Nutritional Predictors of Cardiovascular Risk in Patients after Kidney Transplantation-Pilot Study

Round 1

Reviewer 1 Report

Czaja-Stolc et. al. tried to highlight the association between renal dysfunction and markers of endothelial damage in kidney transplant recipients. The manuscript would benefit from showing the association between these markers and clinical outcomes in transplant recipients. The choice of health volunteers as comparator group is somewhat concerning when the ADMA is elevated in diabetics.

Please consider expanding on the aims of this study at the end of the introduction section. The manuscript will benefit from additional clarification of the final model. The reported format is not quite familiar to most readers. Perhaps, detailed explanation of the regression model will be helpful. Table 1, will benefit from spelling out the parameters, e.g., F% (Body Fat), that was very hard to decipher. 

Author Response

Dear Editors and Reviewers,

On behalf of my coauthors, I would like to thank you for taking the time to review and comment on our manuscript “Nutritional predictors of cardiovascular risk in patients after kidney transplantation - pilot study”. We found the reviewers’ comments helpful in revising the manuscript, and we have carefully considered and responded to each suggestion. All changes will be documented through the Track Changes feature. 

 

Reviewer 1

Czaja-Stolc et. al. tried to highlight the association between renal dysfunction and markers of endothelial damage in kidney transplant recipients. The manuscript would benefit from showing the association between these markers and clinical outcomes in transplant recipients. The choice of health volunteers as comparator group is somewhat concerning when the ADMA is elevated in diabetics.

Response:

The submitted manuscript is a pilot study. In the main work that we are going to prepare, we will try to show the relationship between the investigated markers and clinical outcomes in kidney transplant recipients. Thanks to the performed observation, we will also be able to assess the influence of cardiovascular risk markers on survival.

Many studies have compared the cardiovascular risk in dialysis patients with those after kidney transplantation. For this reason, we chose healthy people as a control group, because kidney transplantation is, in principle, a way to return to a normal lifestyle and to obtain normal kidney function. Unfortunately, due to the small number of study participants, disqualifying people with diabetes would be unfavorable. In Figure 3. we compared the ADMA concentration between KTRs with and without diabetes, and not with healthy people.

 

Please consider expanding on the aims of this study at the end of the introduction section. The manuscript will benefit from additional clarification of the final model. The reported format is not quite familiar to most readers. Perhaps, detailed explanation of the regression model will be helpful. Table 1, will benefit from spelling out the parameters, e.g., F% (Body Fat), that was very hard to decipher. 

 

Response:

The aims of the study have been expanded. The abbreviations "F", „LBM” in Table 1 have been replaced with the full name, which should increase the readability of the article.

We used multivariate egression (Backward Stepwise). In  this  analysis the first step, it consists in constructing a model that includes all potential explanatory variables, and then in the gradual elimination of variables so as to maintain the model with the highest value of the coefficient of determination while maintaining the significance of the parameters. The parameters mentioned by the reviewer were tested, but the model did not meet the significance criterion.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Czaja-Stolc and colleague performed a cross-sectional study for determining the relationship between nutritional parameters and cardiovascular risk. This topic is an interesting point on current clinical practice. However, some major and minor concerns are following:

Major concerns:

1. Nutritional status, ADMA and FGF-23 may be a consequence of end-stage renal disease in majority, not kidney transplantation. I am not sure why the authors compared the outcomes between transplantation with normal healthy volunteers, not ESRD patients who undergoing renal replacement therapy. Again, it is difficult to understand why the authors compared ADMA levels between diabetes and non-diabetes in the study.    
2. As this is a study of transplantation filed, the authors must be following the regulation of the Principles of the Declaration of Istanbul, as well as the Declaration of Istanbul on Organ Trafficking and Transplant Tourism in the ethical part of ‘Methods’. Thus, please mention "The clinical and research activities were consistent with the Principles  of the Declaration of Istanbul, as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism” in the Methods.

3. What is/are the primary outcome(s) in this study. Please clarify in the ‘Methods’.
4. The baseline characteristic of KTRs and healthy controls (age, sex, dialysis vintage, types of transplantations (deceased/living), type of immunosuppression, warm ischemic time, clod ischemic time, etc) should be included in the Table 1.
5. The raw data of eGFR value of the participants in KTRs group seems not a normal distribution (as shown in Figure 4), thus the data of creatinine and eGFR in Table 1 should not be represented with mean±
6. Was there any transplant complication in the cohort, including allograft rejection, infection, etc.?

Minor concerns:

1. The ‘Introduction’ part needs more improvement, particularly the sequence of CKD and after transplantation.
2. Item 2.2 and 2.3, I suggest rewriting as a paragraph that may help easier to follow, and please insert the citation where appropriate.

Author Response

Dear Editors and Reviewers,

On behalf of my coauthors, I would like to thank you for taking the time to review and comment on our manuscript “Nutritional predictors of cardiovascular risk in patients after kidney transplantation - pilot study”. We found the reviewers’ comments helpful in revising the manuscript, and we have carefully considered and responded to each suggestion. All changes will be documented through the Track Changes feature. 

 

 

Reviewer 2

Czaja-Stolc and colleague performed a cross-sectional study for determining the relationship between nutritional parameters and cardiovascular risk. This topic is an interesting point on current clinical practice. However, some major and minor concerns are following:

Major concerns:

1. Nutritional status, ADMA and FGF-23 may be a consequence of end-stage renal disease in majority, not kidney transplantation. I am not sure why the authors compared the outcomes between transplantation with normal healthy volunteers, not ESRD patients who undergoing renal replacement therapy. Again, it is difficult to understand why the authors compared ADMA levels between diabetes and non-diabetes in the study.   

Response:

As mentioned, elevated levels of ADMA, FGF-23 may be a consequence of renal failure, so we did not see the need to compare KTRs to dialysis patients. Many studies have already been done on this topic. We wanted to assess whether a kidney transplant could affect ADMA and FGF-23 levels. We chose healthy people because, in principle, a kidney transplant is a way to return to a normal lifestyle and obtain normal kidney parameters. Unfortunately, some of the patients in our study had eGFR <60, but no one had end-stage renal disease. Due to the small number of study participants, it would be disadvantageous to disqualify such patients. We compared ADMA levels between KTRs with and without diabetes. The purpose of this comparison was to establish the mechanisms by which diabetes influences cardiovascular risk.

 

2. As this is a study of transplantation filed, the authors must be following the regulation of the Principles of the Declaration of Istanbul, as well as the Declaration of Istanbul on Organ Trafficking and Transplant Tourism in the ethical part of ‘Methods’. Thus, please mention "The clinical and research activities were consistent with the Principles  of the Declaration of Istanbul, as outlined in the Declaration of Istanbul on Organ Trafficking and Transplant Tourism” in the Methods.

Response:

Thank you for the suggestion. This information has been added in the Methods.

 

3. What is/are the primary outcome(s) in this study. Please clarify in the ‘Methods’.

Response:

We added: “The primary outcome in our study was finding risk factors for increased ADMA  and FGF 23 concentration  in the stable KTRs.”

 

4. The baseline characteristic of KTRs and healthy controls (age, sex, dialysis vintage, types of transplantations (deceased/living), type of immunosuppression, warm ischemic time, clod ischemic time, etc) should be included in the Table 1.

Response:

Table 1 has been supplemented with available data.

 

5. The raw data of eGFR value of the participants in KTRs group seems not a normal distribution (as shown in Figure 4), thus the data of creatinine and eGFR in Table 1 should not be represented with mean±

Response:

The median value has been added to the Table 1.

 

6. Was there any transplant complication in the cohort, including allograft rejection, infection, etc.?

Response:

No, there wasn’t. This information has been added in Materials and Methods.

 

Minor concerns:

The ‘Introduction’ part needs more improvement, particularly the sequence of CKD and after transplantation.

Response:

Introduction has been improved.

 

Item 2.2 and 2.3, I suggest rewriting as a paragraph that may help easier to follow, and please insert the citation where appropriate.

Response:

Paragraphs have been corrected.

Author Response File: Author Response.pdf

Reviewer 3 Report

Dear Authors,

I read your paper, and I find it of potential interest, but there are some data and analyses that, in my opinion, are necessary to support your conclusions.

• In Table 1, please include the age and sex of the two groups, since potentially they could explain, at least in part, the differences observed.
• It could be interesting to compare obese vs non-obese KTR, such as malnourished vs non-malnourished, or a combination of both. For example, how many obese patients were also malnourished? There were differences in body composition, metabolic markers, or ADMA and FGF23 levels in patients with different nutritional profiles? I think that the authors should give more attention and space to the analysis of these points
• The results of the comparison between patients with high and low ADMA should be presented in a table. Moreover, the authors should explain why they choose 0.66 μmol/l as a cutoff.
• The multivariate analysis should include, as variables also GFR, sex, age, and BMI apart from diabetes. Indeed, all these factors may influence the levels of circulating markers.

Consequently, the discussion should be revised according to the results of the above suggested additional analyses.

Author Response

Dear Editors and Reviewers,

On behalf of my coauthors, I would like to thank you for taking the time to review and comment on our manuscript “Nutritional predictors of cardiovascular risk in patients after kidney transplantation - pilot study”. We found the reviewers’ comments helpful in revising the manuscript, and we have carefully considered and responded to each suggestion. All changes will be documented through the Track Changes feature. 

 

Reviewer 3

 

Dear Authors,

I read your paper, and I find it of potential interest, but there are some data and analyses that, in my opinion, are necessary to support your conclusions.

In Table 1, please include the age and sex of the two groups, since potentially they could explain, at least in part, the differences observed.

Response:

The data has been added.

a

It could be interesting to compare obese vs non-obese KTR, such as malnourished vs non-malnourished, or a combination of both. For example, how many obese patients were also malnourished? There were differences in body composition, metabolic markers, or ADMA and FGF23 levels in patients with different nutritional profiles? I think that the authors should give more attention and space to the analysis of these points

We added table 3 and comments in Results section (we corrected the numbering of tables)

Response:

The number of malnourished patients with excess body weight has been added to the Results.

 

 

The results of the comparison between patients with high and low ADMA should be presented in a table. Moreover, the authors should explain why they choose 0.66 μmol/l as a cutoff.

Response:

The results have been presented in Table 2. For the explanation of choosing a cut-off point was presented in the Discussion.

 

The multivariate analysis should include, as variables also GFR, sex, age, and BMI apart from diabetes. Indeed, all these factors may influence the levels of circulating markers.

Consequently, the discussion should be revised according to the results of the above suggested additional analyses.

Response:

We used multivariate egression (Backward Stepwise). In  this  analysis the first step, it consists in constructing a model that includes all potential explanatory variables, and then in the gradual elimination of variables so as to maintain the model with the highest value of the coefficient of determination while maintaining the significance of the parameters. We added information in Statistical Analysis section and Results.The parameters mentioned by the reviewer were tested, but the model did not meet the significance criterion.

 

Thank you again for providing feedback on our manuscript. We followed all the comments, which positively influenced the quality of our paper. 

 

Sincerely,

Sylwia Małgorzewicz

Department of Clinical Nutrition

Medical University of Gdańsk

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

All my concerns are addressed in the revision version. I have no futher comments.

Reviewer 3 Report

I think that the paper has been improved and now it is acceptable for publication.