Efficacy Of Tolvaptan Research Articles

Tolvaptan and the role of kidney aquaporin-2 abundance in managing volume overload in patients with CKD

ABSTRACT Objective This retrospective study evaluated tolvaptan's efficacy, safety, and predictive indicators in managing volume overload in chronic kidney disease (CKD) patients. Methods CKD patients with volume overload, treated with loop diuretics alone or with tolvaptan at Zhongda Hospital, Southeast University, from 1 March 2022 to 31 December 2023, were included. Patients were divided into loop diuretic (Group C) and loop diuretic combined with tolvaptan (Group T) cohorts. Primary outcomes included volume control, changes in weight, urine output, and laboratory parameters within 1 week post-medication. Adverse events such as hypernatremia and hyperkalemia, etc., were recorded. We further conducted immunohistochemical staining of renal biopsy tissues to investigate the roles of aquaporin-2 (AQP2) in the collecting duct and plasma albumin in predicting the efficacy of tolvaptan. Results Of 174 CKD patients with volume overload, 108 (67.07%) were male. Group C and Group T each comprised 87 patients. At baseline, no significant differences in urine output and weight were noted. By day 3, Group T exhibited a greater increase in urine output (P < .001) and weight reduction (P < .001). At day 7, Group T maintained more significant diuretic effects (P < .001). More Group C patients required ultrafiltration therapy (P = .040). Adverse event rates did not significantly differ. Notably, AQP2 expression in the collecting duct may predict tolvaptan responsiveness, while plasma albumin did not affect efficacy. Conclusion Tolvaptan showed efficacy and safety in managing volume overload in CKD patients. The expression of AQP2 in the collecting duct could predict tolvaptan's efficacy. This study protocol was approved by the Ethics Committee of Zhongda Hospital Affiliated to Southeast University (Approval No. 2023ZDSYLL180-P01, Clinical Trial Registration No. ChiCTR2300075274, Trial Registration Link: https://www.chictr.org.cn/guide.html).

Efficacy of Low-Dosage Tolvaptan for Treatment of Profound Hyponatremia in Syndrome of Inappropriate Antidiuresis: An Open-Label Randomized Controlled Trial

Efficacy of Low-Dosage Tolvaptan for Treatment of Profound Hyponatremia in Syndrome of Inappropriate Antidiuresis: An Open-Label Randomized Controlled Trial

A Case of Good Efficacy of Tolvaptan in a Patient with Markedly Enlarged Polycystic Kidney

A 61-year-old patient with autosomal dominant polycystic kidney disease (Irazabal class 1E) in whom renal function had decreased and kidney size had increased over the past 3 years (change in serum creatinine, 1.3 mg/dL to 1.5 mg/dL; change in total kidney volume, 5632 cm3 to 7301 cm3) was treated with tolvaptan 60 mg/day. After 8 years of tolvaptan treatment, serum creatinine remained at 1.51 mg/dL, and total kidney volume was at 6812 cm3. Adequate salt intake and good weight control may have resulted in good outcomes, even in patients with treatment-resistant giant cystic kidney disease.

Tolvaptan therapy for edema in patients with chronic kidney disease.

Tolvaptan is a vasopressin V2 receptor antagonist that is commonly prescribed to alleviate edema associated with renal diseases. However, the clinical benefits of tolvaptan in chronic kidney disease (CKD) remain unclear. This study aimed to evaluate the effectiveness of tolvaptan in managing edema caused by CKD. The efficacy and treatment regimen of tolvaptan were assessed in a cohort of 96 patients with renal edema and CKD. During the treatment, the patients' creatinine (CR), uric acid (UA), and estimated glomerular filtration rate (eGFR) were monitored as important indicators of kidney function. Coagulation-associated molecules including fibrinogen, D-dimer, and fibrin degradation products (FDPs) were measured. Electrolyte disorders and acute kidney injury were closely monitored. Tolvaptan was administered at a daily dose of 7.5 mg, and 30 mg of edoxaban was administered to manage deep vein thrombosis. During the course of tolvaptan therapy, the eGFR of the patients was not declined. Edema was eliminated in 82.18% of patients. Proteinuria was reduced in the patients (p<0.05). There were no significant changes in serum sodium levels throughout treatment, and no significant difference was observed in blood volume between the end of treatment and baseline levels. Importantly, acute kidney injury did not occur, and renal edema and deep vein thrombosis were successfully treated. As long as a rational treatment regimen is followed, tolvaptan is a safe and effective diuretic for treating edema in CKD, even in the late stages of CKD without reducing residual renal function in the patients.

The role of tolvaptan add-on therapy in patients with acute heart failure: a systematic review and network meta-analysis.

Several conflicting reviews have concluded that the use of loop diuretics is associated with poorer clinical and safety outcomes. Therefore, this study aimed to investigate the efficacy and safety of tolvaptan as an adjunct to conventional diuretic therapy in patients with acute heart failure (AHF). A comprehensive search was conducted on PubMed, Embase, ProQuest, EBSCO, and Cochrane Library until 24 May 2023 to identify randomized controlled trials that compared the effects of tolvaptan with conventional therapy and placebo in patients with AHF. The quality assessment of the included trials was conducted using the Cochrane risk of bias. A network meta-analysis (NMA) was conducted to examine the dosage effect of tolvaptan. A total of 17 studies with 18 reports, involving 10,039 patients, were selected. The tolvaptan add-on therapy significantly alleviated dyspnea [24 h: RR 1.16 (1.04, 1.29), 48 h: RR 1.18 (1.04, 1.33)], reduced body weight within 48 h [Asian group, MD -0.93 (-1.48, -0.38); non-Asian group, MD -2.76 (-2.88, -2.65)], reduced edema [RR 1.08 (1.02, 1.15)], increased serum sodium [non-Asian group, MD 3.40 (3.02, 3.78)], and resulted in a change in serum creatinine [MD -0.10 (-0.18, -0.01)]. No significant differences were observed in mortality and rehospitalization. The NMA suggested that an intermediate dosage (15 mg/day) might offer the best efficacy in reducing dyspnea within 24 h, reducing edema, increasing serum sodium, and lowering the incidence of worsening renal function (WRF). In conclusion, the meta-analysis showed that tolvaptan contributed to the short-term alleviation of congestive symptoms, elevated sodium levels, and a lower incidence of WRF. However, no significant benefits were observed in long-term symptoms, rehospitalization rates, and mortality. An intermediate dosage of tolvaptan might be considered the optimal choice for various clinical outcomes. https://www.crd.york.ac.uk/, PROSPERO (CRD42023420288).

#1636 Treatment of Tolvaptan related polyuria with bendroflumethiazide for ADPKD: Does it really work?

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease worldwide and accounts for 10% of patients on renal replacement therapy. Currently, the arginine vasopressin (AVP) V2 receptor antagonist Tolvaptan is the only available treatment for ADPKD which slows cyst formation and thus the progression of kidney disease by inducing AVP resistance. However, its aquaretic side effects can be debilitating and is the most common reason for medication discontinuation. Thiazides such as bendroflumethiazide are natriuresis-promoting diuretics through their action on the sodium-chloride channel in the distal convoluted tubule that are widely used to treat polyuria in inherited AVP deficiency or resistance. However, there is limited information about their effect in patients treated with Tolvaptan. The aim of this observational study is to review the impact on patients’ quality of life by using a low dose bendroflumethiazide with Tolvaptan in patients with ADPKD who are suffering from Tolvaptan induced aquaretic side effects. Method Details of all patients with ADPKD who are on Tolvaptan with or without bendroflumethiazide who are currently attending the polycystic kidney disease (PKD) clinic at Royal Free London NHS Foundation Trust were obtained, and their medications reviewed. Patients who have previously been or were currently on bendroflumethiazide to enable them to continue Tolvaptan therapy were identified. Information about the impact of bendroflumethiazide on their quality of life and their aquaretic side effects were obtained via phone call. If they discontinued bendroflumethiazide, the reason for this was explored. In addition, eGFR, sodium, potassium, and calcium at the time of bendroflumethiazide initiation as well as at three, six, nine and twelve months post bendroflumethiazide initiation were obtained. Results Out of 136 patients receiving Tolvaptan for treatment of ADPKD at our centre, eight (5.8%) were prescribed bendroflumethiazide for treatment of their aquaretic side effects from Tolvaptan. Two of these eight patients (25%) stopped bendroflumethiazide due to adverse reactions. The remaining six patients (75%) remained on the medication, and all reported significant subjective improvement in their symptoms of polyuria, nocturia and in their overall quality of life. Two of the six patients (33.3%) that remained on bendroflumethiazide had also subsequently increased their Tolvaptan dose. No electrolyte disturbances were noted after initiation of bendroflumethiazide. Conclusion Using bendroflumethiazide appears to improve the quality of life through reduction of polyuria and nocturia in patients suffering from Tolvaptan-induced aquaretic side effects with some patients subsequently able to increase their Tolvaptan dose by taking bendroflumethiazide which might result in augmented therapeutic benefit of Tolvaptan. Further placebo-controlled randomised studies with longitudinal will be needed to determine the true benefit-disbenefit balance of thiazide therapy in patients taking tolvaptan, especially to determine whether there is a negative effect on efficacy of tolvaptan on the underlying ADPKD. However, based on our small observational study, the number of patients needed to determine whether bendroflumethiazide improves the tolerability and medication adherence in patients who are debilitated by the aquaretic side effects of Tolvaptan would be small.

#1891 Evaluating the safety and effectiveness of Tolvaptan for management of adult Korean ADPKD patients (ESSENTIAL study): final report

Abstract Background and Aims Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by Korean FDA in 2015 as a treatment option in autosomal dominant polycystic kidney disease (ADPKD). In order to prescribe Tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease (CKD) stage 1-3. Method Korean patients aged 19 to 50 with rapidly progressing ADPKD were enrolled in the study. The dose titration was performed every one week for a total of 4 weeks. The patient was prescribed Tolvaptan with the maximum tolerable dose up to 120 mg per day. A total duration of Tolvaptan prescription was 24 months. The primary outcome was the incidence of treatment emergent adverse events (TEAE) including drug-induced liver injury (DILI). The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR). Results A total of 117 patients were included in the analysis. Mean age was 38.7 ± 8.4 years old and male were predominant (58.1%). The average TKV was 2066 ± 1094 mL and mean eGFR was 79.7 ± 27.7 mL/min/1.73 m2. Mean duration of Tolvaptan exposure was 1.7 ± 0.6 years and the average daily dose of Tolvaptan was 94.4 ± 24.1 mg/day. A total of 489 treatment-emergent adverse events (TEAE) occurred in 106 (90.6%) patients during study duration. The drug-induced liver injury and aquaresis-related adverse events were two most common adverse events. A total of 17 DILI cases (14.5%) occurred during the study period and mostly within 18-month period. However, liver enzymes were normalized after drug discontinuation The patients with previous history of liver disease as well as those who were prescribed higher dose of Tolvaptan demonstrated higher frequency of DILI. Mean growth rate of TKV after Tolvaptan treatment was 4.5 ± 0.5% and mean eGFR decline rate was -3.0 ± 0.39 mL/min/1.73 m2/year. Comparing with the predicted value from calculation, Tolvaptan attenuated both TKV growth and eGFR decline rate. Conclusion This study is the first post-marketing survey assessing the safety and efficacy of Tolvaptan in Korean ADPKD patients. The incidence of DILI was higher than the previous studies and especially in those with liver disease and higher Tolvaptan prescription dose. While Tolvaptan can effectively reduce TKV and attenuate eGFR decline, the clinicians should be aware of higher frequency of DILI among Korean population.

#2861 Real-life efficacy of tolvaptan for polycystic kidney disease (PKD) and association with patient adherence in London North-West specialist clinic

Abstract Background and Aims Tolvaptan is approved by NICE in the treatment of PKD afterrandomised controlled trials demonstrated a reduction in decline in eGFR. Aquaresis occurs as an effect, and this may limit tolerability as the second dose in a day causes nocturia and disturbed sleep. Thirty-three patients in our specialist PKD clinic were treated based on criteria of bipolar renal length &amp;gt;=15cm and decline in eGFR by &amp;gt; −5 ml/min/yr. We evaluated their real-life outcome regarding measures of adherence including an adapted Basel Assessment of Adherence to Immunosuppressive Medication Scale © (by permissions.nursing.unibas.ch/) originally validated for immunosuppression medications in transplant patients. A further 24 patients had finished treatment at our centre and were excluded as BAASIS could not be applied in hindsight. However, they illustrated a notably high level of intolerance leading to cessation in 16/24 (9 with nocturia, 4 transaminitis, 1 angioedema, 1 rash, 1 fatigue) emphasizing the importance of this work on adherence and response. Method BAASIS addresses recall of treatment adherence in the preceding 4 weeks, all 33 patients currently treated as of 16/1/24 were screened on telephone by two independent auditors with a standard non-judgemental introductory script designed to result in candid engagement. Investigators were blinded to renal outcomes. A decline in eGFR of less than 5 ml/min/yr was defined as treatment response. Results Of the 33 patients included, 14 males and 19 females, median age 49yrs (range 32-72), were on treatment for a mean of 2.7yr (SD 2.2, range 0.3-7.5). Mean eGFR (CKD-EPI) was 58 ml/min (SD 19, range 28-110) at start and 48 ml/mi (SD 23, range 17-102) at end of treatment. Median total daily dose was 120 mg/d (range 60-120). Attendance at clinic for monitoring was 100%. 18/33 patients had responded to treatment, with delta eGFR –0.1 ml/min/year (SD 3.4) versus non-responders’' delta eGFR –13 ml/min/year (SD 8.7) There was a total of 35 instances of non-implementation in 23/33 patients with missed (20 instances), delayed (13 instances) or self-alteration in doses (2 instances). Only 10/33 patient made no failure to implement Tolvaptan at any time. There were 9 patients with non-persistence of Tolvaptan treatment. Associative analysis of renal outcome with adherence was made for all 31 patients who had more than 6 months treatment, 2 patients being excluded because treatment had been too short-term. 25/31 had non-adherence defined by non-implementation or non-persistence or both, but this did not statistically associate with treatment failure ChiSq 1.951 p = 0.16. The element of non-implementation alone was however associated with treatment failure ChiSq 4.949 p = 0.03, this term includes patient behaviour of not taking and mistiming drug taking, and patient-initiated dose reduction and drug holidays. Conclusion Just over half (55%) of currently treated patients had made a clinical response to Tolvaptan. 23/33 patients had non-implementation within the 4 weeks preceding the validated adherence survey, and this was significantly associated with treatment failure. This study is limited to a small single-centre patient cohort but could easily be applied more widely. This study informs shared-decision making and we should encourage our patients to take this high-cost drug in the right amount and at the right times, and notably not to miss doses, thereby to achieve higher clinical response rates.

Clinical efficacy of tolvaptan in acute decompensated heart failure patients with severe aortic stenosis and atrial fibrillation: a sub-analysis from the LOHAS registry.

Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output, respectively. Therefore, the treatment of HF due to severe AS complicated with AF is anticipated to be difficult. Tolvaptan, a vasopressin V2 receptor inhibitor, is effective in controlling acute decompensated heart failure (ADHF) with hemodynamic stability. However, its clinical efficacy against ADHF caused by AS with AF remains to be determined. Clinical information (from September 2014 to December 2017) of 59 patients diagnosed with ADHF due to severe AS (20 patients with AF; 39 patients with sinus rhythm [SR]) was obtained from the LOHAS registry. The registry collected data from seven hospitals and assessed the short-term effects of tolvaptan in patients hospitalized for ADHF with severe AS. We attempted to identify clinical differences from baseline up to 4days, comparing patients with AF (AF group) versus those with SR (SR group). There were no significant differences between the groups in age (83.7 ± 4.5 vs. 85.8 ± 6.9years, respectively; p = 0.11) and aortic valve area (0.60 [0.46-0.73] vs. 0.56 [0.37-0.70] cm2, respectively; p = 0.50). However, left atrial volume was larger (104 [85-126] vs. 87 [64-103] mL, respectively; p < 0.01), whereas stroke volume was lower (51.6 ± 14.8 vs. 59.0 ± 18.7mL, respectively; p = 0.08) in the AF group versus the SR group. Body weight decreased daily from baseline up to day 4 in both groups (from 55.4 to 53.2kg [p < 0.01] and from 53.5 to 51.0kg [p < 0.01], respectively) without change in heart rate. Notably, the systolic blood pressure decreased slightly in the AF group after 2days of treatment with tolvaptan. Short-term treatment with tolvaptan improved HF in patients hospitalized for severe AS, regardless of the presence of AF or SR. After achieving sufficient diuresis, a slight decrease in blood pressure was observed in the AF group, suggesting an appropriate timeframe for safe and effective use of tolvaptan.

Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial

Rationale & ObjectiveBody-mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. Study DesignA retrospective cohort study. Setting & Participants1053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and high risk of rapid disease progression. PredictorEstimates of visceral adiposity extracted from coronal plane MRIs using deep learning. OutcomeAnnual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. Analytical ApproachMultinomial logistic regression and linear mixed models. ResultsIn fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of ≥7% vs. <5% (OR: 4.78 [3.03, 7.47]). The association was stronger in females than males (interaction p<0.01). In linear mixed models with an outcome of % change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (three-way interaction of treatment*time*visceral adiposity p=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual % change in TKV for individuals with a normal BMI (De-Long’s test Z-score: -2.03; p=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in females (fully adjusted OR 1.06 [1.01, 1.11] per 10 unit increase in visceral adiposity) but not males (0.98 [0.95, 1.02]). LimitationsRetrospective; rapid progressors; computational demand of deep learning. ConclusionsVisceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model, independently associates with more rapid kidney growth, and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity.

461 Efficacy of Tolvaptan for Correction of Hyponatremia in Cirrhosis Prior to Liver Transplantation

461 Efficacy of Tolvaptan for Correction of Hyponatremia in Cirrhosis Prior to Liver Transplantation

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.

HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD.MethodsThe HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care.OutcomesThe primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume.ConclusionThe HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Efficacy and safety of postoperative preemptive use of tolvaptan for patients with cirrhosis undergoing hepatectomy for hepatocellular carcinoma.

Optimal choice of diuretics in perioperative management remains unclear in enhanced recovery after liver surgery. This study investigated the efficacy and safety of tolvaptan (oral vasopressin V2-receptor antagonist) in postoperative management of patients with liver injury and hepatocellular carcinoma. The patients clinically diagnosed with liver cirrhosis were included in this study. Clinical outcomes of 51 prospective cohort managed with a modified postoperative protocol using tolvaptan (validation group) were compared with 83 patients treated with a conventional management protocol (control group). Postoperative urine output were significantly larger and excessive body weight increase were reduced with no impairment in renal function or serum sodium levels in the validation group. Although the total amount of discharge and trend of serum albumin level were not significantly different among the groups, global incidence of postoperative morbidity was less frequent (19.6% vs. 44.6%, P=0.005) and postoperative stay was significantly shorter (8 days vs.10 days, P=0.008) in the validation group compared with the control group. Tolvaptan could be safely used for the patients with injured liver in postoperative management after hepatectomy and potentially advantageous in the era of enhanced recovery after surgery with its strong diuretic effect and better fluid management.

Plasma copeptin concentration is a predictor of tolvaptan efficacy in patients with hepatic ascites

AbstractAimsNo solid evidence‐based opinion was raised regarding predictors of the degree of ascites reduction with tolvaptan. This retrospective cohort study aimed to examine whether serum copeptin concentration is a useful predictor of this.MethodsThe study population consisted of 80 patients with liver cirrhosis treated with tolvaptan for hepatic ascites effusions at Nara Medical University Hospital from May 2014 to December 2018. Forty‐three patients who lost &gt;1.5 kg of body weight in the first week after starting tolvaptan were classified as good responders and the remaining 37 as poor responders. Various laboratory parameters were measured immediately before the start of tolvaptan therapy to examine factors associated with predicting its efficacy.ResultsIn the univariate analysis, no significant differences with respect to age (67.6 vs. 69.8 years, p &gt; 0.05), sex, body mass index (24.8 vs. 23.7 kg/m2, p &gt; 0.05), Child–Pugh score (9.4 vs. 9.7, p &gt; 0.05), and Model for End‐stage Liver Disease score (11 vs. 12, p &gt; 0.05) were found between the two groups. Conversely, aspartate transferase and alanine transaminase (ALT) levels were significantly lower in the good response group (52.9 ± 56.3 vs. 68.8 ± 50.7 U/L, p &lt; 0.05; 26.2 ± 30.6 vs. 40.5 ± 33.5 U/L, p &lt; 0.01), whereas serum copeptin and serum sodium concentrations were significantly higher (57.1 ± 15.0 vs. 45.8 ± 16.0 pg/mL, p &lt; 0.01; 136.3 ± 3.4 vs. 133.8 ± 5.8 mEq/L, p &lt; 0.05). In the multivariate analysis, serum copeptin concentration and ALT were statistically significant factors (p &lt; 0.01, p &lt; 0.05). Regression analysis of the association between the tolvaptan efficacy for refractory ascites and pretreatment serum copeptin concentration showed that a copeptin concentration cutoff of 45.9 pg/mL could predict treatment efficacy with a sensitivity, specificity, and area under the curve of 76.7%, 59.5%, and 0.71%, respectively.ConclusionSerum copeptin concentration may be a predictor of tolvaptan efficacy for refractory ascites effusion in Japanese patients with liver cirrhosis.

Long-term low-dose tolvaptan efficacy and safety in SIADH

PurposeTolvaptan, a selective vasopressin V2-receptor antagonist, is approved for the treatment of SIADH-related hyponatremia, but its use is limited. The starting dose is usually 15 mg/day, but recent clinical experience suggests a lower starting dose (<15 mg/day) to reduce the risk of sodium overcorrection. However, long-term low-dose efficacy and safety has not been explored, so far. Aim of our study is to characterize safety and efficacy of long-term SIADH treatment with low-dose Tolvaptan.MethodsWe retrospectively evaluated 11 patients receiving low-dose Tolvaptan (<15 mg/day) for chronic SIADH due to neurological, idiopathic and neoplastic causes. Plasma sodium levels were measured before and 1, 3, 5, 15 and 30 days after starting Tolvaptan and then at 3-month intervals. Anamnestic and clinical data were collected.ResultsMean time spanned 27.3 ± 29.8 months (range 6 months-7 years). Mean plasma sodium levels were within normal range 1, 3 and 6 months after starting Tolvaptan as well as after 1, 2, 3, 5 and 7 years of therapy. Neither osmotic demyelination syndrome nor overcorrection were observed. Plasma sodium levels normalization was associated with beneficial clinical effects. Neurological patients obtained seizures disappearance, improvement in neurological picture and good recovery from rehabilitation. Neoplastic patients were able to start chemotherapy and improved their general condition. Patients did not show hypernatremia during long-term follow-up and reported mild thirst and pollakiuria.ConclusionsThe present study shows that long-term low-dose Tolvaptan is safe and effective in SIADH treatment. No cases of overcorrection were documented and mild side effects were reported.

#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.

The safety and efficacy of tolvaptan in the treatment of patients with autosomal dominant polycystic kidney disease: A systematic review and meta-analysis

BackgroundThe irreversible progression of autosomal dominant polycystic kidney disease (ADPKD) to end-stage renal disease (ESRD) is delayed by tolvaptan. Therefore, we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD. MethodsTwo reviewers independently searched all published randomized controlled trials studies in PubMed, EMBASE, Web of Science and Cochrane databases, extracted data, assessed bias risk and rated the quality of evidence. Data were analyzed by the RevMan software. ResultsWe identified 8 trials including 2135 patients. Both of the decline of estimated glomerular filtration rate (eGFR) [MD=1.89, 95% CI (0.74, 3.04), P=0.001] and total kidney volume (TKV) [MD=−3.32, 95% CI (−4.57, −2.07), P<0.001] were delayed in tolvaptan group compared with placebo group in ADPKD patients. The use of tolvaptan delayed TKV progression in the different-month subgroups [MD=−69.99, 95% CI (−91.05, −48.94), P<0.001]. Tolvaptan reduced renal pain [RR=0.66, 95% CI (0.54, 0.81), P<0.001] and hematuria events [RR=0.55, 95% CI (0.41, 0.74), P<0.001] in ADPKD patients. However, the prevalence of thirst [RR=2.75, 95% CI (2.34, 3.24), P<0.001] and nocturia events [RR=3.01, 95% CI (1.27, 7.11), P=0.01] were increased in tolvaptan group. There is no significant difference of hypertension events [RR=0.92, 95% CI (0.82, 1.03), P=0.13] in tolvaptan group compared placebo group. ConclusionsThis meta-analysis suggests that tolvaptan may improve clinical progression in patients with ADPKD without significantly increasing the risk of adverse reactions.

Neutrophil gelatinase-associated lipocalin predicts the efficacy of tolvaptan for ascites in patients with liver cirrhosis.

Acute kidney injury (AKI) is associated with liver cirrhosis (LC), water retention, diuretics to treat water retention, and a poor prognosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) reportedly predicts a poor prognosis in decompensated LC. This study investigated the usefulness of uNGAL in predicting the short- and long-term effects of tolvaptan (TVP) and the incidence of AKI post-TVP administration. Of the LC cases with water retention, 86 with available pre-treatment uNGAL were analyzed. A short-term response was defined as weight loss of ≥ 1.5kg within the first week; a long-term response was defined as a short-term response without early recurrence. The uNGAL usefulness in predicting the short- and long-term effects of TVP and AKI incidence post-TVP administration was investigated. Short-term effects of TVP were observed in 52 patients. Of these, 15 patients had an early recurrence. In multivariate analysis, significant short-term predictive factors were C-reactive protein (CRP) < 1.4mg/dl, uNa/K ratio ≥ 3.51, and uNGAL < 50.2ng/ml. Patients were classified according to these three cut-off values, with short-term response rates of 92.9%, 68.8%, 26.7%, and 0% for 0, 1, 2, and 3 points, respectively. CRP < 0.94mg/dl and uNGAL < 50.2ng/ml were significant factors for predicting the long-term response of TVP. The AKI incidence post-TVP was 8.1% (n = 7) and was significantly higher among those with uNGAL ≥ 38.1ng/mL. uNGAL is a useful predictor of the short- and long-term efficacy of TVP and can be useful in predicting AKI incidence post-TVP administration.

Efficacy of tolvaptan in postoperative volume therapy for acute Stanford type A aortic dissection

BackgroundDespite the increasing application of tolvaptan in cardiac surgery, there is no information on the use of tolvaptan in Stanford patients with type A aortic dissection. This study aimed to evaluate the postoperative clinical effects of tolvaptan in patients with type A aortic dissection after tafter surgery.MethodsA retrospective analysis was performed on 45 patients treated for type A aortic dissection in our hospital from 2018 to 2020. These included 21 patients who were treated with tolvaptan (Group T) and 24 patients who received traditional diuretics (Group L). The hospital's electronic health records were used to obtain perioperative data.ResultsGroup T did not differ significantly from Group L in terms of the duration of mechanical ventilation, postoperative blood required, length of catecholamine use, or the amount of intravenous diuretic drugs administered (all P > 0.05). The development of postoperative atrial fibrillation was significantly less in the tolvaptan group (P = 0.023). The urine volumes and change in body weight loss were slightly higher in group T than in group L but the differences were non-significant (P > 0.05). Serum potassium, creatinine, and urea nitrogen levels did not differ between the groups in the week after surgery, At the same time, sodium was significantly higher in the Group T group on day 7 after transfer from the ICU (P = 0.001). In Group L, sodium levels were also elevated by day 7 (P = 0.001). On days 3 and 7, serum creatinine and urea nitrogen levels increased in both groups (both P < 0.05).ConclusionsBoth tolvaptan and traditional diuretics were found to be effective and safe for patients with acute Stanford type A aortic dissection. Moreover, tolvaptan may be associated with reducing the incidence of postoperative atrial fibrillation.