Biomarkers Predicting Major Adverse Cardiovascular Events in End-Stage Kidney Disease: A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Davies and colleagues have submitted an analysis of the status of the use of multiple circulating biomarkers in predicting major adverse cardiovascular events (MACE) in end stage kidney disease.

This is an important topic and one that has generated considerable interest.

The manuscript could be strengthened by addressing these two considerations

1. It is not clear to the reader why only these biomarkers were chosen.  Additional markers of endothelial injury and inflammation have been proposed as biomarkers as well.  Was there a reason that these additional biomarkers were not considered?  Similarly for markers of dyslipidemia and altered mineral metabolism.
2. It is not clear exactly what this manuscript adds to the literature and it would be useful for the authors to very explicitly state the main message of this particular study in the context of the multiple studies out looking at biomarkers in CKD.

Author Response

Reviewer 1

Davies and colleagues have submitted an analysis of the status of the use of multiple circulating biomarkers in predicting major adverse cardiovascular events (MACE) in end stage kidney disease.

This is an important topic and one that has generated considerable interest.

The manuscript could be strengthened by addressing these two considerations

1. It is not clear to the reader why only these biomarkers were chosen.  Additional markers of endothelial injury and inflammation have been proposed as biomarkers as well.  Was there a reason that these additional biomarkers were not considered?  Similarly for markers of dyslipidemia and altered mineral metabolism.

While the authors acknowledge other biomarkers have been evaluated, as alluded to above, we have not included these in our analysis due to the small number of papers identified using our search criteria. These are however listed in Supplementary Table 4. In addition, in the interest of space in the journal, the authors considered that there was little to be gained, given the focus of our search on cardiac biomarkers directly related to MACE, based on experience in other work from our group and others.  The majority of our results focus on biomarkers that are routinely available in hospital clinical laboratories, thus enabling translation to clinical practice.

2. It is not clear exactly what this manuscript adds to the literature and it would be useful for the authors to very explicitly state the main message of this particular study in the context of the multiple studies out looking at biomarkers in CKD.

Evidence before this study

We undertook a preliminary search of Medline for existing reviews that specifically focus on cardiac biomarkers in this particular population. Our preliminary investigation identified only a small number of previous reviews in this area, mainly focusing on CKD and not dialysis specifically.

 

Implications of this study:

• Circulating biomarkers, whether used alone or in combination, have the potential to predict MACE in haemo-and peritoneal dialysis, although only 2 studies were found in PD.
• Further evidence is needed to validate the predictive utility of cardiac biomarkers to optimize their clinical application, especially with regard to dichotomous threshold values, or use as a continuous variable. In addition, a combined approach utilising circulating plasma biomarkers and clinical variables should be evaluated to enhance prediction.

 

Potential impact:

The evidence suggests that traditional cardiac biomarkers can improve CV risk prediction in HD and PD, however further evaluation is required of the threshold values chosen and the combination of circulating plasma biomarker and clinical variables. A multivariate risk score should be evaluated to further refine CV risk prediction in this high risk population. Clinical assays for cardiac troponin and natriuretic peptides are available in hospital clinical laboratories, therefore any multivariate model using these analytes would be straightforward to implement if shown to be accurate  and of clinical benefit.

If the reviewers agree the ‘potential impact’ section can be included in the manuscript conclusion.

Reviewer 2 Report

Comments and Suggestions for Authors

In this this study the authors performed a systematic review on the role of biomarkers in predicting major adverse cardiovascular events in patients with ESKD. Given the high cardiovascular burden in this population, identifying effective biomarkers for risk stratification is crucial.

Major Comments

1. The study clearly states its objective of summarizing the current landscape of traditional and novel blood biomarkers for predicting MACE in ESKD patients.
2. The included studies seem appropriate for addressing the research question, focusing on biomarkers and cardiovascular outcomes in ESKD patients.
3. While the review acknowledges novel biomarkers, the manuscript could also emphasize biomarkers associated with inflammation, endothelial function, vascular stiffness, and/or fibrosis.
4. Although the review acknowledges HD and PD when discussing studies, the manuscript does not clarify if biomarker levels and thresholds differ between HD and PD, and whether this affects MACE prediction.
5. Consider adding a column in Table 1 to indicate the CASP score or a summary of the risk of bias for each study.
6. A stronger statement in the introduction about the high cost burden of cardiovascular disease in ESKD patients would further emphasize the clinical impact of the meta analysis.

 

Author Response

Reviewer 2

In this this study the authors performed a systematic review on the role of biomarkers in predicting major adverse cardiovascular events in patients with ESKD. Given the high cardiovascular burden in this population, identifying effective biomarkers for risk stratification is crucial.

Major Comments

1. The study clearly states its objective of summarizing the current landscape of traditional and novel blood biomarkers for predicting MACE in ESKD patients.

Nothing further to add.

2. The included studies seem appropriate for addressing the research question, focusing on biomarkers and cardiovascular outcomes in ESKD patients.

Nothing further to add.

3. While the review acknowledges novel biomarkers, the manuscript could also emphasize biomarkers associated with inflammation, endothelial function, vascular stiffness, and/or fibrosis.

While the authors acknowledge other biomarkers have been evaluated, as alluded to above, we have not included these in our analysis due to the small number of papers identified using our search criteria. These are however listed in Supplementary Table 4. In addition, in the interest of space in the journal, the authors considered that there was little to be gained, given the focus of our search on cardiac biomarkers directly related to MACE, based on experience in other work from our group and others.  The majority of our results focus on biomarkers that are routinely available in hospital clinical laboratories, thus enabling translation to clinical practice.

 

4. Although the review acknowledges HD and PD when discussing studies, the manuscript does not clarify if biomarker levels and thresholds differ between HD and PD, and whether this affects MACE prediction.

There were only 2 studies with  a PD cohort included alongside HD. There was no direct comparison made between the modalities within the study. One study applied the same biomarker threshold to both modalities and the other sutdy used the biomarker as a continuous variable, thereby limiting direct comparison.

5. Consider adding a column in Table 1 to indicate the CASP score or a summary of the risk of bias for each study.

Thank you for the suggestion. The CASP scoring has been included in the supplementary material table 2.

6. A stronger statement in the introduction about the high cost burden of cardiovascular disease in ESKD patients would further emphasize the clinical impact of the meta analysis.

The below sentence has been added to the manuscript introduction alongside references

'In the UK National Health Service the  cost of excess strokes and MIs in the CKD population is estimated at £174–£178 million translating to an estimated £434,618  annual CV morbidity expenditure specifically in the  CKD 5 with macroalbuminuria cohort per 1000 patient years.'

 

 Kerr, M., Bray, B., Medcalf, J., O'Donoghue, D. J., & Matthews, B. (2012). Estimating the financial cost of chronic kidney disease to the NHS in England. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 27 Suppl 3(Suppl 3), iii73–iii80. https://doi.org/10.1093/ndt/gfs269

Darlington, O., Dickerson, C., Evans, M., McEwan, P., Sörstadius, E., Sugrue, D., van Haalen, H., & Garcia Sanchez, J. J. (2021). Costs and Healthcare Resource Use Associated with Risk of Cardiovascular Morbidity in Patients with Chronic Kidney Disease: Evidence from a Systematic Literature Review. Advances in therapy, 38(2), 994–1010. https://doi.org/10.1007/s12325-020-01607-4

 

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The reviewer thanks the authors for their responses. The reviewer does now have a clearer idea of what the authors wanted to accomplish. However, it is not clear that they have actually answered completely the questions posed by this reviewer.

1. What does this review add to the literature?  The first sentence of the discussion states that this is a review and then goes on to state that biomarkers are not well incorporated into the assessment of cardiovascular risk in the CKD population.  No one would disagree with that statement.  How does this review address this gap?
2. One of the single most important observations that the authors made is that the outcomes and definitions chosen from study to study differed, thus making comparisons and recommendations more difficult.  This observation warrants more discussion and ideas on how to improve research in the field.  Along those lines, can the authors be more specific for each of the studies mentioned what their definitions of terms like MACE and cardiac specific death were?  The authors listed studies where the outcome was all cause mortality, which seems somewhat out of line with their stated intent of looking at biomarkers of CV mortality.  How do the authors justify including those studies?

Author Response

Please see attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

N/A

Author Response

We appreciate your time in reviewing this manuscript.