Administration Of Tolvaptan Research Articles

Evaluating the safety and effectiveness of tolvaptan in patients with heart failure and renal impairment: a systematic review and meta-analysis.

Patients with heart failure and concomitant renal impairment are often prescribed loop diuretics, such as furosemide, as the primary treatment. The present meta-analysis is focused on analyzing the safety and efficacy of the implementation of tolvaptan as a novel approach in patients with renal impairment and heart failure. Two reviewers conducted a screening of articles using online databases, including PubMed, Google Scholar, and Embase. Following a comprehensive literature search, seven articles that met all inclusion criteria (patients with heart failure and renal impairment) were selected for analysis. Subsequently, various primary and secondary outcomes were evaluated. The primary outcomes of our study included urine volume, worsening renal function, blood urea nitrogen (BUN) levels, and creatinine levels. Tolvaptan demonstrated superior efficacy in increasing urine output with a standardized mean difference of 2.18 (95% CI 0.62-3.75, p = 0.006) and resulted in a lower incidence of worsening renal function with odds ratio 0.41 (95% CI 0.22-0.77, p = 0.006). Additionally, there was no significant difference in the tolvaptan and conventional treatment groups in changing serum creatinine levels with a standardized mean difference of - 0.37 (95% CI - 0.86 to 0.12, p = 0.135), but tolvaptan tends to decrease blood urea nitrogen levels with a standardized mean difference - 0.18 (95% CI - 0.30 to - 0.06, p = 0.004) in comparison to conventional treatment group. While tolvaptan administration was related to better renal outcomes, unresolved heterogeneities and various factors could have influenced our findings. Further research is needed to evaluate the role of tolvaptan in the treatment of this patient population.

Low-melting mixture solvents as novel solubilizing agents: Improving tolvaptan formulation and therapeutic efficacy

Presently, a significant number of pharmaceutical drugs exhibit poor solubility in water and fall within categories II and IV of the biopharmaceutical classification system. This predicament has prompted the exploration for novel solvents or excipients to enhance the solubility and bioavailability of the active compounds in aqueous environments. Low-melting mixture solvents (LoMMSs) have gained recognition as potential solvents for active pharmaceutical ingredients to improve therapeutic efficacy and delivery. This study focuses on the preparation of a eutectic mixture composed of betaine, malic acid, proline, and water (BE-MA-PR-WA) to enhance the formulation options for tolvaptan, an FDA-approved medication used to treat acute congestive heart failure, which has limited solubility in aqueous solutions. The findings presented in this article represent the first reported results on the administration of LoMMS-solubilized tolvaptan. Furthermore, an examination of the solubility and bioavailability of tolvaptan utilizing this mixture was conducted, alongside an assessment of its toxicity. The solubility of tolvaptan in BE-MA-PR-WA (1:1:1:7) increased 483 times compared to solubility in water. Toxicity studies indicated that the LoMMS formulation BE-MA-PR-WA was safe for oral administration. The oral bioavailability of tolvaptan was significantly increased by 1.9-fold in the BE-MA-PR-WA than that in water. In addition, the 5-hour urine volume of rats indicated that BE-MA-PR-WA also enhanced the diuretic effects of tolvaptan in rats. The findings suggest that BE-MA-PR-WA enhance the solubility and bioavailability of tolvaptan, and are deemed non-toxic. Consequently, LoMMS may be deemed promising solubilizing agents, potentially facilitating the absorption of poorly bioavailable medications.

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

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. 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±12.8years; late group, n=97; age: 80.3±10.8years). 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±14.8cm/s before tolvaptan vs. 5.6±15.7cm/s after tolvaptan, P=0.002; Δmean PSV: 0.4±12.3 vs. 4.9±12.7cm/s, P=0.002; Δmax EDV: -0.2±3.5 vs. 1.4±4.0cm/s, P=0.001; Δmean EDV: -0.0±3.1 vs. 1.1±3.4cm/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). 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.

Protocol to evaluate the efficacy and safety of tolvaptan in patients with refractory ascites after liver resection: an open-label, single-arm phase I/II study.

In patients with chronic liver diseases such as cirrhosis, massive ascites after hepatic resection is the cause of prolonged hospitalization and worsening prognosis. Recently, the efficacy of tolvaptan in refractory ascites has been reported; however, there are no reports on the efficacy or safety of tolvaptan for refractory ascites after hepatic resection. This study aims to evaluate the efficacy of early administration of tolvaptan in patients with refractory ascites after hepatic resection. This is an open-label, single-arm phase I/II study. This study subject will comprise patients scheduled for hepatic resection of a liver tumor. Patients with refractory ascites after hepatic resection (drainage volume on postoperative day 1 ≥5ml/body weight 1kg/day) will be treated with tolvaptan. The primary endpoint will include the maximum change in body weight after hepatic resection relative to the preoperative baseline. The secondary endpoints will include drainage volume, abdominal circumference, urine output, postoperative complication rate (heart failure and respiratory failure), number of days required for postoperative weight gain because of ascites to decrease to preoperative weight, change in improvement of postoperative pleural effusion, total amount of albumin or fresh frozen plasma transfusion, type and amount of diuretics used, and postoperative hospitalization days. This trial will evaluate the efficacy and safety of tolvaptan prophylaxis for refractory ascites after hepatic resection. As there are no reports demonstrating the efficacy of tolvaptan prophylaxis for refractory ascites after hepatic resection, the authors expect that these findings will lead to future phase III trials and provide valuable indications for the selection of treatments for refractory postoperative ascites.

Long-Term Effects of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Predictors of Treatment Response and Safety over 6 Years of Continuous Therapy.

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (-8.77-20.58 mL/min/1.73 m2). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis-a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration.

Pharmacokinetics, pharmacodynamics and safety of 15mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

Association of Early Tolvaptan Treatment and Length of In Hospital Stay in Elderly Patients with Acute Decompensated Heart Failure.

Long hospital stay is associated with high costs and poor quality of life in elderly patients with heart failure (HF). This study aimed to investigate the association of early administration of tolvaptan with length of hospital stay among elderly patients with HF. The cohort included elderly patients (age ≥ 75 years) admitted to Shinonoi General Hospital between July 2016 and December 2018 with a primary diagnosis of acute decompensated HF treated with tolvaptan. Patients who died during hospitalization, patients who had acute coronary syndrome, patients who required treatment in the intensive care unit, and patients who had already taken tolvaptan before admission were excluded. Patients were divided into two groups according to the median duration of admission to tolvaptan administration: those who received tolvaptan within 1 day (24 h) after admission (early treatment group) and those for whom tolvaptan was prescribed after 1 day (24 h) or more from hospitalization (add-on group). We compared the length of hospital stay between the two groups and investigated the relationship between early tolvaptan administration and length of hospital stay. Of 110 enrolled patients (median age 85 years), 56 (51%) received tolvaptan within 1 day (24 h) after admission. The median length of hospital stay was 22 [14-35] days. The length of hospital stay was significantly shorter in the early treatment group (16 [11-22] days vs. 30 [21-46] days, p < 0.001). On multivariable regression analysis, early tolvaptan was associated with shorter hospital stay after adjusting for age, sex, serum creatinine, B-type natriuretic peptide, continuous dobutamine, and whether they live alone (partial regression coefficient -16.213, p < 0.001). Linear regression analysis showed a positive relationship between time of tolvaptan administration and length of hospital stay (R2 = 0.564, p < 0.001). Early tolvaptan administration was associated with reduced length of hospital stay in elderly HF.

Hyponatremia in the Elderly Induced by Risperidone: A Case Report

Hyponatremia due to risperidone is a rare complication that can be associated with drowsiness, confusion to coma and seizures. We report a case of a 92-year-old female with delirium combined with pulmonary infection who developed severe hyponatremia after 30 days of risperidone treatment, and the patient’s blood sodium gradually increased to normal after administration of concentrated sodium chloride, tolvaptan and gradual reduction of risperidone dosage until discontinuation. Through clinical observation, the mechanism of hyponatremia caused by risperidone is related to the Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Immediate drop of urine osmolality upon tolvaptan initiation predicts impact on renal prognosis in patients with ADPKD.

Tolvaptan, a vasopressin V2 receptor antagonist, is used for treating autosomal dominant polycystic kidney disease (ADPKD). We focused on changes in urinary osmolality (U-Osm) after tolvaptan initiation to determine whether they were associated with the therapeutic response to tolvaptan. This was a single-centre, prospective, observational cohort study. Seventy-two patients with ADPKD who received tolvaptan were recruited. We analysed the relationship between changes in U-Osm and annual estimated glomerular filtration rate (eGFR) in terms of renal prognostic value using univariable and multivariable linear regression analyses. The mean value of U-Osm immediately before tolvaptan initiation was 351.8±142.2 mOsm/kg H2O, which decreased to 97.6±23.8 mOsm/kg H2O in the evening. The decrease in U-Osm was maintained in the outpatient clinic 1 month later. However, the 1-month values of U-Osm showed higher variability (160.2±83.8 mOsm/kg H2O) than did those in the first evening of tolvaptan administration. Multivariate analysis revealed that the baseline eGFR, baseline urinary protein and U-Osm change in the evening of the day of admission (initial U-Osm drop) were significantly correlated with the subsequent annual change in eGFR. U-Osm can be measured easily and rapidly, and U-Osm change within a short time after tolvaptan initiation may be a useful index for the renal prognosis in actual clinical practice.

Effect of early administration of tolvaptan on pleural effusion post-hepatectomy.

This study evaluated the efficacy of tolvaptan administration at the early stage after hepatectomy to control pleural effusion and improve the postoperative course. Patients were administered tolvaptan (7.5mg) and spironolactone (25mg) from postoperative day 1 to postoperative day 5 (tolvaptan group, n = 68) for 13months. Early administration of tolvaptan was not provided in the control group (n = 68); however, diuretics were appropriately administered according to the patient's condition. The amount of pleural effusion on computed tomography on postoperative day 5 was compared between the two groups. The amount of pleural effusion and increase in body weight on postoperative day 5 showed significant differences in both groups (p < 0.001 and p = 0.019, respectively). However, the rate of pleural aspiration and the duration of postoperative hospitalization were comparable between the groups. The amount of intraoperative blood loss and lack of early administration of tolvaptan were identified as independent risk factors contributing to pleural effusion on multivariate analysis. Early administration of tolvaptan to patients after hepatectomy was found to be capable of controlling postoperative pleural effusion and increase in body weight, but it did not reduce the rate of pleural aspiration or the hospitalization period.

THU239 Tolvaptan For SIADH Management In Children

Abstract Disclosure: M. Igarashi: None. T. Kashima: None. H. Doi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None. [Background] Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is common after brain surgery and its’ management is difficult. In Japan, tolvaptan was approved for SIADH management in adults, but there are limited reports on the use of tolvaptan for SIADH in children.We presented two cases which showed triphasic response after neurosurgery and was treated with tolvaptan for SIADH phase. We will also summarize other cases which were treated with tolvaptan for SIADH phase after neurosurgery in discussion. [Case] Case1 is a 5-month-old boy with choroid plexus papilloma.A tumor resection was performed after chemotherapy. After tumor resection, serum sodium level went up to 171 mEq/L with diluted polyuria. So he was diagnosed as diabetes insipidus and treated with vasopressin. The dose of vasopressin was decreased and it was stopped on postoperative day (POD) 6, but serum sodium level further decreased and he was diagnosed as SIADH. Water restriction and hypertonic saline administration were performed. Tolvaptan at a dose of 0.1mg/kg was administered and sodium level improved from 123 mEq/L to 137 mEq/L.However, urine volume was decreased again and sodium level went down to 132 mEq/L, so tolvaptan was administered again. After second administration of tolvaptan, polyuria lasted and sodium level went up to 145 mEq/L, which was managed with temporary use of vasopressin. Case 2 is a 6-year-old girl with craniopharyngioma. After tumor resection, polyuria was observed and she was diagnosed as diabetes insipidus, which was treated with vasopressin.On POD 4, she was diagnosed as SIADH. Since water restriction was not effective, tolvaptan was administered twice (0.1mg/kg and 0.4mg/kg respectively). After second administration of tolvaptan, due to polyuria and diluted urine sodium level went up to 161 mEq/L, which was treated with vasopressin. Diluted urine and polyuria lasted, so finally she was diagnosed as diabetes insipidus. [Discussion] Tolvaptan was used for the management of SIADH that was resistant to water restriction or salt supplementation and it was useful for improving or maintaining sodium level. However, in some case, hypernatremia due to excessive free water excretion was caused after the dose of tolvaptan was increased. The appropriate dosage of tolvaptan has not yet been established. The risk of rapid sodium elevation should be considered and monitoring of water balance and sodium level was needed after using tolvaptan. [Conclusion] Tolvaptan could be an effective option for the management of SIADH, but frequent monitoring of sodium level is needed. Presentation: Thursday, June 15, 2023

#4209 A COMPARATIVE RETROSPECTIVE STUDY OF PATIENTS WITH ADPKD: FIRST RESULTS RELATING TO THE USE OF TOLVAPTAN

Abstract Background and Aims Autosomal Dominant Polycystic Disease (APKD) is the fourth leading cause of End Stage Renal Failure (ESRD). Since 2015, the administration of Tolvaptan has been approved in patients with APKD at high risk of progression to ESRD (Mayo classification system, classes 1C-D). Method In this study we compare the characteristics of APKD patients who received Tolvaptan (45/15 mg) in relation to those who did not receive but followed the periodic check-up. These are 33 people with an average age of 44.17± 13.6 years. Tolvaptan was administered to 9 (27.3%) patients who met the Mayo classification criteria for its administration. The mean follow-up time for all the patients was 11.41±7.4 months and for those taking tolvaptan it was 10.6±3.9 months. Values ​​of urea, creatinine, plasma sodium, specific gravity and urine osmolarity were determined at the start of follow-up and compared with those at the last visit. Results A significant reduction was observed in the values ​​of urea, osmolality and specific gravity of urine after one year of tolvaptan use compared to the group that did not receive the treatment and thus no titration of the drug dose was needed. In the same group, marginally higher values ​​of the plasma sodium were observed, but within normal limits. The indicators of renal function in both groups did not show any change. Conclusion At one year of follow-up, APKD patients who received Tolvaptan did not exhibit worsening of the kidney function. We observed changes in the values of urea, urine specific gravity and urine osmolarity associated with our instructions to drink more water, showing good compliance with the treatment.

#5882 BENEFIT OF LONG-TERM TOLVAPTAN ADMINISTRATION ON KIDNEY DISEASE PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: A SINGLE-CENTRE EXPERIENCE

Abstract Background and Aims Tolvaptan introduction in autosomal dominant polycystic kidney disease (ADPKD) treatment has significantly modified kidney disease progression in these patients. The efficacy and safety of tolvaptan in the management of ADPKD has already been demonstrated by TEMPO and REPRISE trials, however studies examining the long-term outcomes are limited. The aim of our study was to evaluate the long-term administration of tolvaptan in patients with ADPKD in our center. Method ADPKD patients treated with tolvaptan for at least one year were included in the study. Demographic, laboratory, and total kidney volume (TKV) data were collected. Kidney disease progression was assessed by comparing observed and predicted glomerular filtration rate (eGFR), based on the Mayo Clinic prediction model, at the last visit. Results Forty-one patients, 22 males, with ADPKD were studied. Median age at initial visit was 35 years (IQR 27-42), and median time on tolvaptan treatment was 24 months (IQR 18-33). Six (14.6%) patients discontinued tolvaptan after at least one year on treatment. Patients were classified according to the Mayo Clinic imaging classification into 1C (n = 8), 1D (n = 16) and 1E (n = 17). Those who received tolvaptan showed a lower eGFR decline from baseline compared to predicted (eGFR 66.7±32.7 vs 61.5±29.1, p&amp;lt;0.001), while a greater benefit was observed in Class 1E (eGFR 60.1±36.5 vs 52.4±29.5, p = 0.003) and in patients with eGFR&amp;gt;45ml/min (eGFR 79.4±28.8 vs 73±25.2, p = 0.001). Conclusion Our initial experience from long-term administration of tolvaptan in patients with ADPKD demonstrates benefit on kidney disease progression. The widespread use of tolvaptan in a larger number of patients and their long-term follow up are necessary to draw more secure conclusions.

Early Commencement and Long-Term Continuation of Tolvaptan Treatment Attenuate Functional Impairment of Renal Vasopressin V2 Receptors and Improve Clinical Outcomes in Patients with Heart Failure.

Preserved urinary excretion of aquaporin 2, an index for the function of vasopressin V2 receptor (V2-R), has been reported to predict a favorable response of heart failure patients to treatment with tolvaptan. In this study, we investigated the long-term effects of tolvaptan treatment on clinical outcomes and V2-R function in patients with acute decompensated heart failure (ADHF). We enrolled 90 consecutive patients who were hospitalized in Sapporo Medical University Hospital for ADHF and treated with tolvaptan in the BOREAS-ADHF registry and analyzed patients who continued taking tolvaptan after discharge. The effect of tolvaptan treatment on rehospitalization for HF or death was investigated according to whether the V2-R function was preserved (first morning urine osmolarity ≥ 352 mOsm/L, High-Uosm) or impaired (Uosm < 352 mOsm/L, Low-Uosm). During a median follow-up period of 443 days, significantly fewer patients in the High-Uosm group experienced adverse events than did patients in the Low-Uosm group (P < 0.001). Among the patients with High-Uosm, early commencement of tolvaptan administration (on or before day 7 of hospitalization, Early/High-Uosm) significantly reduced adverse events compared to late administration (after day 7 of hospitalization, Late/High-Uosm). Uosm measured during the long-term follow-up period after discharge was significantly reduced compared to that before commencement of tolvaptan administration in the Late/High-Uosm group (from 468 ± 88 to 395 ± 108 mOsm, -18.3 ± 19.6%, P < 0.05) but not in the Early/High-Uosm group (from 478 ± 115 to 455 ± 133 mOsm, -0.50 ± 35.3%, P = 0.66). These findings indicate that early commencement and long-term continuation of tolvaptan treatment attenuate functional impairment of V2-R and improve clinical outcomes in ADHF patients with preserved V2-R function.

Impact of the time-to-target rate of urine volume concept on the outcome of acute decompensated heart failure

BackgroundEarly decongestion with diuretics could improve clinical outcomes. This study aimed to examine the impact of the time-to-target rate of urine volume (T2TUV) concept on the outcome of acute decompensated heart failure (ADHF). MethodsThis multicenter retrospective study included 1670 patients with ADHF who received diuretics within 24 h of admission. T2TUV was defined as the time from admission to the rate of urine volume of 100 ml/h. The primary outcomes were in-hospital death, mortality, and re-hospitalization for 1 year. ResultsA total of 789 patients met the inclusion criteria (T2TUV on day 1, n = 248; day 2–3, n = 172; no target rate UV, n = 369). In-hospital mortality in the day 1 group was significantly lower (2.7% vs. 5.9% vs. 11.1%; p < 0.001) than that of other groups. The mortality and re-hospitalization for 1 year in the day 1 group was significantly lower (event-free rate: 67.7% vs. 54.1% vs. 56.9%; log-lank p = 0.004) than that of other groups. In multivariate analysis, predictors of T2TUV at day 1 were age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01–1.04, p = 0.007), previous hospitalized heart failure (OR: 1.47, 95% CI: [1.03–2.12], p = 0.03), N-terminal-pro B type natriuretic peptide per 1000 pg/ml (OR: 1.02, 95% CI: 1.01–1.04, p = 0.007), carperitide (OR: 0.69, 95% CI: 0.48–0.99, p = 0.05), and early administration of tolvaptan (OR: 0.6, 95% CI: 0.42–0.85, p = 0.004). ConclusionsT2TUV of less than day 1 was associated with lower in-hospital mortality and decreased mortality and re-hospitalization at 1 year.

Factors associated with readmission after long-term administration of tolvaptan in patients with congestive heart failure.

We investigated the factors associated with readmission in patients with congestive heart failure (HF) receiving long-term administration of tolvaptan (TLV) to support treatment decisions for HF. This retrospective cohort study included 181 patients with congestive HF who received long-term administration of TLV. Long-term administration of TLV was defined as the administration of TLV for 60 days or longer. The outcome was a readmission event for worsening HF within 1 year after discharge. Significant factors associated with readmission were selected using multivariate analysis. To compare the time to readmission using significant factors extracted in a multivariate analysis, readmission curves were constructed using the Kaplan-Meier method and analysed using the log-rank test. The median age was 78 years (range, 38-96 years), 117 patients (64.6%) were males, and 77 patients (42.5%) had a hospitalisation history of HF. Readmission for worsening HF within 1 year after long-term TLV treatment occurred in 62 patients (34.3%). In the multivariate analysis, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 (odds ratio, 3.22; 95% confidence interval, 1.661-6.249; P = 0.001) was an independent significant factor. When eGFR at discharge was divided into two groups (eGFR < 30 vs. eGFR ≥ 30), readmission rates within 1 year were 53.3% vs. 25.4%, respectively ( P = 0.001). We revealed that eGFR was strongly associated with readmission in patients with HF who received long-term administration of TLV. Furthermore, we showed that eGFR is an important indicator in guiding treatment of HF in patients receiving TLV.

Predictors of Poor Very Early Diuretic Response and Effectiveness of Early Tolvaptan in Symptomatic Acute Heart Failure.

Diuretic response (DR) in patients with symptomatic acute decompensated heart failure (ADHF) has an impact on prognosis. This study aimed to identify predictive factors influencing acute 6h poor DR and to assess DR after early administration of tolvaptan (TLV). This multicenter retrospective study included 1670 patients who were admitted for ADHF and received intravenous furosemide within 1h of presentation in clinical scenario 1 or 2 defined based on initial systolic blood pressure ≥100mmHg with severe symptoms (New York Heart Association class III or IV (n=830). The score for the poor DR factors in the very acute phase was calculated in patients treated with furosemide-only diuretics (n=439). The DR to TLV administration was also assessed in patients who received an additional dose of TLV within 6h (n=391). The time since discharge from the hospital for a previous heart failure <3 months (odds ratio [OR] 2.78, 95% confidence interval [CI] 1.34-5.83; p=0.006), loop diuretics at admission (OR 3.05, 95% CI 1.74-5.36; p<0.0001), and estimated glomerular filtration rate (eGFR) <45mL/min/1.73m2 (OR 2.99, 95% CI 1.58-5.74; p=0.0007) were independent determinants of poor DR. The frequency of poor DR according to the risk stratification group was low risk (no risk factor), 18.9%; middle risk (one risk factor), 33.1%; and high risk (two to three risk factors), 58.0% (p<0.0001). All risk groups demonstrated a significantly lower incidence of poor DR with early TLV administration: 10.7% in the early TLV group versus 18.9% in the loop diuretics group (p=0.09) of the low-risk group; 18.4% versus 33.1% (p=0.01) in the middle-risk group, and 20.2% versus 58.0% (p<0.0001) in the high-risk group. Early administration of TLV in patients with predicted poor DR contributed to a significant diuretic effect and suppression of worsening renal function.

Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease. Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model. Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response. Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.

Epidemiology, causes, and management of ascites; a systematic review

The main malignancy of hepatocytes, hepatocellular carcinoma (HCC) is a medical condition with a poor prognosis. Spontaneous bacterial peritonitis (SBP), a common infection in individuals with cirrhosis and ascites, has high morbidity and mortality. Thus this study aimed to investigate the prevalence, etiology, and treatment of ascites. English-language articles were collected from 2015 to 2023 demonstrating the management of epidemiology, causes, and management of ascites. Overall, there were 5 articles. Surveys and analyses of national databases were the most widely used methods (n=5). Sociodemographic information, symptoms, warning signals, risk factors, historical medical conditions, findings from significant investigations, and potential advanced management alternatives were all gathered. Intractable ascites indicated a bad prognosis in people with liver cirrhosis and frequently aggravated decompensated hepatic cirrhosis. Treatment and management options vary. Aldosterone blockers and loop diuretics are the mainstays for the treatment of ascites in cirrhotic patients, while vasopressin receptor antagonists are infrequently utilized. The sodium-glucose cotransporter 2 (SGLT2) inhibitors might be a novel ascites treatment with a different mechanism than currently prescribed drugs, according to recent findings. Additionally, urinary neutrophil gelatinase-associated lipocalin can be used to predict the incidence of acute kidney injury following the administration of tolvaptan and is a helpful predictor of tolvaptan\&amp;apos;s short- and long-term effectiveness.

PS-C18-7: EFFECT OF TOLVAPTAN IN PATIENTS WITH CHRONIC KIDNEY DISEASE STAGE G5 AND IMPACT OF CONCOMITANT USE OF THIAZIDE DIURETICS

Objective: Tolvaptan, a vasopressin V2 receptor antagonist, is used to treat congestive heart failure (CHF). Its diuretic effect in patients with severe renal dysfunction remains poorly characterized. Thiazide diuretics decrease urinary volume (UV) in patients with nephrogenic diabetes insipidus, in which V2 receptor function is absent. Likewise, thiazide diuretics may decrease UV in patients receiving tolvaptan. Design and method: This retrospective cohort study included inpatients with chronic kidney disease stage G5, in whom tolvaptan was administered for CHF. UVs at 24-h pre- and post-tolvaptan administration as well as 30-day dialysis initiation were compared between patients with and without thiazide diuretics. Results: Thiazide diuretics were used in 26 of 106 recruited patients (73.4 ± 13.0 years, estimated glomerular filtration rate: 8.07 ± 3.13 mL/min/1.73 m2). In contrast to those who received thiazide diuretics (1177.3 ± 686.5 vs. 1173.1 ± 629.1 mL/day, p = 0.93), patients without thiazide diuretics had significantly higher 24-h UV pre- and post-tolvaptan administration (1043.4 ± 645.6 vs. 1422.2 ± 774.0 mL/day, p &lt; 0.001). In a multivariate regression model, the use of thiazide diuretics was significantly associated with decreased 24-h UV (beta coefficient, -486.7 [95% confidence interval (CI), -674.5 to -298.8]) and increased urine osmolality (beta coefficient, 37.7 [95% CI, 17.1–58.4]), bodyweight (beta coefficient, 0.62 [95% CI, 0.31–0.92]) and 30-day dialysis initiation (odds ratio 3.40 [95% CI, 1.18–9.82]) after tolvaptan administration. Conclusions: Tolvaptan had significant diuretic effects on patients with CHF, even in those with severe renal dysfunction. Concomitant use of thiazide diuretics diminished these effects.