Use Of Tolvaptan Research Articles

Leveraging Explainable Artificial Intelligence (XAI) for Expert Interpretability in Predicting Rapid Kidney Enlargement Risks in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is the predominant hereditary factor leading to end-stage renal disease (ESRD) worldwide, affecting individuals across all races with a prevalence of 1 in 400 to 1 in 1000. The disease presents significant challenges in management, particularly with limited options for slowing cyst progression, as well as the use of tolvaptan being restricted to high-risk patients due to potential liver injury. However, determining high-risk status typically requires magnetic resonance imaging (MRI) to calculate total kidney volume (TKV), a time-consuming process demanding specialized expertise. Motivated by these challenges, this study proposes alternative methods for high-risk categorization that do not rely on TKV data. Utilizing historical patient data, we aim to predict rapid kidney enlargement in ADPKD patients to support clinical decision-making. We applied seven machine learning algorithms—Random Forest, Logistic Regression, Support Vector Machine (SVM), Light Gradient Boosting Machine (LightGBM), Gradient Boosting Tree, XGBoost, and Deep Neural Network (DNN)—to data from the Polycystic Kidney Disease Outcomes Consortium (PKDOC) database. The XGBoost model, combined with the Synthetic Minority Oversampling Technique (SMOTE), yielded the best performance. We also leveraged explainable artificial intelligence (XAI) techniques, specifically Local Interpretable Model-Agnostic Explanations (LIME) and Shapley Additive Explanations (SHAP), to visualize and clarify the model’s predictions. Furthermore, we generated text summaries to enhance interpretability. To evaluate the effectiveness of our approach, we proposed new metrics to assess explainability and conducted a survey with 27 doctors to compare models with and without XAI techniques. The results indicated that incorporating XAI and textual summaries significantly improved expert explainability and increased confidence in the model’s ability to support treatment decisions for ADPKD patients.

Prognostic effect of a vasopressin V2 receptor antagonist in acute congestive heart failure patients with hypoperfusion, the wet-cold pattern.

This study investigated whether the oral vasopressin V2 receptor antagonist tolvaptan has beneficial effects on mortality in real-world congestive heart failure (CHF) patients with hypoperfusion (i.e. the wet-cold pattern), from the viewpoint of cardiorenal syndrome. Data on 5511 consecutive CHF patients were extracted from the Tokyo CCU Network data registry. Congestion and hypoperfusion were defined by Nohria-Stevenson clinical profiles at the time of hospitalization. Propensity scores for tolvaptan use were calculated for each patient and used to assemble two matched cohorts of patients receiving tolvaptan or not in the CHF with and without hypoperfusion groups. Of the entire study cohort, 1073 patients (19%) had CHF with hypoperfusion (i.e. the wet-cold pattern). In-hospital mortality was significantly higher for CHF patients with than without hypoperfusion (log-rank, P < 0.001). The rate of tolvaptan use did not differ significantly between CHF patients with and without hypoperfusion (15% vs. 14%, respectively; P = 0.7848). In the propensity-matched CHF with hypoperfusion cohort, there was a significant association between the use of tolvaptan and a reduction in in-hospital mortality (log-rank, P = 0.0052). Conversely, in the matched CHF without hypoperfusion cohort, tolvaptan use was not associated with in-hospital mortality (log-rank, P = 0.4417). There was a significant association between the use of tolvaptan and a reduction in in-hospital mortality in CHF patients with, but not without, hypoperfusion. These findings hint at possible individualized therapies for patients with CHF.

Long-term effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease

Background and objectivesEvidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. Material and methodsA single-center observational study (2016–2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. ResultsA total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (−3.52ml/min/1.73m2 [−4.98%] vs −3.98ml/min/1.73m2 [−8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. ConclusionsThis study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.

#2119 Long-term efficacy of tolvaptan therapy in patients with ADPKD

Abstract Background and Aims Currently, the only available therapy to ameliorate disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) is tolvaptan, a vasopressin V2 receptor antagonist. Real-life data on tolvaptan treatment effect is sparce, with several limitations including restricted follow-up, relatively small patient groups, no control groups, or only data reported on kidney function without total kidney volume. We studied, therefore, the long-term effect of tolvaptan on kidney function as well as kidney growth in a relatively large number of real-life ADPKD patients and controls. Moreover, we investigated the effect of salt and protein intake on long-term treatment efficacy. Method Data from two national ADPKD cohorts were pooled. Kidney function (creatinine-based eGFR) was measured at least yearly and total kidney volume (TKV, measured by MRI or CT) at least 3-yearly. Salt and protein intake were measured by 24 h urine excretion. To investigate the long-term effects of tolvaptan we assessed change in eGFR and TKV before as well as after start of tolvaptan using linear mixed effects models. For this purpose, we excluded the acute treatment effect from start to 6 months after initiation of tolvaptan. As a control group, we included all patients who were not treated with tolvaptan, assessing change in eGFR and TKV before and after the theoretical start of treatment (based on the average time of tolvaptan initiation observed in the tolvaptan-treated group) as well as a matched control group. Subgroup analyses of salt and protein intake were based on the median urinary excretion of sodium or urea. Results 697 patients (47 ± 12 years, 59.1% female) were included, of which 104 patients used tolvaptan. Mean duration of tolvaptan use was 6.0 ± 4.5 years (range: 0.8 to 15.6). Tolvaptan use reduced yearly eGFR decline by 17.4% (−4.43 to −3.66 mL/min/1.73 m2/year, p = 0.03, number of measurements: n = 817), whereas in the non-tolvaptan control group after the theoretical start of treatment, eGFR decline increased by 13.3% (−1.95 to −2.21 mL/min/1.73 m2/year, p = 0.2, n = 2804). Long-term TKV growth did not change after start of tolvaptan treatment (4.90 to 5.53%/year, p = 0.5, n = 316). Similar results were obtained in the matched control group. A more substantial treatment effect of tolvaptan on eGFR slope was noted in patients with high compared to low salt intake (assessed as ≥ versus &amp;lt; median urinary sodium excretion of 146 mmol/24 h (difference 1.62 (0.22 to 3.02) mL/min/1.73 m2/year, p = 0.02). Subgroup analysis according to median protein intake did not show a significant difference in tolvaptan treatment effect. Conclusion In this study, with real-life patient data, long-term follow-up, and a control group, we found that tolvaptan attenuated long-term kidney function decline but, notably, did not influence kidney growth. Higher daily salt intake was associated with a more substantial tolvaptan treatment effect, perhaps due to higher vasopressin levels before treatment, and consequently more vasopressin antagonism by tolvaptan.

#510 Evaluating tolvaptan as a protective agent for cardiac insufficiency in peritoneal dialysis patients

Abstract Introduction Peritoneal dialysis serves as a highly effective renal replacement therapy, offering prolonged preservation of residual renal function, improved blood pressure regulation, and enhanced quality of life. While diuretics are generally considered safe and beneficial in this context, their efficacy may be limited in certain cases. Background and Aims The rationale behind investigating the potential benefits of tolvaptan in peritoneal dialysis stems from existing studies in Asia, where the use of tolvaptan has been approved in this population. These studies, conducted on patients undergoing peritoneal dialysis, indicate notable improvements in urine output and key heart failure indicators such as Left Ventricular Mass Index (LVMI) and Brain Natriuretic Peptide (BNP). Materials &amp; Methods Recognizing the significance of these findings, a recent meta-analysis was conducted to comprehensively assess the collective data. The meta-analysis encompassed data from five pertinent studies involving a total of 70 peritoneal dialysis patients, with an average age of 66.1 ± 15 years. Participants received tolvaptan in doses of up to 15 mg, and the mean follow-up period was 8.2 ± 3.9 months. Results Results from the meta-analysis revealed a significant increase in urine volume in two out of four instances (Mean Difference [MD]= +554.5 cc [379,730], I²=61.5). While most studies did not indicate substantial changes in body weight or renal kt/V, a notable reduction in Left Ventricular Mass Index was evident in two studies (MD= -43.28 [-84.9,-1.6], I²=80.6%). Additionally, a substantial reduction in BNP was reported in one study, with no documented adverse events across the studies. Conclusion As an adjunct therapy, tolvaptan exhibits potential benefits in volume control, potentially contributing to improved cardiac function in peritoneal dialysis patients. The findings of this study align with existing research, highlighting the positive impact of tolvaptan on heart failure markers. Nevertheless, further high-quality studies are imperative to consolidate and validate these observed benefits in the peritoneal dialysis population.

#2031 Exploring the utility of serum proteomics for outcome prediction of autosomal polycystic kidney disease (ADPKD)

Abstract Background and Aims ADPKD is an inherited disorder characterized by the development of cysts in both kidneys, leading to renal enlargement and a gradual decline in renal function. It is the leading cause of end stage renal disease (ESRD) with an estimated prevalence of 1:1000. The estimated glomerular filtration rate (eGFR) is the calculated estimation of kidney function by using different equations. The eGFR equation used in this study is Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI, 2009) equation, which includes serum creatinine level, age, and gender. eGFR is also frequently used for assessing overall health of ADPKD patients, classifying the disease stages, and determining appropriate therapeutic interventions. As in ADPKD, clinical symptoms manifest typically in later disease stages, early diagnosis is crucial to slow the disease progression and improve patients’ life quality. This study has two main objectives: (1) the identification of molecular and clinical parameters associated with the annual eGFR decline and (2) the development of a predictive model for future eGFR in patients with ADPKD using serum proteomics. This research aims to advance more effective strategies for the misdiagnosis, stratification, and treatment of ADPKD by combining proteomic and clinical parameters. Method Utilizing retrospective eGFR values (n = 7187) of patients with ADPKD (n = 1291) recruited from the AD(H)PKD patient cohort, the annual decline in eGFR (slope) was calculated. A minimum of three eGFR values and the absence of tolvaptan use (a medication that inhibits the mechanisms underlying eGFR decline) were inclusion criteria. In order to determine the slope, robust linear regression was applied. Prior to the analyses, patients whose slopes were clinically extreme (−10 &amp; &amp;gt;5 mL/min/1.73 m2 per year) were excluded. Total of 2469 eGFR values from 219 ADPKD patients were included in this study. To derive a feature set (FS) suitable for slope prediction, the least absolute shrinkage and selection operator (LASSO) was applied independently to two subsets of the serum proteome (SP) data: (i) SP alone and (ii) SP in conjunction with key clinical variables: age, gender, eGFR, and MAYO class (SPMC). Linear regression (LR) models were constructed using the acquired FSs individually (SP and SPMC), and cross-validation (CV) was incorporated to prevent overfitting. Following that, prediction models were generated and compared in terms of their ability to predict slopes and were visualized for an overview. Results Using feature selection, four features associated with slope were identified in both SP and SPMC data. Three of those features were proteomic-based and common to both feature sets (SC and SPMC). LR models exhibited stability in R2s in test sets of CV, indicating no sign of overfitting. Therefore, the LR slope prediction models were built with SP and SPMC feature sets by using all available data. The adjusted R2 of SP and SCMP LR models were 0.274 (R2 = 0.287, F(4,213) = 21.48, p = 6.74 × 10−15) and 0.301 (R2 = 0.317, F(5,208) = 19.31, p = 8.94 × 10−16). This step was followed by the slope prediction of the same patients (internal validation) to examine models’ prediction capacity by comparing the predicted to observed slopes. According to comparisons, our LR models predict closer to actual slope if slope is greater than −5 and lower than 0 mL/min/1.73 m2 per year. Most of the observed slopes were in between the specified thresholds, which explains why the model is working well. However, the deviations between predicted and the observed slopes increases as the slopes exceed this range. Conclusion Identified biomarkers could be used for how the disease will progress, however, fine-tuning of the models might be necessary. Even though there were patients with positive and extremely negative eGFR slopes, our model accurately predicts slopes in the previously specified range. These extreme cases might also be responsible for models’ reduced accuracy outside of that range. One possible solution could be to use weighted lasso to reduce the effect of “extreme” slopes on the models.

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.

Treatment for patients with autosomal dominant polycystic kidney disease in the chronic kidney disease without kidney replacement therapy in real-world clinical practice: a descriptive retrospective cohort study.

In real-world clinical practice, treatments selected for patients with autosomal dominant polycystic kidney disease (ADPKD) in the chronic kidney disease (CKD) without kidney replacement therapy (KRT) have not been reported. This study investigated the oral treatments used in these patients and the changes in their use in recent years. Additionally, we studied the factors affecting tolvaptan dose reduction or discontinuation. This retrospective cohort study was conducted using the medical records of 160 hospitals in Japan. Patients with ADPKD or polycystic kidney disease registered on the database between January 2014 and December 2020 were selected. Changes in prescription proportions over time were assessed using the Cochran-Armitage test. We focused on patients prescribed with >15 mg of tolvaptan daily to identify the factors related to its dose reduction or discontinuation and used Multivariate Cox regression analysis to evaluate them. Tolvaptan use in patients with ADPKD in the CKD without KRT stage has increased. As of 2020, 25% of patients were treated with tolvaptan. Overall, 3639 patients with ADPKD were enrolled in the database, of whom 156 were treated with tolvaptan. Of these, 64 patients (41%) reduced or discontinued tolvaptan during the observation period. The presence of an estimated glomerular filtration rate <60 mL/min/1.73 m2 at the beginning of the treatment was associated with a higher risk of tolvaptan dose reduction or discontinuation. The proportion of patients with ADPKD treated with high-dose tolvaptan is increasing. However, patients with late-stage CKD tended to reduce or discontinue tolvaptan.

Real-life use of tolvaptan in ADPKD: a retrospective analysis of a large Canadian cohort

Tolvaptan is the first disease-modifying drug proven to slow eGFR decline in high-risk patients with ADPKD. However, barriers from the patient perspective to its use in real-life settings have not been systemically examined in a large cohort. This was a single-center, retrospective study of 523 existing or new patients with ADPKD followed at the Center for Innovative Management of PKD in Toronto, Ontario, between January 1, 2016 to December 31, 2018. All patients underwent clinical assessment including total kidney volume measurements and Mayo Clinic Imaging Class (MCIC). Those who were deemed to be at high risk were offered tolvaptan with their preference (yes or no) and reasons for their choices recorded. Overall, 315/523 (60%) patients had MCIC 1C-1E; however, only 96 (30%) of them were treated with tolvaptan at their last follow-up. Among these high-risk patients, those not treated versus treated with tolvaptan were more likely to have a higher eGFR (82 ± 26 vs. 61 ± 27 ml/min/1.73 m2), CKD stages 1–2 (79% vs. 41%), and MCIC 1C (63% vs. 31%). The most common reasons provided for not taking tolvaptan were lifestyle preference related to the aquaretic effect (51%), older age ≥ 60 (12%), and pregnancy/family planning (6%). In this real-world experience, at least 60% of patients with ADPKD considered to be at high risk for progression to ESKD by imaging were not treated with tolvaptan; most of them had early stages of CKD with well-preserved eGFR and as such, were prime targets for tolvaptan therapy to slow disease progression. Given that the most common reason for tolvaptan refusal was the concern for intolerability of the aquaretic side-effect, strategies to mitigate this may help to reduce this barrier to tolvaptan therapy.

Examination about clinical efficacy and safety of active use of tolvaptan for decompensated congestive heart failure cases

Abstract Background In Japan, Tolvaptan is approved for use as a potent oral diuretic, mainly for severe congestive heart failure. However, over time since the launch of Tolvaptan, there have been many reports of its usefulness when used earlier in milder cases. Based on this background, in August 2015, our facility introduced a clinical pathway (PATH) for acute care for cases with decompensated congestive heart failure (DCHF), in which immediate use of tolvaptan with conventional diuretics ware stipulated to keep patient’s activity by early diuresis. Purpose In this study, we verified the clinical usefulness and safety of PATH for DCHF that prescribes the active use of tolvaptan. Methods From April 2014 to July 2022, 846 DCHF cases admitted to our hospital for the first time were included. They were divided into two groups, N-group(154 cases before introduction of PATH) and P-group(692 cases introduced PATH and prescribed Tolvaptan as stipulated). We investigated their implementation status of each medical treatment in acute phase and hospitalization period(HP), and compared the difference between the two groups. And in P-group, we investigated the occurrence of adverse event(AE), deterioration of renal function (R-event) and hypernatremia (N-event) that required unplanned discontinuation of tolvaptan use, and we investigated the clinical features about the cases with each adverse event. Results There was almost no difference in the patient background before admission or the patient's condition at admission. In P-group, the performance rate of each acute medical care for DCHF was lower and their performance period was shorter compared in N-group. The performance rate of cardiac rehabilitation was higher and its starting time was earlier in P-group. (Figure 1) As a result, HP was significantly shorter in P-group. AE incidence in P-group were 2.2%(R-event) and 4.8%(N-event). Mean age tended to be higher and cognitive function was lower in both AE cases. Cases with R-event were more likely to have pre-existing renal insufficiency. In N-event cases, their activity level before admission was lower and blood sodium level at admission was higher. Most of the N-event(85%) occurred within 7 days.(Figure 2) Conclusions With the introduction of unique clinical pathway that stipulates the active use of tolvaptan, the acute care of cases with decompensated congestive heart failure had been greatly simplified and streamlined, and the hospitalization period had been shortened. Although it is unlikely that all the results were due to the medicinal effects of Tolvaptan, it was thought that the realization of early mobilization due to its strong diuretic effect was linked to these results. A certain rate of feared adverse events, especially hypernatremia, was found to occur, but the rate appeared to be acceptable. However, in elderly and cognitively impaired cases, special caution seemed to be required for several days after the start of tolvaptan use.Figure 1Figure 2

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

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.

The characteristics and outcomes in patients with acute heart failure who used tolvaptan: from KCHF registry.

The use of tolvaptan is increasing in clinical practice in Japan. However, the characteristics of patients who used tolvaptan and the timing of its use in patients with acute heart failure (AHF) are not fully elucidated. Among consecutive 4056 patients in the Kyoto Congestive Heart Failure registry, we analysed 3802 patients after excluding patients on dialysis, prior or unknown tolvaptan use at admission, and unknown timing of tolvaptan use, and we divided them into two groups: tolvaptan use (N=773) and no tolvaptan use (N=3029). The prevalence of tolvaptan use varied widely from 48.7% to 0% across the participating centres. Factors independently associated with tolvaptan use were diabetes, poor medical adherence, oedema, pleural effusion, hyponatraemia, estimated glomerular filtration rate<30mL/min/1.73m2 , moderate/severe tricuspid regurgitation, dobutamine infusion within 24h, and additional inotropes infusion beyond 24h after admission. The mortality rate at 90days after admission was significantly higher in the tolvaptan use group than in the no tolvaptan use group (14.3% vs. 8.6%, P=0.049). However, after adjustment, the excess mortality risk of tolvaptan use relative to no tolvaptan use was no longer significant (hazard ratio=1.53, 95% confidence interval=0.77-3.02, P=0.22). Patients with tolvaptan use had a longer hospital stay [median (interquartile range): 22 (15-34) days vs. 15 (11-21) days, P<0.0001] and a higher prevalence of worsening renal failure (47.0% vs. 31.8%, P<0.0001) and worsening heart failure (24.8% vs. 14.4%, P<0.0001) than those without. AHF patients with tolvaptan use had more congestive status with poorer in-hospital outcomes and higher short-term mortality than those without tolvaptan use. https://clinicaltrials.gov/ct2/show/NCT02334891 (NCT02334891) and https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017241 (UMIN000015238).

#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.

#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.

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.

Predictors of in-hospital mortality in elderly patients with heart failure treated with tolvaptan.

We conducted an analysis of first-time tolvaptan users (≥80 years old) to determine the factors associated with the prognosis of elderly patients with heart failure. We retrospectively analyzed 66 consecutive patients with worsening heart failure (aged ≥80 years) who were admitted to Fujita Health University Bantane Hospital from 2011 to 2016 and treated with tolvaptan. Differences between the in-hospital death and survival groups were evaluated. Multivariate logistic regression analysis was also performed to identify the risk factors for mortality. Sixty-six patients were included, and 26 patients died during the index hospitalization. The patients who died had a significantly higher prevalence of ischemic heart disease; a higher heart rate; higher levels of plasma C-reactive protein, blood urea nitrogen (BUN), and creatinine; a lower serum albumin level; and a lower estimated glomerular filtration rate than surviving patients. The proportion of patients requiring early initiation of tolvaptan treatment (within 3 days of admission) was significantly higher in surviving patients. On the basis of multivariate logistic regression analysis, although a high heart rate and high BUN levels were independent factors for in-hospital prognosis, they were not significantly associated with the early use of tolvaptan (≤3 days vs. ≥4 days; odds ratio=0.39; 95% confidence interval=0.07-2.21; p=0.29). This study revealed that a higher heart rate and higher BUN levels were independent factors for in-hospital prognosis in elderly patients who received tolvaptan and that early tolvaptan use may not always be effective in elderly patients.

Prognostic Impact of the Early Use of Tolvaptan in Elderly Patients with Acute Decompensated Heart Failure.

The number of elderly patients with acute decompensated heart failure (ADHF) is increasing, and it is often difficult to treat. This study aimed to evaluate the efficacy and safety of using tolvaptan early after hospitalization in elderly patients with ADHF and the prognosis one year after hospitalization. This study enrolled 185 patients with ADHF who were admitted for the first time. Tolvaptan was administered within 24 h after admission. These patients were assigned to two groups: over 80 years old (n = 109) and under 80 years old (n = 76). There were no significant differences between the two groups in the occurrence of MACCE within one year (25% vs. 20%, p = 0.59). All-cause mortality was significantly higher in the over-80 group (12% vs. 2%, p = 0.01). There were no significant differences in the incidence of worsening renal failure (11% vs. 7%, p = 0.46) and hypernatremia (5% vs. 9%, p = 1.0), and in the duration of hospitalization (19.2 days vs. 18.8 days, p = 0.8). Tolvaptan might be effective and safe in elderly patients with ADHF, and there was no difference in the incidence of MACCE within one year.

Drug repurposing in autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease is characterized by progressive kidney cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the only drug approved to treat patients with autosomal dominant polycystic kidney disease who have rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of autosomal dominant polycystic kidney disease is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition because of its cost-efficiency and time-efficiency and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat autosomal dominant polycystic kidney disease and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.

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.