From Prehabilitation to Rehabilitation: A Systematic Review of Resistance Training as a Strategy to Combat Sarcopenia in Pre- and Post-Liver Transplant Patients

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present a systematic review regarding sarcopenia and resistance training in the pre and post liver transplant population.  The authors' focus was on RCT with narrow scope.

However 1. it would be of benefit to provide context in regards to sarcopenia and its affects on pre and post transplant survival in both the introduction and discussion

2. Did any of the RCT's address this question

3. Of the studies including in the analysis I am assuming all patients who were enrolled were then listed and/or transplanted? If this could be explicitly clarified through the tables it would be helpful as well.

4. The author's repeatedly emphasize resistance training and the risk of complications of portal htn. I believe the authors do not need to repeat this multiple times as the point is made sufficiently in the introduction.

5. The tables and figures should be placed at the end of the paper as per standard format. Their inclusion in the middle of the paper prior to the discussion is disruptive to the content of the manuscript.

6. Finally do the authors have any of their own experience to provide insight into the effectiveness of these strategies i.e. do these prehab strategies increased likelihood to transplant, length of hospital stay, readmission rate. 

Author Response

Reviewer 1

 

The authors present a systematic review regarding sarcopenia and resistance training in the pre and post liver transplant population.  The authors' focus was on RCT with narrow scope.

 

However 1. it would be of benefit to provide context in regards to sarcopenia and its affects on pre and post transplant survival in both the introduction and discussion

 

We thank the reviewer for this valuable suggestion. We agree that providing context on the impact of sarcopenia on pre- and post-liver transplant survival is essential to enhance the relevance and clarity of the review. We have now added a paragraph to the introduction, detailing the prognostic significance of sarcopenia in both pre- and post-transplant populations, with appropriate references.

 

2. Did any of the RCT's address this question

 

We thank the reviewer for this insightful question. While the included RCTs primarily assessed improvements in sarcopenia-related parameters such as muscle strength, aerobic capacity, and physical performance, none of the studies specifically evaluated pre- and post-transplant survival outcomes as a primary endpoint. However, we note that Aamann et al. (2023) reported a reduction in hospital admissions and all-cause mortality over a 3-year follow-up in cirrhotic patients undergoing resistance training, though this study did not focus exclusively on post-transplant patients. The remaining RCTs, including Moya-Nájera et al. and Ergene et al., examined functional and quality-of-life outcomes in post-transplant populations but did not report survival data. We have now clarified this point in the manuscript’s Discussion section.

 

3. Of the studies including in the analysis I am assuming all patients who were enrolled were then listed and/or transplanted? If this could be explicitly clarified through the tables it would be helpful as well.

 

We thank the reviewer for this important observation. Upon reviewing the included studies, we note that while some RCTs enrolled only patients already listed for liver transplantation (e.g., Zenith et al., Wallen et al.), other studies included broader cohorts of cirrhotic patients, some of whom may not have been formally listed for transplantation (e.g., Aamann et al., Kruger et al.). The post-transplant RCTs (Moya-Nájera et al. and Ergene et al.) exclusively enrolled patients who had undergone liver transplantation. We acknowledge that the listing and transplantation status of participants was not consistently detailed across all studies, and we have clarified this information in the Methods section.

 

4. The author's repeatedly emphasize resistance training and the risk of complications of portal htn. I believe the authors do not need to repeat this multiple times as the point is made sufficiently in the introduction.

 

We thank the reviewer for this helpful observation. We agree that the safety considerations related to resistance training in the context of portal hypertension were overemphasized in the manuscript. To address this, we have streamlined the discussion by removing repetitive sections in the Discussion that reiterated these safety concerns.

 

5. The tables and figures should be placed at the end of the paper as per standard format. Their inclusion in the middle of the paper prior to the discussion is disruptive to the content of the manuscript.

 

This was done as per guidance provided in the Instructions for Authors and in the journal template. We have left the Tables in the same place.

 

6. Finally do the authors have any of their own experience to provide insight into the effectiveness of these strategies i.e. do these prehab strategies increased likelihood to transplant, length of hospital stay, readmission rate.

 

We thank the reviewer for this thoughtful question. Yes, we have clinical and research experience with resistance training interventions in cirrhotic patients, and we have previously presented preliminary data on this topic at the United European Gastroenterology Week (UEGW). Our findings included improvements in fatigue and quality of life in compensated cirrhotics undergoing resistance training. We have now cited our own work at the end of the Discussion section to provide additional insight and support for the effectiveness of these strategies in real-world clinical settings.

Reviewer 2 Report

Comments and Suggestions for Authors

We congratulate the authors for conducting this systematic review on resistance training as a strategy to improve sarcopenia in patients both pre- and post-liver transplant.

The authors reported that resistance training interventions resulted in significant improvements in aerobic capacity, anthropometric parameters, physical performance, and reduced postoperative hospital stay in patients with liver transplant.

The review is well-written, covers an interesting topic, and adheres to PRISMA reporting guidelines. However, we have some comments and concerns regarding the methodology and results.

Major

1. We suggest that more specific data should be provided in the results section within the abstract. The aim and methodology are clearly explained, although the presentation of the results within the abstract should be improved.

“The resistance training interventions resulted in significant improvements in aerobic capacity, anthropometric parameters, physical performance, and reduced postoperative hospital stay”.

2.- It is stated that non-randomized trials and studies with missing data were excluded.

Although we do have some concerns regarding two studies included.

• Al-Judaibia et al. [60]. It seems to be a retrospective cohort study, rather than a prospective randomized controlled trial. It should be considered and then excluded.
• Nóbrega et al. This is a study protocol, and therefore the data is not complete, and therefore should be considered for exclusion.

3.-In Table 1, the title of the upper right cell reads “Number of patients who achieved the outcome with intervention vs. comparison.” Are all the numbers listed in the column labelled 'number of patients'? It seems that some results are provided as rate of improvement rather than number of patients. We suggest correcting it.

4.- Some numbers in the last column have shifted and do not match the labeled results.

5.- We have some concerns about how the results are presented, as no specific rates or percentages are provided for the included studies. Although this study is not a meta-analysis, and therefor pooled effects estimates can not be provided, some more specific rate or percentages could be provided within the results.

6.- The risk of bias has not been assessed for all the included studies.

 

Minor.

Notably, the Global Burden of Disease Study (GBD) 2017 reports an increase in decompensated cirrhosis cases from 5.2 million in 1990 to 10.6 million in 2017 [1]. We suggest using

“reported” rather than reports. (page 1, line 35).

Author Response

Reviewer 2

 

We congratulate the authors for conducting this systematic review on resistance training as a strategy to improve sarcopenia in patients both pre- and post-liver transplant. The authors reported that resistance training interventions resulted in significant improvements in aerobic capacity, anthropometric parameters, physical performance, and reduced postoperative hospital stay in patients with liver transplant. The review is well-written, covers an interesting topic, and adheres to PRISMA reporting guidelines. However, we have some comments and concerns regarding the methodology and results.

 

We sincerely thank the reviewer for their thoughtful and encouraging feedback. We are grateful for the positive remarks regarding the quality of writing, relevance of the topic, and adherence to PRISMA guidelines. We appreciate the time and care taken to review our work and fully agree that the methodological points raised are important to strengthen the rigor of our manuscript. We have carefully addressed each of the comments and made the corresponding revisions, which we detail in the responses that follow.

 

We suggest that more specific data should be provided in the results section within the abstract. The aim and methodology are clearly explained, although the presentation of the results within the abstract should be improved. “The resistance training interventions resulted in significant improvements in aerobic capacity, anthropometric parameters, physical performance, and reduced postoperative hospital stay”.

 

We thank the reviewer for highlighting the need for greater specificity in the abstract results. We have revised the Results section of the abstract to include more detailed, quantitative outcomes from the included RCTs, including improvements in peak VO₂, 6-minute walk distance, muscle thickness, and strength measures. These changes provide clearer insight into the magnitude and clinical relevance of the findings.

 

It is stated that non-randomized trials and studies with missing data were excluded.

Although we do have some concerns regarding two studies included.

Al-Judaibia et al. [60]. It seems to be a retrospective cohort study, rather than a prospective randomized controlled trial. It should be considered and then excluded.

Nóbrega et al. This is a study protocol, and therefore the data is not complete, and therefore should be considered for exclusion.

 

We thank the reviewer for this important point. We acknowledge that Al-Judaibi et al. is a retrospective cohort study and not a randomized controlled trial. However, we chose to include this study due to its large sample size and quasi-experimental design, which compares outcomes before and after the structured implementation of a standardized exercise training program in a real-world transplant setting. The study design closely simulates a pragmatic trial and contributes meaningful data on hospital length of stay and readmission, which are underreported outcomes in the RCTs reviewed. We have now clarified in the Methods that this study was included as an exception due to its structured intervention and comparative design, and it is labeled appropriately in the tables. In contrast, the Nóbrega study was excluded due to the lack of outcome data, as it is a study protocol only.

 

In Table 1, the title of the upper right cell reads “Number of patients who achieved the outcome with intervention vs. comparison.” Are all the numbers listed in the column labelled 'number of patients'? It seems that some results are provided as rate of improvement rather than number of patients. We suggest correcting it.

 

We thank the reviewer for this clarification. We agree that the title was misleading and not all values represented absolute patient counts. We have now revised the column header and ensured that all outcome data are presented using standardized effect sizes or units of measure (e.g., meters for 6MWD, mL/kg/min for VO₂). This ensures consistency and clarity across the table.

 

Some numbers in the last column have shifted and do not match the labeled results.

 

We appreciate the reviewer pointing this out. We have carefully revised the alignment of all numerical entries to correspond accurately with their associated variables. The entire table has been rebuilt to correct formatting errors and improve structure.

 

We have some concerns about how the results are presented, as no specific rates or percentages are provided for the included studies. Although this study is not a meta-analysis, and therefore pooled effects estimates cannot be provided, some more specific rates or percentages could be provided within the results.

 

We fully agree. The revised table now includes quantitative outcomes such as VO₂ max changes, walk distances, strength improvements, and muscle mass gains wherever available. This enhances the clinical interpretability of the findings even in the absence of a formal meta-analysis.

 

The risk of bias has not been assessed for all the included studies.

 

We thank the reviewer for highlighting this important methodological issue. In response, we have now conducted a formal risk of bias assessment for all included randomized controlled trials using the Cochrane Risk of Bias tool (RoB 2) and incorporated a summary of findings into the Results section. We also acknowledge that the retrospective cohort study by Al-Judaibi et al. carries inherent risk of bias due to its design, and this has been explicitly noted in the manuscript.

 

Notably, the Global Burden of Disease Study (GBD) 2017 reports an increase in decompensated cirrhosis cases from 5.2 million in 1990 to 10.6 million in 2017 [1]. We suggest using “reported” rather than reports. (page 1, line 35).

 

We have adjusted this as per your request.

Reviewer 3 Report

Comments and Suggestions for Authors

Thank you very much for the opportunity to review the manuscript.

The authors present a systematic review of exercise interventions to overcome sarcopenia in pre- and post-liver transplantation. Given that sarcopenia is highly prevalent among liver transplant recipients and is well known to negatively affect postoperative recovery, the overall aim of this study is meaningful. However, several areas require revision and clarification.

1. A more fundamental concern is whether the studies included in this review were conducted in the pre-transplant setting. According to Table 1, most studies identified changes in aerobic capacity and muscle strength as primary or secondary outcomes. However, it is difficult to find data evaluating the effect of pre-transplant exercise interventions on post-transplant outcomes. A detailed analysis of each study, as well as the authors' owninterpretation of these findings, would enhance the value of this paper.
2. The authors state that exercise interventions are safe even in patients with decompensated liver cirrhosis. While I agree with the potential benefits of aerobic and resistance training, safety remains a concern. It would be helpful to provide more practical recommendations regarding what types and intensities of exercise might be appropriate for patients with different degrees of liver disease severity and sarcopenia.
3. Although aerobic exercise also appears to have positive effects, the conclusions only focus on resistance training programs. Is there any specific reason for that?
4. In the Results section, the studies are presented in a just list-like manner. It would improve readability to group studies with similar purposes or outcomes, providing comprehensive paragraphs.
5. While the tables include much information about each study, the current format appears overly dense and spans several pages, which disturbs readability. The tables should be revised to enhance visual accessibility.

Author Response

Reviewer 3

 

Thank you very much for the opportunity to review the manuscript. The authors present a systematic review of exercise interventions to overcome sarcopenia in pre- and post-liver transplantation. Given that sarcopenia is highly prevalent among liver transplant recipients and is well known to negatively affect postoperative recovery, the overall aim of this study is meaningful. However, several areas require revision and clarification.

 

We sincerely thank the reviewer for taking the time to assess our manuscript and for acknowledging the clinical relevance of our study. We greatly appreciate the recognition of our aim to address sarcopenia in liver transplant populations through a systematic review of exercise-based interventions. We have carefully considered all suggestions and concerns raised and have revised the manuscript accordingly to enhance its clarity, methodological rigor, and clinical applicability. Detailed responses to each point are provided below.

 

A more fundamental concern is whether the studies included in this review were conducted in the pre-transplant setting. According to Table 1, most studies identified changes in aerobic capacity and muscle strength as primary or secondary outcomes. However, it is difficult to find data evaluating the effect of pre-transplant exercise interventions on post-transplant outcomes. A detailed analysis of each study, as well as the authors' own interpretation of these findings, would enhance the value of this paper.

 

We thank the reviewer for this insightful observation. We agree that the long-term impact of pre-transplant exercise interventions on post-transplant outcomes remains a critical knowledge gap in the current literature. As reflected in our revised Results and Discussion sections, none of the included randomized controlled trials directly evaluated post-transplant clinical outcomes such as survival or complications following pre-transplant exercise interventions. In response, we have added a paragraph in the Discussion to acknowledge the indirect nature of most findings and emphasize the need for future studies to investigate longitudinal outcomes that span the transplant continuum.

 

The authors state that exercise interventions are safe even in patients with decompensated liver cirrhosis. While I agree with the potential benefits of aerobic and resistance training, safety remains a concern. It would be helpful to provide more practical recommendations regarding what types and intensities of exercise might be appropriate for patients with different degrees of liver disease severity and sarcopenia.

 

We appreciate the reviewer’s concern regarding the safety of exercise interventions in patients with advanced liver disease. Across the included studies, no major adverse events—such as variceal bleeding, falls, or hepatic decompensation—were reported, even in patients with decompensated cirrhosis. While detailed stratification by liver disease severity was not uniformly available across studies, we agree that further research is needed to define optimal exercise types and intensities for specific subgroups.

 

Although aerobic exercise also appears to have positive effects, the conclusions only focus on resistance training programs. Is there any specific reason for that?

 

We thank the reviewer for this observation. The focus on resistance training in our conclusions reflects the specific aim of this systematic review, which was to evaluate the impact of resistance-based interventions on sarcopenia in liver transplant candidates and recipients. While several included studies incorporated aerobic components, the primary intervention of interest—as defined in our inclusion criteria—was resistance training, given its direct effects on muscle mass and strength.

 

In the Results section, the studies are presented in a just list-like manner. It would improve readability to group studies with similar purposes or outcomes, providing comprehensive paragraphs.

 

We thank the reviewer for this suggestion. Our intention in the Results section was to present a structured summary of each study’s intervention and outcomes in a concise and comparable manner. Given the heterogeneity in study designs, populations, and measured outcomes, we felt it was most transparent to describe each trial individually. Broader thematic synthesis and comparison across studies have been incorporated into the Discussion section, where we contextualize and interpret the data collectively.

 

While the tables include much information about each study, the current format appears overly dense and spans several pages, which disturbs readability. The tables should be revised to enhance visual accessibility.

 

Thank you for this important feedback. We have completely restructured Table 1 to enhance clarity and accessibility. Redundant content was removed, columns were standardized, and outcome measures were expressed in uniform units across all studies. The layout now improves readability and usability without

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Acceptable for publication

Reviewer 2 Report

Comments and Suggestions for Authors

I would to once again congratulate the authors for performing this study. The authors have responded to all my comments and concerns and clearly improved the quality of the manuscript. I have no further comments. 

Reviewer 3 Report

Comments and Suggestions for Authors

The revision has appropriately addressed my comments and has been suitably improved.