicillin/clavulanic acid and tolvaptan. CASE PRESENTATION: A 41 years old woman with diagnosis of ADPKD had been in treatment with tolvaptan for 16 weeks when an elevation of liver enzyme levels was detected. She had taken autonomously amoxicillin/clavulanic acid (in doses of 825/175 mg twice a day for 7 days) about 5 weeks before. The timing of the event and the kind of hepatocellular injury could be attributed to the concomitance of medication of tolvaptan and amoxicillin/clavulanic acid. CONCLUSION: We highlight the need to careful monitor hepatic enzyme levels in order to recognize early hepatic side effects in ADPKD patients in treatment with tolvaptan and amoxicillin/clavulanic acid.

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model.

BACKGROUND: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. METHODS: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3',5'-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. RESULTS: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. CONCLUSIONS: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

Tolvaptan use in children and adolescents with autosomal dominant polycystic kidney disease: rationale and design of a two-part, randomized, double-blind, placebo-controlled trial.

This report describes the rationale and design of a study assessing tolvaptan in children with autosomal dominant polycystic kidney disease (ADPKD). Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial. Phase B is a 2-year, open-label extension. The target population is at least 60 children aged 12-17 years, diagnosed by family history and/or genetic criteria and the presence of ≥ 10 renal cysts, each ≥ 0.5 cm on magnetic resonance imaging. Subjects will be allocated into 4 groups: females 15-17 years; females 12-14 years; males 15-17 years; and males 12-14 years. Up to 40 subjects aged 4-11 years may also enroll, provided they meet the entry criteria. Weight-adjusted tolvaptan doses, titrated once to achieve a tolerated maintenance dose, and matching placebo will be administered twice-daily. Assessments include spot urine osmolality and specific gravity (co-primary endpoints), height-adjusted total kidney volume, estimated glomerular filtration rate, pharmacodynamic parameters (urine volume, fluid intake and fluid balance, serum sodium, serum creatinine, free water clearance), pharmacokinetic parameters, safety (aquaretic adverse events, changes from baseline in creatinine, vital signs, laboratory values including liver function tests), and generic pediatric quality of life assessments.Conclusion: This will be the first clinical study to evaluate tolvaptan in pediatric ADPKD. What is Known: • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder causing the development of cysts that impede kidney function over time and eventually induce renal failure • There are few data on the effects of tolvaptan, the only treatment approved for adults to slow disease progression, in pediatric ADPKD patients with early-stage disease What is New: • A phase 3, placebo-controlled study is evaluating tolvaptan over 3 years in children and adolescents with ADPKD • This study is designed to account for challenges of tolvaptan dosing and outcome assessment specific to the pediatric population.

The Role of Tolvaptan Administration After Cardiac Surgery: A Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of tolvaptan in fluid management after cardiac surgery compared with conventional diuretic treatment. DESIGN: Systematic review of the literature with meta-analyses. SETTING: The Medline, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and Google Scholar databases were searched from inception to July 30, 2018. PARTICIPANTS: The study comprised 759 patients undergoing cardiac surgery. INTERVENTIONS: Tolvaptan administration (n = 397) or standard diuretic therapy (n = 398). MEASUREMENTS AND MAIN RESULTS: Ten studies were included in the present meta-analysis. Tolvaptan administration was associated with a significantly faster return to preoperative body weight (mean difference [MD)] -1.48 d, 95% confidence interval [CI] -1.92 to 1.03), shorter duration of hospital stay (MD -2.58 d, 95% CI -5.09 to -0.07), lower incidence of acute kidney injury (odds ratio 0.34, 95% CI 0.16-0.69), and greater urine output (MD 0.47 L/d, 95% CI 0.25-0.69) and sodium levels (MD 2.85 mEq/L, 95% CI 1.90-3.80). No significant differences were present regarding duration of intensive care unit stay (MD -0.09 d, 95% CI -0.33 to 0.15), arrhythmia incidence (odds ratio 0.58, 95% CI 0.33-1.02), and serum creatinine values (MD -0.08 mg/dL, 95% CI -0.20 to 0.04). CONCLUSIONS: The outcomes of the present meta-analysis suggest the promising role of tolvaptan administration in the management of fluid retention in patients after cardiac surgery. Future large-scale clinical trials should be conducted to fully elucidate its efficacy and to assess the optimal treatment protocol to be applied in the clinical setting.

Safety and Effectiveness of Tolvaptan Administration after Total Arch Replacement.

BACKGROUND: Postoperative fluid overload in cardiovascular surgery is associated with increased mortality and morbidity. Recently, tolvaptan (TLV), a selective vasopressin V2 antagonist, has been used for perioperative fluid management. This study aimed to validate the safety and effectiveness of TLV administration after total arch replacement (TAR) using selective cerebral perfusion. METHODS: From August 2016 to December 2016, 11 patients who had undergone TAR for thoracic aortic aneurysm were included in this study. In addition to the conventional diuretics furosemide (20 mg) and spironolactone (25 mg), TLV (7.5 mg) was administered orally. RESULTS: TLV increased urine output 1-3 days after administration. Body weight was gradually and steadily reduced until discharge. Neither renal nor liver dysfunction was recognized during the TLV administration. CONCLUSION: The concomitant use of TLV and conventional diuretics is safe and effective for fluid management after TAR using cardiopulmonary bypass, selective cerebral perfusion, and hypothermic circulatory arrest.

Good response to tolvaptan shortens hospitalization in patients with congestive heart failure.

Tolvaptan has been gradually spread to use as a potent diuretic for congestive heart failure in the limited country. However, the response to this aquaretic drug still is unpredictable. A total of 92 patients urgently hospitalized due to congestive heart failure and treated with tolvaptan in addition to standard treatment was retrospectively analyzed. Responder of tolvaptan treatment was defined as a patient with peak negative fluid balance greater than 500 mL/day, and clinical profiles were compared between 76 responders and 16 non-responders. Responders started to increase daily urine volume (UV) from Day 1 through Day 3. In contrast, non-responders showed no significant increase in daily UV from the baseline up to Day 5. Time between admission and tolvaptan administration was shorter in responders, even without statistical significance (3.3 vs. 4.6 days, p = 0.053). Multivariate analysis revealed that blood urea nitrogen (BUN) [cutoff: 34 mg/dL, odds ratio (OR) 9.0, 95% confidence interval (CI) 1.42-57.3, p < 0.01] and plasma renin activity (PRA) (cutoff: 4.7 ng/mL/h, OR 6.1, 95% CI 1.01-36.4, p < 0.01) at baseline were independent predictors for tolvaptan responsiveness. It suggests that renal perfusion may affect tolvaptan-induced UV. Finally, durations of stay in intensive care unit and total hospitalization were significantly shorter in responders (median: 6.0 vs. 13.0 days, p = 0.022; 15.0 vs. 25.0 days, p = 0.016, respectively). Responders of tolvaptan have lower BUN and renin activity at baseline, and shorten hospitalization period. Trial Registration The study was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) with the identifier UMIN000023594. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024988.

Impact of chronic kidney disease on the diuretic response of tolvaptan in acute decompensated heart failure.

AIM: This study investigated the relationship between the initial diuretic response to tolvaptan and clinical predictors for tolvaptan responders in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: Patients (153) with ADHF (clinical scenario 2 or 3 with signs of fluid retention) who were administered tolvaptan were enrolled. Tolvaptan (15 or 7.5 mg) was administered for at least 7 days to those patients in whom fluid retention was observed even after standard treatment. The maximum urine volume immediately after tolvaptan administration showed good correlations with the ejection fraction and estimated glomerular filtration rate that were independent predictors of the urine volume (UV) responders (≥1500 mL increase in urine volume). The diuretic response (in terms of maximum diuresis) diminished with advancing chronic kidney disease (CKD) stage and concomitant deterioration of the renal function. Furthermore, advanced CKD was a significant negative predictor for the body weight (BW) responders (2.0% decrease in the body weight within 1 week after starting tolvaptan). As compared with non-CKD, the presence of advanced CKD predicts poor diuretic response for both UV and BW responders. CONCLUSIONS: The diuretic response following tolvaptan administration gradually diminished with progressive deterioration of the CKD stage. Worsening renal function was not observed. Tolvaptan is effective in treating CS2 or CS3 ADHF patients who present fluid retention and congestion, suggesting its potential efficacy for fluid management in the ADHF patients with CKD without worsening the renal function.

Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults.

PURPOSE: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium. METHODS: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose. RESULTS: In SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h. CONCLUSION: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

Safety and effectiveness of tolvaptan for fluid management after pediatric cardiovascular surgery.

BACKGROUND: Postoperative fluid management is important after open heart surgery, because cardiopulmonary bypass evokes an abnormal inflammatory response and increases vascular permeability, especially in pediatric patients. We assessed the safety and effectiveness of tolvaptan for management of postoperative fluid retention after congenital heart surgery. METHODS AND RESULTS: This retrospective study analyzed data from 43 children with uncomplicated congenital heart disease who underwent open heart surgery between September 2013 and August 2016. The patients were divided into two groups. Group N (n = 18; September 2013 through May 2014) received the conventional oral diuretics alone, and Group T (n = 25; June 2014 through August 2016) received a single dose of tolvaptan (0.45 mg/kg) in addition to the conventional oral diuretic therapy. Data were collected, while patients who received intensive care were assessed and compared between groups. Add-on tolvaptan use was associated with increased urinary output standardized by body weight (54.3 ± 4.5 vs 47.3 ± 19.1 mL/kg; p = 0.043), decreased additional intravenous diuretic dose standardized by body weight (0.26 ± 0.23 vs 0.62 ± 0.48 mg/kg; p = 0.001), and a smaller decrease in central venous pressure (1.3 ± 2.7 vs 1.9 ± 3.8 mmHg; p = 0.019). Laboratory analysis showed that electrolyte concentrations in blood and urine did not significantly differ between groups. CONCLUSIONS: Tolvaptan appears to be effective and safe for management of postoperative fluid retention after congenital heart surgery.

Early treatment with tolvaptan improves diuretic response in acute heart failure with renal dysfunction.

BACKGROUND: Poor response to diuretics is associated with worse prognosis in patients with acute heart failure (AHF). We hypothesized that treatment with tolvaptan improves diuretic response in patients with AHF. METHODS: We performed a secondary analysis of the AQUAMARINE open-label randomized study in which a total of 217 AHF patients with renal impairment (eGFR < 60 mL/min/1.73 m2) were randomized to either tolvaptan or conventional treatment. We evaluated diuretic response to 40 mg furosemide or its equivalent based on two different parameters: change in body weight and net fluid loss within 48 h. RESULTS: The mean time from patient presentation to randomization was 2.9 h. Patients with a better diuretic response showed greater relief of dyspnea and less worsening of renal function. Tolvaptan patients showed a significantly better diuretic response measured by diuretic response based both body weight [-1.16 (IQR -3.00 to -0.57) kg/40 mg vs. -0.51 (IQR -1.13 to -0.20) kg/40 mg; P < 0.001] and net fluid loss [2125.0 (IQR 1370.0-3856.3) mL/40 mg vs. 1296.3 (IQR 725.2-1726.5) mL/40 mg; P < 0.001]. Higher diastolic blood pressure and use of tolvaptan were independent predictors of a better diuretic response. CONCLUSIONS: Better diuretic response was associated with greater dyspnea relief and less WRF. Early treatment with tolvaptan significantly improved diuretic response in AHF patients with renal dysfunction.

Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials.

Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P < 0.0001) at day 4, and 6.9 versus 1.0 mEq/L (P < 0.0001) at day 30; the observed treatment effects were similar to those in the overall SIADH population (i.e., with and without cancer) at both time points. Serum sodium normalization was observed in 6/12 and 0/13 subjects at day 4 and 7/8 and 2/6 subjects at day 30 in the tolvaptan and placebo groups, respectively (P < 0.05 for both). Common treatment-emergent AEs for tolvaptan were consistent with previously reported results. In this post hoc study of the SALT trial population, oral tolvaptan was an effective and safe therapy for the treatment of hyponatremia in subjects with SIADH and cancer.

Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome.

This case report discusses the clinical indication for immunosuppressants in patients with idiopathic membranous nephropathy (IMN). Because this disease occasionally shows spontaneous remission, it is necessary to determine the predictive values for a therapeutic effect in order to provide appropriate treatment. Two distinct cases described herein illustrate the different effects of tolvaptan in responders and non-responders, according to the pre-treatment levels of AQP-2 immunostaining in the samples from renal biopsy and urinary levels of AQP-2 and osmolality, suggesting that these values may be useful predictors of response to tolvaptan in patients with nephrotic IMN.

Short-Term, Low-Dose Use of Tolvaptan as a Bridge Therapy to Expedite Liver Transplant for Severe Hyponatremic, Cirrhotic Patients With High Model for End-Stage Liver Disease Scores.

For patients on liver transplant waiting lists, hyponatremia is associated with increased mortality before transplant and complications during the early posttransplant period. Conventional therapies, such as fluid restriction or hypertonic saline infusion, are of limited value. We describe 2 patients with high Model for End-Stage Liver Disease scores (> 30) who were referred to our unit for expedited liver transplant. While on waiting lists, these patients developed severe hyponatremia (< 125 mEq/L) that was refractory to conventional therapies. Low-dose, short-term tolvaptan therapy (15 mg/d for 5 d) was then administered, as a bridge therapy to transplant, resulting in prompt restoration of serum sodium levels without any major clinical event. One patient died a few days later as no suitable grafts were available. The other received a liver transplant, and the outcome was uneventful. In conclusion, our report demonstrates that a short-term, low-dose tolvaptan-based strategy promptly resolves hyponatremia in patients who are on expedited waiting lists for liver transplant, allowing surgery with improved sodium levels and possibly limiting peritransplant complications.

Predictive factors for responders to tolvaptan in fluid management after cardiovascular surgery.

OBJECTIVE: To identify the predictive factors for responders to tolvaptan, a novel vasopressin type 2 receptor antagonist for fluid management after cardiovascular surgery. METHODS: Between January 2013 and May 2014, 113 patients were treated with tolvaptan for fluid management after cardiovascular surgery. As indicators for the effects of tolvaptan, change in bodyweight during the tolvaptan administration period and correlations with perioperative factors were assessed. Thirty-one patients were administered tolvaptan at the first day after surgery (early tolvaptan group). In this group, urine volume during the 6 h before the initial tolvaptan administration was compared with that at 6 h after administration. RESULTS: For all the patients, the change in bodyweight during the tolvaptan administration period significantly correlated with pre-operative serum creatinine (r = 0.19, p = 0.04) and albumin levels before tolvaptan administration (r = -0.29, p = 0.002). In the early tolvaptan group, the ratio of urine volume at 6 h before and 6 h after the initial tolvaptan administration significantly correlated with the pre-operative serum creatinine level (r = 0.43, p = 0.02), the serum albumin level before tolvaptan administration (r = -0.50, p = 0.004), and change in bodyweight (r = 0.38, p = 0.03). CONCLUSIONS: In patients undergoing cardiovascular surgery, deteriorating renal function, increased bodyweight, and hypoalbuminemia were found to be predictive factors for responders to tolvaptan for postoperative fluid management.

The efficacy of tolvaptan in the perioperative management of chronic kidney disease patients undergoing open-heart surgery.

PURPOSE: The perioperative management of chronic kidney disease (CKD) patients undergoing open-heart surgery is challenging. In this study, we evaluated the effects of tolvaptan in CKD patients after open-heart surgery. METHODS: Between 2010 to 2015, 731 patients underwent open-heart surgery in our hospital. We consecutively selected 71 patients with stage IIIa-IV CKD and divided them into two groups. Those who received tolvaptan postoperatively were defined as the "Tolvaptan group" (n = 25) and those who did not were defined as the "Non-tolvaptan group" (n = 46). We compared the urine volume of postoperative days (POD) 1 and 2, the number of days to return to preoperative body weight (BW), and the change in the postoperative estimated glomerular filtration rate (eGFR). RESULTS: In the tolvaptan group, the urine volume was significantly larger (P = .04) and the duration to preoperative BW tended to be shorter. Overall, the postoperative change in the eGFR tended to be better in the tolvaptan group (P = .008). In particular, we found a significantly better trend in CKD stage IV (P = .04) patients and in the patients, whose cardiopulmonary bypass (CPB) time was longer than 120 min (P = .03). CONCLUSIONS: Tolvaptan can safely be used for CKD patients undergoing open-heart surgery and can provide a feasible urine volume without leading to a deterioration of their renal function.

Administration of tolvaptan with reduction of loop diuretics ameliorates congestion with improving renal dysfunction in patients with congestive heart failure and renal dysfunction.

In patients with congestive heart failure and renal dysfunction, high dose of diuretics are necessary to improve congestion, which may progress to renal dysfunction. We examined the efficacy of tolvaptan with reduction of loop diuretics to improve renal function in patients with congestive heart failure and renal dysfunction. We conducted a multicenter, prospective, randomized study in 44 patients with congestive heart failure and renal dysfunction (serum creatinine concentration ≥1.1 mg/dl) treated with conventional diuretics. Patients were randomly divided into two groups: tolvaptan (15 mg) with a fixed dose of diuretics or with reducing to a half-dose of diuretics for 7-14 consecutive days. We examined the change of urine volume, body weight, serum creatinine and electrolyte concentrations in each group. Both groups demonstrated significant urine volume increase (724 ± 176 ml/day in the fixed-dose group and 736 ± 114 ml/day in the half-dose group) and body weight reduction (1.6 ± 1.5 kg and 1.6 ± 1.9 kg, respectively) from baseline, with no differences between the two groups. Serum creatinine concentration was significantly increased in the fixed-dose group (from 1.60 ± 0.47 to 1.74 ± 0.66 mg/dl, p = 0.03) and decreased in the half-dose group (from 1.98 ± 0.91 to 1.91 ± 0.97 mg/dl, p = 0.10). So the mean changes in serum creatinine concentration from baseline significantly differed between the two groups (0.14 ± 0.08 mg/dl in the fixed-dose group and -0.07 ± 0.19 mg/dl in the half-dose group, p = 0.006). The administration of tolvaptan with reduction of loop diuretics was clinically effective to ameliorate congestion with improving renal function in patients with congestive heart failure and renal dysfunction.