Loop Diuretics and Sarcopenia: A Potential Association
Round 1
Reviewer 1 Report
The authors have provided a decent summary of the involvement of Loop diuretics in triggering sarcopenia under different health conditions. The review is well-written and well-organized. I think considering the following aspects in the review will provide more strength to the content.
The review considered only clinical studies demonstrating a potential association between Loop diuretics and sarcopenia. Authors nowhere discussed the possible molecular mechanism by which Loop diuretics induce sarcopenia. As a part of the discussion, authors should consider discussing the possible disease mechanism and the involvement of different signaling pathways in the potential association between Loop diuretics and sarcopenia. Considering left-out literature on animal studies and other in-vitro studies might be helpful.
Author Response
Dear Editor of Muscles,
We wish to thank you for considering our review article for publication in Muscles and for allowing us to resubmit a revised version of our manuscript. In addition, we would like to thank the reviewers for their insightful comments and suggestions, which have been helpful in order to improve and strengthen our manuscript. We have carefully revised our manuscript, according to the comments made by the reviewers and please find below the changes that we have made, using the highlight green mode in MS Word, to our initial submission.
RESPONSE TO THE REFEREES
# Reviewer 1
The authors have provided a decent summary of the involvement of Loop diuretics in triggering sarcopenia under different health conditions. The review is well-written and well-organized. I think considering the following aspects in the review will provide more strength to the content.
Response: Thank you for your positive comment.
The review considered only clinical studies demonstrating a potential association between Loop diuretics and sarcopenia. Authors nowhere discussed the possible molecular mechanism by which Loop diuretics induce sarcopenia. As a part of the discussion, authors should consider discussing the possible disease mechanism and the involvement of different signaling pathways in the potential association between Loop diuretics and sarcopenia. Considering left-out literature on animal studies and other in-vitro studies might be helpful.
Response: Thank you for your insightful comment. The direct mechanisms concerning loop diuretics and sarcopenia are neither described by the current literature nor are clear and our potential assumptions might lead us to unclear results. Only diseases which are linked to sarcopenia and the diseases mechanisms inducing sarcopenia are described in the investigated studies and are already well-established. At this point, we would like to underlie that the main goal of this non-systematic review article is to demonstrate the studies which depicted any possible association between sarcopenia and loop diuretics and give further food for thought for deeper research, specifically laboratory research apart from clinical research, which could clarify these mechanisms.
Looking forward to hearing from you in due course,
Nikolaos D. Karakousis, MD, MSc, PhD
Author Response File: 
Author Response.docx
Reviewer 2 Report
Abstract (these comments are more directed to improve the quality of this paper):
- Results section is lengthy and doesn't provide fully clear context on the argument/point of discussion after reading through it twice. Consider revising.
- Conclusion section needs more context
Introduction
- Lines 40-42 need to be addressed ("This meeting,...") -- don't really understand the point you're trying to make.
- Take out optimum in line 46.
- Line 57, algorithm, not algorism (from the context of the sentence, looks like algorithm is the more appropriate term)
- To be quite honest, there is a tremendous amount of material in the introduction related to sarcopenia that doesn't really need to be in the article. The title of the article is Loop diuretics and sarcopenia, and you only address the diuretics towards the end of the introduction with much less content. The sarcopenia content is fine and all but doesn't really contribute to the paper as a reader and distracts from your main message with this paper. Some of this content does support or provide information related to the studies you cite/discuss in the results section but consider revising for brevity. Consider eliminating a majority of the content concerning measurements for sarcopenia (lines 69-116) -- particularly exercise/nutritional information which can and is addressed later on in the discussion.
- You spend 2-3 sentences addressing any type of connection between these two topics (loop diuretics and sarcopenia). Should be a little more content in my opinion.
- Introduction in its entirety is well-written but needs major changes to get it focused/on-track with the point of the article's title.
Some comments in no particular order:
- That there are only 5 studies examined is somewhat concerning. It lends the question that are there more studies addressing this topic through a more exhaustive literature search?
- A point worth addressing (discussion section) is the challenges/difficulties of assessing and determining sarcopenia -- there's not necessarily a common approach to diagnosing it -- and this is also evidenced in your studies. Comments/discussion of this and its limitations to your manuscript need addressed.
- There's no mechanistic link between LD and sarcopenia. How/why do you theorize the link? This should be included.
- The discussion (and somewhat the conclusion) could use some significant improvements. The discussion skips right to limitations without much thought/comparison/discussion of the results and the topic.
- How do you consider trying to tease apart potential interactions between factors contributing to sarcopenia (e.g., age, lifestyle, associated disease, medications) in your link between LD and sarcopenia? Some food for thought in the discussion section.
Needs minor grammar modifications throughout.
Author Response
Dear Editor of Muscles,
We wish to thank you for considering our review article for publication in Muscles and for allowing us to resubmit a revised version of our manuscript. In addition, we would like to thank the reviewers for their insightful comments and suggestions, which have been helpful in order to improve and strengthen our manuscript. We have carefully revised our manuscript, according to the comments made by the reviewers and please find below the changes that we have made, using the highlight green mode in MS Word, to our initial submission.
RESPONSE TO THE REFEREES
#Reviewer 2
Abstract (these comments are more directed to improve the quality of this paper):
- Results section is lengthy and doesn't provide fully clear context on the argument/point of discussion after reading through it twice. Consider revising.
Response: We thank the reviewer for this comment. We have made the appropriate change.
- Conclusion section needs more context
Response: We thank the reviewer for this comment. We have made the appropriate alteration.
Introduction
- Lines 40-42 need to be addressed ("This meeting,...") -- don't really understand the point you're trying to make.
Response: We thank the reviewer for this comment. The lined were eliminated from our revised manuscript.
- Take out optimum in line 46.
Response: We thank the reviewer for this comment. The word was eliminated from our revised manuscript.
- Line 57, algorithm, not algorism (from the context of the sentence, looks like algorithm is the more appropriate term)
Response: We thank the reviewer for this comment. The word was corrected in our revised manuscript.
- To be quite honest, there is a tremendous amount of material in the introduction related to sarcopenia that doesn't really need to be in the article. The title of the article is Loop diuretics and sarcopenia, and you only address the diuretics towards the end of the introduction with much less content. The sarcopenia content is fine and all but doesn't really contribute to the paper as a reader and distracts from your main message with this paper. Some of this content does support or provide information related to the studies you cite/discuss in the results section but consider revising for brevity. Consider eliminating a majority of the content concerning measurements for sarcopenia (lines 69-116) -- particularly exercise/nutritional information which can and is addressed later on in the discussion.
Response: We thank the reviewer for this comment. The basic idea is surely the concept of sarcopenia which seems to concern the scientific community, especially when linked to diseases and medications. The interplay concerns LD use as part of diseases linked to sarcopenia, with no specific mechanisms in humans demonstrated by the current literature, concerning the direct interplay of sarcopenia and LD, justifying the small part concerning LD in our manuscript. Nevertheless, we eliminated one part concerning measurement, but not a great part of this section because we firmly believe that measurement should be thoroughly highlighted due to its importance and impact on sarcopenia screening. As for the interventions, we utilized discussion as a means of future suggestions and research ideas and a result we decided to use introduction as a means to highlight interventions after a thorough presentation of sarcopenia clinical issue.
- You spend 2-3 sentences addressing any type of connection between these two topics (loop diuretics and sarcopenia). Should be a little more content in my opinion.
Response: Thank you for this comment. We tried to give more attention to the part of results concerning the interplay of these two entities. This is the reason why we do not provide many information at this point of the manuscript, trying to stimulate a more critical approach by the readers concerning this topic.
- Introduction in its entirety is well-written but needs major changes to get it focused/on-track with the point of the article's title.
Response: Thank you very much for this insightful comment. We revised the introduction.
Some comments in no particular order:
- That there are only 5 studies examined is somewhat concerning. It lends the question that are there more studies addressing this topic through a more exhaustive literature search?
Response: Thank you very much for this comment. According to key words and search data bases, these are for now the existing studies demonstrating this interplay.
- A point worth addressing (discussion section) is the challenges/difficulties of assessing and determining sarcopenia -- there's not necessarily a common approach to diagnosing it -- and this is also evidenced in your studies. Comments/discussion of this and its limitations to your manuscript need addressed.
Response: Thank you very much for this comment. The appropriate change/add was made in discussion section.
- There's no mechanistic link between LD and sarcopenia. How/why do you theorize the link? This should be included.
Response: Thank you very much for this insightful comment. The number of studies is small, while there is no description concerning potential mechanism between LD and sarcopenia in humans. In this article we tried to demonstrate the existing literature concerning observational studies, in order to stimulate further laboratory and experimental research, relying on mainly on the idea that polypharmacy is associated with frailty and muscle mass alterations.
- The discussion (and somewhat the conclusion) could use some significant improvements. The discussion skips right to limitations without much thought/comparison/discussion of the results and the topic.
Response: Thank you very much for this insightful comment. We mainly focus on that because the outcomes of studies are quite clearly depicted at the results section, table and conclusions.
- How do you consider trying to tease apart potential interactions between factors contributing to sarcopenia (e.g., age, lifestyle, associated disease, medications) in your link between LD and sarcopenia? Some food for thought in the discussion section.
Response: Thank you very much for this kind comment. At this moment, the existing literature does not suggest or validate other interactions.
Looking forward to hearing from you in due course,
Nikolaos D. Karakousis, MD, MSc, PhD
Author Response File: Author Response.docx
Reviewer 3 Report
In the present manuscript, the authors present the results obtained from a non-systematic review of the literature, with the aim of proposing a relationship between the administration of loop diuretics and the appearance of sarcopenia in these patients. The subject is interesting for the field and due to the common use of this medication in the treatment of chronic diseases with increasing prevalence, it is of current interest in the field of knowledge and health practice. In addition, it deals with a relationship that has not been studied much, which gives it originality and relevance.
The manuscript is well written, easy to read and follow, and provides current and sufficient references for the topic it deals with.
However, there are some key aspects of the article that, in my opinion, could be improved:
1.- The introduction of the article delves into the explanation of the diagnosis and evaluation of the evolution of sarcopenia. Although it is an interesting section to read and provides clinically important information, it is too long, taking into account that this is not directly related to the objective of this article, even more so, considering that the introduction fails to establish a clear link between sarcopenia and loop diuretics, at least theoretically, based on previous evidence or on the justified reasoning of the authors. Rather, the two are presented to us as unconnected subjects whose relationship seems to be found in the results only by chance.
2.- In the methodology, I believe that the authors should justify why they have excluded those studies carried out in animals, if they were relevant for the objective of this review. Animal studies allow us to unravel and better understand the biological, biochemical and physiological mechanisms in a controlled environment, providing a solid foundation to better establish the relationship between an external intervention such as loop diuretics and a biological event, as well as the mechanisms that determine that relationship, whether or not it is cause-effect
3.- The authors are grateful for the creation of a summary table of the consulted studies, however it would be even more appreciated if the main results collected in the corresponding boxes were more summarized, since they are more detailed in the main text and the main idea should be provided in the table so that the reader can quickly grasp it.
4.- In the discussion of the results, the authors must delve into some mechanistic or pathophysiological hypothesis of why this association occurs and, if possible, elaborate a figure that helps to summarize said process graphically and visually.
As an additional comment, I suggest to the authors that it is not necessary to remember in each section that it is a non-systematic review, it is assumed that a narrative review like this is not, and it is also very well established in the methodology.
For these reasons, I believe that this article should have major reviews before being published in Muscle.
Thanks to the authors for their work and to the editors for allowing me to review this manuscript.
Author Response
Dear Editor of Muscles,
We wish to thank you for considering our review article for publication in Muscles and for allowing us to resubmit a revised version of our manuscript. In addition, we would like to thank the reviewers for their insightful comments and suggestions, which have been helpful in order to improve and strengthen our manuscript. We have carefully revised our manuscript, according to the comments made by the reviewers and please find below the changes that we have made, using the highlight green mode in MS Word, to our initial submission.
RESPONSE TO THE REFEREES
#Reviewer 3
In the present manuscript, the authors present the results obtained from a non-systematic review of the literature, with the aim of proposing a relationship between the administration of loop diuretics and the appearance of sarcopenia in these patients. The subject is interesting for the field and due to the common use of this medication in the treatment of chronic diseases with increasing prevalence, it is of current interest in the field of knowledge and health practice. In addition, it deals with a relationship that has not been studied much, which gives it originality and relevance. The manuscript is well written, easy to read and follow, and provides current and sufficient references for the topic it deals with.
Response: Thank you for your kind comment.
However, there are some key aspects of the article that, in my opinion, could be improved:
1.- The introduction of the article delves into the explanation of the diagnosis and evaluation of the evolution of sarcopenia. Although it is an interesting section to read and provides clinically important information, it is too long, taking into account that this is not directly related to the objective of this article, even more so, considering that the introduction fails to establish a clear link between sarcopenia and loop diuretics, at least theoretically, based on previous evidence or on the justified reasoning of the authors. Rather, the two are presented to us as unconnected subjects whose relationship seems to be found in the results only by chance.
Response: Thank you for the insightful comments. In our opinion, our main target was to thoroughly describe sarcopenia, due to the fact that the investigated studies mainly focus on diseases treated with LD and their impact on sarcopenia. So the main parameter, is the disease related sarcopenia in all these studies, along with the use of LD. Their relationship is also found in the results along with the table and conclusions, but it is based on observation and our aim was to activate the research community to further assess their potential and observation-based interplay using laboratory protocols and means apart from observational studies. In our discussion section, we clearly propose potential future approaches.
2.- In the methodology, I believe that the authors should justify why they have excluded those studies carried out in animals, if they were relevant for the objective of this review. Animal studies allow us to unravel and better understand the biological, biochemical and physiological mechanisms in a controlled environment, providing a solid foundation to better establish the relationship between an external intervention such as loop diuretics and a biological event, as well as the mechanisms that determine that relationship, whether or not it is cause-effect
Response: Thank you for your comment. The main goal of our study was to demonstrate and reveal the existing observational studies showing a potential interplay among diseases linked to LD use and sarcopenia in humans. The utilization of animal studies, even if we agree with your point, is something that at this point is not relevant with the aim of our study. Maybe in the near future another review article could demonstrate the potential association between these two entities using animal or in silico studies.
3.- The authors are grateful for the creation of a summary table of the consulted studies, however it would be even more appreciated if the main results collected in the corresponding boxes were more summarized, since they are more detailed in the main text and the main idea should be provided in the table so that the reader can quickly grasp it.
Response: Thank you for your comment. The appropriate changes and eliminations were made.
4.- In the discussion of the results, the authors must delve into some mechanistic or pathophysiological hypothesis of why this association occurs and, if possible, elaborate a figure that helps to summarize said process graphically and visually.
Response: Thank you for your comment. The number of studies is small, while there is no description concerning potential mechanism between LD and sarcopenia in humans. In this article we tried to demonstrate the existing literature concerning observational studies, in order to stimulate further laboratory and experimental research, relying on mainly on the idea that polypharmacy is associated with frailty and muscle mass changes.
As an additional comment, I suggest to the authors that it is not necessary to remember in each section that it is a non-systematic review, it is assumed that a narrative review like this is not, and it is also very well established in the methodology. For these reasons, I believe that this article should have major reviews before being published in Muscle.
Response: Thank you for your comment. The appropriate alterations were made.
Thanks to the authors for their work and to the editors for allowing me to review this manuscript.
Response: Thank you for your positive comment.
Looking forward to hearing from you in due course,
Nikolaos D. Karakousis, MD, MSc, PhD
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
I recommend the editor to accept the article in present format.
Author Response
Dear Editor of Muscles,
We wish to thank you for considering our review article for publication in Muscles and for allowing us to resubmit a revised version of our manuscript. In addition, we would like to thank the reviewers for their insightful comments and suggestions, which have been helpful in order to improve and strengthen our manuscript. We have carefully revised our manuscript, according to the comments made by the reviewers and please find below the changes that we have made, using the highlight green mode in MS Word, to our initial submission.
RESPONSE TO THE REFEREES
# Reviewer 1
I recommend the editor to accept the article in present format.
Response: Thank you for your positive comment.
Author Response File: Author Response.docx
Reviewer 2 Report
Thanks for addressing most of my concerns/suggestions.
Proofread 1 more time, I found a few small grammar errors.
Author Response
Dear Editor of Muscles,
We wish to thank you for considering our review article for publication in Muscles and for allowing us to resubmit a revised version of our manuscript. In addition, we would like to thank the reviewers for their insightful comments and suggestions, which have been helpful in order to improve and strengthen our manuscript. We have carefully revised our manuscript, according to the comments made by the reviewers and please find below the changes that we have made, using the highlight green mode in MS Word, to our initial submission.
RESPONSE TO THE REFEREES
#Reviewer 2
Thanks for addressing most of my concerns/suggestions.
Response: We thank the reviewer for this comment.
Proofread 1 more time, I found a few small grammar errors.
Response: We thank the reviewer for this comment. We have made the appropriate changes.
Looking forward to hearing from you in due course,
Nikolaos D. Karakousis, MD, MSc, PhD
Author Response File: Author Response.docx
Reviewer 3 Report
I am satisfied by the author's responses.
Thank you very much for their work.
Author Response
Dear Editor of Muscles,
We wish to thank you for considering our review article for publication in Muscles and for allowing us to resubmit a revised version of our manuscript. In addition, we would like to thank the reviewers for their insightful comments and suggestions, which have been helpful in order to improve and strengthen our manuscript. We have carefully revised our manuscript, according to the comments made by the reviewers and please find below the changes that we have made, using the highlight green mode in MS Word, to our initial submission.
RESPONSE TO THE REFEREES
#Reviewer 3
I am satisfied by the author's responses.
Response: Thank you for your kind comment.
Thank you very much for their work.
Response: Thank you for your comment and providing your precious time to review our manuscript.
Best Regards,
Nikolaos D. Karakousis, MD, MSc, PhD
Author Response File: Author Response.docx
Round 3
Reviewer 2 Report
Thanks for your efforts on the original manuscript and the revisions. Nice work.
