The Role of Cardio-Renal Inflammation in Deciding the Fate of the Arteriovenous Fistula in Haemodialysis Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Arteriovenous fistula (AVF) maturation failure is the “Achilles heel” for hemodialysis patient. The authors in this review carefully summarized the inflammation in different types of vascular cells on AVF maturation failure. They showed that inflammatory responses in endothelial cells (ECs) and immune cells lead to EC dysfunction and cytokine secretion These responses result in activation of vascular smooth muscle cells (VSMCs) and loss of AVF patency. They also carefully summarized the impact of several comorbidities related to ESRD on EC inflammation and AVF maturation. Moreover, sex-associated differences were included in the manuscript. Finaly, they potential therapeutic options were discussed. Thus, this is a well written and organized review in AVF area. The reviewer has the following concern.

1.      Patients receiving hemodialysis have several comorbidities, the authors cited that dialysis accelerated atherosclerosis cause adverse remodeling of AVFs. Since vascular calcification is another popular comorbidity in ESRD patients, its effect on EC function and AVF maturation should be discussed.

2.      In figure 1, the reviewer measured the diameters of “matured AVF” and “initial failed AVF”, and found they are same. However, based on the description in the text, the failed AVF should have a smaller lumen size (smaller diameter) compared to the matured AVF. This mistake should be corrected.

3.      References are required for sentence “Mechanistically, endothelial injury, such as that induced by TNF-β results in mitochondrial reactive oxygen species (ROS) generation” at lines 131-132.

4.      The authors have cited their own group’s study to support the roles of vitamin D3 on EC function. Citations from other groups should be included.

5.      The a-SMA and calponin are located in cytoplasm in VSMCs, they are not “secreted” protein. Please replace the “secret” with “express” in sentence “This contractile state is where proliferation is lowest, and the cells continue to secrete the protein markers α‐ smooth muscle actin and calponin [88]”.

6.      The following sentence at line 265 is not clear. “As these proteins are still being secreted, low proliferation continues to occur until dedifferentiation begins.”

Comments for author File: Comments.pdf

Author Response

Reviewer 1

Arteriovenous fistula (AVF) maturation failure is the “Achilles heel” for hemodialysis patient. The authors in this review carefully summarized the inflammation in different types of vascular cells on AVF maturation failure. They showed that inflammatory responses in endothelial cells (ECs) and immune cells lead to EC dysfunction and cytokine secretion These responses result in activation of vascular smooth muscle cells (VSMCs) and loss of AVF patency. They also carefully summarized the impact of several comorbidities related to ESRD on EC inflammation and AVF maturation. Moreover, sex-associated differences were included in the manuscript. Finaly, they potential therapeutic options were discussed. Thus, this is a well written and organized review in AVF area. The reviewer has the following concern.

1. Patients receiving hemodialysis have several comorbidities, the authors cited that dialysis accelerated atherosclerosis cause adverse remodelling of AVFs. Since vascular calcification is another popular comorbidity in ESRD patients, its effect on EC function and AVF maturation should be discussed.
   Thank-you to the reviewer for this comment. We agree that vascular calcification is a highly prevalent and important comorbidity in the (cardio)vascular system of the dialysis dependent patient. Calcified vessels are usually selected against by the surgeon in deciding upon a suitable place to create an AVF, but there is still a systemic propensity towards calcifying vessels which likely are also responsible for a degree of the underlying endothelial dysfunction. To this end, we have included some additional text discussing and reflecting on the role of calcification in these processes.
   
   
2. In figure 1, the reviewer measured the diameters of “matured AVF” and “initial failed AVF”, and found they are same. However, based on the description in the text, the failed AVF should have a smaller lumen size (smaller diameter) compared to the matured AVF. This mistake should be corrected.
   We wish to thank the reviewer for pointing this out. The graphic has been updated to accurately reflect visually how the text describes the picture.
   
   
3. References are required for sentence “Mechanistically, endothelial injury, such as that induced by TNF-β results in mitochondrial reactive oxygen species (ROS) generation” at lines 131-132.
   This oversight has been corrected and the appropriate references have been added, as well as the extra words “secondary to repeated needling” for additional clarity.
   
   
4. The authors have cited their own group’s study to support the roles of vitamin D3 on EC function. Citations from other groups should be included.
   We agree that further supporting references outside of our group strengthen the argument and as such we have added further citations describing both in vitro and in vivo approaches in CKD/uraemia contexts showing Vit D3 improving endothelial function. Presently our group is the only team to have described the role for vit D3 directly in an AVF context, but other research teams have investigated its role in CKD and uraemia more broadly- which have now been discussed.
   
   
5. The a-SMA and calponin are located in cytoplasm in VSMCs, they are not “secreted” protein. Please replace the “secret” with “express” in sentence “This contractile state is where proliferation is lowest, and the cells continue to secrete the protein markers α‐ smooth muscle actin and calponin [88]”. We thank the reviewer for identifying this error, and the sentence in question has been corrected to now read “This contractile state is where proliferation is lowest, and the cells continue to express the protein markers α-smooth muscle actin and calponin [88]”.
   
   
6. The following sentence at line 265 is not clear. “As these proteins are still being secreted, low proliferation continues to occur until dedifferentiation begins.” The sentence has been updated to now read “Whilst these proteins continue to be expressed, low proliferation will continue until dedifferentiation begins.” To describe the relationship between protein expression and cell behaviour.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Kane J and co-authors carry out a profound review of the mechanisms that at the cellular level could be responsible for the failure of arteriovenous fistula. The review is clear and the bibliography is extremely detailed and updated, however the work lends itself to numerous criticisms:

The failure of the arteriovenous fistula results from numerous biological, mechanical, and hydraulic factors. Enumerating all the effects of inflammation on individual cellular components makes us lose sight of the overall picture. Furthermore, all the cells involved can influence each other and experiments carried out on individual cellular elements could give us information that is not useful for understanding the entire process. The high failure rate of arteriovenous fistulas also depends on the increasingly higher age of dialysis patients. Therefore, the initial state of the vessels the build the fistula, is also very important, which the review does not analyze at all. Finally, the title of the review is very misleading: what does cardio-renal inflammation mean, not all fistulas fail but uremic patients are all affected by an underlying inflammatory condition

Author Response

Kane J and co-authors carry out a profound review of the mechanisms that at the cellular level could be responsible for the failure of arteriovenous fistula. The review is clear and the bibliography is extremely detailed and updated, however the work lends itself to numerous criticisms:

 

The failure of the arteriovenous fistula results from numerous biological, mechanical, and hydraulic factors. Enumerating all the effects of inflammation on individual cellular components makes us lose sight of the overall picture.

We wholeheartedly agree with this statement, AVF failure must be viewed as a holistic combined picture to most completely understand it. However, given this is a special edition of Cells, in the Cells of the Cardiovascular system section, we have focused on the individual cellular components of the vascular bed.

 

Relatedly, in Figure 2 and throughout the manuscript we discuss and show how the individual cellular components of the vasculature interact with the cells around them and influence the local micro-environment. However, for the avoidance of doubt we have included a specific section to briefly mention and discuss the important factors separate to inflammation.

 

Furthermore, all the cells involved can influence each other and experiments carried out on individual cellular elements could give us information that is not useful for understanding the entire process. The high failure rate of arteriovenous fistulas also depends on the increasingly higher age of dialysis patients. Therefore, the initial state of the vessels the build the fistula, is also very important, which the review does not analyse at all.

We agree that there are numerous other factors which play some role in the process of AVF failure and these should not be diminished. Despite this we feel a review is best served by being a highly specific examination of a germane timely area and given the rapidly expanding body of work describing the effects of inflammation on AVF failure, we chose to focus the review on this.

 

Choosing this specific focus allowed us to write an appropriate and comprehensively detailed update and avoid superficiality by trying to cover too many areas inside a reasonable word count. In the section regarding endothelial cells, we also discuss how the comorbidities inherent to ESKD lead to a baseline worsened endothelial function, change the initial state of the vessel, and as such impact upon the maturation success of the AVF.

 

Additionally, drifting too far from a focus on Cells, given the journal and section would not be appropriate- we leave it in the capable hands of other groups to fully review the salient and important impact of demographic influences, sociological trends, or surgical site selection decisions or other such non-Cell focused criteria. However, for the avoidance of doubt we have included a section discussing some of the other factors involved in AVF failure separate to inflammation including age, sex, surgical focus and socioeconomic factors.

 

Finally, the title of the review is very misleading: what does cardio-renal inflammation mean, not all fistulas fail but uremic patients are all affected by an underlying inflammatory condition

Cardiorenal inflammation is broadly common syntax to describe the interaction between the renal and cardiovascular systems. Inflammation from both organ systems negatively impacts the other, and this interaction and interplay is the eminent challenge in our field. The interaction between the cardiovascular systems and renal systems is the focus of the current review.  

 

It is correct so state that not all fistulas fail, and this is one of the main thrusts of the present review and forms the foundation of studies in this field. Comprehensively understanding why some fail and some do not would solve the issues of vascular access. Before that point however, understanding why some fistulas fail and some do not require complete understanding of the vascular biology at play. We acknowledge the influence of many other factors, but as was discussed previously the angle we take in this review is to describe the role for inflammation. Hence the title, the role of cardio-renal inflammation in deciding if an AVF will fail or succeed.

 

We sincerely hope these answers satisfactorily resolve the reviewers’ concerns, and once more wish to thank them for their time.

 

 

 

Author Response File: Author Response.docx