Abstract
Background/Aim: We evaluated the efficacy and safety of tolvaptan for autosomal dominant polycystic kidney disease (ADPKD) in real-world practice. Patients and Methods: 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. Results: 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. Conclusion: Tolvaptan was effective against ADPKD in a real-world setting. Moreover, the safety of tolvaptan was confirmed.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. It develops progressively, resulting in numerous enlarging cysts in both kidneys and decreased renal function. In Japan, there are estimated to be approximately 30,000 ADPKD patients, and 3-5% of ADPKD patients are on dialysis (1). ADPKD is a heterogeneous disorder resulting from mutations in two genes, PKD1 and PKD2 (2, 3). It is said that the incidence of ADPKD is about ¼,000 in Japan (1), and according to recent data, it is less than 5 per 10,000 in Europe (4). Symptom onset usually occurs between the ages of 30 to 40 years old (5). Approximately 50% of patients develop end-stage renal failure in their 60s and consequently need renal replacement therapy (6). The main clinical hallmark of ADPKD is the development of fluid-filled renal cysts, leading to organ enlargement; chronic kidney disease (CKD); and various complications, such as hypertension, liver cysts, urolithiasis, renal-cystic infections, and intracranial aneurysms (7-9).
Tolvaptan, a vasopressin V2-receptor antagonist, suppresses the binding of vasopressin to the V2-receptor in renal epithelial cells, and in animal models of ADPKD vasopressin V2-receptor blockade has been shown to inhibit the growth of renal cysts and the associated decline in renal function (10-14). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 clinical trial, a global, multicenter study that included patients from Japan, tolvaptan slowed total kidney volume (TKV) growth and the decline in renal function over a 3-year period compared with a placebo in patients with ADPKD (15). Subsequently, in 2014 Japan became the first country in the world to approve tolvaptan for the treatment of ADPKD. We retrospectively investigated the current status of ADPKD, and the efficacy and safety of tolvaptan for ADPKD patients in real-world practice.
Patients and Methods
Study subjects. This was a retrospective study, which used data extracted from electronic medical records. Twenty-seven patients who were diagnosed with ADPKD at the Department of Urology, Teikyo University Chiba Medical Center (Ichihara, Japan), between January 2014 and December 2022 were included in this study. When diagnosing ADPKD, it is important to determine the presence/absence of a family history of the disease. If there is a family history, there should be at least 3 cysts in each kidney on ultrasonography and at least 5 cysts in each kidney on computed tomography (CT) and magnetic resonance imaging (MRI). If there is no family history, CT and MRI should show at least 3 cysts in each kidney before the age of 15 years and at least 5 cysts in each kidney after the age of 16 years. However, the following diseases should also be excluded: multiple simple renal cysts, renal tubular acidosis, polycystic kidney, multilobular renal cysts, medullary cystic disease, polycystic atrophic kidney, and autosomal recessive polycystic kidney disease.
At the initial consultation, we examined the patient’s blood; performed urine analysis, brain MRI, abdominal CT, abdominal MRI, and echocardiography; checked whether the patient had any complications or a family history of ADPKD; and measured the TKV using abdominal MRI. Brain MRI was performed to confirm whether a cerebral aneurysm was present. Abdominal CT was carried out to confirm whether renal calculi, renal cystic hemorrhaging, or liver cysts were present. Echocardiography was performed to confirm the presence/absence of cardiovascular disease. At 6- to 12-month intervals, blood samples, echography, and MRI were periodically conducted, and the TKV and rate of its enlargement were measured. In cases involving a TKV of more than 750 ml and an annual TKV increase of more than 5%, as measured by MRI, the patient was indicated for treatment with tolvaptan, and hence, such treatment was initiated.
To facilitate the administration of tolvaptan, the patients were generally hospitalized for one night and two days. The patients took 15 mg tolvaptan in the evening after their admission, with instructions about adequate drinking provided, and 45 mg tolvaptan the following morning. Blood and urine samples were collected on the day of admission and the next day. During their hospitalization, the patients’ urinary volume, water consumption, weight, and blood pressure were measured, and the patients were taught to perform these measurements at home. In addition, a longitudinal analysis of blood data was performed after the start of tolvaptan treatment. Regarding renal function, the mean eGFR was evaluated for 36 months during the tolvaptan treatment. Tolvaptan was followed by dose escalation.
Ethical approval. The institutional review board of Teikyo University approved this study (TUIC- 21-204).
Statistical analysis. Statistical analyses were carried out to identify clinical parameters that differed significantly between the tolvaptan-treated group and untreated group. The results are shown as the mean±SE. The Mann–Whitney U-test and Chi-squared test were used for the statistical analyses. All analyses were performed with JMP version 10 (SAS Institute Inc., Cary, NC, USA). A probability value of <0.05 was considered statistically significant.
Results
Table I shows the patients’ background characteristics. A total of 27 patients who had been diagnosed with ADPKD were included in this study. Fourteen patients (12 males, 2 females) were prescribed tolvaptan. At diagnosis, the eGFR was inversely correlated with the TKV (p=0.048) (Figure 1). In the tolvaptan-treated group, the mean age, eGFR at the initial treatment, duration of tolvaptan treatment, and pretreatment TKV were 60 years, 45.6, 2.8 years, and 2,390 ml, respectively. The pretreatment CKD grade was available for all patients: 1 case, grade 2; 6 cases, grade 3a; 6 cases, grade 3b; and 1 case, grade 4 (Table I). The mean period from the initial consultation to the start of tolvaptan treatment was 19 months. The duration of hospitalization was 2 days, and there were no cases in which longer hospitalization was required. All patients were able to take 60 mg tolvaptan.
At both one day and one month after the start of tolvaptan treatment, the patients’ renal dysfunction had slightly deteriorated (p=0.58), and their serum sodium concentrations had significantly increased (p=0.03) (Table II). During tolvaptan treatment, the patients’ eGFR tended to have decreased at one month, but it had increased after 3 months. After one year’s tolvaptan treatment, the patients’ eGFR exhibited a mean reduction of −5.5 ml/min/1.73 m2. Moreover, the mean eGFR tended to decrease until 24 months, but it was increased at 36 months (Figure 2). A maximum dose of 120 mg was administered in four cases. Of the 14 eligible patients, tolvaptan was discontinued in two patients. One patient self-discontinued, and the other patient was referred for hemodialysis due to deterioration of renal function. There were no adverse events, and hence, it was considered that tolvaptan treatment is safe.
Discussion
The present study involved a retrospective investigation of tolvaptan treatment for ADPKD in real clinical practice at a single institution. There have been two previous reports about such treatment in a real-world setting (16, 17), and there has been only one study involving more than 10 cases (17). Therefore, we proudly declare that this study is very valuable. Moreover, this study showed the efficacy and safety of tolvaptan treatment. However, due to the observed increases in the patients’ serum sodium concentrations, it is suggested that it is necessary to perform blood sampling analyses on the day after the start of tolvaptan treatment and then periodically.
The TEMPO 3:4 phase III clinical trial was conducted to evaluate the efficacy of tolvaptan treatment over 3 years (15). Subsequently, in 2014, Japan became the first country in the world to approve tolvaptan for the treatment of ADPKD. Furthermore, the Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) trail revealed that tolvaptan resulted in a slower decline in the eGFR over a 1-year period in patients with later-stage ADPKD than a placebo (18). In the practical guidelines for PKD in Japan, tolvaptan treatment was recommended as a grade 1A treatment for ADPKD patients whose disease is expected to progress rapidly.
The starting dose of tolvaptan is set at 60 mg/day (morning: 45 mg, evening: 15 mg). The initial round of treatment must occur in a hospitalized setting. Then, after checking that it is appropriate for the patient, the dose should be gradually increased to 90 mg/day and then 120 mg/day, with an interval of at least one week between each increase. In addition, to check for hypernatremia and liver dysfunction, laboratory blood analyses must be performed at least once a month. At our institution, the length of hospital stay required for the initial treatment is, as a rule, one night and two days, and none of the patients in this study required longer hospital stays. It has been reported that daily urine output was 8,000 ml after the administration of 60 mg/day tolvaptan (19), thus sufficient guidance regarding water consumption must be provided. There are no clear criteria regarding at what level of renal function tolvaptan treatment should be initiated. As advanced CKD can increase in stage relatively quickly, we suggest that tolvaptan treatment should be started in patients with CKD3a. Torres et al. reported that the difference in the reduction in renal function between their tolvaptan-treated patients and their placebo-treated patients was greatest among patients with CKD stage 3a, which supports our findings (18).
With regard to the efficacy of tolvaptan, in our patients the mean reduction in the eGFR seen after one year of tolvaptan treatment was −5.5 ml/min/1.73 m2. Although this was greater than the decline in the eGFR seen after one year’s tolvaptan treatment in the REPRISE trial, the mean eGFR observed after 3 years’ tolvaptan treatment was similar to that seen after the 1st year. Thus, renal function was maintained at roughly the same level for 36 months from the start of treatment. This appeared to be due to the appropriate administration of tolvaptan. In future studies, it will be important to extend the duration of the observation period and evaluate more cases. The increases in the serum sodium concentration seen at 1 day and 1 month after the start of tolvaptan treatment were within the normal range and did not result in the discontinuation of tolvaptan. Furthermore, the patients did not experience liver dysfunction, and hence, the tolvaptan treatment could be continued. There were two cases of discontinuation, one of which involved the initiation of hemodialysis due to the deterioration of the patient’s renal function, whereas the other case involved self-discontinuation. In the case in which hemodialysis was initiated, it was considered that the patient’s renal function had deteriorated early because they had CKD stage 4 disease and a TKV of 5,800 ml at the start of treatment. Therefore, tolvaptan treatment in patients with large TKV should be examined further. As there was a case of self-discontinuation, we consider that it is important to verify each patient’s understanding of tolvaptan.
We would like to emphasize several limitations of our study. First, it was a retrospective cohort study, which involved the extraction of electronically stored clinical data, and the sample size was small. However, ADPKD is a hereditary disease, and thus the number of available patients is limited. Therefore, the present study is considered to be highly meaningful, despite the small number of cases. It will be necessary to establish a system in which cases are intensively gathered at a single institution, and it will also be necessary to hire and educate doctors in the treatment of ADPKD. Second, the timing and intervals for increasing the dose of tolvaptan have not yet been standardized. The present study demonstrated that the deterioration of renal function was prevented for 3 years after the start of tolvaptan treatment. Consequently, we were able to verify the renal function- protecting effects of increasing the dose of tolvaptan. It is expected that physician-led tolvaptan escalation will facilitate better management of ADPKD patients. Third, in this study, we could only evaluate the patients by collecting blood samples. Since ADPKD is a hereditary disease, the environment surrounding the patient, including their blood relations, should also be considered. It is also necessary to provide patient care, including genetic counseling, to patients’ children.
Conclusion
The present study demonstrated that the administration of tolvaptan for ADPKD in real-world practice at a single institution was effective and safe in terms of its ability to preserve renal function. In the future, we must examine the timing of the initiation of tolvaptan treatment, the timing of tolvaptan dose escalation, the psychological care of patients, and patients’ environments.
Footnotes
Authors’ Contributions
HM designed the study and acquired the data. HM prepared and edited the article. NS, KS, AO, KH, TS, KA, SK, and YN were involved in the patient care and reviewed the electronic records. All of the Authors have read and approved the article.
Conflicts of Interest
The Authors state that they have no conflicts of interest relating to this study.
- Received January 13, 2023.
- Revision received January 18, 2023.
- Accepted January 19, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).