Efficacy Of Tolvaptan Research Articles

Efficacy and safety of tolvaptan in acute heart failure patients during long-distance transportation.

Treating patients with acute heart failure is difficult at the local hospitals in medically depopulated areas where cardiologists are generally absent. These patients require long-distance and time-consuming transportation to the intensive care units. It is well known that tolvaptan is effective for the treatment of congestive heart failure, but the effect of prehospital tolvaptan use in patients is not well evaluated. The aim of this study was to evaluate the efficacy and safety of prehospital tolvaptan use in patients with acute congestive heart failure who require long-distance and time-consuming transportation. This retrospective study included 30 patients who were newly diagnosed with acute heart failure at Wakkanai City Hospital and transported to Nayoro City General Hospital between January 2013 and May 2020. The patients were classified into those who received tolvaptan (tolvaptan group, n=18) and did not receive tolvaptan (control group, n=12). The percentage of patient survival at discharge did not show a statistically significant difference between the groups (100% [tolvaptan] vs. 91% [control], p=0.414). During transportation, the percentage of patients in the tolvaptan group who required increased oxygen doses was statistically significantly lower than that in the control group (0% vs. 36%, p=0.0181). Patients in the tolvaptan group had statistically significantly shorter intensive care unit stays (median: 2days vs. 6days, p=0.0376), less days to discontinuation of oxygen (median: 2.8days vs. 6.9days, p<0.00125), and less days to ambulation (median: 1.5days vs. 7.5days, p=0.0362) compared with the control group. In the tolvaptan group, blood pressure was not different; however, heart rate was statistically significantly reduced (99±21 vs. 88±21 beats per minute, p=0.016) during transportation. The use of tolvaptan in patients with acute heart failure requiring long-distance transport is safe and may show better clinical course compared with conventional therapies.

Serum Copeptin and Zinc-α2-glycoprotein Levels Are Novel Biomarkers of Tolvaptan Treatment in Decompensated Cirrhotic Patients with Ascites.

Objective The efficacy of tolvaptan, an orally active vasopressin V2-receptor antagonist, has recently been reported in patients with massive ascites unresponsive to conventional diuretics. However, the effect of tolvaptan varies among patients. Recently, the prognostic role of the tolvaptan response in cases of decompensated liver cirrhosis (LC) has been attracting increasing attention. Using serum copeptin (vasopressin precursor), zinc-α2-glycoprotein (ZAG), cystatin C (renal biomarker), neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP), we explored which factors portend a good response to tolvaptan in LC patients with ascites. Methods We enrolled 113 LC patients and divided them into the tolvaptan treatment group and non-treatment group. Tolvaptan (3.75 or 7.5 mg/day) was administrated to 38 LC patients with ascites, and a follow-up assessment was performed after a 7-day tolvaptan treatment regimen. Results We determined the predictive ability for kidney and/or liver damage of serum copeptin, ZAG, cystatin C, NGAL and L-FABP levels in all patients. After 7-day tolvaptan treatment, 19 patients had lost more than 1.5 kg of body weight (Responders), while 19 showed no marked change in their body weight (Non-responders). Basal blood urea nitrogen (BUN) (p=0.0014), serum copeptin (p=0.0265) and serum ZAG levels (p=0.0142) were significantly higher in the Non-responders than in the Responders. BUN (odds ratio 7.43, p=0.0306), copeptin (odds ratio 9.12, p=0.0136) and ZAG (odds ratio 7.43, p=0.0306) were determined to be predictive factors of drug responsiveness using a multivariate logistic regression analysis. Conclusion Serum BUN, copeptin and ZAG levels predict the patient response to tolvaptan, even when measured prior to treatment.

Right ventricular contractility affects the clinical efficacy of add-on tolvaptan following hospitalization for heart failure in patients with significant tricuspid regurgitation.

Tricuspid regurgitation (TR) is a common condition that is independently associated with high mortality rates in patients with heart failure (HF). Several studies have demonstrated the clinical efficacy of add-on tolvaptan in patients hospitalized for HF. However, the effects of add-on tolvaptan in patients with significant TR are less well understood. Among the patients with moderate-to-severe TR assessed by transthoracic echocardiography during hospitalization for congestive HF, 39 patients who could complete the clinical course after starting add-on tolvaptan were included in the study. Rehospitalization due to HF and cardiac death were defined as adverse cardiac events in this study. We investigated the presence or absence of cardiac events within 2years following the introduction of tolvaptan and evaluated echocardiographic functional parameters associated with cardiac events. The average patient age was 75 ± 14years, and 23 patients (59%) experienced adverse cardiac events within 2years after add-on tolvaptan administration. Serum creatinine (mg/dL) and brain natriuretic peptide (pg/mL) concentrations at discharge were significantly higher in patients with cardiac events than in those without cardiac events {1.48 [1.02-1.58] vs. 1.07 [0.79-1.41], p = 0.03; 526 [414-1044] vs. 185 [104-476], p = 0.01, respectively}. The presence or absence of past hospitalization for HF was also significantly higher in the event-positive group compared to event-free group (78 vs. 44%, p = 0.04). Comparison of echocardiographic parameters revealed that patients with cardiac events had a significantly lower left ventricular ejection fraction (40 ± 16 vs. 49 ± 15%, p = 0.049) and lower right ventricular fractional area change (RVFAC) (35 ± 12 vs. 45 ± 10%, p = 0.008) than those without cardiac events. Multiple logistic regression analysis revealed that RVFAC and past hospitalization for HF were independently associated with cardiac events following the introduction of tolvaptan (odds ratio, 0.934 and 4.992; p = 0.048 and 0.04, respectively). Right ventricular contractility as well as past history of admission for HF, left ventricular ejection fraction, renal function, and brain natriuretic peptide level at discharge may reflect the clinical outcomes after HF hospitalization in patients with significant TR who were treated with tolvaptan.

Effect of oral tolvaptan for 1 year in patients with functional mitral regurgitation.

The effect of the oral selective vasopressin V2-receptor antagonist tolvaptan for chronic phase therapy on patients with FMR remains unclear. We aimed to determine the efficacy of oral tolvaptan in patients with significant functional mitral regurgitation (FMR) to reduce the mortality and rehospitalization due to worsening heart failure (HF). We enrolled 219 patients (mean age 76 ± 9years, 59.4% men) who were admitted at our hospital due to congestive HF during different two 1-year periods. The patients were divided into 2 groups: those who had significant FMR (MR ≥ grade 2 [n = 76]) and those who did not (MR < grade 2 [n = 143]) at discharge. The patients were further divided into a study group that received tolvaptan during follow-up and a control group that did not receive tolvaptan. We used an inverse probability of treatment weighting method with the primary end point defined as overall all-cause mortality and rehospitalization due to worsening HF within 1year. Of the 76 patients with significant FMR at discharge, 2 of 20 (10%) who were administered tolvaptan died and 8 (40%) were readmitted to a hospital. Of the 56 patients who did not receive tolvaptan, 2 (3.5%) died and 18 (27.5%) required rehospitalization. After multiple adjustments, there were no significant differences for overall survival and rehospitalization between the groups (log-rank p = 0.700 and 0.510, respectively). Our results suggest that oral tolvaptan administration in addition to conventional diuretics had less impact on outcomes in patients with significant FMR.

A genome-wide association study identifying SVEP1 variant as a predictor of response to tolvaptan for cirrhotic ascites.

Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites. From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5kg decrease of BW) were included in the GWAS and replication study. Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR=3.55, P=2.01×10-8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR=0.92, P=.003; OR=1.02, P=.02 and OR=3.98, P=.000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234+BUN*0.077+Na*-0.179) (1+exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774. SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Safety and efficacy of Tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance

BackgroundTolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has been limited real-world data on the safety and efficacy of tolvaptan.MethodsThis post-marketing surveillance was conducted to evaluate the long-term safety and the efficacy of tolvaptan in Japanese patients with ADPKD in real-world clinical settings. The baseline characteristics of 1630 patients treated with tolvaptan are reported. Safety analysis comprises evaluation of adverse drug reactions (ADRs). The efficacy evaluation includes percent change in total kidney volume (TKV) and change in estimated glomerular filtration rate (eGFR) before and after tolvaptan treatment.ResultsMean age was 49.7 ± 11.2 years and 843 (51.7%) patients were male. Baseline TKV was 2158 ± 1346 mL and eGFR was 44.4 ± 21.7 mL/min/1.73 m2. The majority of CKD patients were stage G3b (27.0%) and G4 (30.1%). Frequently reported ADRs were hepatic function abnormal (8.3%), thirst (8.2%), and hyperuricaemia (6.9%). The frequency of ALT elevation (> 30 and > 90 IU/L) was slightly high (32.9 and 8.3%) to previous studies. After tolvaptan treatment, the annual rate of percentage change in TKV reduced from 11.68%/year to 2.73%/year (P < 0.0001). Similar results were also obtained for the effect on change in eGFR from − 3.31 to − 2.28 mL/min/1.73 m2/year after initiation of tolvaptan treatment (P = 0.0403).ConclusionThere were no major problems with safety of tolvaptan treatment and comparable efficacy for TKV and eGFR was observed in relation to the previous pivotal two randomized control trials in this post-marketing surveillance.

Efficacy and safety of tolvaptan in treatment of heart failure combined with hyponatremia after acute myocardial infarction

Efficacy and safety of tolvaptan in treatment of heart failure combined with hyponatremia after acute myocardial infarction

Overweight and Obesity and Progression of ADPKD.

On the basis of earlier observations, we evaluated the association between overweight and obesity and rapid progression of autosomal dominant polycystic kidney disease in participants in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial. More importantly, we also determined whether efficacy of tolvaptan was attenuated in individuals with baseline overweight or obesity. A total of 1312 study participants with relatively early-stage autosomal dominant polycystic kidney disease (mean eGFR 78±22 ml/min per 1.73 m2) who were at high risk of rapid progression were categorized by body mass index (BMI; calculated using nonkidney weight) as normal weight (18.5-24.9 kg/m2; n=670), overweight (25.0-29.9 kg/m2; n=429), or obese (≥30 kg/m2; n=213). Linear and multinomial logistic regression models were used to determine the association of baseline overweight and obesity with change in total kidney volume (TKV) over the 3-year study period. In fully adjusted models, higher BMI was associated with greater annual percent change in TKV (difference of 1.20 [95% confidence interval (95% CI), 0.85 to 1.55] per five-unit higher BMI). Overweight and obesity were associated with higher odds of annual percent change in TKV of ≥7% versus <5% (overweight: odds ratio, 2.04 [95% CI, 1.45 to 2.87]; obese: odds ratio, 4.31 [95% CI, 2.83 to 6.57] versus normal weight). eGFR decline did not differ according to BMI (fully adjusted difference in decline of -0.95 [95% CI, -2.32 to 0.40] ml/min per 1.73 m2 per year per five-unit higher BMI). The three-way interaction (treatment×time×BMI group) was not statistically significant in linear mixed models with an outcome of TKV (log-transformed estimated coefficient comparing the treatment effect for overweight versus normal weight: 0.56% [95% CI, -0.70% to 1.84%] per year; P=0.38; obese versus normal weight: 0.07% [95% CI, -1.47% to 1.63%] per year; P=0.93) or eGFR (estimated coefficient comparing overweight versus normal weight: -0.07 [95% CI, -0.95 to 0.82] ml/min per 1.73 m2 per year; P=0.88; obese versus normal weight: 0.22 [95% CI, -0.93 to 1.36] ml/min per 1.73 m2 per year; P=0.71). Overweight and particularly obesity are strongly and independently associated with kidney growth, but not eGFR slope, in the TEMPO 3:4 trial, and tolvaptan efficacy is irrespective of BMI categorization. Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4, NCT00428948.

POS-269 EFFICACY AND SAFETY OF TOLVAPTAN IN TYPE 4 CARDIORENAL SYNDROME Abstract paid for submission 2020-A-WCN21-0618(100985411245)

Cardiorenal syndrome poses great challenges to treating physicians. Diuretic resistance is common and adds to morbidity of these patients. Many patients do need dialysis due to this issue. Combination of diuretics had been used for diuretic resistance. There is paucity of literature on use of tolvaptan in patients with type 4 renal syndrome. Therefore we undertook this study to see for efficacy and safety of tolvaptan in patients those did not respond to maximal dose of torsemide and metolazone

Postoperative Tolvaptan Use in Left Ventricular Assist Device Implantation Patients: The TOLVAD Study

<h3>Purpose</h3> Tolvaptan, a selective vasopressin type-2 antagonist, has been shown to increase serum sodium (Na) and urine output in hyponatremic left ventricular assist device (LVAD) patients in retrospective studies. We aimed to assess the efficacy of tolvaptan in this population in a prospective, randomized study. <h3>Methods</h3> We conducted a prospective, randomized, non-blinded study of LVAD recipients with post-operative hyponatremia (Na < 135 mEq/L). Eligible patients were randomized to receive tolvaptan 15 mg daily in addition to standard care vs standard care alone. The primary outcome was change in Na level and renal function, measured by estimated glomerular filtration rate (eGFR), from the first post-operative day of hyponatremia to discharge. <h3>Results</h3> A total of 33 patients were consented, 30 of whom developed post-operative hyponatremia. Two were excluded due to new onset renal failure requiring hemodialysis prior to development of hyponatremia. Of 28 eligible patients (21% women, 54% Black, 32% ischemic cardiomyopathy) 15 were randomized to tolvaptan (TLV), and 13 were randomized to standard care alone (No-TLV). Patients in TLV had a significant increase in Na from randomization to discharge, 133 (IQR 132-134) to 135 mEq/L (IQR 134-137), <i>p</i>=0.018, while those in No-TLV did not have a significant change in Na, 133 (IQR 132-134) to 134 mEq/L (IQR 132-136), <i>p</i>=0.15 (1A). There were no significant differences in renal function in either arm of the study: eGFR 76 (IQR 51-99) to 80 mL/min/1.73m² (IQR 66-90), <i>p</i>=0.97 in TLV versus eGFR 78 (IQR 56-115) to 115 mL/min/1.73m² (IQR 56-120), <i>p</i>=0.13 in No-TLV (1B). Patients in TLV had significantly more urine output than those in No-TLV during their first 24 hours of hyponatremia (3294 vs 2155 mL, <i>p=</i>0.043) and during last 24 hours of hyponatremia prior to sodium correction (4177 vs 2739 mL, <i>p<</i>0.001) (1C). <h3>Conclusion</h3> Tolvaptan improves Na in hyponatremic post-operative LVAD patients when compared to those not receiving tolvaptan without adversely impacting renal function.

Clinical Experience of the Efficacy and Safety of Low-dose Tolvaptan Therapy in a UK Tertiary Oncology Setting.

In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy. To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy. Retrospective evaluation in a tertiary cancer center. Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ± 4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ± 9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01). In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.

The role of tolvaptan in managing hyponatremia in small cell lung cancer patients with SIADH: a retrospective study of 23 cases.

BackgroundExisting studies have shed light on the treatment of small cell lung cancer (SCLC), but data on tolvaptan for the treatment of hyponatremia in SCLC patients remain scarce. Furthermore, the most appropriate initial dose has not been identified. This study aimed to assess the effectiveness, safety, and survival rate associated with tolvaptan in regard to controlling hyponatremia in SCLC patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and to explore the appropriate initial dose.MethodsA total of 23 SCLC patients with SIADH treated with tolvaptan were retrospectively reviewed between 2011 and 2019, and the efficacy and safety of tolvaptan were evaluated and compared between a 3.75 mg dose and doses higher than 3.75 mg. Then, the Kaplan-Meier method was used to calculate overall survival (OS) and draw survival curves.ResultsIn our center, patients had a mean age of 61.7±8.2 years. The mean plasma sodium level after hypertonic saline treatment was (120.7±7.5) mmol/L. The doses of tolvaptan were distributed as follows: 3.75 mg (10 patients), 5 mg (5 patients), 7.5 mg (4 patients), and 15 mg (4 patients). After 3 days of tolvaptan treatment, the mean plasma sodium level was (136.0±4.1) mmol/L, which was significantly higher than the plasma sodium level on admission and before tolvaptan treatment (P<0.05). The mean time for tolvaptan to correct the plasma sodium level was (3.7±5.8) days, and no significant difference was found between the 3.75 mg group and the above 3.75 mg group (P>0.05). Adverse events were observed in 1 patient who presented with severe lethargy and confusion. The median OS was 14.1 months.ConclusionsIn summary, no significant difference was found between the 3.75 mg group and the above 3.75 mg group. Less than 15 mg of tolvaptan is enough to stabilize sodium levels for most patients. There is a risk of overcorrection of plasma sodium when using 15 mg of tolvaptan. Tolvaptan can quickly improve performance status and may bring survival benefits to patients. The effect of tolvaptan in patients with SCLC and SIADH should be confirmed.

Preservation of kidney function irrelevant of total kidney volume growth rate with tolvaptan treatment in patients with autosomal dominant polycystic kidney disease

BackgroundTolvaptan slowed the rates of total kidney volume (TKV) growth and renal function decline over a 3-year period in patients with autosomal dominant polycystic kidney disease (ADPKD) enrolled in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial (NCT00428948). In this post hoc analysis of Japanese patients from TEMPO 3:4, we evaluated whether the effects of tolvaptan on TKV and on renal function are interrelated.MethodsOne hundred and forty-seven Japanese patients from TEMPO 3:4 were included in this analysis (placebo, n = 55; tolvaptan, n = 92). Tolvaptan-treated patients were stratified into the responder group (n = 37), defined as tolvaptan-treated patients with a net decrease in TKV from baseline to year 3, and the non-responder group (n = 55), defined as tolvaptan-treated patients with a net increase in TKV.ResultsMean changes during follow-up in the placebo, responder, and non-responder groups were 16.99%, − 8.33%, and 13.95%, respectively, for TKV and − 12.61, − 8.47, and − 8.58 mL/min/1.73 m2, respectively, for estimated glomerular filtration rate (eGFR). Compared with the placebo group, eGFR decline was significantly slowed in both the responder and non-responder groups (P < 0.05).ConclusionTolvaptan was effective in slowing eGFR decline, regardless of TKV response, over 3 years in patients with ADPKD in Japan. Treatment with tolvaptan may have beneficial effects on slowing of renal function decline even in patients who have not experienced a reduction in the rate of TKV growth by treatment with tolvaptan.

Efficacy and safety of tolvaptan after pediatric congenital heart disease surgery.

It is not clear whether tolvaptan is safe and effective irrespective of various underlying clinical conditions including the functional ventricle morphology, chromosomal abnormalities, and renal function after complex pediatric congenital heart disease surgery. Also, the appropriate dose of tolvaptan in these patients has not been previously identified. We retrospectively assessed the urine volume, body weight, patient clinical characteristics, laboratory data, and vital signs before and on days 1 and 7 of the tolvaptan administration after congenital heart disease surgery. Also, we assessed the relationship between the tolvaptan dose and its effects. A total of 86 patients were included the study. The mean time from the surgery to the tolvaptan administration was 23.5 ± 3.7days. After administering tolvaptan, the urine volume significantly increased and body weight significantly decreased from baseline by days 1 and 7 (p < 0.0001). The urine volume significantly increased more in the survivors than the deceased. Of the 22 patients who had low serum sodium concentrations at baseline, 20 had an increased serum sodium concentration on day 7. The clinical effect of tolvaptan was not affected by the functional ventricle morphology, chromosomal abnormalities, or renal function. There was a positive correlation between the tolvaptan dose and change in the urine volume until a tolvaptan dose of up to 0.3mg/kg/day but not at more than 0.3mg/kg/day. Tolvaptan administration is safe and effective after congenital heart disease surgery irrespective of various underlying clinical conditions. Though the urine volume tends to increase until a tolvaptan dose of up to 0.3mg/kg/day in pediatric congenital heart disease patients, there was no further benefit with more than 0.3mg/kg/day.

The Efficacy and Renal Protective Effect of Tolvaptan in Chronic Kidney Disease Patients after Open-Heart Surgery.

Purpose: Unlike loop diuretics, tolvaptan is reported to have a renal protective effect. The purpose of this study was to retrospectively assess the efficacy of tolvaptan administration in chronic kidney disease (CKD) patients following open-heart surgery.Methods: From February 2017 to August 2020, 75 patients with preoperative CKD stages IIIb–V were enrolled in this study and were divided into two groups: the control group (n = 30) and the tolvaptan group (n = 45). All patients routinely received conventional diuretics starting from postoperative day (POD) 1. Tolvaptan at 7.5–15 mg/day was administered if the patients had persistent fluid retention or poor response to conventional diuretics.Results: Tolvaptan administration was initiated at a mean of POD 2.9 ± 2.2, and the mean dosing period was 4.1 ± 3.0 days. The mean time to return to the preoperative body weight in the control and tolvaptan groups was similar. However, estimated glomerular filtration rate (eGFR) was significantly increased at the time when body weight reached the preoperative level and at discharge in the tolvaptan group than in the control group.Conclusion: This study demonstrated the renal protective effect of tolvaptan even in advanced CKD patients after open-heart surgery.

Urinary exosome proteomic profiling defines stage-specific rapid progression of autosomal dominant polycystic kidney disease and tolvaptan efficacy

ADPKD is the most common genetic disease of the kidney leading to end-stage renal disease necessitating renal replacement therapy at any time between the 1st and 8th decades of life due to widely variable rates of disease progression. This presents significant patient anxiety and a significant prognostic and therapeutic challenge. Tolvaptan is the only approved drug licensed to slow ADPKD progression by reducing renal cystic expansion but side-effects can limit its efficacy.To address the need to identify new biomarkers to monitor progression of ADPKD and to evaluate the therapeutic effects of Tolvaptan, proteomic analysis was conducted on defined (40-100nm) urinary exosomes isolated from ADPKD patients phenotyped and clinically monitored over a 10-year period. Comparative Gene Ontology analysis of Tandem Mass Tag labelled mass spectrometry-derived protein profiles from urinary exosomes from ADPKD patients with rapid (>10ml/min/5 years decline in estimated glomerular filtration rate) versus slow progression showed distinctive patterns of pathway up-regulation. Clear discrimination between rapid and slowly-progressive profiles were seen in all stages functional decline in ADPKD patients whether with mild (>70ml/min), moderate (50-69ml/min) or severe (<49ml/min) disease at onset. Discriminatory pathways and proteins included Notch-, integrin- and growth factor-signalling; microtubular kinase, vesicular proteins and epidermal growth factor substrates.Confocal microscopy of fluorescently-labelled normal versus ADPKD epithelial cell-derived exosomes in vitro also identified ADPKD-dependent abnormalities in intracellular vesicular trafficking and implicated changes in ADPKD-dependent exosome secretion and target cell uptake as factors underlying urinary exosome excretion biomarker properties.Comparative proteomic analysis of urinary exosomal proteins in individual patients before and after treatment with Tolvaptan for 4 years also identified distinct patterns of pathway modification dependent on the degree of effectiveness of the therapeutic response. Up-regulation of Wnt-pathway and vesicular proteins were characteristic of urinary exosomes from ADPKD patients with good responses to Tolvaptan while upregulation of angiogenesis pathways and additional molecular forms of vasopressin receptor AVPR2 were characteristic in urinary exosomes of ADPKD patients with poor responses.Taken together, these studies conclude that proteomic profiling of urinary exosome biomarkers provides a specific, sensitive and practical non-invasive method to identify and monitor the rate of disease progression and the effects of Tolvaptan therapy in individual ADPKD patients. This provides a means to identify those patients most likely to benefit maximally from therapy and to progress towards a personalization of ADPKD prognosis and management.

A Post Hoc Analysis of Tolvaptan (TOL) Efficacy and Safety in Slowing Rate of Renal Function Decline in Subjects with Very Late-Stage Autosomal Dominant Polycystic Kidney Disease (ADPKD)

A Post Hoc Analysis of Tolvaptan (TOL) Efficacy and Safety in Slowing Rate of Renal Function Decline in Subjects with Very Late-Stage Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Furosemide as a factor to deteriorate therapeutic efficacy of tolvaptan in patients with decompensated cirrhosis.

To optimize the therapeutic strategy for patients with decompensated cirrhosis manifesting hepatic ascites and/or edema, factors affecting the outcome of patients receiving tolvaptan were evaluated. The subjects were 165 patients receiving tolvaptan including 116 patients (70%) also treated with furosemide. The therapeutic efficacy of tolvaptan was defined as "effective" when a body weight reduction of 1.5kg or more was obtained within 1week. The long-term outcome was defined as "favorable" when the ascites-related events-free duration was prolonged following tolvaptan treatment, compared with that before treatment, or ascites-related events were absent for at least 120days during treatment based on the hazard function analysis. Tolvaptan was effective in 115 patients (70%). Among them, the long-term outcome was evaluated in 99 patients and was favorable in 70 patients (71%). A multivariate analysis revealed that the serum blood urea nitrogen levels at baseline (odds ratio 0.960 per +1mg/dL, P = 0.021) and the type of tolvaptan initiation (planned vs. emergent; 3.695, P < 0.001) were associated with therapeutic efficacy, while the furosemide dose (0.280 per +20mg/day, P = 0.014) and previous ascites-related events (0.074, P < 0.001) were associated with the long-term outcome. Receiver operating curve analyses identified the optimal cut-off values for the furosemide dose as 15mg/day (P < 0.001). Furthermore, the cumulative survival rates in patients receiving furosemide at 15mg/day or less were significantly higher than those in the remaining patients (P = 0.048). Furosemide given at baseline contributed to an unfavorable outcome in patients receiving tolvaptan; consequently, tolvaptan should be given before increasing the furosemide dose.

Genetics May Predict Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Background: Tolvaptan is the only therapeutic drug for autosomal dominant polycystic kidney disease (ADPKD). The influence of mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) on the treatment effects of tolvaptan is not well documented in the literature. Methods: We retrospectively evaluated the relationship between genotype and the efficacy of tolvaptan in 18 patients with ADPKD who had been treated at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020. Results: The annual change in estimated glomerular filtration rate (ΔeGFR/y) from before to after tolvaptan was from a median of −5.5 to −2.5 mL/min/1.73 m² in the PKD1 truncating group, −3.3 to −2.4 mL/min/1.73 m² in the PKD1 non-truncating group, −3.1 to −1.6 mL/min/1.73 m² in the PKD2 group, and −1.9 to −2.6 mL/min/1.73 m² in the group with no PKD1/2 mutation. The median degrees of improvement of ΔeGFR/y were 2.5 (45%), 0.4 (10%), 0.6 (28%), and −0.7 (−37%) mL/min/1.73 m², respectively. Compared with the group of patients with any PKD1/2 mutation, the group with no PKD1/2 mutation showed significantly less improvement in ΔeGFR/y with tolvaptan (0.6 vs. −0.7 mL/min/1.73 m², respectively; p = 0.01) and significantly less improvement in the annual rate of increase in total kidney volume (TKV) with tolvaptan (−6.7 vs. −1.1%, respectively; p = 0.02). Conclusion: Patients with ADPKD and no PKD1/2 mutation showed less improvement in ΔeGFR/y and the annual rate of increase in TKV with tolvaptan. Detecting PKD1/2 mutations may be useful for predicting the effectiveness of tolvaptan.

Differences in pharmacological property between combined therapy of the vasopressin V2-receptor antagonist tolvaptan plus furosemide and monotherapy of furosemide in patients with hospitalized heart failure

BackgroundTolvaptan has been shown to improve congestion in heart failure patients. The purpose of this study was to evaluate the pharmacology and clinical efficacy of combined tolvaptan and furosemide therapy. MethodsThis study included 40 patients with systemic volume overload who were hospitalized for heart failure. Patients who showed no improvement in the condition after receiving 20 mg intravenous furosemide were included and were randomly selected to receive tolvaptan as an add-on to furosemide or to receive an increased dose of furosemide. We evaluated the bioelectrical impedance analyzer parameters, the parameters of the inferior vena cava using echocardiography, vital signs, body weight, urine output, and laboratory data for 5 days. ResultsIn the changes from baseline between intracellular water volume (ICW) and extracellular water volume (ECW) after additional use of tolvaptan or furosemide from Day 1 to Day 5, there were no significant differences observed between ICW and ECW over 5 days in the tolvaptan + furosemide group, although differences were found in the furosemide group from Day 2 onward. Changes in the respiratory collapse of inferior vena cava increased significantly, and systolic blood pressure decreased significantly only in the furosemide group. ConclusionsThe present study clearly demonstrates that combined therapy with tolvaptan and furosemide removed excess ICW and ECW to an equal extent, while furosemide alone primarily removed ECW, including intravascular water.