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.

Renal ultrasonography predicts worsening renal function in patients with heart failure under tolvaptan administration.

AIMS: Renal dysfunction in patients with chronic heart failure predicts a poor prognosis. Tolvaptan has a diuretic effect in patients with chronic kidney disease and heart failure without adverse effects on renal function. We aimed to determine the effects of tolvaptan and predictors of worsening renal function in patients with heart failure. METHODS AND RESULTS: This post hoc analysis was a sub-analysis of a single-centre prospectively randomized trial on the early and short-term tolvaptan administration. We enrolled 201 participants with decompensated heart failure between January 2014 and March 2019 (early group, n = 104; age: 79.0 ± 12.8 years; late group, n = 97; age: 80.3 ± 10.8 years). Renal ultrasonography was performed before and after the administration of tolvaptan. Urine output and oral water intake significantly increased during tolvaptan administration. The difference between water intake and urine volume increased during tolvaptan administration. Changes in body weight, blood pressure, heart rate, and estimated glomerular filtration rate (eGFR) in both groups were comparable. The changes in peak-systolic velocity (PSV), acceleration time (AT) of the renal arteries, and resistance index were comparable. The changes in PSV and end-diastolic velocity (EDV) of the interlobar arteries increased following tolvaptan administration (Δmax PSV: 0.0 ± 14.8 cm/s before tolvaptan vs. 5.6 ± 15.7 cm/s after tolvaptan, P = 0.002; Δmean PSV: 0.4 ± 12.3 vs. 4.9 ± 12.7 cm/s, P = 0.002; Δmax EDV: -0.2 ± 3.5 vs. 1.4 ± 4.0 cm/s, P = 0.001; Δmean EDV: -0.0 ± 3.1 vs. 1.1 ± 3.4 cm/s, P = 0.003). The renal artery AT was negatively correlated with the eGFR (Δmax AT: beta = -0.2354, P = 0.044; Δmean AT: beta = -0.2477, P = 0.035). CONCLUSIONS: Tolvaptan increased the PSV and EDV of the interlobar artery, which may mean tolvaptan increased renal blood flow. The renal artery AT may be a surrogate for worsening renal function.

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.

Efficacy and safety of balovaptan for socialisation and communication difficulties in autistic adults in North America and Europe: a phase 3, randomised, placebo-controlled trial.

BACKGROUND: There are no approved pharmacological therapies to support treatment of the core communication and socialisation difficulties associated with autism spectrum disorder in adults. We aimed to assess the efficacy, safety, and pharmacokinetics of balovaptan, a vasopressin 1a receptor antagonist, versus placebo in autistic adults. METHODS: V1aduct was a phase 3, randomised, placebo-controlled, double-blind trial, conducted at 46 sites across six countries (the USA, the UK, France, Italy, Spain, and Canada). Eligible participants were aged 18 years or older with an intelligence quotient (IQ) of 70 or higher, and met the criteria for moderate-to-severe autism spectrum disorder (DSM-5 and Autism Diagnostic Observation Schedule). Participants were randomly allocated (1:1), with an independent interactive voice or web-based response system, to receive balovaptan (10 mg) or placebo daily for 24 weeks. Randomisation was stratified by an individual's baseline Vineland-II two-domain composite (2DC) score (<60 or ≥60), sex, region (North America or rest of world), and age (<25 years or ≥25 years). Participants, study site personnel, and the sponsor were masked to treatment assignment. The primary endpoint was change from baseline in Vineland-II 2DC score (the mean composite score across the Vineland-II socialisation and communication domains) at week 24. The primary analysis was done with ANCOVA in the intention-to-treat population. The V1aduct study was terminated for futility after around 50% of participants completed the week 24 visit. This trial is registered with ClinicalTrials.gov (NCT03504917). FINDINGS: Between Aug 8, 2018, and July 1, 2020, 540 people were screened for eligibility, of whom 322 were allocated to receive balovaptan (164 [51%]) or placebo (158 [49%]). One participant from the balovaptan group was not treated before trial termination and was excluded from the analysis. 60 participants in the balovaptan group and 55 in the placebo group discontinued treatment before week 24. The sample consisted of 64 (20%) women and 257 (80%) men, with 260 (81%) participants from North America and 61 (19%) from Europe. At baseline, mean age was 27·6 years (SD 9·7) and mean IQ score was 104·8 (18·1). Two (1%) participants were American Indian or Alaska Native, eight (2%) were Asian, 15 (5%) were Black or African American, 283 (88%) were White, four (1%) were of multiple races, and nine (3%) were of unknown race. Mean baseline Vineland-II 2DC scores were 67·2 (SD 15·3) in the balovaptan group and 66·2 (17·7) in the placebo group. The interim futility analysis showed no improvement for balovaptan versus placebo in terms of Vineland-II 2DC score at week 24 compared with baseline, with a least-squares mean change of 2·91 (SE 1·52) in the balovaptan group (n=79) and 4·75 (1·60) in the placebo group (n=71; estimated treatment difference -1·84 [95% CI -5·15 to 1·48]). In the final analysis, mean change from baseline in Vineland-II 2DC score at week 24 was 4·56 (SD 10·85) in the balovaptan group (n=111) and 6·83 (12·18) in the placebo group (n=99). Balovaptan was well tolerated, with similar proportions of participants with at least one adverse event in the balovaptan group (98 [60%] of 163) and placebo group (104 [66%] of 158). The most common adverse events were nasopharyngitis (14 [9%] in the balovaptan group and 19 [12%] in the placebo group), diarrhoea (11 [7%] and 14 [9%]), upper respiratory tract infection (ten [6%] and nine [6%]), insomnia (five [3%] and eight [5%]), oropharyngeal pain (five [3%] and eight [5%]), and dizziness (two [1%] and ten [6%]). Serious adverse events were reported for two (1%) participants in the balovaptan group (one each of suicidal ideation and schizoaffective disorder), and five (3%) participants in the placebo group (one each of suicidal ideation, panic disorder, limb abscess, urosepsis, colitis [in the same participant with urosepsis], and death by suicide). No treatment-related deaths occurred. INTERPRETATION: Balovaptan did not improve social communication in autistic adults. This study provides insights into challenges facing autism spectrum disorder trials, including the considerable placebo response and the selection of appropriate outcome measures. FUNDING: F Hoffmann-La Roche.

Suitable Dose of Long-Term Tolvaptan to Reduce Heart Failure Rehospitalizations.

The short-term effectiveness of tolvaptan (TLV) for heart failure (HF) has been established, but the long-term effects are controversial. We investigated HF patients who could not discontinue both loop diuretics and TLV at discharge from AURORA (Acute Heart Failure Registry in Osaka Rosai Hospital). We compared the following factors at discharge between the RH group, consisting of patients with rehospitalizations due to worsening HF within 1 year after discharge (RH group), and non-RH group: age, gender, blood pressure, history of HF admission, electrocardiogram and echocardiographic parameters, atherosclerotic risk factors, laboratory data, and medications. Furthermore, we compared the effects of long-term low-dose TLV (≤ 7.5 mg/day) and high-dose TLV on HF rehospitalizations. The RH group consisted of 81 patients (58.7%). A multivariate analysis revealed that a history of HF admission and the TLV dose were independently and significantly associated with 1-year HF rehospitalizations. A receiver operating characteristic curve revealed that 7.5 mg of TLV was a suitable cutoff value for 1-year HF rehospitalizations. The Kaplan-Meier curves demonstrated that the HF rehospitalization free ratio was significantly higher in the low-dose TLV group (≤ 7.5 mg/day) than in high-dose TLV group over 1 year.In conclusion, the TLV dose, in addition to a history of HF admission, was associated with 1-year HF rehospitalizations in diuretic-dependent HF patients. In these patients, long-term low-dose TLV (≤ 7.5 mg/day) may be favorable for reducing HF rehospitalizations.

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.

A cross-sectional survey of hospitalization and blood tests implementation status in patients who received tolvaptan under 75 years of age using a Japanese claims database.

BACKGROUND: Hypernatremia and liver injury are typical adverse effects of tolvaptan. Therefore, hospitalization and frequent monitoring of serum sodium concentration and liver function are necessary for tolvaptan initiation. We performed a cross-sectional survey to evaluate these situations. RESEARCH DESIGN AND METHODS: We employed the Japanese claims database, which contains data of patients aged < 75 years. Patients who were newly prescribed tolvaptan for fluid accumulation induced by chronic heart failure (FA-CHF) or liver cirrhosis (FA-LC) from January 2011 to June 2017 were included. We evaluated the hospitalization status and implementation of serum sodium and liver function tests in the evaluation period, based on the Japanese package insert. RESULTS: Of 1,173 patients, 347 and 117 were enrolled in FA-CHF and FA-LC groups, respectively. Among them, 10.7% (FA-CHF group) and 5.13% (FA-LC group) were prescribed tolvaptan without hospitalization. In the FA-CHF group, 11.0% and 17.6% did not undergo serum sodium and liver function tests even once in the evaluation period, respectively, compared with 12.0% and 12.8% in the FA-LC group. CONCLUSIONS: Our results highlight the deviation from Japanese package insert recommendations. This approach can be applied to other drugs and provides important perspectives on pharmacovigilance research.

Bioavailability and pharmacokinetic profile of balovaptan, a selective, brain-penetrant vasopressin 1a receptor antagonist, in healthy volunteers.

BACKGROUND: Balovaptan is a potent, selective vasopressin 1a receptor antagonist. The early-phase pharmacokinetics (PK) of balovaptan are reported. RESEARCH DESIGN AND METHODS: Two Phase 1 studies (overall N = 93) assessed single- and multiple-dose balovaptan PK in healthy adults. One (N = 16) assessed absolute oral bioavailability (10 mg or 50 mg) vs a [13C]-balovaptan microdose. The other (N = 77) explored single- (0.5-76 mg) and multiple-dose (14 days; 12-52 mg/day) - randomized 6:2 balovaptan:placebo per dose - PK, dose proportionality, and the effect of food on single-dose (32 mg) Cmax and AUCinf. RESULTS: Absolute balovaptan bioavailability was high (103-116%). Steady-state (Day 14) balovaptan PK was approximately dose proportional with a half-life of 45-47 hours, but single-dose Cmax increased more than dose proportionally and half-life was inversely dose-proportional - a discordance partially attributable to a dose-and-time-dependent volume of distribution. Accumulation (Day 1-Day 14) was inversely dose-proportional (~3.5 [12 mg] to ~1.8 [52 mg]). There was no relevant effect of a high-fat meal on single-dose balovaptan exposure. There were no safety signals: 2/93 subjects discontinued for adverse events. CONCLUSIONS: Balovaptan was well tolerated at single (≤76 mg) and multiple (≤52 mg/day) doses, with a PK profile supportive of once-daily administration without food restrictions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03764449; NCT01418963.

Prediction of a clinically effective dose of THY1773, a novel V1B receptor antagonist, based on preclinical data.

THY1773 is a novel arginine vasopressin 1B (V1B ) receptor antagonist that is under development as an oral drug for the treatment of major depressive disorder (MDD). Here we report our strategy to predict a clinically effective dose of THY1773 for MDD in the preclinical stage, and discuss the important insights gained by retrospective analysis of prediction accuracy. To predict human pharmacokinetic (PK) parameters, several extrapolation methods from animal or in vitro data to humans were investigated. The fu correction intercept method and two-species-based allometry were used to extrapolate clearance from rats and dogs to humans. The physiologically based pharmacokinetics (PBPK)/receptor occupancy (RO) model was developed by linking free plasma concentration with pituitary V1B RO by the Emax model. As a result, the predicted clinically effective dose of THY1773 associated with 50% V1B RO was low enough (10 mg/day, or at maximum 110 mg/day) to warrant entering phase 1 clinical trials. In the phase 1 single ascending dose study, TS-121 capsule (active ingredient: THY1773) showed favorable PKs for THY1773 as expected, and in the separately conducted phase 1 RO study using positron emission tomography, the observed pituitary V1B RO was comparable to our prediction. Retrospective analysis of the prediction accuracy suggested that the prediction methods considering plasma protein binding, and avoiding having to apply unknown scaling factors obtained in animals to humans, would lead to better prediction. Selecting mechanism-based methods with reasonable assumptions would be critical for the successful prediction of a clinically effective dose in the preclinical stage of drug development.

Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism.

BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) are treated with a vasopressin V2 receptor antagonist (V2RA) to slow disease progression. This drug increases vasopressin considerably in these patients with already elevated baseline levels. Vasopressin is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis through V1 and V3 receptor activation. It is unknown whether this increase in vasopressin during V2RA treatment affects glucocorticoid production. METHODS: Twenty-seven ADPKD patients were studied on and off treatment with a V2RA and compared to age- and sex-matched healthy controls and IgA nephropathy patients, the latter also matched for kidney function. Vasopressin was measured by its surrogate copeptin. Twenty-four-hour urinary excretions of cortisol, cortisone, tetrahydrocortisone, tetrahydrocortisol, allotetrahydrocortisol, and the total glucocorticoid pool were measured. RESULTS: At baseline, ADPKD patients demonstrated a higher copeptin concentration in comparison with healthy controls, while urinary excretion of cortisol and cortisone was lower (medians of 0.23 vs. 0.34 µmol/24 h, p = 0.007, and 0.29 vs. 0.53 µmol/24 h, p < 0.001, respectively). There were no differences in cortisol and cortisone excretion compared to IgA nephropathy patients. Cortisol, cortisone, and total glucocorticoid excretions correlated with kidney function (R = 0.37, 0.58, and 0.19, respectively; all p < 0.05). Despite that V2RA treatment resulted in a 3-fold increase in copeptin, only cortisone excretion increased (median of 0.44 vs. baseline 0.29 µmol/24 h, p < 0.001), whereas no changes in cortisol or total glucocorticoid excretion were observed. CONCLUSIONS: Increased concentration of vasopressin in ADPKD patients at baseline and during V2RA treatment does not result in activation of the HPA axis. The impaired glucocorticoid production in these patients is related to their degree of kidney function impairment.

Durable response without recurrence to Tolvaptan improves long-term survival.

BACKGROUND: Decompensated liver cirrhosis patients with refractory ascites or pleural effusion have a poor prognosis. Tolvaptan has been used for treating water retention associated with cirrhosis. However, despite the short-term response, water retention recurrence is still observed in some cases. This study aimed to clarify the water retention recurrence rate and the relationship between long-term response without recurrence and prognosis. METHODS: Altogether, 100 patients with decompensated cirrhosis treated with tolvaptan were retrospectively analyzed. Recurrence was evaluated according to the criteria of the EASL clinical practice guideline. The recurrence rate and prognosis of non-responders, patients with recurrence, and long-term responders were analyzed. The baseline factors related to short-term response, recurrence, and long-term response were also evaluated. RESULTS: Approximately 31.0% of the short-term responders had recurrence. Although there was no significant difference in the prognosis by short-term response (p = 0.07), the long-term responders had a significantly better prognosis than those with recurrence and non-responders (p < 0.01). Low CRP levels and high urinary Na/K ratios were significant factors related to short-term response, and the presence of acute kidney injury was also a factor related to non-response. The low CRP level (relapse: < 1.10 mg/dl, long-term response: < 0.94 mg/dl) was identified as a factor related to recurrence and long-term response. CONCLUSION: The long-term responders without recurrence had a significantly better prognosis. CRP was a useful predictor for long-term response, whereas renal function parameters were useful predictors for short-term response. Inflammation control may be important for long-term response and prognosis in cirrhosis patients with water retention.

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.

[Tolvaptan in ADPKD: a turning point or an unsustainable therapy? One year of "real life" experience].

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic kidney disease, alone responsible for over 10% of patients with end-stage renal disease, and with an important impact on public health. Tolvaptan (TOLV) has recently been approved in many European countries for its ability to slow disease progression in patients that are eligible for treatment. Nevertheless, the doctor's choice to prescribe the drug and the patient's compliance are strongly influenced by the aquaretic effect complications. In a cohort of patients pertaining to the Nephrology clinic of the AOU Federico II of Naples and treated with TOLV, we assessed not only the adherence to the treatment and the safety of the drug, but also the real feasibility of this therapy through specific questionnaires on sleep quality, abdominal-renal pain, quality of life and patients' general satisfaction. Within the limits of preliminary data and on the basis of the responses of our population, followed for a period of at least one year and administered the maximum titration dosage, it can be asserted that the doubts regarding the real compliance of the patients can be overcome.

Tolvaptan add-on therapy in patients with acute heart failure: A systematic review and meta-analysis.

This study aimed to investigate the short-term efficacy and safety of tolvaptan as an add-on to traditional diuretics in patients with acute heart failure (AHF). The PubMed, EMBASE, Cochrane Library, and Web of Science databases were comprehensively searched for all randomized controlled trials (RCTs) that examined AHF patients treated with tolvaptan as a combination therapy with traditional diuretics published on or before December 2, 2019. Efficacy indicators such as improved dyspnea, reduced edema, and changes in urine output and body weight were evaluated. In-hospital mortality and worsening renal function (WRF) were measured as safety indicators. Data from the published literature included in this study were independently extracted by two reviewers. The Cochrane risk of bias tool was used to evaluate the quality of the included RCTs. Twelve RCTs involving 5577 patients admitted for AHF were included. Compared with traditional diuretics alone, add-on tolvaptan significantly relieved dyspnea, reduced weight, increased total urine volume and changes in urine volume from baseline, reduced edema, and increased serum sodium concentration in the short term without increasing the mortality. Most importantly, a low dose of tolvaptan (7.5-15 mg/d) significantly reduced the incidence of WRF, while a high dose (30 mg/d) had the opposite effect. Short-term add-on tolvaptan in hospitalized AHF patients could significantly relieve shortness of breath, reduce body weight, improve edema, and increase urine output and serum sodium concentrations without increasing mortality. The protective effects of add-on tolvaptan against WRF, however, were observed at low doses, but not at high doses.

Vasopressin antagonist efficacy and safety in volume-overloaded critically ill patients: a new therapeutic alternative.

Objectives: To assess tolvaptan's efficacy and safety in critical care patients with volume overload. Methods: Prospective observational study. Twenty-eight patients in the recovery phase from multiple organ failure and with volume overload refractory to conventional therapy treated with tolvaptan were included. Results: Patients received an initial daily dose of 3.75 (n=1), 7.5 (n=8) and 15 (n=19) mg of tolvaptan. Median treatment duration was 2 days (range: 1 to 12). All patients presented an increase in 24 hours diuresis after the first dose (median increase from baseline (IQR)=1114 (285-1943) mL), with a median net daily fluid loss of 1007 mL (456-2380) mL after 24 hours. High diuretic efficacy (daily fluid loss higher than 0.5 L with tolvaptan first dose) was detected in 18 patients (64.3%). Initial hyponatraemia was present in 16 (57.1%) patients, while overly rapid correction with tolvaptan treatment occurred in two patients without clinical consequences. Two patients presented hypophosphataemia after treatment. Conclusion: Tolvaptan is an effective therapeutic option in critically ill patients with volume overload refractory to conventional diuretics. Further studies are required to evaluate its safety profile and its effect on short-term outcomes and mortality.

Tolvaptan therapy to treat severe hyponatremia in pediatric nephrotic syndrome.

BACKGROUND: Tolvaptan is a selective oral vasopressin V2-receptor antagonist. Some data have implicated stimulation of arginine vasopressin (AVP) as an important factor in oedema formation in a rodent model of nephrotic syndrome (NS) and adult NS patients. We report case of pediatric NS with severe hyponatremia efficiently treated by tolvaptan. CASE/DIAGNOSIS - TREATMENT: A 22-month-old girl presented first with NS. She remained nephrotic after a 30-day course of oral steroids. Tacrolimus was inefficient and there was no response to plasma exchanges (15 sessions on a daily basis). She had severe oedema and ascites. Thus, in addition to immunosuppressive therapy, she received diuretics, furosemide 5 mg/kg/day, and amiloride 1 mg/kg/day, and required water restriction. She was hypertensive and was treated with a full dose of calcium inhibitor (amlodipine 0.5 mg/kg/day). After2 months of treatment, serum sodium reached 116 mmol/L and urinary osmolarity 547 mosmol/L, suggesting an inappropriate AVP secretion. Tolvaptan was introduced at 0.3 mg/kg/day and progressively increased to 3 mg/kg/day on day 4, leading to a partial correction of serum sodium (130 mmol/l) and a urinary osmolarity decrease to 90 mosmol/L. Tolvaptan was then continued at the dose of 3 mg/kg/day with unchanged serum sodium, without hypernatremia or dehydration. Her weight decreased from 14.8 k to 14 k, but oedema still persisted. CONCLUSION: Tolvaptan was very efficient in this case of hyponatremia associated with steroid-resistant NS. Tolvaptan should be considered in the management of therapy-resistant hyponatremia in patients with NS.

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.

Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients with cirrhotic ascites: an observational study.

BACKGROUND: Prognostic value or clinical implications of fluid status monitoring in liver cirrhosis are not fully elucidated. Tolvaptan, an orally available, selective vasopressin V2-receptor antagonist approved for hyponatremia in the United States and European Union. It is also used for cirrhotic ascites at a relatively low dose (3.75 mg to 7.5 mg) in Japan, exerts its diuretic function by excreting electrolyte-free water. We hypothesized that bioimpedance-defined dynamic changes in fluid status allow prediction of response of V2 antagonism and survival in cirrhotic patients. METHODS: In this prospective observational study, 30 patients with decompensated liver cirrhosis who were unresponsive to conventional diuretics were enrolled. Detailed serial changes of body composition that were assessed by using non-invasive bioimpedance analysis (BIA) devices, along with biochemical studies, were monitored at 5 time points. RESULTS: Sixteen patients were classified as short-term responders (53%). Rapid and early decrease of BIA-defined intracellular water, as soon as 6 h after the first dose (ΔICWBIA%-6 h), significantly discriminated responders from non-responders (AUC = 0.97, P < 0.0001). ΔICWBIA%-6 h was highly correlated with the change of BIA-derived phase angle of trunk, e.g. reduced body reactance operated at 50 kHz after 24 h of the first dose of tolvaptan. Lower baseline blood urea nitrogen and lower serum aldosterone were predictive of a rapid and early decrease of ICWBIA. A rapid and early decrease of ICWBIA in response to tolvaptan was also predictive of a better transplant-free survival. CONCLUSIONS: BIA-defined water compartment monitoring may help predict short-term efficacy and survival in decompensated cirrhotic patients treated with tolvaptan.

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.