Literature DB >> 35176098

Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use.

Hiroki Mizuno1,2, Akinari Sekine3, Tatsuya Suwabe1, Daisuke Ikuma1, Masayuki Yamanouchi1, Eiko Hasegawa3, Naoki Sawa1, Yoshifumi Ubara1, Junichi Hoshino2,3.   

Abstract

Polycystic liver disease (PLD) is a common extrarenal complication of autosomal dominant polycystic kidney disease (ADPKD), which causes compression-related syndrome and ultimately leads to liver dysfunction. Tolvaptan, a V2 receptor antagonist, is widely used to protect kidney function in ADPKD but its effect on PLD remains unknown. An observational cohort study was conducted to evaluate tolvaptan's effect on patients with PLD due to ADPKD. After screening 902 patients, we found the 107 ADPKD patients with PLD who met the criteria of tolvaptan use in Japan. Among them, tolvaptan was prescribed for 62 patients (tolvaptan group), while the other was defined as the non-tolvaptan group. Compared with the non-tolvaptan group, the tolvaptan group had larger height-adjusted total kidney volume (median 994(range 450-4152) mL/m, 513 (405-1928) mL/m, p = 0.01), lower albumin level (mean 3.9±SD 0.4 g/dL, 4.3±0.4g/dL, p<0.01), and higher serum creatinine level (1.2±0.4 mg/dL, 0.9±0.2 mg/dL, p<0.01). Although the median change in annual growth rate of total liver volume (TLV) was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6-18.7) %/year)(p = 0.52), 20 (43.5%) patients in the tolvaptan group experienced a decrease in the growth rate of TLV (responders). A multivariable logistic regression model adjusting for related variables showed that older age (odds ratio 1.15 [95% CI 1.01-1.32]) and a higher growth rate of TLV in the non-tolvaptan period (odds 1.45 95% CI 1.10-1.90) were significantly associated with responders. In conclusion, the change in annual growth rate of TLV in ADPKD patients taking tolvaptan was not statistically different compared with that in ADPKD patients without taking tolvaptan. However, tolvaptan may have the potential to suppress the growth rate of TLV in some PLD patients due to ADPKD, especially in older patients or those that are rapid progressors of PLD. Several limitations were included in this study, therefore well-designed prospective studies were required to confirm the effect of tolvaptan on PLD.

Entities:  

Mesh：

Substances：

Year:  2022        PMID： 35176098      PMCID： PMC8853523          DOI： 10.1371/journal.pone.0264065

Source DB:  PubMed          Journal:  PLoS One        ISSN： 1932-6203            Impact factor:   3.240


Introduction

Polycystic liver disease (PLD) is a rare inherited disease characterized by the development of multiple cysts in the liver [1, 2]. Although genetic analysis has revealed that various genes are related to PLD [3], more than ninety percent of older patients with autosomal dominant polycystic kidney disease (ADPKD) have hepatic cysts [4]. In severe cases, the mass effects reduce patient quality of life and sometimes lead to mortality due to liver dysfunction [5-7]. Previous studies have shown that the progression of PLD was faster in specific patients, especially in younger women, which suggested that estrogen was related to cyst growth [8, 9]. Current medical therapies for symptomatic PLD include surgical interventions or several drugs that reduce intracellular cyclic adenosine monophosphate (cAMP). Although surgical interventions [10-12] can reduce the mass effects of PLD, these treatments have little impact on the progression of PLD, whereas somatostatin analogs (SAs) are approved for clinical use and have been proven to decrease the growth rate of PLD [9, 13–18]. Another drug that reduces intracellular cAMP is the vasopressin 2 receptor (V2R) antagonist tolvaptan, which decreases the progression of ADPKD, suppresses the decline in renal function [3, 19, 20], and has the potential to prolong the time before ESKD onset [21]. Although the influence of tolvaptan on PLD has not yet been fully understood, some case reports showed that hepatic cyst volume decreased after taking tolvaptan [22, 23]. Therefore, tolvaptan could be a candidate for additional medical intervention in addition to the current treatment strategy. As far as we know, there have been no observational studies describing the changes in both the total liver volume (TLV) and total kidney volume (TKV) in each patient, or describing the influence of tolvaptan on PLD in ADPKD. Therefore, we conducted a retrospective cohort study to investigate the natural history of changes in TLV and TKV and analyze the effect of tolvaptan on the PLD growth rate in patients with ADPKD, as well as to identify the prognostic factors associated with treatment effectiveness.

Materials and methods

Study design

To evaluate the effect of tolvaptan on PLD in patients with ADPKD, we conducted two types of analyses. First, we compared the changes in the annual growth of the total liver volume (TLV) between patients taking tolvaptan (tolvaptan group) and without tolvaptan (non-tolvaptan group). Second, we compared the changes in the annual growth of the total liver volume (TLV) before and after taking tolvaptan in tolvaptan group. To investigate the prognostic factors associated with the suppressive effect of tolvaptan on the growth rate of TLV, the tolvaptan group was classified into responders and non-responders according to the adjusted change in growth rate after tolvaptan use. The inclusion criteria of the cohort were patients who visited Toranomon hospital and Toranomon hospital Kajigaya between January 2012 and December 2019, were over 20 years old, were diagnosed with ADPKD [24] and PLD [1], met the Japanese criteria of tolvaptan use for ADPKD (TKV > 750 mL, annual growth rate of TKV ≥ 5% per year), and whose TLV was greater than 2,000 mL. The exclusion criteria were patients who had chronic liver dysfunction, had difficulty consuming adequate water, were pregnant, or did not provide written informed consent. In addition, patients who received physical interventions for PLD, such as percutaneous cyst drainage, cyst fenestration, and trans-arterial embolization (TAE) of the hepatic artery were excluded in the primary analysis, while patients who received physical interventions for PLD less than one year before enrollment was included in the secondary analysis. The standard dose of tolvaptan was 60 mg per day, which was increased to 120 mg if increasing dosing found was to be safe and tolerable, and the duration of tolvaptan use was more than 6 months. The prescription of tolvaptan was implemented as standard-of-care throughout the study period and the assignment of patients to tolvaptan was made at the discretion of the respective treating physician. All data were retrieved from the database at Toranomon hospital and they were fully anonymized before we accessed them. This study followed the principles of the Helsinki declaration and was approved by the Toranomon Hospital Institutional Review Board in 2017 (IRB number 1475). The IRB waived the requirement for informed consent as this was a retrospective study.

Variables and outcome

The clinical data included sex, various dates (enrollment, diagnosis, computed tomography (CT), start and cessation of tolvaptan), BMI, menopausal status (assessed by the self-reported questionnaire), comorbidities (hypertension, and diabetes mellitus), previous medical history (angiotensin converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), or ursodeoxycholic acid (UDCA)), history of physical interventions for PLD, and menstrual status self-reported by patients. Laboratory data included albumin, aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total-bilirubin, partial thromboplastin time, creatine, and glomerular filtration rate as estimated by the Japanese equation [25]. Laboratory data were obtained within 1 month of when the first liver imaging was conducted. We applied CTs performed during the annual checkups for renewing intractable disease, and applied these data to calculate the TLV and TKV; however, there was no additional exposure to radiation during this study. The CTs were performed with 5 mm slices without contrast media. Volumetry was performed by using the 3D image analysis system, “SYNAPSE VINCENT”, which semiautomatically traces the area of the targeted organs of each slice and integrates each slice volume. The tracing was conducted by two technicians (C.N., and Y.M.) who did not know the response to tolvaptan. After double checking by H.M. and Y.U., each TLV was defined as the mean value of the TLVs traced by the two technicians. These data were inspected by the data monitoring and independent audit committee. The non-tolvaptan period in the tolvaptan group was defined as the time between the start of observation and the last CT before the initiation of tolvaptan, while the tolvaptan period in the same group was defined as the time between the first day of tolvaptan and the time of the last CT before the cessation of tolvaptan or December 2019, whichever came first. Whereas, in the non-tolvaptan group, we divided the observational period into the former and latter observational period in order to compare the outcomes of the tolvaptan group. To minimize the carry-over effect of other interventions, if patients experienced any other intervention for PLD, data for one year after such treatment was excluded from both observational periods. In addition, we set up the dataset that consisted of the patients who had no history of interventions. The primary outcome was defined as the change from the baseline annual growth rate of TLV (ΔTLV%), which was calculated as the absolute subtraction of growth rate of TLV in the non-tolvaptan period of tolvaptan group from that in tolvaptan period or of growth rate of TLV in the former observational period of the non-tolvaptan group to that in latter observational period. The annual growth rates of TLV and TKV were defined as the slope as estimated by using a linear model from more than two measurements in each period. In secondary analysis, to analyze the prognostic factors, we divided the tolvaptan group into two groups according to their ΔTLV%. Responders were defined as those with negative ΔTLV%, while non-responders were defined as those with a positive ΔTLV%.

Statistical analysis

The categorical data were described as numbers and percents and were analyzed by chi-square tests or two-tailed Fisher’s exact test as appropriate, while continuous variables which were normal distribution were described as the mean and standard deviation and were analyzed by student’s t-test and continuous variables that is not normal distribution are described as the median, minimum, and maximum and were analyzed by Wilcoxon rank-sum test. Coefficient of correlation was evaluated by Spearman’s rank correlation test. Any p-values below 0.05 were considered significant. To determine the suppressive effect of tolvaptan on TLV, logistic regression models were implemented. The adjusted factors in the logistic regression analysis were age, sex, body mass index (BMI), mean blood pressure, height adjusted TKV (HtTKV), maintenance dose of tolvaptan and variables for which the p-values were below 0.05. All statistical analyses were conducted by using R version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline characteristics

The study flow chart is shown in Fig 1. Between January 2012 and December 2019, tolvaptan was prescribed to 295 out of 902 ADPKD patients with preserved kidney function (eGFR>15 mL/min/1.73 m2) who visited our hospitals due to PLD or ADPKD. Among them, a total of 46 cases were eligible for the tolvaptan group and 16 patients were for the non-tolvaptan group. In the tolvaptan group, twenty-three patients (50.0%) were male and the mean patient age was 51.8 years old. The median height adjusted TLV (HtTLV) was 1068 (range 557–6691) mL/m, while the mean HtTKV was 994 (450–4152) mL/m. Hypertension was diagnosed in 36 out of 46 (78.3%) patients. The proportions of patients using ACEi/ARB, and UDCA were 65.2% and 2.2%, respectively. Laboratory data showed that the mean and SD of eGFR was 50.5±20.2 mL/min/1.73 m2. Forty percent of patients had proteinuria with a median of 0.08 (0.01, 1.69) g/gCre, and 13.0% had hematuria. Their mean serum albumin was 3.9±0.4 g/dL, their mean total bilirubin was 0.7±0.2 g/dL and all patients were classified as Child-Pugh A. Comparing to the non-tolvaptan group, tolvaptan group had larger mean HtTKV (p<0.01), lower serum albumin level (p<0.01), and higher serum creatinine level (p<0.01) (Table 1).
Fig 1

Flow chart of patients.

In total 902 patients, tolvaptan was prescribed for 295 patients. Among them, 46 patients were eligible for the tolvaptan group. In the other 607 patients, 16 patients were eligible for the non-tolvaptan group. PLD: polycystic liver disease, PKD: polycystic kidney disease, ADPKD: autosomal dominant polycystic kidney disease, TLV%: annual growth rate of total liver volume.

Table 1

The baseline demographic and laboratory data of the tolvaptan group and non-tolvaptan group.

Tolvaptan group Control
n = 46 n = 16 p value
Baseline characteristics
Male n(%)23(50.0)10(62.5)0.39
Age(y.o.)51.8±10.348.7±14.40.45
Height(cm)166.2±9.7166.1±12.00.99
Body weight(kg)63.5±11.962.2±10.00.68
Body-mass index(kg/m2)22.9±322.6±2.90.72
Systolic blood pressure(mmHg)127.2±15121.8±11.90.18
Diastolic blood pressure(mmHg)80.8±10.477.7±11.50.39
Height adjusted total liver volume(mL/m)1068(557–6691)918(640–4177)0.38
Height adjusted total kidney volume(mL/m)994(450–4152)513(405–1928) <0.01 **
Comorbidities, n(%)
Hypertensionn(%)36(78.3)12(75.0)0.79
Diabetes mellitusn(%)2(4.3)0(0.0)0.40
Medications, n(%)
Angiotensin converting enzyme inhibitor or angiotensin II receptor blockern(%)30(65.2)10(62.5)0.84
Ursodeoxycholic acidn(%)1(2.2)0(0.0)0.55
Laboratory values (serum)
Platelet count(*103/μL)228.6±61.7243.1±75.30.60
Albumin(g/dL)3.9±0.44.3±0.4 <0.01 **
Aspartate aminotransferase(IU/L)18.8±5.621.7±5.40.09
Alanine aminotransferase(IU/L)16.0±8.418.3±7.60.32
Alkaline phosphatase(IU/L)190.2±74.8174.8±63.40.44
Gamma glutamyltransferase(IU/L)35.4±37.236.6±31.90.90
Total bilirubin(mg/dL)0.7±0.20.7±0.20.48
Uric acid(mg/dL)6.2±1.45.6±1.70.27
Creatinine(mg/dL)1.2±0.40.9±0.2 <0.01 **
eGFR(mL/min/1.73m2)50.5±20.273.7±23.5 <0.01 **
Prothrombin time(%)103.3±9.6101.9±10.40.73
Laboratory values (urine)
Hematurian(%)6(13)2(12.5)0.96
Proteinuria(g/gCre)0.08(0.01–1.69)0.06(0.01–0.25)0.15
N-acetyl-D-glucosamine(U/mL)5.1±2.94.5±1.80.44

Flow chart of patients.

In total 902 patients, tolvaptan was prescribed for 295 patients. Among them, 46 patients were eligible for the tolvaptan group. In the other 607 patients, 16 patients were eligible for the non-tolvaptan group. PLD: polycystic liver disease, PKD: polycystic kidney disease, ADPKD: autosomal dominant polycystic kidney disease, TLV%: annual growth rate of total liver volume.

Exposure

During the tolvaptan period, the mean duration of tolvaptan use was 3.4±1.34 years. The mean maintenance dose was 65.1±29.7mg per day. The cessation of tolvaptan use was found in 11 out of 46 patients for the following reasons: missing the follow up (n = 2), declining the prescription (n = 1), liver dysfunction (n = 3), polyuria (n = 2), and kidney dysfunction below eGFR 30 mL per minutes per 1.73 meter square (n = 3), which did not affect the growth rate of TLV and TKV.

Analysis of the whole cohort

In total, 359 CT examinations among 46 patients of tolvaptan group and 71 CT examinations among 16 patients of non-tolvaptan group were used to calculate the TLV. In the tolvaptan group, the mean and SD of the examinations of each patient were 2.8±1.2 in the non-tolvaptan period and 5.0±1.8 in the tolvaptan period. The mean duration between the first CT and the last CT in the non-tolvaptan period was 2.3±1.2 years, and in the tolvaptan period it was 2.2±0.9 years. Whereas, in the non-tolvaptan group, the mean and SD of the examinations of each patient were 2.6±1.0 in the former observational period and 2.7±0.6 in the latter observational period. The mean duration of the former observational period in the non-tolvaptan group was 2.6±1.0 years, and that of the latter observational period was 2.4±1.5 years.

Annual growth rate of TLV and TKV

In tolvaptan group, the median growth rate of TLV in the non-tolvaptan period and in the tolvaptan period were 1.2 (range -6.9, 16.3) %/year and 2.4 (-8.6, 17.6) %/year, respectively, with a median difference in the annual change in TLV of -0.8 (-15.9, 16.7) %/year (p = 0.78). On the contrary, in the non-tolvaptan group, the median growth rate of TLV in the former observational period and in the latter observational period were 0.2 (-4.8, 15.6) %/year and 1.2 (-5.3, 17.8) %/year, respectively, with median difference in the annual change in TLV of 2.0 (-15.6, 16.6) %/year. The median difference in the annual change in TLV was not statistically different between the tolvaptan group and the non-tolvaptan group (p = 0.52) (Fig 2).
Fig 2

Comparison of the change in annual growth rate of total liver volume between the tolvaptan group and the non-tolvaptan group.

The median difference in the annual change in TLV was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6, 18.7)) (p = 0.52, Wilcoxon rank sum test). TLV; total liver volume, ΔTLV %; change in annual growth rate of TLV.

Comparison of the change in annual growth rate of total liver volume between the tolvaptan group and the non-tolvaptan group.

The median difference in the annual change in TLV was not statistically different between the tolvaptan group (-0.8 (-15.9, 16.7) %/year) and the non-tolvaptan group (1.7 (-15.6, 18.7)) (p = 0.52, Wilcoxon rank sum test). TLV; total liver volume, ΔTLV %; change in annual growth rate of TLV. On the other hand, the median difference of the annual change in TKV of tolvaptan group and the non-tolvaptan group were 0.2 (-39.3, 22.5) %/year and 0.7 (-7.6, 23.4) %/year, respectively, which was not statistically different between groups (p = 0.39) (Fig 3).
Fig 3

Comparison of the change in annual growth rate of total kidney volume between the tolvaptan group and the non-tolvaptan group.

The median difference in the annual change in TKV was not statistically different between the tolvaptan group (0.2 (range -30.3, 22.5)) and the non-tolvaptan group (2.0 (-15.6, 16.6)) (p = 0.39, Wilcoxon rank sum test). TKV: total kidney volume, ΔTKV%: the change in growth rate of TKV.

Comparison of the change in annual growth rate of total kidney volume between the tolvaptan group and the non-tolvaptan group.

The median difference in the annual change in TKV was not statistically different between the tolvaptan group (0.2 (range -30.3, 22.5)) and the non-tolvaptan group (2.0 (-15.6, 16.6)) (p = 0.39, Wilcoxon rank sum test). TKV: total kidney volume, ΔTKV%: the change in growth rate of TKV.

Analysis of the prognostic factors of annual growth rate of TLV

To identify the predictors of response to tolvaptan, secondary analysis was conducted in the tolvaptan group. As shown in Fig 4, 20 out of 46 patients (43.5%) experienced a decline in the ΔTLV% after taking tolvaptan, we defined them as responders. The other 26 patients (56.5%), who experienced an increase in ΔTLV% after taking tolvaptan, were categorized as non-responders. Compared with the non-responders, responders had a higher annual change in TLV in the non-tolvaptan period (4.5 (-3.2–16.3) vs -0.7 (-6.9–5.2) percent per year, p<0.01). Differences in HtTLV, kidney function, liver function and dose of tolvaptan were not statistically significant between the groups (Table 2). The daily dose of tolvaptan (S1 Fig) and menopausal status (S2 Fig) were not significantly different between responder and non-responder and both were not associated with ΔTLV% and responder rate.
Fig 4

The spaghetti plotting of the annual liver growth rate before and after tolvaptan use.

In the tolvaptan group, the median growth rate of TLV before tolvaptan use was 1.23 (range -6.9, 16.3) %/year and that after tolvaptan use was 2.4 (-8.6, 17.6) %/year. Although, the growth rate of TLV did not statistically change after tolvaptan use (p = 0.78, Wilcoxon test for paired observations), 20 out of 46 patients (43.5%) experienced a decline in the change in annual growth rate of TLV (ΔTLV%) after taking tolvaptan, we defined them as responders (red circle). The other 26 patients (56.5%), who experienced an increase in ΔTLV% after taking tolvaptan, were categorized as non-responders (blue circle). TLV: total liver volume, ΔTLV%: change in annual liver growth rate of TLV.

Table 2

The baseline demographic and laboratory data of responders and non-responders.

ResponderNon-responder
n = 20n = 26p value
Baseline characteristics
Malen(%)9(45.0)14(53.8)0.67
Age(years old)57.2±9.947.6±8.60.09
Height(cm)163.5±9.0168.2±9.80.24
Body weight(kg)62.1±11.164.6±12.40.64
Body-mass index(kg/m2)23.1±2.922.7±3.00.58
Systolic blood pressure(mmHg)129.2±13.2125.7±16.10.38
Diastolic blood pressure(mmHg)80.0±9.481.4±11.00.81
Height adjusted total liver volume(mL/m)1170(629–6691)1007(557–3380)0.39
Height adjusted total kidney volume(mL/m)1033(477–4152)979(450–3515)0.55
Annual growth rate of TLV(%/year)4.5(-3.2–16.3)-0.7(-6.9–5.2)<0.01 **
Annual growth rate of TKV(%/year)7.5(-4.7–46.6)2.7(-12.8–19.8)0.17
post menopausal femalen(%)7(87.5)5(83.3)0.61
Dose of tolvaptan(mg/day)57.4±32.572.1±27.30.12
Comorbidities
Hypertensionn(%)17(85.0)19(73.1)0.25
Diabetes mellitusn(%)1(5.0)1(3.8)0.81
Medications
Angiotensin converting enzyme inhibitor or angiotensin II receptor blockern(%)15(75.0)15(57.7)0.08
Ursodeoxycholic acidn(%)1(5.0)0(0.0)0.24
Laboratory values (serum)
Platelet count(*103/μL)223.5±78.9232.5±43.80.29
Albumin(g/dL)3.9±0.33.8±0.40.68
Aspartate aminotrasferase(IU/L)18.8±4.218.9±6.50.39
Alanine aminotransferase(IU/L)14.3±5.417.2±9.90.96
Alkaline phosphatase(IU/L)202.2±82.9181.1±66.50.41
Gamma glutamyltransferase(IU/L)31.4±21.638.5±45.40.93
Total bilirubin(mg/dL)0.7±0.20.7±0.30.87
Uric acid(mg/dL)6.2±1.56.1±1.30.47
Creatinine(mg/dL)1.3±0.61.2±0.30.21
eGFR(mL/min/1.73m2)46.8±21.453.3±18.70.26
Prothrombin time(%)103.0±11103.6±8.20.74
Laboratory values (urine)
Hematurian(%)4.0(20.0)2(7.7)0.64
Proteinuria(g/gCre)0.11(0.01–1.69)0.08(0.02–0.55)0.75
N-acetyl-D-glucosamine(U/mL)5.9±3.14.4±2.60.27

The spaghetti plotting of the annual liver growth rate before and after tolvaptan use.

In the tolvaptan group, the median growth rate of TLV before tolvaptan use was 1.23 (range -6.9, 16.3) %/year and that after tolvaptan use was 2.4 (-8.6, 17.6) %/year. Although, the growth rate of TLV did not statistically change after tolvaptan use (p = 0.78, Wilcoxon test for paired observations), 20 out of 46 patients (43.5%) experienced a decline in the change in annual growth rate of TLV (ΔTLV%) after taking tolvaptan, we defined them as responders (red circle). The other 26 patients (56.5%), who experienced an increase in ΔTLV% after taking tolvaptan, were categorized as non-responders (blue circle). TLV: total liver volume, ΔTLV%: change in annual liver growth rate of TLV.

Prognostic factors of annual growth rate of TLV

In logistic regression analysis, the unadjusted model showed that older age (odds ratio 3.00 [95% CI 1.37–6.55, p<0.01) and a higher growth rate of TLV at baseline (odds ratio 1.41 [95% CI 1.13–1.75], p<0.01) were associated with the responders. After adjusting for baseline variables including sex, age, BMI, mean blood pressure, height adjusted TKV, annual change in TLV in the non-tolvaptan period, a medical history of UDCA and maintenance dose of tolvaptan, older age (odds ratio 1.15 [95% CI 1.01–1.32]) and a higher growth rate of TLV in the non-tolvaptan period (odds 1.45 95% CI 1.10–1.90) were significantly associated with the responders (Table 3).
Table 3

Logistic regression model analyzing the prognostic factors of the growth rate of TLV in ADPKD.

UnadjustedAdjusted
PredictorsOdds95% CIp-valueOdds95% CIp-value
Male0.70(0.22–2.26)0.555.55(0.45–68.97)0.18
Age(10years old)3.00(1.37–6.55) 0.01 *1.15(1.01–1.32) 0.04 *
Body-mass index(kg/m2)1.05(0.86–1.28)0.630.93(0.65–1.34)0.69
Mean blood pressure(mmHg)1.00(0.95–1.06)0.950.98(0.91–1.06)0.68
Height adjusted total kidney volume(100mL/m)1.03(0.96–1.11)0.410.94(0.82–1.07)0.33
Annual change of total liver volume(%/year)1.41(1.13–1.75) <0.01 **1.45(1.1–1.9) 0.01 *
Ursodeoxychcolic acid7.88*106(0.00-e2868.45)0.992.65*107(0.00-e4720.20)0.99
Dose of tolvaptan(30mg/day)0.98(0.96–1.00)0.110.98(0.96–1.01)0.29

Abbreviations. ADPKD: autosomal dominant polycystic kidney disease. TLV: total liver volume.

Abbreviations. ADPKD: autosomal dominant polycystic kidney disease. TLV: total liver volume.

Analysis of the patients including the history of physical interventions to the polycystic liver

In order to re-evaluate the prognostic factors of tolvaptan, we conducted the analysis of the cohort including patients with the physical interventions of polycystic liver, such as trans-arterial embolization of liver (liver TAE) and liver cyst drainage. In this cohort, eighty-two patients were eligible to the tolvaptan group and twenty-five patients were eligible to the non-tolvaptan group. Even in this setting, patients in the tolvaptan group had large htTKV, higher creatinine level, lower eGFR and lower serum albumin level than in those who in the non-tolvaptan group (S1 Table). In addition, 25 (30.5%) patients had a history of liver TAE and 19 (23.2%) patients had a history of liver cyst drainage. The median volume of cyst drainage was 656 (140–2575) in the tolvaptan group, which was smaller than that in the non-tolvaptan group(1100(450–3385), p-value<0.01). Both interventions were conducted more than one year before the observational period.

Change in annual growth rate of TLV and TKV

The median ΔTLV% was not statistically different between the tolvaptan group (0.7 (-35.0, 54.2) %/year) and the non-tolvaptan group (1.7 (-15.6, 18.7) %/year) (p = 0.29) (S3 Fig). Whereas, the median ΔTKV% in tolvaptan group and the non-tolvaptan group were 0.2 (-42.0, 50.9) %/year and 1.1 (-55.0, 23.4) %/year, respectively and the reduction of annual growth rate in TKV was larger in tolvaptan group than in the control group (p = 0.02) (S4 Fig). In the tolvaptan group of this subgroup, forty-four patients (53.7%) were the responders, who had more rapid progression of annual growth rate of TLV than non-responders at baseline (S2 Table). In logistic regression analysis adjusted by related variables (sex, age, body-mass index, height adjusted total kidney volume, annual change of total liver volume in the non-tolvaptan period, history of taking ursodeoxycholic acid, volume of drainage), only baseline annual growth rate in total liver volume (odds 1.17 [95% CI 1.01–1.36], p = 0.04) were significantly associated with the responders (S3 Table).

Discussion

In this study, the change in the annual growth rate of TLV was not statistically significant between the tolvaptan group and the non-tolvaptan group. However, we found that more than half of the tolvaptan group experienced a decrease in the annual growth rate of TLV after the initiation of tolvaptan use and these patients had a more rapid TLV growth rate at baseline. After adjusting for related variables, older age and a rapid progression of TLV were associated with the responders to tolvaptan. V2R is now known to be more widely expressed in the kidney, including thick ascending limb of Henle [26, 27]. In the polycystic kidney, the concentration of intracellular cAMP is increased and plays a key role in the progression of ADPKD [28]. In the polycystic liver, cAMP is also a main target signal of SAs, which reduces the intracellular cAMP via the somatostatin receptor, which may decrease proliferation in the polycystic liver [9, 13–18]. Additionally, a recent study showed that V2R was expressed on cholangiocytes from patients with ADPKD and the proliferation of these cholangiocytes was inhibited by a V2R antagonist in vitro [29]. These findings suggest that tolvaptan would be expected to slow the progression of PLD in the clinical setting. In this observational study, we noticed that there were a certain number of responders whose TLV growth rates were decreased after tolvaptan use, although the change in annual growth rate of TLV was not different between the groups and the median growth rate of TLV seemed almost consistent before and after tolvaptan use overall. We observed that older age was a factor associated with responders to tolvaptan in this study, while female sex was not. Previous studies showed that younger age [8, 9], larger HtTLV [8], and female sex [9] had a higher annual growth rate of liver. In this study, we chose the inclusion criteria including Japanese criteria of tolvaptan use for ADPKD and younger female patients aged under 45 years old was only 8.7 percent and premenopausal female patients was only 14.3 percent of all female patients in the tolvaptan group. Therefore, less active polycystic liver disease might have been included in our study. These baseline differences could reduce the response to tolvaptan. Another predictor of decreasing PLD growth rate was a higher baseline PLD growth rate. In a previous randomized control study, patients with a higher liver growth rate responded well to SAs [9]. In addition, in patients with ADPKD, a higher percentage with progression to TKV showed the greater effects of tolvaptan on TKV [3, 30, 31], which suggested that a higher growth rate would be a good prognostic marker for medical interventions related to cAMP. Although the change in annual liver growth rate was not statistically different, the secondary analysis for the tolvaptan group were consistent with those of previous studies, however, careful interpretations will be necessary to apply these results in clinical practice. The spontaneous reduction of polycystic liver was previously reported by [8, 9] and 30–44% of the patients without any intervention. Majority of these patients were over 48 years old [8]. In this study, mean age in our patients was older than previous studies, and the reduction of annual growth rate of TLV could be partially explained by this spontaneous reduction. However, logistic analysis statistically showed that the higher annual growth rate of TLV was the predictor of reduction of annual liver growth rate, meaning the disease-modifying effect of tolvaptan other than the spontaneous reduction was suggested. The strength of this study is that this is the first observational study to evaluate the effect of tolvaptan on PLD using a relatively large number of patients with PLD as compared to previous studies. Furthermore, to minimize the intraobserver and interobserver variance, we used multiple CT examinations with a semiautomated system to calculate the estimated liver growth. Although our cohort only consisted of liver-cyst dominant patients with ADPKD, such characteristics were commonly found in previous studies of PLD due to ADPKD [9, 13–18, 29], and medical therapy other than SAs is an unmet need for these patients. Several limitations still exist in our study. First, this is the retrospective observational study and cause-and-effect of the results was not determined. Second, because of the inclusion criteria of this study, external validity of our results was limited if the use of tolvaptan was considered to the patients of younger female patients with large PLD without ADPKD or liver dominant PLD with ADPKD. Third, the genetic evaluation was not conducted, which meant that some genetic heterogeneity might have existed in our cohort. However, it has been reported that the genotype of ADPKD does not influence the severity or progression of PLD [8]. Fourth, the change of annual growth rate of TKV was not significantly different between tolvaptan group and non-tolvaptan group. This might suggest that the less active patients were included in terms of polycystic kidney disease. Therefore, more active ADPKD patients having both kidney and liver should have been selected. Finally, although sex did not predict the suppressive effects of tolvaptan on the PLD growth, the expression of estrogen and its receptor on cholangiocytes have been shown to be related to the growth rate of the liver [32]. Furthermore, in our study, information about the number of births and the duration of exposure to oral contraceptives were not collected from the medical chart. Although menopausal status was collected from only about half of female patients in the tolvaptan group, subgroup analysis about menopausal status showed it did not change the response of tolvaptan. Hence, additional well-designed prospective studies are necessary to analyze the effect of tolvaptan on PLD. In conclusion, compared to the non-tolvaptan group, the annual growth rate in total TLV in ADPKD patients taking tolvaptan did not decrease in the entire cohort. However, subgroup analysis revealed that 43.5% in the tolvaptan group experienced the reduction of the annual growth rate of TLV and after adjusting for several related factors, older age and a higher growth rate of TLV were associated with the reduction of the annual growth rate of TLV. PLD is one of the intractable diseases with limited treatment options, and the mass effects of PLD often reduce patient quality of life and can sometimes be life-threatening. Although some interventional studies are required to confirm the effectiveness of tolvaptan for PLD, our results may help guide clinical practice for PLD patients.

Analysis of dose effect of tolvaptan on polycystic liver disease.

To assess the dose effect of tolvaptan on the change in annual growth rate of total liver volume (TLV), the original tolvaptan group were stratified by daily dose of tolvaptan, less than 30mg, 60mg, 90mg, and mg. However, we could not find the any trends of change in annual growth rate of total liver volume nor response rate associated to the dose of tolvaptan. Abbreviation.ΔTLV% change in annual growth rate of TLV. (PDF) Click here for additional data file.

Spaghetti plotting of annual growth rate of total liver volume before and after tolvaptan use in premenopausal and postmenopausal patients.

The annual growth rate of total liver volume was not change in premenopausal female(n = 2) and in postmenopausal female (n = 12). Red circle represents the responder defined as the patients whose annual liver growth rate of total liver volume decreased after tolvaptan use, while the blue circle represents the non-responder defined as the patients whose annual liver growth rate of total liver volume increased. Abbreviation. TLV%: annual growth rate of total liver volume. (PDF) Click here for additional data file.

Comparison of the change in annual growth rate of total liver volume between the tolvaptan group and the non-tolvaptan group in patients including the history of physical interventions for polycystic liver.

The median change in the annual growth rate of total liver volume (TLV) was not statistically different between the tolvaptan group (-0.7 (range -35.0, 54.2) %/year) and the non-tolvaptan group (1.7 (-15.6, 18.7) %/year) (p = 0.29, Wilcoxon rank sum test). ΔTLV %: change in annual growth rate of TLV. (PDF) Click here for additional data file.

Comparison of the change in annual growth rate of total kidney volume between the tolvaptan group and the non-tolvaptan group in patients including the history of physical interventions for polycystic liver.

The median difference in the annual growth rate in total kidney volume (TKV) was larger in the tolvaptan group (0.2 (-42.0, 50.9)) than in the non-tolvaptan group (1.1 (-55.0, 23.4)) (p = 0.02, Wilcoxon rank sum test). Abbreviation. ΔTKV%: the change in growth rate of TKV. (PDF) Click here for additional data file.

The baseline demographic and laboratory data of the tolvaptan group and non-tolvaptan group in patients without the history of interventions for polycystic liver.

(DOCX) Click here for additional data file.

The baseline demographic and laboratory data of responders and non-responders in patients without the history of interventions for polycystic live.

(DOCX) Click here for additional data file.

Logistic regression model analyzing the prognostic factors of the growth rate of TLV in ADPKD in patients without the history of interventions for polycystic liver.

(DOCX) Click here for additional data file. (DOCX) Click here for additional data file. 10 Jun 2021 PONE-D-21-12669 Potential effect of tolvaptan on polycystic liver disease with ADPKD PLOS ONE Dear Dr. Mizuno, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Sorry for the delayed response.  The experts raised several serious concerns.  Authors should seek for the advice from statistician if the method are proper and type I and II errors are avoided.  Authors should add the statistician on the authorship to share the responsibility. Please submit your revised manuscript by Jul 25 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see:  http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at  https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols . We look forward to receiving your revised manuscript. Kind regards, Tatsuo Shimosawa, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your ethics statement in the manuscript and in the online submission form, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. 3. Please include the following information in your Methods: 1) Whether the use of tolvaptan was implemented as standard-of-care at your hospital throughout the study period. 2) Whether assignment of patients to tolvaptan was made at the discretion of the treating physician or for the purposes of research. 4. Please note that PLOS does not permit references to 'data not shown.' Authors should provide the relevant data within the manuscript, the Supporting Information files, or in a public repository. If the data are not a core part of the research study being presented, we ask that authors remove any references to these data. 5.Thank you for stating the following in the Financial Disclosure section: "This work was supported by J.H’s competitive research grant from Otsuka Pharm, Japan, and a research grant from the Okinaka Memorial Institute for Medical Research, and H.M’s research grant from Toranomon Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you received funding from a commercial source: Otsuka Pharm Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Partly ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No Reviewer #4: No ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: No ********** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: Yes ********** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The analysis is simple but appropriate for the conducted analysis. However, the figures 2-4 look strange. I do not know what information they should provide nor is it explained in the paper. The figures are not related to the numerical analysis but provide a visual overview, which is good to provide. They are just unclear! Please discuss them in detail. Reviewer #2: PLD is one of the most frequent complications of ADPKD, and is an important intractable disorder with limited treatment option. Previous studies suggested that somatostatin analogue may retard the progression of PLD. Although tolvaptan, a vasopressin V2R antagonist, has been approved to prevent PKD progression, its effect on PLD remains unclear. Till date, several case studies have reported that tolvaptan may be effective in controlling PLD; nonetheless, there are currently no observational studies involving a larger number of patients. In this study by Mizuno et al., the authors have retrospectively analyzed the effect of tolvaptan on PLD in 82 patients. They examined a total of 667 CT scans, and both total liver volume (TLV) and total kidney volume (TKV) were calculated in an unbiased approach using Synapse Vincent. Although the growth rate of TLV was not altered before and after tolvaptan treatment, the authors found that approximately half of patients showed the reduction in TLV (responders). They went on to demonstrate that several factors such as older age, higher annual change in TLV, and use of UDCA were associated with the responders. A logistic regression analysis after adjustment further demonstrated that older age and a higher growth rate of TLV in non-tolvaptan period were significantly associated with the response to tolvaptan. Overall, the manuscript is clearly written and methods contain sufficient detail. The study deals with clinically significant problem, with the major strength lying in the fact that the authors compared the TLV before and after tolvaptan treatment in more than 80 patients. Given that there is currently scarce evidence in the literature regarding the effect of tolvaptan on PLD, the manuscript will add an important information that is helpful to clinicians in this field. There are, however, several concerns that need to be addressed. 1. Although there were 902 patients with PLD or PKD in total, less than 10% were analyzed in this study, which may constitute a limitation. Given that there were more than 600 patients who did not take tolvaptan, authors might want to calculate the growth rate of TLV in those patients with CT scans available, and compare the rate with the 82 eligible patients. This analysis would make the study more comprehensive, even if the growth rate is not significantly altered. 2. The authors showed that the median growth rate of TLV did not change after taking tolvaptan. However, it is unclear whether the study participants did show response to tolvaptan in terms of growth rate of TKV. 3. The maintenance dose of tolvaptan in each group was not described in Table 1. Was the dosage not associated with the response in PLD? 4. Figures and figure legends need improvement. - In Figure 2, there is no explanation what blue and red lines mean. This figure also needs the label (A or B) according to the text. - Order of Figure 3 and Figure 4 could be the other way around. In the main text, Figure 3 is supposed to show the association between TLV and TKV, whereas Figure 4 should show the delta TLV% before and after tolvaptan. - Figure 4 (association between PLD and PKD): please add correlation coefficient and p value. - Legends in each figure need more information so that the readers can understand without referring to the main text. 5. Page 8, line 3. aldosterone > angiotensin II 6. Page 9, line 16 (statistical analysis). Is the statistical analysis two-tailed or one-tailed? Please describe. 7. Page 17, line 15-16; consider revising the sentence. V2R is now known to be more widely expressed in the kidney, including thick ascending limb of Henle (Ref: PMID 32035616 and 17626156). 8. “Height adjust total liver volume” in figure legends could be “Height adjusted total liver volume”. Reviewer #3: Dear authors, While the efficacy of Tolvaptan in reducing renal cyst growth has been established, its efficacy in complicating extrarenal cysts, particularly in more frequent hepatic cysts, is unknown at present. This study tried to analyze this point, and it is considered to be a informative study with significant clinical advantages, even if the result is positive or negative. However, there are several issues to be resolved as shown below. Major Comment #1 This study was a retrospective observational study design without a control group, and the analysis is restricted to individuals with ADPKD who meet the Japanese National criteria for tolvaptan use. Thus, the effect of tolvaptan on hepatic cysts in patients with less severe or less active PKDs or hepatic cysts in patients with predominant hepatic than renal cysts is not included in the analysis. It should be specified that this study is an analysis restricted to hepatic cysts in subjects with ADPKD who met the criteria for tolvaptan use, including title. Although the significance of this study is clearly understandable, I believe that it is inappropriate to refer directly to the effects of tolvaptan in restrospective single arm observation, not in randomized controlled trial, and that careful representation or description is desirable. Comment #2 Cases with or without hepatic cyst drainage or TAE are mixed in the study population. In such cases with physical interventions, organic changes or damages may have been occurred in the pericystic tissues associated with invasions, and it is considered inappropriate to analyse populations that may differ qualitatively. Alternatively, it should be discussed that physical interventions are independent of the effects of cyst growth or tolvaptan. I would like to ask for the opinions of the authors. Even if the sample size is reduced, it is considered that the population should be restricted to patients without those physical interventions, or that the subgroup analyses should be added at the least. Comment #3 It is of great interest that responder, non-responder analysis showed that the more active PLDs, the more pronounced the cyst reduction after tolvaptan use, as well as their efficacy in renal cysts. The results strongly suggest that a similar mechanism to inhibition or reduction of renal cyst growth by tolvaptan may apply to hepatic cysts. On the other hand, it is not well understandable that there was no correlation between kidney volume reduction and liver volume reduction in the responder group. The influence of the drainage cases and TAE cases may be concerned, but how do the authors consider this point? Comment #4 There is a lack of discussion of the impact of spontaneous shrinkage of hepatic cysts. In Ref-8, as a consequence of a large observational study of PLDs, it is reported that spontaneous reduction of hepatic volume is observed in 30% of cases in the population. Ref-9 has also reported a reduction in hepatic volume in half of placebo group. In this study, the liver volume is reduced in about half of the subjects, but how to consider the involvement of spontaneous reduction should be discussed. Minor Comment #1 In a stratified analysis of responder and non-responder, adjustments for variables have been described, however, specific method for this statistical procedure has not been described in the text. Comment #2 Inconsistencies are seen in figure description in the text and figure numbering (e.g. Fig. 2B in P14L7). In addition, both Fig. 2 and Fig. 4 are not represented in A and B. Reviewer #4: Polycystic liver disease leads to pain and suffering in many individuals with autosomal dominant polycystic kidney disease. This interesting study examines changes in total liver volume in a cohort of individuals who took tolvaptan and followed longitudinally. About 50% experienced a reduction in liver volume and about 50% experienced a continued increase in liver volume. The paper is well written. However I am concerned about the statistics. There are number of extreme outlier cases who could have influenced the data analysis. Overall we may be seeing a regression to the mean. Please mark individuals that had TAE or liver volume reducing procedures on the graph. Please add figure showing both females that were pre and post menopausal and describe what happened to their total liver volumes. If there is a positive effect of tolvaptan on total liver volume then one might expect a dose -response effect. No dose information has been provided. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: No Reviewer #4: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 31 Aug 2021 Dear Editor and Reviewers Thank you for reviewing our manuscript “Potential effect of tolvaptan on polycystic liver disease with ADPKD [PONE-D-21-12669]” and offering valuable advices during the tough situation by COVID19 pandemic. We also appreciate the time and effort you and each of the reviews have dedicated to providing insightful feed back on our paper. In addition, thanks to your generous kindness of extending the deadline of resubmission, we have finished answering all the comments. The revised manuscript would be improved over the initial manuscript. We have addressed your comments with point-by-point responses and revised the manuscript accordingly. We would like to send two versions, clean and marked one and as well as the ppt file of graphic abstract. Response to Editor and Reviewers’ comments Editor: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf RESPONSE: We had changed all the file naming according to PLOS ONE’s style requirements. 2. In your ethics statement in the manuscript and in the online submission form, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information. RESPONSE: We had added the expression describing fully anonymized before we accessed data on page 7 line 17 and the sentence on page 8 line 1-2. 3. Please include the following information in your Methods: 1) Whether the use of tolvaptan was implemented as standard-of-care at your hospital throughout the study period RESPONSE: In this retrospective observational study, tolvaptan was used standard-of-care. We have added the following sentence “The use of tolvaptan was implemented as standard-of care throughout the study period” on Page 7 Line 14-15. 2) Whether assignment of patients to tolvaptan was made at the discretion of the treating physician or for the purposes of research. RESPONSE: In this retrospective observational study, tolvaptan was prescribed by the treating physician not by the purpose of research. We have added the following sentence “the assignment of patients to tolvaptan was made at the discretion of the treating physician”, on Page 7 Line 16. 4. Please note that PLOS does not permit references to 'data not shown.' Authors should provide the relevant data within the manuscript, the Supporting Information files, or in a public repository. If the data are not a core part of the research study being presented, we ask that authors remove any references to these data. RESPONSE: After conducting the revising analysis, we considered that this information is not a core part, therefore, we decline the expression ‘data not shown’, on Page 25 Line 13. 5. Financial Disclosure section: "This work was supported by J.H’s competitive research grant from Otsuka Pharm, Japan, and a research grant from the Okinaka Memorial Institute for Medical Research, and H.M’s research grant from Toranomon Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." We note that you received funding from a commercial source: Otsuka Pharm Please provide an amended Competing Interests Statement that explicitly states this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development, marketed products, etc. Within this Competing Interests Statement, please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your amended Competing Interests Statement within your cover letter. We will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests RESPONSE: We have amended Competing Interests Statement on cover letter and we have added the sentence you offered. Reviewer #1: The analysis is simple but appropriate for the conducted analysis. However, the figures 2-4 look strange. I do not know what information they should provide nor is it explained in the paper. The figures are not related to the numerical analysis but provide a visual overview, which is good to provide. They are just unclear! Please discuss them in detail. RESPONSE: Thank you for pointing out figure 2-4’s roles played on this article. After re consideration during revising process, data of figure 2 and figure 4 did not directly related to the major conclusion on this article. Therefore, we declined resubmitting figure 2 and figure 4. Whereas, since figure 3 was the primary outcome of this study, we decided to keep using it, then the figure number was changed from figure 3 to figure 4 in the revised manuscript. In addition, we added the figure caption on Page 17 Line 12. Reviewer #2: Thank you for providing us with the suggestive comment on our article. We totally agreed with your comment 1, the necessity of the control group. Although it took an enormous time to find the appropriate control group after screening 902 patients, we found 25 patients who were eligible to the control group. Compared with this control group, we could not find the statistical difference of the change in the annual growth rate of TLV between groups. However, we hope this revising process would strengthen our article and give more meaningful suggestions to the future study. In order to answer the all the valuable comments from editors and reviews, we decided to decline figure 2 and 4 of the initial manuscript, then we added 2 figures (figure 2 and figure3) and supporting information including 4 figures and 3 tables. Figure 3 of the initial manuscript left as figure 4. 1. Although there were 902 patients with PLD or PKD in total, less than 10% were analyzed in this study, which may constitute a limitation. Given that there were more than 600 patients who did not take tolvaptan, authors might want to calculate the growth rate of TLV in those patients with CT scans available, and compare the rate with the 82 eligible patients. This analysis would make the study more comprehensive, even if the growth rate is not significantly altered. RESPONSE: We agreed with the statistical limitation of this original manuscript of single arm observational study. Therefore, we decided to find the control group that would be compared to the tolvaptan group. After screening 902 patients to find the appropriate control group, defined ADPKD patients with polycystic liver and fulfilled Japanese criteria of tolvaptan use, and had more than three times CT scanning. We finally found 25 patients that met the prescription criteria of tolvaptan in Japan and set it as a control group. Compared to this control group, the tolvaptan group were larger height adjusted TKV, higher serum creatinine level, and lower eGFR. We divided the observational period of the control group and compared the difference of annual liver growth rate, but there was no statistical difference. We added the method of this analysis on Page 6, Line 15-17, and the result of this analysis from page 15 line 6 to page 16 line 7 including figure 2 of revised manuscript. We hope these results will make this article have more statistical robustness. 2. The authors showed that the median growth rate of TLV did not change after taking tolvaptan. However, it is unclear whether the study participants did show response to tolvaptan in terms of growth rate of TKV. RESPONSE: Thank you for giving us the important advice to evaluate the effect of tolvaptan on polycystic kidney. The annual change in TKV of the tolvaptan group was 0.2 (-42.0, 50.9) %/year while that of the control group was and -1.1 (-55.0, 23.4) %/year. The effect of tolvaptan on the growth rate of TKV was neither significant in this study. We thought that this fact would be partially derived from the liver-dominant ADPKD and less progressive ADPKD patients were selected in this study. We added this result from page 15 line 16 to page 16 line 1 and on figure 3 as well as this limitation on page 25 line 17. 3. The maintenance dose of tolvaptan in each group was not described in Table 1. Was the dosage not associated with the response in PLD? RESPONSE: We added the dose of tolvaptan in Table1 and Table2. We created the four categories according to the dose of tolvaptan, however, there was no trend that suggested the dose effect of tolvaptan on response rate or decline of liver growth rate. We added the result of this subgroup analysis on page 17 line 8 and on Supporting Information Figure S1. 4. Figures and figure legends need improvement. - In Figure 2, there is no explanation what blue and red lines mean. This figure also needs the label (A or B) according to the text. RESPOND: Thank you for pointing out the insufficient contents of the legend. As mentioned above. During the revising process, however, we reconsider that the result of this figure was not directly related to the major conclusion of this study, therefore, we decided to decline this figure. - Order of Figure 3 and Figure 4 could be the other way around. In the main text, Figure 3 is supposed to show the association between TLV and TKV, whereas Figure 4 should show the delta TLV% before and after tolvaptan. - Figure 4 (association between PLD and PKD): please add correlation coefficient and p value. - Legends in each figure need more information so that the readers can understand without referring to the main text. RESPONSE: Thank you for pointing out the insufficient contents of the legend. We added the figure legends on figure 4 (delta TLV% before and after tolvaptan) and added the statistical information into the figure. The result of figure3 (the association between TLV and TKV) was not directly related to the major conclusion of this study, so we decided to decline this figure, 5. Page 8, line 3. aldosterone > angiotensin II RESPONSE: We have changed the word above (Page8, line 7). 6. Page 9, line 16 (statistical analysis). Is the statistical analysis two-tailed or one-tailed? Please describe. RESPONSE: We conducted two-tailed Fisher’s exact test. We added the expression “two-tailed” in Method section on page 10 line 9. 7. Page 17, line 15-16; consider revising the sentence. V2R is now known to be more widely expressed in the kidney, including thick ascending limb of Henle (Ref: PMID 32035616 and 17626156). RESPONSE: Thank you for showing us valuable reference articles. We adopted the sentence above from Page22, Line 18 to Page 23, Line 1 and added the reference articles. 8. “Height adjust total liver volume” in figure legends could be “Height adjusted total liver volume”. RESPONSE: We have changed the expression in figure legends. Reviewer #3: Dear authors, While the efficacy of Tolvaptan in reducing renal cyst growth has been established, its efficacy in complicating extrarenal cysts, particularly in more frequent hepatic cysts, is unknown at present. This study tried to analyze this point, and it is considered to be a informative study with significant clinical advantages, even if the result is positive or negative. However, there are several issues to be resolved as shown below. RESPONSE: Thank you for providing us the suggestive comment on our article. After reconsidering the design of this study, subgroup analysis for the patients without the history of physical intervention were conducted to minimized their effect on PLD. We hope this revising data will strengthen our article and give more meaningful suggestion to the future study. Major Comment #1 This study was a retrospective observational study design without a control group, and the analysis is restricted to individuals with ADPKD who meet the Japanese National criteria for tolvaptan use. Thus, the effect of tolvaptan on hepatic cysts in patients with less severe or less active PKDs or hepatic cysts in patients with predominant hepatic than renal cysts is not included in the analysis. It should be specified that this study is an analysis restricted to hepatic cysts in subjects with ADPKD who met the criteria for tolvaptan use, including title. Although the significance of this study is clearly understandable, I believe that it is inappropriate to refer directly to the effects of tolvaptan in restrospective single arm observation, not in randomized controlled trial, and that careful representation or description is desirable. RESPONSE: We agreed with your suggestion to change more suitable title for this study. In this revised manuscript, we conducted the analysis by using control group, however, several limitation still had existed and the patients included in this study was limited within the ADPKD patients who met the Japanese criteria of tolvaptan use. Therefore, we changed the title to “Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use”. We hope this title would be more precisely described and more suitable to be accepted. Comment #2 Cases with or without hepatic cyst drainage or TAE are mixed in the study population. In such cases with physical interventions, organic changes or damages may have been occurred in the pericystic tissues associated with invasions, and it is considered inappropriate to analyse populations that may differ qualitatively. Alternatively, it should be discussed that physical interventions are independent of the effects of cyst growth or tolvaptan. I would like to ask for the opinions of the authors. Even if the sample size is reduced, it is considered that the population should be restricted to patients without those physical interventions, or that the subgroup analyses should be added at the least. RESPONSE: We agree with subgroup analysis for the patients without the history of the physical intervention. After excluding the physical intervention, such as liver trans-arterial embolization and drainage for liver cyst, 46 patients were eligible for analysis. In this group, there was no significant difference of annual liver growth rate before and after the tolvaptan use, however, 20(43.4%) patients had experienced the reduction of liver growth rate, responder. Multivariable regression analysis adjusted related variables showed that age and baseline liver growth significantly predicted the responder. We deleted the carry-over effect of trans-arterial embolization of liver from the paragraph about limitation of this study in the discussion part, then we added these results as subgroup analysis from page 21, line 2 to page 22, line 8 and on Supporting Information. We believe that these subgroup analysis will more efficiently exclude the carry-over effect of physical intervention and will make our result more clearly understandable. . Comment #3 It is of great interest that responder, non-responder analysis showed that the more active PLDs, the more pronounced the cyst reduction after tolvaptan use, as well as their efficacy in renal cysts. The results strongly suggest that a similar mechanism to inhibition or reduction of renal cyst growth by tolvaptan may apply to hepatic cysts. On the other hand, it is not well understandable that there was no correlation between kidney volume reduction and liver volume reduction in the responder group. The influence of the drainage cases and TAE cases may be concerned, but how do the authors consider this point? RESPONSE: As we mentioned in the response to comment#2, we conducted subgroup analysis for the patients without the history of the physical intervention. Although the rate of the responder was reduced after excluding these interventions, the prognostic factors related to the responders were the same as that of the main analysis. The result of the main analysis contained such carry-over effects related to the physical intervention, however, we believe this well-designed subgroup analysis minimized this concerned effect. Comment #4 There is a lack of discussion of the impact of spontaneous shrinkage of hepatic cysts. In Ref-8, as a consequence of a large observational study of PLDs, it is reported that spontaneous reduction of hepatic volume is observed in 30% of cases in the population. Ref-9 has also reported a reduction in hepatic volume in half of placebo group. In this study, the liver volume is reduced in about half of the subjects, but how to consider the involvement of spontaneous reduction should be discussed. RESPONSE: Thank you for pointing out this spontaneous effect. We totally agree that, in our study, the reduction of the annual growth rate of TKV was partially explained by this phenomenon because the patients of this study were older than previous studies. However, the logistic regression analysis adjusting related variables showed that higher growth rate of TLV as well as older age significantly predicted responders. Therefore, we consider that the reduction observed in our study would be not fully derived from the spontaneous reduction of PLD. Although it was difficult to estimate the rate of spontaneous reduction, we added this problem from page 24 line 12 to page 25 line 1. Minor Comment #1 In a stratified analysis of responder and non-responder, adjustments for variables have been described, however, specific method for this statistical procedure has not been described in the text. RESPONSE: We wrote down the method on Page 10 line 14-18. Comment #2 Inconsistencies are seen in figure description in the text and figure numbering (e.g. Fig. 2B in P14L7). In addition, both Fig. 2 and Fig. 4 are not represented in A and B. RESPONSE: Thank you for pointing out incorrect numbers of figure 2 and figure4. However, we decided to decline these figures in revised manuscript. Reviewer #4: RESPONSE: Thank you for providing us the suggestive comment on our article. Dose effect of tolvaptan and menopausal status were evaluated by conducting subgroup analysis. In addition, we set the control group after screening 902 patients again secondary analysis was conducted for patients without the history of intervention to polycystic liver to minimized the carry-over effect of such therapies. After reconsidering the values of figures, we decided to decline figure 2 and figure 3 because we considered that these figures did not directly represent the main result of this study. We hope that these revisions would make more appropriate this study design. Polycystic liver disease leads to pain and suffering in many individuals with autosomal dominant polycystic kidney disease. This interesting study examines changes in total liver volume in a cohort of individuals who took tolvaptan and followed longitudinally. About 50% experienced a reduction in liver volume and about 50% experienced a continued increase in liver volume. The paper is well written. However I am concerned about the statistics. There are number of extreme outlier cases who could have influenced the data analysis. Overall we may be seeing a regression to the mean. Please mark individuals that had TAE or liver volume reducing procedures on the graph. RESPONSE: Thank you for the carry-over effect of the physical intervention of polycystic liver, such as liver trans-arterial embolization and liver cyst drainage. We decided to decline to use figure 2 and figure 4 in the revised manuscript however, we conducted the secondary analysis about patients without the history of physical intervention in this major revision. We added this subgroup analysis from page 21, line2 to page 22, line 8 and on Supporting Information. Please add figure showing both females that were pre and post menopausal and describe what happened to their total liver volumes. RESPONSE: We collected the data about menopausal status about female patients in the tolvaptan group. Among them, we found the status only from 44 female patients. From the subgroup analysis for the groups according to the menopausal status, however, the annual growth rate of TLV was not significantly different before and after tolvaptan use. We added the result in Supporting Information and on page17 line 8-10. If there is a positive effect of tolvaptan on total liver volume then one might expect a dose -response effect. No dose information has been provided. RESPONSE: We conducted the subgroup analysis to evaluate the dose effect of tolvaptan. The tolvaptan group were divided into the four categories according to the maintenance dose of tolvaptan, however, there was no trend that suggested the dose effect of tolvaptan on response rate or decline of liver growth rate. We added the result of this subgroup analysis on page 17 line 8 and on Supporting Information Figure S1. ******************************************************************************************* Again, thank you for giving us the valuable comments in order to strengthen our manuscript. For these seven weeks we have been trying hard to incorporate your feedback and we hope that these revisions persuade you to consider the acceptance of our submission. Sincerely, Hiroki Mizuno. Nephrology Center Toranomon Hospital Kajigaya, Japan hilomiz@yahoo.co.jp +08-44-3588-5111 Submitted filename: 20210726 letter to editor and rebuttal letter.docx Click here for additional data file. 25 Oct 2021
PONE-D-21-12669R1
Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use
PLOS ONE Dear Dr. Mizuno, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Most of the concerns are clarified, however, there still remains serious problem.  Authors should reanalyze and solve problem pointed out by a reviewer. Please submit your revised manuscript by Dec 09 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:
A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Tatsuo Shimosawa, M.D., Ph.D. Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #2: All comments have been addressed Reviewer #3: All comments have been addressed Reviewer #4: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes Reviewer #3: Partly Reviewer #4: Partly ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: No ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: No ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #2: Yes Reviewer #3: Yes Reviewer #4: No ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #2: The reviewer would like to thank the authors for revising the manuscript according to the comments. This reviewer is satisfied with the revision. Reviewer #3: Dear authors, Thank you for responding to your opinion about the title. I believe that modification of the title has led to a more accurate representation of the study design. And, it is grateful to respond to the previous commentary that the case which carried out physical intervention should be analyzed as a subgroup. In this revised version, total liver volume of patients administered tolvaptan was compared with that of patients who met the criteria of tolvaptan use in Japan and were not administered tolvaptan. However, this study has been conducted as a retrospective longitudinal observational study and is not a prospective randomized controlled trial. Therefore, it is unlikely that patients who do not receive tolvaptan in this analysis are adequate as a control group because the selection bias of whether or not to use tolvaptan occurs when the treatment of choice was performed on the tolvaptan use. In addition, it is considered that it should be corrected to "non-tolvaptan" rather than “control”. However, it is favorable that the authors are trying to objectively assess the effectiveness of tolvaptan while there is a limitation in the retrospective study. However, it is problematic that the authors described "53.6% of ADPKD patients taking tolvaptan experienced the reduction of the annual growth rate of TLV" as a conclusion. The outcome of this revised version is that tolvaptan is not efficacious in reducing hepatic cysts. Therefore, it may be concluded from statistical analyses that the reduction in TLV seen in about half of tolvaptan users is not of particular significance. I would like to know the author’s opinion on this issue. The following is my personal opinions, but it is generally known that the TKV-reducing or-suppressing effects of tolvaptan are deviated in individual case. The same situation may be true for TLV reduction, and there may be an analysis of TLV reduction limitedly in the subgroup showing responder on TKV. Minor Are the ∆TLV% described on the Y-axis in Fig. 2 and annual liver growth rate on the X-axis in Fig. 4 not identical? If the same, the representations should be unified. Reviewer #4: I still find that representation of the data as it is presented in the manuscript is problematic although The authors have striven to accommodate my concerns. There were more cyst drainage and HAEs in the Tolvaptan group than the control group. The manuscript body should focus on the tolvapan and control group differences excluding the patents who had other volume reductive interventions, specifically cyst drainage and hepatic artery embolization so as that it represents impact of Tolvaptan on PKD and not the multiple volume reducing procedures. The manuscript body should report the study findings after the exclusion of these cases with cyst drainage and HAE from both groups as they complicated/confound the analysis. The main result is shown in figure S3 representing the correct group of patients with PLD who did not have any other volume -reducing procedures. This analysis should be moved to the main manuscript as the main result. The current figure representing changes in TLV including those with other volume reducing procedures should be moved to supplemental data. Text in abstract, results section and discussion of the paper should be edited accordingly. Figure 1 flow diagram should be modified to should reflect that these cases with volumes reductive procedures were removed from both tolvaptan and control group analyses. If all cyst drainage procedures are aggregated as opposed to being divided by indication (cyst infection versus routing drainage), one would expect there will be a difference between cases and controls. Please also summate these cases in tables 1 and 2 to determine whether they have statistical significance between the two groups. How much fluid was removed by these drainage procedures? Please add this volumes to tables 1 and 2. The 16 with volume reducing procedures should be removed from the figure 4 the responder/ non responder main analysis in the main body of the paper. How was post menopausal defined? Please describe this in the methods. Page 14, line 13: Analysis of whole patients- change this as it is not good English Supplemental figures have no labels as uploaded. Figure S4- is this the correct title? ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #2: No Reviewer #3: No Reviewer #4: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 5 Jan 2022 Dear Editor and Reviewers Thank you for reviewing our manuscript “Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use [PONE-D-21-12669R1]” and offering valuable advices. We also appreciate the time and effort you have dedicated to providing insightful feedback on our paper. We have addressed to your comments with point-by-point responses and revised the manuscript accordingly. We would like to send two copies, clean and marked versions and as well as the pdf file of four figures. Response to Editor and Reviewers’ comments To Editor Dear Editor Thank you for reviewing our first manuscript. In order to answer the reviewer#4’s suggestion, we decided to amend the whole part of the method and result of the first revision, because the patients with a history of physical interventions needed to be excluded in the main analysis. As a result, in this second revision, the number of patients in the cohort reduced from 107 to 62, however, we expect that this amendment would make our study clearer to understand the true effect of tolvaptan on PLD without bothering the carry-out effect of physical interventions of PLD. It would be appreciated if you could review the new manuscript of the second revision. Reviewer #2 Dear Reviewers Thank you for reviewing our first manuscript. In order to minimize the carry-out effect of physical interventions of PLD, which was pointed out by another reviewer, we excluded the patients having the previous history of such procedures including cyst drainage and trans-arterial embolization for liver arteries. In this second revision, however, the conclusion of the results was consistent with the first revision although the number of patients reduced from 107 to 62. It would be grateful that you could review our manuscript in this new study design. To Reviewer #3 Dear Reviewer #3: Thank you for pointing out the valuable suggestion to strengthen our manuscript. As reviewer #4 pointed out, in this second revision, the inclusion criteria were modified in order to exclude the carry-out effect of the physical intervention of PLD. The number of eligible patients decreased from 107 to 62, however, we believe this revision would make our study more efficient to analyze the tolvaptan’s effect on PLD. “Thank you for responding to your opinion about the title. I believe that modification of the title has led to a more accurate representation of the study design. And, it is grateful to respond to the previous commentary that the case which carried out physical intervention should be analyzed as a subgroup. In this revised version, total liver volume of patients administered tolvaptan was compared with that of patients who met the criteria of tolvaptan use in Japan and were not administered tolvaptan. However, this study has been conducted as a retrospective longitudinal observational study and is not a prospective randomized controlled trial. Therefore, it is unlikely that patients who do not receive tolvaptan in this analysis are adequate as a control group because the selection bias of whether or not to use tolvaptan occurs when the treatment of choice was performed on the tolvaptan use. In addition, it is considered that it should be corrected to "non-tolvaptan" rather than “control”. However, it is favorable that the authors are trying to objectively assess the effectiveness of tolvaptan while there is a limitation in the retrospective study.” RESPONSE: We agree with your idea of describing “non-tolvaptan group” because tolvaptan was not intended to be prescribed for these patients. We have changed all the expression from “control group to “non-tolvaptan group” “However, it is problematic that the authors described "53.6% of ADPKD patients taking tolvaptan experienced the reduction of the annual growth rate of TLV" as a conclusion. The outcome of this revised version is that tolvaptan is not efficacious in reducing hepatic cysts. Therefore, it may be concluded from statistical analyses that the reduction in TLV seen in about half of tolvaptan users is not of particular significance. I would like to know the author’s opinion on this issue.” RESPONSE: As well as in the first revision, the primary analysis of the difference of annual growth rate of tolvaptan in this second revision was not significantly different between tolvaptan group and non-tolvaptan group. Therefore, we considered that the tolvaptan’s effect on the annual growth rate of TLV was not established in this retrospective observational study, and then, we decided to describe the conclusion as follows. “the change in annual growth rate of TLV in ADPKD patients taking tolvaptan was not statistically different compared with that in ADPKD patients without taking tolvaptan. However, tolvaptan may have the potential to suppress the growth rate of TLV in some PLD patients due to ADPKD, especially in older patients or those that are rapid progressors of PLD.” “The following is my personal opinions, but it is generally known that the TKV-reducing or-suppressing effects of tolvaptan are deviated in individual case. The same situation may be true for TLV reduction, and there may be an analysis of TLV reduction limitedly in the subgroup showing responder on TKV.” RESPONSE: Thank you for giving us the valuable suggestions about the association between TKV responder and TLV responder. Although the dose effect of tolvaptan on TLV was not found in our study, and as you mentioned the individual variability of tolvaptan’s effect existed in our cohort, in this cohort of secondary revision, we found that the response rates of TLV in patients with responder on TKV (64.9%) was larger than that in non-responder on TKV (45.2 %) (p<0.01). In addition, the change of annual liver growth rate was mildly associated with the change of the annual kidney growth rate (p<0.01) although rho was relatively lower level (rho=0.34). These facts may imply that some molecular mechanism expressed in both liver and kidney, such as polycystin-1 might be related to the effect of tolvaptan on liver or kidney although the expression rate of polycystin-1 was not detected in our study. Minor “Are the ∆TLV% described on the Y-axis in Fig. 2 and annual liver growth rate on the X-axis in Fig. 4 not identical? If the same, the representations should be unified.” RESPONSE: delta TLV% represents the difference of annual liver growth rate between observational period and tolvaptan period, while TLV% in Fig 4 represents the annual liver growth rate. We unified these expressions between figures. Reviewer #4: Dear Reviewer #4 Thank you for reviewing the manuscript of our first revision and giving us valuable suggestions to improve our study-design. We decided to adopt the new inclusion criteria you suggested. In order to answer all the comments you gave us, we had changed the method, result, and discussion part as well as figures and tables. “I still find that representation of the data as it is presented in the manuscript is problematic although The authors have striven to accommodate my concerns. There were more cyst drainage and HAEs in the Tolvaptan group than the control group. The manuscript body should focus on the tolvapan and control group differences excluding the patents who had other volume reductive interventions, specifically cyst drainage and hepatic artery embolization so as that it represents impact of Tolvaptan on PKD and not the multiple volume reducing procedures. The manuscript body should report the study findings after the exclusion of these cases with cyst drainage and HAE from both groups as they complicated/confound the analysis. The main result is shown in figure S3 representing the correct group of patients with PLD who did not have any other volume -reducing procedures. This analysis should be moved to the main manuscript as the main result. The current figure representing changes in TLV including those with other volume reducing procedures should be moved to supplemental data. Text in abstract, results section and discussion of the paper should be edited accordingly. Figure 1 flow diagram should be modified to should reflect that these cases with volumes reductive procedures were removed from both tolvaptan and control group analyses.” RESPONSE: As you suggested, the inclusion criteria were modified to exclude the physical interventions for PLD and we have changed the method section, the flow diagram of figure1 according to the new inclusion criteria. In addition, we have changed the main result of figure 2 and 3 by using the sub-group analysis of the manuscript of first revision by using figure S3 and S4. “If all cyst drainage procedures are aggregated as opposed to being divided by indication (cyst infection versus routing drainage), one would expect there will be a difference between cases and controls. Please also summate these cases in tables 1 and 2 to determine whether they have statistical significance between the two groups. How much fluid was removed by these drainage procedures? Please add this volumes to tables 1 and 2.” RESPONSE: After we have collected the data of cyst drainage, we found that there was no statistical difference of the volume of cyst drainage between tolvaptan group and the non-tolvaptan group. These data were added in table S1 and figure S2. “The 16 with volume reducing procedures should be removed from the figure 4 the responder/ non responder main analysis in the main body of the paper.” RESPONSE: We have excluded the 16 patients from figure 4. “How was post menopausal defined? Please describe this in the methods.” RESPONSE: The menopausal status was determined by self-reported questionnaire. We added the method on page 8 line 8. “Page 14, line 13: Analysis of whole patients- change this as it is not good English” RESPONSE: We have changed the expression as following “Analysis of the patients including the history of physical intervention for the polycystic liver ” “Supplemental figures have no labels as uploaded.” RESPONSE: We had added the labels of supplemental figures. “Figure S4- is this the correct title?” RESPONSE: We have corrected the titles of figure S3 and S4. ******************************************************************************************* Again, thank you for giving us the valuable comments in order to strengthen our manuscript. We hope that these revisions persuade you to consider the acceptance of our submission. Sincerely, Hiroki Mizuno. Nephrology Center Toranomon Hospital Kajigaya, Japan hilomiz@yahoo.co.jp +08-44-3588-5111 Submitted filename: 20211209 letter to editor and rebuttal letter.docx Click here for additional data file. 3 Feb 2022 Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use PONE-D-21-12669R2 Dear Dr. Mizuno, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Tatsuo Shimosawa, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: (No Response) Reviewer #4: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #3: Yes Reviewer #4: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes Reviewer #4: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #3: Yes Reviewer #4: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #3: Yes Reviewer #4: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #3: I thank you for your sincere responses. I accept all of your responses. Just one, “Control” in Table 1 should be replaced with “non-tolvaptan group”. Reviewer #4: The authors have addressed my concerns in their rebuttal. The revised manuscript is much improved. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #3: No Reviewer #4: No 7 Feb 2022 PONE-D-21-12669R2 Potential effect of tolvaptan on polycystic liver disease for patients with ADPKD meeting the Japanese criteria of tolvaptan use Dear Dr. Mizuno: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Tatsuo Shimosawa Academic Editor PLOS ONE
  32 in total

Review 1.  Medical and surgical treatment options for polycystic liver disease.

Authors:  Joost P H Drenth; Melissa Chrispijn; David M Nagorney; Patrick S Kamath; Vicente E Torres
Journal:  Hepatology       Date:  2010-12       Impact factor: 17.425

2.  Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease.

Authors:  Marie C Hogan; Tetyana V Masyuk; Linda J Page; Vickie J Kubly; Eric J Bergstralh; Xujian Li; Bohyun Kim; Bernard F King; James Glockner; David R Holmes; Sandro Rossetti; Peter C Harris; Nicholas F LaRusso; Vicente E Torres
Journal:  J Am Soc Nephrol       Date:  2010-04-29       Impact factor: 10.121

3.  Somatostatin analogues improve health-related quality of life in polycystic liver disease: a pooled analysis of two randomised, placebo-controlled trials.

Authors:  M K Neijenhuis; T J G Gevers; F Nevens; M C Hogan; V E Torres; W Kievit; J P H Drenth
Journal:  Aliment Pharmacol Ther       Date:  2015-07-01       Impact factor: 8.171

4.  Unified criteria for ultrasonographic diagnosis of ADPKD.

Authors:  York Pei; James Obaji; Annie Dupuis; Andrew D Paterson; Riccardo Magistroni; Elizabeth Dicks; Patrick Parfrey; Benvon Cramer; Eliecer Coto; Roser Torra; Jose L San Millan; Robert Gibson; Martijn Breuning; Dorien Peters; David Ravine
Journal:  J Am Soc Nephrol       Date:  2008-10-22       Impact factor: 10.121

5.  Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data.

Authors:  Tom J G Gevers; Joanna Inthout; Anna Caroli; Piero Ruggenenti; Marie C Hogan; Vicente E Torres; Frederik Nevens; Joost P H Drenth
Journal:  Gastroenterology       Date:  2013-05-07       Impact factor: 22.682

6.  Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial.

Authors:  Maria V Irazabal; Jaime D Blais; Ronald D Perrone; Ron T Gansevoort; Arlene B Chapman; Olivier Devuyst; Eiji Higashihara; Peter C Harris; Wen Zhou; John Ouyang; Frank S Czerwiec; Vicente E Torres
Journal:  Kidney Int Rep       Date:  2016-08-06

7.  Tolvaptan for the Treatment of Enlarged Polycystic Liver Disease.

Authors:  Hiroki Mizuno; Junichi Hoshino; Tatsuya Suwabe; Keiichi Sumida; Akinari Sekine; Yoichi Oshima; Masahiko Oguro; Kyohei Kunizawa; Masahiro Kawada; Rikako Hiramatsu; Noriko Hayami; Eiko Hasegawa; Masayuki Yamanouchi; Naoki Sawa; Kenmei Takaichi; Yoshifumi Ubara
Journal:  Case Rep Nephrol Dial       Date:  2017-07-19

8.  Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model.

Authors:  Hayley Bennett; Phil McEwan; Karina Hamilton; Karl O'Reilly
Journal:  BMC Nephrol       Date:  2019-04-23       Impact factor: 2.388

9.  The management of polycystic liver disease by tolvaptan.

Authors:  Tsuneo Takenaka; Soichiro Miura; Masaki Kitajima
Journal:  Clin Mol Hepatol       Date:  2019-06-13

10.  Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.

Authors:  Emilie Cornec-Le Gall; Jaime D Blais; Maria V Irazabal; Olivier Devuyst; Ron T Gansevoort; Ron D Perrone; Arlene B Chapman; Frank S Czerwiec; John Ouyang; Christina M Heyer; Sarah R Senum; Yannick Le Meur; Vicente E Torres; Peter C Harris
Journal:  Nephrol Dial Transplant       Date:  2018-04-01       Impact factor: 5.992
View more
  1 in total

Review 1.  Treatment of Polycystic Liver Disease: Impact on Patient-reported Symptom Severity and Health-related Quality of Life.

Authors:  Renée Duijzer; Thijs R M Barten; Christian B Staring; Joost P H Drenth; Tom J G Gevers
Journal:  J Clin Gastroenterol       Date:  2022-08-19       Impact factor: 3.174
  1 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.