The HEART-FGF Study: Cardiovascular Remodeling and Risk Stratification by FGF-23 in Patients with CKD: An Integrative Cross-Sectional Study of Cardiac, Renal, and Mineral Parameters

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled ‘The HEART-FGF Study: Cardio-vascular Remodeling and Risk Stratification by FGF-23 in patients with CKD: An Integrative Cross-Sectional Study of Cardiac, Renal, and Mineral Parameters’ written by Dhruv Jain et al. presents interesting findings on the utility of FGF23 as a predictive biomarker of cardiovascular risk in patients with chronic kidney disease.

The authors conducted a cross-sectional study to investigate the associations between serum FGF-23 levels and a range of blood and cardiac imaging parameters. The analysis revealed several statistically significant associations, revealing promising potential of FGF-23 as a biomarker for cardiovascular risk stratification in patients with chronic kidney disease.

The manuscript is scientifically sound and well-structured. The scientific rationale is clearly articulated. The manuscript has appropriate references and the English language is generally clear. However, despite the statistical significance of the findings, the clinical relevance of the observed associations appears limited. I have identified several issues that require attention.

General concept comments

1. Tables 2, 3, and 4 present results of correlation analysis performed between various clinical and biochemical parameters. While several of these correlations are reported as statistically significant, the corresponding correlation coefficients are relatively low (approximately 0.3). It indicates rather weak associations, raising concerns regarding clinical relevance of demonstrated correlations. I suggest the authors interpret their findings with greater criticism and to address these limitations in the Discussion section.
2. The interpretation of correlation results always should consider both the numerical strength of correlation coefficients and the visual assessment of correlated variables on a scatter plots. Scatter plots are essential for detecting non-linear relationships, outliers, and third variable effects that might not be apparent from a correlation coefficient alone, but are important to avoid misinterpretation of results. Therefore, I strongly suggest the authors to provide scatter plots of the most relevant correlations, maybe in a supplementary materials, to facilitate a more accurate and transparent interpretation of the results. This addition would enhance the robustness of the analytical approach and help prevent potential misinterpretations.

Specific comments

1. Please ensure that all abbreviations used in the Abstract are explained (e.g., eGFR, iPTH).
2. The continuous variables included in Table 1 and Figure 1 are not consistent. Table 1 lacks information about cholesterol levels and BUN, while Figure 1 lacks histograms of eGFR, FGF-23, iPTH, and phosphorus levels. Furthermore, Table 1 and Figure 1 lack other parameters mentioned in 2.5 section (e.g., creatinine, uric acid, lipids). Also, information regarding cardiovascular risk stratification of patients can be added to the Table 1. I recommend to add missing data to Table 1 and Figure 1 to make the presented data more consistent and complete. Additionally, the font size in Figure 1 and Figure 3 is very small, which affects readability. The font should be enlarged to ensure the plot is clear and easy to interpret.
3. For clarity, all abbreviations presented in figures and tables should be explained in the corresponding figure and table legends.
4. The high number of correlation coefficients in Figure 2 may hinder the clarity and interpretability of the heatmap. If it is possible in the tool used by the authors, I recommend to apply an ordering algorithm, such as hierarchical clustering or another similarity-based arrangement, to reorder the variables based on the similarity of their correlation coefficients. This approach would allow for the grouping of similar correlation coefficients and improve visual coherence, facilitating the interpretation of complex interrelationships among the measured parameters.
5. Please ensure that all abbreviations in the Abbreviations section are used in the text.

I believe that my suggestions will help the authors to improve the quality of the manuscript.

Author Response

The Editor,

JVD, MDPI

We sincerely thank  the editor and both reviewers for their thorough evaluation of our manuscript entitled “The HEART-FGF Study: Cardio-vascular Remodeling and Risk Stratification by FGF-23 in patients with CKD: An Integrative Cross-Sectional Study of Cardiac, Renal, and Mineral Parameters.” We have carefully considered all comments and revised the manuscript accordingly. Below, we provide a detailed point-by-point response. Reviewer comments are reproduced in italics, followed by our responses.

Reviewer 1

General concept comments

Comment 1:
Tables 2, 3, and 4 present results of correlation analysis performed between various clinical and biochemical parameters. While several of these correlations are reported as statistically significant, the corresponding correlation coefficients are relatively low (approximately 0.3). It indicates rather weak associations, raising concerns regarding clinical relevance of demonstrated correlations. I suggest the authors interpret their findings with greater criticism and to address these limitations in the Discussion section.

Authors’ Response:
We agree with the reviewer that correlation coefficients of approximately 0.3 indicate weak associations. In the revised Discussion, we have added a critical appraisal of these findings, clearly distinguishing between statistical significance and clinical relevance. We now explicitly highlight that while FGF-23 shows promise as a biomarker, the observed associations in our cohort are modest and warrant cautious interpretation.

Comment 2:
The interpretation of correlation results always should consider both the numerical strength of correlation coefficients and the visual assessment of correlated variables on a scatter plots. Scatter plots are essential for detecting non-linear relationships, outliers, and third variable effects that might not be apparent from a correlation coefficient alone, but are important to avoid misinterpretation of results. Therefore, I strongly suggest the authors to provide scatter plots of the most relevant correlations, maybe in a supplementary materials, to facilitate a more accurate and transparent interpretation of the results. This addition would enhance the robustness of the analytical approach and help prevent potential misinterpretations.

Authors’ Response:
We appreciate this valuable suggestion. We have now generated scatter plots for the most clinically relevant correlations. These plots have been included in the Supplementary Materials (Supplementary Figures A-K). This addition strengthens the transparency and robustness of our analysis.

Specific comments

Comment 3:
Please ensure that all abbreviations used in the Abstract are explained (e.g., eGFR, iPTH).

Authors’ Response:
We have revised the Abstract to ensure that all abbreviations, including eGFR and iPTH, are fully spelled out at first mention.

Comment 4:
The continuous variables included in Table 1 and Figure 1 are not consistent. Table 1 lacks information about cholesterol levels and BUN, while Figure 1 lacks histograms of eGFR, FGF-23, iPTH, and phosphorus levels. Furthermore, Table 1 and Figure 1 lack other parameters mentioned in 2.5 section (e.g., creatinine, uric acid, lipids). Also, information regarding cardiovascular risk stratification of patients can be added to the Table 1. I recommend to add missing data to Table 1 and Figure 1 to make the presented data more consistent and complete. Additionally, the font size in Figure 1 and Figure 3 is very small, which affects readability. The font should be enlarged to ensure the plot is clear and easy to interpret.

Authors’ Response:
We thank the reviewer for this important observation. We have revised Table 1 to include cholesterol levels, BUN, creatinine, uric acid, and lipid parameters, along with cardiovascular risk stratification data. Figure 1 has been used to show selected variables which are most clinically relevant- we can surely add others if you insist but that would increase the length of the article and effect readability.  We have also enlarged the font size in Figures 1 and 3 to improve readability.

Comment 5:
For clarity, all abbreviations presented in figures and tables should be explained in the corresponding figure and table legends.

Authors’ Response:
We have revised all figure and table legends to ensure that abbreviations are explained at first use.

Comment 6:
The high number of correlation coefficients in Figure 2 may hinder the clarity and interpretability of the heatmap. If it is possible in the tool used by the authors, I recommend to apply an ordering algorithm, such as hierarchical clustering or another similarity-based arrangement, to reorder the variables based on the similarity of their correlation coefficients. This approach would allow for the grouping of similar correlation coefficients and improve visual coherence, facilitating the interpretation of complex interrelationships among the measured parameters.

Authors’ Response:
We appreciate this insightful suggestion. We appreciate the comment and the idea but sadly our software doesn’t allow this. We will have to stick to the same however we have added a detailed legend to help the authors.

Comment 7:
Please ensure that all abbreviations in the Abbreviations section are used in the text.

Authors’ Response:
We have carefully reviewed the entire manuscript to ensure consistency between the Abbreviations section and the main text. All abbreviations are now used appropriately and explained at first mention.

We are grateful to both reviewers for their constructive comments, which have substantially improved the quality and clarity of our manuscript. All suggested changes have been incorporated, and we believe the revised version is now significantly strengthened.

Yours sincerely,

Dr. Yashendra Sethi

Subharti Medical College

Editor: Diabetes and Metabolic Syndrome: Clinical Research & Reviews, BMC Public Health, Frontiers & PLOS ONE

Cofounder: PearResearch, Innores International, Vigyaved Healthcare, Research Fellow: Lumen Foundation

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript, titled ‘The HEART-FGF Study: Cardio-vascular Remodeling and Risk Stratification by FGF-23 in patients with CKD: An Integrative Cross-Sectional Study of Cardiac, Renal, and Mineral Parameters, holds potential for publication in this journal but requires the following revisions. The authors are advised to revise it carefully.

Comments for authors

1. The abstract is well structured and presented, but the limitations of this study need to be highlighted in one sentence.
2. The introduction is well-written.
3. Methods 2.5,2.6.2.7, and 2.9 sections should be written as paragraphs, not in points.
4. The results are explained well, but high-resolution figures (1 and 3) are needed; currently, figure pixels break while being maximized.
5. The font format of tables and the main manuscript's font format is different. Please follow the journal guidelines.
6. Discussion: The results are well compared, and the limitations of this study have been provided. For a broader spectrum of the study, the authors have provided future perspectives; however, they need to discuss in the context of how to minimize these limitations by using the appropriate methods in the future.
7. In the discussion section, remove the subheadings and start with a new paragraph.
8. The important point is that this manuscript's similarity index is 26%. Please follow the journal guidelines and minimize by up to 15%.

Author Response

Reviewer 2

Comment 1:
The abstract is well structured and presented, but the limitations of this study need to be highlighted in one sentence.

Authors’ Response:
We have revised the Abstract to include a sentence acknowledging the limitations of our study, specifically the cross-sectional design and modest correlation strengths.

Comment 2:
The introduction is well-written.

Authors’ Response:
We thank the reviewer for this positive feedback.

Comment 3:
Methods 2.5, 2.6.2.7, and 2.9 sections should be written as paragraphs, not in points.

Authors’ Response:
We have revised these sections to be written in continuous paragraph form, ensuring a smoother flow and consistency with journal formatting.

Comment 4:
The results are explained well, but high-resolution figures (1 and 3) are needed; currently, figure pixels break while being maximized.

Authors’ Response:
We have replaced Figures 1 and 3 with high-resolution versions to ensure clarity even at higher magnification.

Comment 5:
The font format of tables and the main manuscript's font format is different. Please follow the journal guidelines.

Authors’ Response:
We have reformatted all tables to match the journal’s prescribed font style and size, ensuring uniformity throughout the manuscript.

Comment 6:
Discussion: The results are well compared, and the limitations of this study have been provided. For a broader spectrum of the study, the authors have provided future perspectives; however, they need to discuss in the context of how to minimize these limitations by using the appropriate methods in the future.

Authors’ Response:
We agree with this valuable point. In the revised Discussion, we have elaborated on how future prospective longitudinal studies with larger sample sizes, multi-center recruitment, and advanced statistical modeling could address the limitations observed in our cross-sectional analysis.

Comment 7:
In the discussion section, remove the subheadings and start with a new paragraph.

Authors’ Response:
We have removed subheadings from the Discussion and reorganized it into cohesive paragraphs, in line with the reviewer’s suggestion.

Comment 8:
The important point is that this manuscript's similarity index is 26%. Please follow the journal guidelines and minimize by up to 15%.

Authors’ Response:
We have carefully revised the manuscript to reduce textual similarity. All sentences with potential overlap have been rephrased, ensuring originality and adherence to the journal’s requirement of a similarity index below 15%.

We are grateful to both reviewers for their constructive comments, which have substantially improved the quality and clarity of our manuscript. All suggested changes have been incorporated, and we believe the revised version is now significantly strengthened.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I appreciate the efforts of the authors to respond to my comments. I have two minor remarks. First, the correlation coefficients presented in supplementary figures are different from corresponding those in Table 1. Please check and clarify this discrepancy. Second, Figure 1 appears to have a complementary rather than central role in supporting the main findings. Therefore, I recommend that the authors consider relocating it to the Supplementary Materials, where it would be more appropriately placed and also expanded as I mentioned in my previous comments. I have no further comments.

Author Response

COMMENT 1: I appreciate the efforts of the authors to respond to my comments. I have two minor remarks. First, the correlation coefficients presented in supplementary figures are different from corresponding those in Table 1. Please check and clarify this discrepancy. Second, Figure 1 appears to have a complementary rather than central role in supporting the main findings. Therefore, I recommend that the authors consider relocating it to the Supplementary Materials, where it would be more appropriately placed and also expanded as I mentioned in my previous comments. I have no further comments.

AUTHORS' RESPONSE: 

We sincerely thank the reviewer for carefully pointing out the inconsistency in the correlation plots. Upon rechecking, we realized that an incorrect correlation test had been mistakenly applied to the supplementary graphs, leading to mismatched values. This has now been corrected, and all supplementary figure 2 (A–K) have been updated to align with the values reported in Table 2 of the main manuscript.

In addition, as per the reviewer’s suggestion, Figure 1 has been moved to the supplementary files for better clarity and presentation.

We are deeply grateful for the reviewer’s insightful comments and constructive guidance, which have significantly improved the rigor and clarity of our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript should be published in this journal in its current form. The authors have answered my concerns adequately. 

Author Response

Reviewer 2 Comment:
“This manuscript should be published in this journal in its current form. The authors have answered my concerns adequately.”

Authors’ Response:
We sincerely thank Reviewer 2 for the positive feedback and encouraging recommendation for publication. We are grateful for the reviewer’s thoughtful input during the review process, which has helped us refine and strengthen the manuscript.