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All the concerns were adequately addressed. No further comments.
Dear authors,
I acknowledge your efforts to improve the manuscript and to explain your statements to the reviewers. However, please note that opposite opinions of the experts who reviewed your manuscript exist. Therefore, the change of the very certain tone of the conclusion is not an optional request. Please, make the minor change needed to lessen the certainty of the found relationship.
Please lessen the grade of certainty in the manuscript's conclusion.
**PeerJ Staff Note**: Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
No comment
Not comment
NO comment
Line 218: Hematuria is not required for the diagnosis of CKD, based on KDIGO definitions, therefore unclear why hematuria AND proteinuria was necessary to be present fro the diagnosis
The conclusion in the abstract: Perhaps saying may be related to GFR decline. Your results have some publication bias therefore definitive conclusions may not be drawn
There are still substantial issues identified by Reviewer 1.
These are improved, however the language is still verbose and authors should clearly present information, especially in the discussion
This has improved however some clarity is still needed as to which specific variables were selected, and the basis for excluding the 5 studies from the final analyses
Given the hetergenecity of the study findings and publication bias, unclear if association with GFR decline and High Homocysteine levels can be determined by this study. Perhaps including these also as limitations. What was the pooled SMD after the trim and fill analysis?
The authors had answered reviwers' comments, completely.
No comments
No comment
Please better justify the rational of the study and explain in more detail the used methodology. Please pay careful attention to the criticism of the study selection raised by the third reviewer.
**PeerJ Staff Note:** Please ensure that all review, editorial, and staff comments are addressed in a response letter and that any edits or clarifications mentioned in the letter are also inserted into the revised manuscript where appropriate.
1.. The abstract needs to have more detail on methodology such as the inclusion and exclusion criteria and precise search methods
2. The introduction lacks clarity, and many statements are quite general and non-specific and made without any references.
3. The writing is excessively verbose and lacks clarity
4. There are a few grammatical errors which should be fixed throughout the manuscript.
5. There is no rationale for the study.
6. The results are unclear, with some of the study methodology presented in the results and no reporting of the actual study findings
7. Graph axes are labeled using acronyms without a key to explain these
8. The discussion describes the methodology rather than a meaningful interpretation of the results and implications for science/practice.
1. There is no aim nor clear hypotheses to be tested in the study, this is not explicitly stated. I am unclear as to the outcome of interest and associations to be investigated. Eg are we examining associations of hyperhomocyteinemia with incident CKD or CKD progression
2. Line 207. KDIGO/KDOQI based definition of CKD is eGFR <60 or proteinuria (albuminuria), unclear why hematuria AND proteinuria used as a definition for CKD
3. The precise search strategy is not stated in the methods
4. Some of the studies had different cut offs for elevated homocysteine levels. How then can standardized mean differences between CKD and non CKD groups be valid?
1.Overall, the rationale, methods, and results are not presented clearly or transparently. There is no aim or hypothesis to be tested. The impact and novelty are inaccessable, likely due to insufficient scientific rigor and reporting. The manuscript is difficult to read and no conclusions have been drawn from the data presented.
Hyperhomocysteinemia has been associated with incident CKD and eGFR decline, but confounded other factors (eg Hypertension, diabetes). Chen et al, in a metanalysis of 79416 patients enrolled in 7 studies (PMID: 37612681) showed (Pooled OR, 2.09; 95% CI, 1.72–2.55) increased risk of CKD with hyperhomocystemia using similar study definitions. Therefore, how will this study add to the data on CKD?
The manuscript is clearly written in professional, unambiguous language.
The present meta-analysis was executed with the primary aim of a comprehensive exploration of the correlation between hyperhomocysteinemia (HHcy) and the glomerular filtration rate (GFR) within the cohort of chronic kidney disease patients (CKD).
To clarify the relationship between elevated homocysteine on effect on glomerular filtration rate, a systematic search in PubMed, Embase, and Cochrane databases and reference lists was done.
Two RCTs and eight cross-sectional studies (7364 patients) were included.
The findings are clear and unambiguous,
Authors poined out the limitations of this study and put all important literature references (45) for this article, but it is important to translate ref 34 and make some correction in ref 43 and 45.
Authors provided figures (1-7) and table (1), clear and legible.
There is not any concern about duplication or manipulation of images.
There was not any concerns regarding similarities to other articles.
In my opinion there is not any authors' competing interests.
In this thoughtfully designed and well-executed study, authors provide a compelling argument for importance of hyperhomocysteinemia (HHcy) in CKD pts.
The correlation between HHC and the risk of CKD was analyzed.
Methods are described with sufficient details and information to replicate.
Authors present results of all sensitivity analyses conducted to assess the robustness of the synthesized results.
The information provided were adequate for understanding this very interesting original research.
The field of nephrology has been slow in moving beyond the utilization of creatinine as an indicator for chronic kidney disease. Authors confirming the link between chronic kidney disease and Hcy.
The findings suggest that elevated Hcy levels portend a deleterious impact on renal function in CKD patients, with a high likelihood of precipitating a decline in GFR.
All data analysis and the generation of visual representations, including graphs and plots, were carried out using Stata version 12.0 for the Windows 8 operating system.Statistical power is adequate.
The findings of this original article have implications for every day clinical practice, underlining the indispensability of factoring in Hcy levels during the management and risk stratification of CKD patients.
The findings described by the author correlate with the results.
The Discussion is concise and clearly organized.
The conclusions made are substantiated by the evidence presented.
Dear Authors,
You proposed in this systematic review/meta-analysis unique insights and value-added contributions that are essential for understanding and management of kidney disease,
Congratulations
My recommendation is minor revision because You have to translate ref 34 and make some correction in ref 43 and 45.
Dear authors:
Thanks for the opportunity to review the draft.
In general, there were some weaknesses of scientific scope in the study design:
1-1. Most of the included studies were cross-sectional, limiting the ability to establish a causal relationship between hyperhomocysteinemia (HHcy) and decreased glomerular filtration rate (GFR). Longitudinal studies would be required to explore causality more effectively.
1-2. Instead of relying heavily on cross-sectional data, including longitudinal studies to assess better causality between hyperhomocysteinemia (HHcy) and glomerular filtration rate (GFR) decline. This will clarify whether elevated homocysteine levels lead to CKD progression over time.
2. Despite subgroup and sensitivity analyses, some residual heterogeneity persisted due to differences in study design, patient characteristics, and measurement methods across the included studies.
3. Conduct subgroup analyses based on other key factors, such as CKD stage, age groups, comorbid conditions (e.g., diabetes), and ethnicities, to better understand how HHcy affects different populations.
Instead of relying heavily on cross-sectional data, including longitudinal studies to assess better causality between (HHS) and glomerular filtration rate (GFR) decline. This will clarify whether elevated homocysteine levels lead to CKD progression over time.
1. Despite subgroup and sensitivity analyses, some residual heterogeneity persisted due to differences in study design, patient characteristics, and measurement methods across the included studies.
2. Conduct subgroup analyses based on other key factors, such as CKD stage, age groups, comorbid conditions (e.g., diabetes), and ethnicities, to better understand how HHcy affects different populations.
No Comment
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