Reviewer’s report
Title: Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients
with cirrhotic ascites: an observational study
Version: 0 Date: 19 Jul 2019
Reviewer: Cyriac Abby Philips
Reviewer's report:
1.A better change to the title of the study:
Current: Clinical implications of fluid status monitoring under add-on vasopressin V2 antagonism for
hepatic ascites in decompensated liver cirrhosis: an observational study
Suggested: Clinical implications with tolvaptan on monitored fluid status in patients with cirrhosis and
ascites: an observational study
2.Role of fluid non-invasive fluid monitoring has been evaluated by Davenport et al. Please
include this study and its core discussions in the introduction and discussion part.
Davenport A, Argawal B, Wright G, et al. Can non-invasive measurements aid clinical assessment of
volume in patients with cirrhosis?. World J Hepatol. 2013;5(8):433-438.
3.The authors mention 'We hypothesized that dynamic changes in fluid status allow prediction of
response of V2 antagonism and survival in cirrhotic patients'.
Please provide details on
a)Definition of changes in fluid status
b)Published data - preclinical or clinical on derivation of such hypothesis - that is change in
defined fluid status that is shown to affect survival outcomes
4.What is the rationale for using Tolvaptan in patients with normal sodium levels? Was it only for
free water clearance? 
5.The patients and methods section should be well clarified and simplified. It is not clear what the
authors wish to study - it is mentioned that the major purpose is to study shifts in fluid status with add
on tolvaptan and then the authors mention that their aim is not to study effectiveness of tolvaptan.
However, these statements seem contrary. It is due to tolvaptan that the fluid shifts occur. Hence the
authors are in reality, studying effects of tolvaptan and subsequent fluid shifts and clinical outcomes.
The following is suggested or advised for more detail, to improve on the current version:
a)Spell out very clearly Aims, Objectives - primary and secondary. 
b)Give a well-defined inclusion and exclusion criteria.
c)Define persistent ascites. Define all of ascites related clinical events as per The International
Ascites Club definition
d)Why did not the authors exclude refractory ascites and HRS-CKD?
e)Please provide study definitions in one section and do not scatter
f)Describe the rationale for using low dose tolavaptan
g)Please provide details on diet advice and its adherence/compliance monitoring in the patients
enrolled
6.Include a CONSORT flow diagram of the whole patient population inclusive of those included
and excluded with reasonable reasons and final defined patient group in the study
7.Please include a comparator group - matched patients not on Tolvaptan. Defining improvement
in survival within groups is not an effective method to identify efficacy of treatment. Propensity score
matching can also be performed if complete patient data set is available. 
8.Responders and non responders may be placed as a sub group analysis. 
9.Please reassess the sample size with respect to patients enrolled. In my honest opinion the
current sample size seem very less and over analysis has been performed in the small group leading to
heterogenous analysis result with significance. 
10.Please provide details on adverse events. How many patients developed hypernatremia? What
was the incidence of AKI in the study patients?
11.Discuss all of the studies done in cirrhosis and ascites and tolvaptan use. The authors have
missed some important studies in their discussion. For example:
Tahara T, Mori K, Mochizuki M, et al. Tolvaptan is effective in treating patients with refractory ascites
due to cirrhosis. Biomed Rep. 2017;7(6):558-562.
Tajiri K et al. Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis.
Dig Dis. 2018;36(4):314-321. 
The authors need to be selective in their discussion: first, discuss the lacunae in current literature based
on which, the authors chose to perform this study. Second, discuss pertinent study findings. Third,
compare the study findings with what is currently known in literature. And lastly, provide future
directions. The discussion is very haphazard currently. A lot of unnecessary discussion on pathogenesis
and  pathophysiology  may  be  avoided  as  authors  have  not  studied  complete  water  and  sodium
homeostasis in their patients. 
12.The  use  of  BIA in  cirrhosis  needs  to  be  validated.  How  accurate  are  these  findings  in
comparison to data in literature in similar patients and with different BIA techniques?
13.The discussion on hepatocyte injury and inflammation and role of aldosterone etc… needs to be
taken out as authors have not studied these aspects in their patients. Please strictly adhere to the current
study methodology - findings and pertinent result discussions.
14.Please provide a detail on all the limitations of this study and future prospects. There are many
limitations to this study conclusions - for example, deviation from definitions at inclusion, use of
tolvaptan  in  patients  without  hyponatremia  and  absence  of  clear-cut  inclusion,  exclusion  criteria,
absence of a control group, improper randomization and possible selection bias and conclusions based
on non-validated methods for fluid monitoring. Please address these accordingly or rectify in the
revised version.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
I declare that I have no competing interests
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title: Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients
with cirrhotic ascites: an observational study
Version: 0 Date: 19 Jul 2019
Reviewer: Cyriac Abby Philips
Reviewer's report:
1.A better change to the title of the study:
Current: Clinical implications of fluid status monitoring under add-on vasopressin V2 antagonism for
hepatic ascites in decompensated liver cirrhosis: an observational study
Suggested: Clinical implications with tolvaptan on monitored fluid status in patients with cirrhosis and
ascites: an observational study
2.Role of fluid non-invasive fluid monitoring has been evaluated by Davenport et al. Please
include this study and its core discussions in the introduction and discussion part.
Davenport A, Argawal B, Wright G, et al. Can non-invasive measurements aid clinical assessment of
volume in patients with cirrhosis?. World J Hepatol. 2013;5(8):433-438.
3.The authors mention 'We hypothesized that dynamic changes in fluid status allow prediction of
response of V2 antagonism and survival in cirrhotic patients'.
Please provide details on
a)Definition of changes in fluid status
b)Published data - preclinical or clinical on derivation of such hypothesis - that is change in
defined fluid status that is shown to affect survival outcomes
4.What is the rationale for using Tolvaptan in patients with normal sodium levels? Was it only for
free water clearance? 
5.The patients and methods section should be well clarified and simplified. It is not clear what the
authors wish to study - it is mentioned that the major purpose is to study shifts in fluid status with add
on tolvaptan and then the authors mention that their aim is not to study effectiveness of tolvaptan.
However, these statements seem contrary. It is due to tolvaptan that the fluid shifts occur. Hence the
authors are in reality, studying effects of tolvaptan and subsequent fluid shifts and clinical outcomes.
The following is suggested or advised for more detail, to improve on the current version:
a)Spell out very clearly Aims, Objectives - primary and secondary. 
b)Give a well-defined inclusion and exclusion criteria.
c)Define persistent ascites. Define all of ascites related clinical events as per The International
Ascites Club definition
d)Why did not the authors exclude refractory ascites and HRS-CKD?
e)Please provide study definitions in one section and do not scatter
f)Describe the rationale for using low dose tolavaptan
g)Please provide details on diet advice and its adherence/compliance monitoring in the patients
enrolled
6.Include a CONSORT flow diagram of the whole patient population inclusive of those included
and excluded with reasonable reasons and final defined patient group in the study
7.Please include a comparator group - matched patients not on Tolvaptan. Defining improvement
in survival within groups is not an effective method to identify efficacy of treatment. Propensity score
matching can also be performed if complete patient data set is available. 
8.Responders and non responders may be placed as a sub group analysis. 
9.Please reassess the sample size with respect to patients enrolled. In my honest opinion the
current sample size seem very less and over analysis has been performed in the small group leading to
heterogenous analysis result with significance. 
10.Please provide details on adverse events. How many patients developed hypernatremia? What
was the incidence of AKI in the study patients?
11.Discuss all of the studies done in cirrhosis and ascites and tolvaptan use. The authors have
missed some important studies in their discussion. For example:
Tahara T, Mori K, Mochizuki M, et al. Tolvaptan is effective in treating patients with refractory ascites
due to cirrhosis. Biomed Rep. 2017;7(6):558-562.
Tajiri K et al. Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis.
Dig Dis. 2018;36(4):314-321. 
The authors need to be selective in their discussion: first, discuss the lacunae in current literature based
on which, the authors chose to perform this study. Second, discuss pertinent study findings. Third,
compare the study findings with what is currently known in literature. And lastly, provide future
directions. The discussion is very haphazard currently. A lot of unnecessary discussion on pathogenesis
and  pathophysiology  may  be  avoided  as  authors  have  not  studied  complete  water  and  sodium
homeostasis in their patients. 
12.The  use  of  BIA in  cirrhosis  needs  to  be  validated.  How  accurate  are  these  findings  in
comparison to data in literature in similar patients and with different BIA techniques?
13.The discussion on hepatocyte injury and inflammation and role of aldosterone etc… needs to be
taken out as authors have not studied these aspects in their patients. Please strictly adhere to the current
study methodology - findings and pertinent result discussions.
14.Please provide a detail on all the limitations of this study and future prospects. There are many
limitations to this study conclusions - for example, deviation from definitions at inclusion, use of
tolvaptan  in  patients  without  hyponatremia  and  absence  of  clear-cut  inclusion,  exclusion  criteria,
absence of a control group, improper randomization and possible selection bias and conclusions based
on non-validated methods for fluid monitoring. Please address these accordingly or rectify in the
revised version.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
I declare that I have no competing interests
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title: Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients
with cirrhotic ascites: an observational study
Version: 0 Date: 19 Jul 2019
Reviewer: Cyriac Abby Philips
Reviewer's report:
1.A better change to the title of the study:
Current: Clinical implications of fluid status monitoring under add-on vasopressin V2 antagonism for
hepatic ascites in decompensated liver cirrhosis: an observational study
Suggested: Clinical implications with tolvaptan on monitored fluid status in patients with cirrhosis and
ascites: an observational study
2.Role of fluid non-invasive fluid monitoring has been evaluated by Davenport et al. Please
include this study and its core discussions in the introduction and discussion part.
Davenport A, Argawal B, Wright G, et al. Can non-invasive measurements aid clinical assessment of
volume in patients with cirrhosis?. World J Hepatol. 2013;5(8):433-438.
3.The authors mention 'We hypothesized that dynamic changes in fluid status allow prediction of
response of V2 antagonism and survival in cirrhotic patients'.
Please provide details on
a)Definition of changes in fluid status
b)Published data - preclinical or clinical on derivation of such hypothesis - that is change in
defined fluid status that is shown to affect survival outcomes
4.What is the rationale for using Tolvaptan in patients with normal sodium levels? Was it only for
free water clearance? 
5.The patients and methods section should be well clarified and simplified. It is not clear what the
authors wish to study - it is mentioned that the major purpose is to study shifts in fluid status with add
on tolvaptan and then the authors mention that their aim is not to study effectiveness of tolvaptan.
However, these statements seem contrary. It is due to tolvaptan that the fluid shifts occur. Hence the
authors are in reality, studying effects of tolvaptan and subsequent fluid shifts and clinical outcomes.
The following is suggested or advised for more detail, to improve on the current version:
a)Spell out very clearly Aims, Objectives - primary and secondary. 
b)Give a well-defined inclusion and exclusion criteria.
c)Define persistent ascites. Define all of ascites related clinical events as per The International
Ascites Club definition
d)Why did not the authors exclude refractory ascites and HRS-CKD?
e)Please provide study definitions in one section and do not scatter
f)Describe the rationale for using low dose tolavaptan
g)Please provide details on diet advice and its adherence/compliance monitoring in the patients
enrolled
6.Include a CONSORT flow diagram of the whole patient population inclusive of those included
and excluded with reasonable reasons and final defined patient group in the study
7.Please include a comparator group - matched patients not on Tolvaptan. Defining improvement
in survival within groups is not an effective method to identify efficacy of treatment. Propensity score
matching can also be performed if complete patient data set is available. 
8.Responders and non responders may be placed as a sub group analysis. 
9.Please reassess the sample size with respect to patients enrolled. In my honest opinion the
current sample size seem very less and over analysis has been performed in the small group leading to
heterogenous analysis result with significance. 
10.Please provide details on adverse events. How many patients developed hypernatremia? What
was the incidence of AKI in the study patients?
11.Discuss all of the studies done in cirrhosis and ascites and tolvaptan use. The authors have
missed some important studies in their discussion. For example:
Tahara T, Mori K, Mochizuki M, et al. Tolvaptan is effective in treating patients with refractory ascites
due to cirrhosis. Biomed Rep. 2017;7(6):558-562.
Tajiri K et al. Survival Benefit of Tolvaptan for Refractory Ascites in Patients with Advanced Cirrhosis.
Dig Dis. 2018;36(4):314-321. 
The authors need to be selective in their discussion: first, discuss the lacunae in current literature based
on which, the authors chose to perform this study. Second, discuss pertinent study findings. Third,
compare the study findings with what is currently known in literature. And lastly, provide future
directions. The discussion is very haphazard currently. A lot of unnecessary discussion on pathogenesis
and  pathophysiology  may  be  avoided  as  authors  have  not  studied  complete  water  and  sodium
homeostasis in their patients. 
12.The  use  of  BIA in  cirrhosis  needs  to  be  validated.  How  accurate  are  these  findings  in
comparison to data in literature in similar patients and with different BIA techniques?
13.The discussion on hepatocyte injury and inflammation and role of aldosterone etc… needs to be
taken out as authors have not studied these aspects in their patients. Please strictly adhere to the current
study methodology - findings and pertinent result discussions.
14.Please provide a detail on all the limitations of this study and future prospects. There are many
limitations to this study conclusions - for example, deviation from definitions at inclusion, use of
tolvaptan  in  patients  without  hyponatremia  and  absence  of  clear-cut  inclusion,  exclusion  criteria,
absence of a control group, improper randomization and possible selection bias and conclusions based
on non-validated methods for fluid monitoring. Please address these accordingly or rectify in the
revised version.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I recommend additional statistical review
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
I declare that I have no competing interests
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
assistant