Tolvaptan Treatment Research Articles

#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<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>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.

#3034 PHASE 3 TRIAL OF TOLVAPTAN IN PEDIATRIC AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): TWO YEARS OF DATA FROM AN OPEN-LABEL EXTENSION

Abstract Background and Aims The 1-year, randomized, placebo-controlled phase (Phase A) of a 2-part trial of tolvaptan in children/adolescents with ADPKD (NCT02964273) demonstrated acceptable safety/tolerability and evidence of vasopressin V2 receptor antagonism. A 2-year, open-label extension (Phase B) evaluated longer-term outcomes. Method By entry criteria, participants at Phase A baseline were aged 4-17 years, had a diagnosis of ADPKD, estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, and body weight ≥20 kg. Participants in the tolvaptan and placebo arms who completed Phase A could enter Phase B to receive open-label tolvaptan for 24 months. Dosing was based on body weight and tolerability, with tolvaptan re-initiated in participants who had received tolvaptan in Phase A to preserve the blind until Phase A completion. Phase B post-baseline study visits occurred at Week 1, Months 1, 6, 12, 18, and 24. Laboratory assessments to monitor safety were performed monthly, with more frequent liver function testing if any indication of liver injury was detected. eGFR and height-adjusted total kidney volume (htTKV) were calculated using the mixed model repeated measures method with model terms treatment, visit, treatment by visit, and baseline by visit interaction. To exclude the acute hemodynamic effect of tolvaptan, change in eGFR after week 1 of treatment is shown. Results Of 83 Phase A completers, 81 (42 prior tolvaptan, 39 prior placebo) enrolled in Phase B; 33/42 (78.6%) prior tolvaptan and 30/39 (76.9%) prior placebo participants completed the Phase B Month 24 visit on tolvaptan. The average daily tolvaptan dose was 41.1 mg in the prior tolvaptan group (mean [SD] age 14.3 [3.2] years) and 38.0 mg in the prior placebo group (13.9 [2.9] years). Adherence determined by returned drug was ≥90% in 32/42 (76.2%) participants in the prior tolvaptan group and 28/39 (71.8%) in prior placebo. In Phase A, eGFR increased in the tolvaptan group and decreased in the placebo group (significant difference at Month 6), with significant benefit maintained at most assessment visits in Phase B for the prior tolvaptan group compared to the prior placebo group (Figure 1A). Growth in htTKV on MRI (participants ages 12-17) was slowest during the first year of tolvaptan treatment, as shown by the slope of htTKV during Phase A in the tolvaptan group and during year 1 of Phase B in the prior placebo group (Figure 1B), with growth rates higher thereafter, although sample sizes did not permit meaningful statistical comparison of the changes. Scores on pediatric health-related quality of life assessment instruments, including the PedsQL Generic Core Scale and the PedsQL Multidimensional Fatigue Scale, remained stable during both phases and indicated low health-related quality of life burden and high functioning. The most common adverse events in Phase B (>15% participants overall; prior tolvaptan and prior placebo, respectively) were headache (36%, 44%), nasopharyngitis (26%, 33%), rhinitis (26%, 10%), oropharyngeal pain (21%, 18%), pyrexia (19%, 18%), cough (17%, 21%), abdominal pain (12%, 31%), polyuria (5%, 33%). Eleven participants overall experienced elevated liver enzymes by investigator report (no prespecified enzyme levels were required to report an event): 6 recovered without intervention, treatment was interrupted in 4, and in 1 tolvaptan was withdrawn for a reason other than the hepatic event. No participant met predefined laboratory criteria for serious drug-induced liver injury in either phase. There were no notable differences between prior tolvaptan and prior placebo in Tanner staging progression or change from baseline in growth percentile in Phase B. Conclusion Consistent with adult data in the TEMPO 3:4 and TEMPO 4:4 trials, children and adolescents who received tolvaptan during a randomized trial exhibited eGFR benefit relative to those who received placebo, a difference that was preserved during a 2-year, open-label extension. As in adults, kidney volume growth was higher after 1 year of treatment. Tolvaptan exhibited acceptable safety and good tolerability, with few discontinuations and a low quality of life burden.

Copeptin in autosomal dominant polycystic kidney disease: real-world experiences from a large prospective cohort study.

The identification of new biomarkers in autosomal-dominant polycystic kidney disease (ADPKD) is crucial to improve and simplify prognostic assessment as a basis for patient selection for targeted therapies. Post hoc analyses of the TEMPO 3:4 study indicated that copeptin could be one of those biomarkers. Copeptin was tested in serum samples from patients of the AD(H)PKD study. Serum copeptin levels were measured using a time-resolved amplified cryptate emission (TRACE)-based assay. In total, we collected 711 values from 389 patients without tolvaptan treatment and a total of 243 values (of which 64 were pre-tolvaptan) from 94 patients on tolvaptan. These were associated with rapid progression and disease-causing gene variants and their predictive capacity tested and compared with the Mayo Classification. As expected, copeptin levels showed a significant negative correlation with estimated glomerular filtration rate (eGFR). Measurements on tolvaptan showed significantly higher copeptin levels (9.871pmol/L vs 23.90pmol/L at 90/30mg; P<.0001) in all chronic kidney disease stages. Linear regression models (n=133) show that copeptin is an independent predictor of eGFR slope. A clinical model (including eGFR, age, gender, copeptin) was nearly as good (R2=0.1196) as our optimal model (including height-adjusted total kidney volume, eGFR, copeptin, R2=0.1256). Adding copeptin to the Mayo model improved future eGFR estimation. Copeptin levels are associated with kidney function and independently explained future eGFR slopes. As expected, treatment with tolvaptan strongly increases copeptin levels.

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.

Total body fluid is the factor that affects the pharmacokinetics of tolvaptan, and its efficacy, in acute worsening heart failure patients.

The optimal starting dose of tolvaptan to effectively improve fluid retention in patients with heart failure (HF) is unknown. This study explored the factors affecting the pharmacokinetics (PKs) and pharmacodynamics of tolvaptan in patients with decompensated HF. We prospectively enrolled patients who were slated to receive tolvaptan because of volume overload associated with chronic HF. Blood samples were collected to measure tolvaptan concentrations before and 4, 8, 12-15, 24, and 144 h after administration. Additionally, demographic parameters, coadministered drugs, and body fluid composition were evaluated. Multiple regression analysis to detect PK parameters for the prediction of body weight (BW) loss at day 7 after the initiation of tolvaptan treatment and PK analysis to explore the factors affecting the PKs of tolvaptan were performed. In total, 165 blood samples were obtained from 37 patients. The predictors of weight loss on day 7 were area under the curve (AUC0-∞ ) of tolvaptan. PK analysis of the data revealed a strong correlation between CL/F and Vd/F, but no correlation between CL/F and kel (r = .95 and .06, respectively). A significant correlation was observed between total body fluid and Vd/F, and this correlation remained statistically significant even after adjusting for BW (r = .49, p < .05). Fat was also significantly correlated with Vd/F before adjusting for BW, on the other the correlation disappeared after adjusting BW. The optimal dose of tolvaptan based on total body fluid levels in individual patients could result in the alleviation of fluid retention in patients with HF.

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

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

Comment on: Benefits of tolvaptan on early dyspnea relief in patients with acute heart failure: A meta-analysis.

Comment on: Benefits of tolvaptan on early dyspnea relief in patients with acute heart failure: A meta-analysis.

Efficacy and safety of tolvaptan for refractory fluid collection and edema in the terminal cancer patients.

Tolvaptan, a vasopressin V2 receptor antagonist, is an oral diuretic. Patients with terminal cancer develop marked fluid retention, and oral diuretics other than tolvaptan have been used as treatments without clear therapeutic effects. Herein, we aimed to study the efficacy and safety of tolvaptan in patients with terminal cancer. Tolvaptan was administered at a dose of 7.5mg/day to 29 patients (median, 72 years) between August 2017 and February 2020. The duration of tolvaptan treatment ranged from 1 to 85 days (mean, 18.5 days). Median albumin (Alb) and transthyretin (TTR) levels on admission were 2.3g/dL (1.2-4.2g/dL) and 8.9mg/dL (2.1-38.2g/dL), respectively. Median Alb and TTR levels 1 month after treatment initiation remained at 2.3g/dL (0.8-2.9g/dL) and 8.6mg/dL (0.8-23.7mg/dL), respectively. Regarding renal function indicators, median blood urea nitrogen (BUN) and creatinine levels on admission were 19.9mg/dL (8.6-49.3mg/dL) and 0.81mg/dL (0.38-2.25mg/dL), respectively. Median BUN and creatinine levels 1 month after treatment initiation were 23.4mg/dL (13.5-34.0mg/dL) and 0.91mg/dL (0.39-2.41mg/dL), respectively. No patients had hypernatremia on admission, and no effects of tolvaptan on the blood sodium level were found 1 month after treatment initiation. The median potassium level on admission was 4.2mEq/dL (2.9-5.0mEq/dL); tolvaptan treatment had no effects on blood potassium level. Tolvaptan is effective and safe for treating fluid retention refractory to conventional diuretics in patients with terminal cancer.

PS-C26-10: THE PROPKD SCORE IS ASSOCIATED WITH THE PROGRESSION OF RENAL INVOLVEMENT IN PATIENTS WITH POLYCYSTIC KIDNEY DISEASE TREATED WITH TOLVAPTAN

Background: The PROPKD score has been proposed to evaluate the risk of the progression to end stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD), based on gender (male: 1point), hypertension under 35 years old (2 points), urological event under 35 years old (2 points), and gene mutation (PKD1 truncating mutation: 4 points, PKD1 non-truncating mutation: 2 points, PKD2: 0 point). Although tolvaptan has benefits for renal involvement, whether PROPKD score could predict future renal involvement in patients with ADPKD treated with tolvaptan is unknown. Thus, we explored the effects of tolvaptan on the annual changes in total kidney volume (%TKV) and estimated glomerular filtration rate (%eGFR) according to the PROPKD score in these patients. Methods: 32 ADPKD patients treated tolvaptan for at least a year were retrospectively analyzed (the mean observation period: 3.6 years). We examined the decline in renal function, %TKV by computed tomography, and gene mutation. The association between %eGFR and %TKV change before and after tolvaptan treatment, annual TKV change (%TKV) and PROPKD score was analyzed. Results: We identified gene mutations in ADPKD patients: PKD1 truncating mutation (n = 15), PKD1 non-truncating mutation (n = 5), PKD2 mutation (n = 6), and mutation not found (n = 6). Mean %TKV and eGFR were 1843 ± 986 ml and 54.7 ± 21.0 ml/min/1.73 m2, respectively. The mean PROPKD score was 3.3 ± 2.4 points and showed a significant negative correlation with %eGFR before and after tolvaptan treatment (p = 0.044/0.016), and no significant correlation with %TKV before and after tolvaptan treatment. Conclusion: The higher PROPKD score, the faster the decrease in %eGFR during tolvaptan therapy, suggesting that the PROPKD score may be useful as a predictor of the risk of progression to renal failure after tolvaptan introduction.

Efficacy and Safety of Tolvaptan for Patients With Autosomal Dominant Polycystic Kidney Disease in Real-world Practice: A Single Institution Retrospective Study.

We evaluated the efficacy and safety of tolvaptan for autosomal dominant polycystic kidney disease (ADPKD) in real-world practice. We retrospectively reviewed the cases of 27 patients who had been diagnosed with ADPKD between January 2014 and December 2022. Among them, 14 patients received tolvaptan (60 mg/day; morning: 45 mg, night: 15 mg) after being admitted for 2 days. In the outpatient clinic, blood and urine samples were taken monthly. The mean age, pretreatment estimated glomerular filtration rate (eGFR), treatment duration, and total kidney volume were 60 years, 45.6 ml/min/1.73 m2, 2.8 years, and 2,390 ml, respectively. One month later, the patients' renal dysfunction had worsened slightly, and their serum sodium concentrations had significantly increased. After one year, the mean reduction in the eGFR was -5.5 ml/min/1.73 m2 Moreover, at 3 years the patients' renal function was stable. No hepatic dysfunction or electrolyte abnormalities were noted, although discontinuation occurred in two cases. Tolvaptan treatment is considered to be safe. Tolvaptan was effective against ADPKD in a real-world setting. Moreover, the safety of tolvaptan was confirmed.

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

We investigated the factors associated with readmission in patients with congestive heart failure (HF) receiving long-term administration of tolvaptan (TLV) to support treatment decisions for HF. This retrospective cohort study included 181 patients with congestive HF who received long-term administration of TLV. Long-term administration of TLV was defined as the administration of TLV for 60 days or longer. The outcome was a readmission event for worsening HF within 1 year after discharge. Significant factors associated with readmission were selected using multivariate analysis. To compare the time to readmission using significant factors extracted in a multivariate analysis, readmission curves were constructed using the Kaplan-Meier method and analysed using the log-rank test. The median age was 78 years (range, 38-96 years), 117 patients (64.6%) were males, and 77 patients (42.5%) had a hospitalisation history of HF. Readmission for worsening HF within 1 year after long-term TLV treatment occurred in 62 patients (34.3%). In the multivariate analysis, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (odds ratio, 3.22; 95% confidence interval, 1.661-6.249; P = 0.001) was an independent significant factor. When eGFR at discharge was divided into two groups (eGFR < 30 vs. eGFR ≥ 30), readmission rates within 1 year were 53.3% vs. 25.4%, respectively (P = 0.001). We revealed that eGFR was strongly associated with readmission in patients with HF who received long-term administration of TLV. Furthermore, we showed that eGFR is an important indicator in guiding treatment of HF in patients receiving TLV.

The role of tolvaptan in pulmonary hypertension: A retrospective study.

Pulmonary hypertension (PH) is a severe form of pulmonary vascular disease that can lead to right heart failure (RHF). Nearly 2-thirds of patients with PH die within 5 years. Studies suggest that a new diuretic medication, called tolvaptan (TLV), can be used to treat PH. However, there is still insufficient evidence to confirm its effectiveness. Therefore, we investigated the role of TLV in patients with PH. This retrospective study included 73 patients with PH hospitalized in Shanghai Pulmonary Hospital between November 2019 and March 2022. All patients received 7.5 to 15.0 mg of TLV for 3 to 21 days starting at admission, in addition to targeted drugs and traditional diuretic therapy. The outcomes included the blood pressure, urine and water intake volumes, electrolyte concentrations, and renal, liver, and cardiac function indexes before and after TLV treatment. In addition, we assessed the clinical symptoms and adverse reactions during the treatment. After TLV treatment, the water intake and urine volumes significantly increased, and body weight, diastolic blood pressure (DBP) and mean arterial pressure significantly decreased. Total bilirubin, direct bilirubin, N-terminal pro-brain natriuretic peptide, and serum uric acid (UA) levels after TLV treatment were significantly lower than before treatment. After TLV treatment, dyspnea significantly improved in 71 of 73 patients, and lower limb edema disappeared in 42 of 53 patients. No obvious adverse reactions occurred during the TLV treatment period. These results suggest that adding TLV to targeted drug and traditional diuretic therapies is effective for patients with PH. However, more data are required to support these findings.

The Analysis of Long-Term Course of Tolvaptan Treatment and the Study Using Kidney and Liver Derived Cyclic AMP in Autosomal Dominant Polycystic Kidney Disease

The Analysis of Long-Term Course of Tolvaptan Treatment and the Study Using Kidney and Liver Derived Cyclic AMP in Autosomal Dominant Polycystic Kidney Disease

Tolvaptan treatment is associated with altered mineral metabolism parameters and increased bone mineral density in ADPKD patients.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a unique bone and mineral phenotype. The impact of tolvaptan treatment on mineral metabolism and bone mineral density (BMD) is unknown. We conducted an analysis in the Bern ADPKD Registry, a prospective observational cohort study. Mineral metabolism parameters were measured at baseline and every 12months thereafter. BMD was determined by dual-energy X-ray absorptiometry at baseline and after 3years. Multivariable mixed-effects regression models were applied to assess changes in mineral metabolism parameters and BMD associated with tolvaptan treatment. A total of 189 participants (122 without and 67 with subsequent tolvaptan treatment) were included in the analysis. During follow-up, tolvaptan treatment was associated with increased BMD at the femoral neck {β=0.092 [95% confidence interval (CI) 0.001-0.183], P=.047}. In addition, tolvaptan treatment was associated with higher plasma magnesium [β=0.019 (95% CI 0.001-0.037), P=.037], bicarbonate [β=0.972 (95% CI 0.242-1.702), P=.009] and urine pH [β=0.214 (95% CI 0.056-0.372), P=.008] and lower parathyroid hormone [β=-0.191 (95% CI -0.328 to -0.053), P=.006], 1,25(OH)D3 [β=-0.126 (95% CI -0.235 to -0.164), P=.024] and fractional urinary magnesium excretion [β=-0.473 (95% CI -0.622 to -0.324), P<.001]. Chronic tolvaptan treatment is associated with increased femoral BMD and significant changes in both mineral metabolism and acid-base parameters in ADPKD patients.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease

BackgroundTolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking.MethodsA model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death.ResultsWhen treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively.ConclusionsThe model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.

Outcomes from the Northeast England cohort of autosomal dominant polycystic kidney disease (ADPKD) patients on tolvaptan.

Autosomal dominant polycystic kidney disease (ADPKD) is a cause of end-stage kidney disease (ESKD). The vasopressin V2-receptor antagonist tolvaptan has been shown within randomized clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a Northeast England cohort of adult ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real-world clinic setting. Other inclusion criteria involved a pre-treatment decline in greater than 2.5 ml/min/1.73m2/year based on readings for a 3 year period, and ability to tolerate and maintain tolvaptan treatment for at least 12 months. We calculated based on eGFR slopes, predicted time to reach ESKD with and without tolvaptan therapy. The cohort of patients included 21 from the Northeast of England. The mean rate of eGFR decline prior to treatment was -6.02 ml/min/1.73m2/year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.47 ml/min/1.73m2/year, gaining a mean 8 years and 4 months delay to reach ESKD. The majority of patients (n=19) received and tolerated full dose tolvaptan (90 mg/30 mg). The real-life use of tolvaptan gave a dramatic improvement in eGFR slopes, much more than previously reported in clinical studies. These effects may be in part due to careful patient identification, selection and inclusion of patients who were able to tolerate tolvaptan therapy, excellent compliance with medication and a "tolvaptan clinic" effect where great personal care was given to these patients.

Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD patients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors. Methods: This is an observational retrospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demographics, treatment dose, and reported symptoms were collected from October 2018 to March 2021. Results: Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%), and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients had elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%). Conclusion: We pre­sent the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clinical implications and the pathophysiological mechanism of CK elevation in this population.

Benefits of tolvaptan on early dyspnea relief in patients with acute heart failure: A meta-analysis.

Considering the prevalence of dyspnea in acute heart failure (AHF), its reduction is important to both patients and caregivers. This meta‐analysis was performed to determine the efficacy and safety of tolvaptan on early dyspnea relief in patients with AHF. A systematic search was made of PubMed, Embase, Web of Science, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of AHF with tolvaptan, compared with placebo or blank, were reviewed. Studies were pooled to relative risk (RR), with 95% confidence interval (CI). Five RCTs (enrolling 4857 participants) met the inclusion criteria. Tolvaptan presented significant effects on 12 h dyspnea relief (RR: 1.98; 95% CI: 1.24−3.15; p = .004), 24 h/day 1 dyspnea relief (RR: 1.15; 95% CI: 1.07−1.24; p = .0003), 48 h dyspnea relief (RR: 1.20; 95% CI: 1.06−1.36; p = .004), and 72 h dyspnea relief (RR: 1.18; 95% CI: 1.02−1.37; p = .03). No significant increase was noticed in the incidence of worsening renal function in tolvaptan group (RR: 1.10; 95% CI: 0.87−1.39; p = .43). Tolvaptan treatment significantly improved patient‐assessed dyspnea early and persistently in patients with AHF.

Cisterna chyli as an optimal marker of tolvaptan response in severe cirrhotic ascites

For patients with cirrhosis, no definitive predictor of the efficacy and prognosis of tolvaptan treatment exists. We assessed the cisterna chyli’s utility as an optimal marker. We retrospectively enrolled 172 patients with cirrhosis. The effect of tolvaptan was evaluated using post-treatment survival time. The overall response to tolvaptan was 52.3%. The median cisterna chyli diameter was 4.1 mm. Of 172 patients, 100 were included in the pilot set and 72 in the validation set. According to the Youden index, the cisterna chyli diameter’s cutoff value was 4 mm, with a sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of 92%, 83%, 86%, 91%, 5.43, and 0.09, respectively, in the pilot set. The area under the curve of the cisterna chyli diameter for evaluating tolvaptan’s effect was 0.911 and 0.988 in the pilot and validation sets, respectively. During multivariate analysis, cisterna chyli narrowing and furosemide treatment were significant predictive factors for tolvaptan’s insufficient effect. Cumulative liver transplantation-free survival rates were significantly higher in patients with cisterna chyli dilatation than in those without (p = 0.028). Our findings suggest a strong association of cisterna chyli with tolvaptan treatment response in patients with cirrhosis and hepatic edema.

MO009: Creatine-Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment

Abstract BACKGROUND AND AIMS Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side-effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD patients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors. METHOD This is an observational prospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demographics, treatment dose and reported symptoms were collected from October 2018 to March 2021. RESULTS Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%) and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%). CONCLUSION We present the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clinical implications and the pathophysiological mechanism of CK elevation in this population.