A Historical Perspective on Uremia and Uremic Toxins

Round 1

Reviewer 1 Report

This article historically outlines three stages of understanding and recognition of uremic toxins, from the accumulation of waste products to uremia remnant syndrome and following remote sensing and signaling. However, it is not worth publishing. Although there is some elaboration on the current understanding of uremic toxins, it has not analyzed how the understanding of these uremic toxins can help in the clinical prevention and treatment of uremia. Therefore, it has not brought new ideas or much novelty. I suggest it should be make major modification before resubmitting it.

Author Response

We appreciate the reviewer's feedback but are a bit confused given the first recommendation from the journal was to provide a comprehensive overview of uremia and its impact on various in vitro systems. We opted to adhere to the journal’s initial request, rather than changing the focus of the article upon request of a single reviewer. However, we concur that incorporating a more clinical section on the topic of prevention and treatment would be beneficial.

We have included a section discussing the therapeutic aspects of removing residual uremic toxins. It is important to emphasize that there is still a significant amount of work that has to be done in this area. Although we have evidence that our therapies can reduce the levels of certain toxins, there is a lack of substantial evidence on the actual clinical outcomes. We hope the reviewer agrees with this addition.

Reviewer 2 Report

This paper provided an overview/review of uremia and uremic toxins, which was well-written and defined. Even though there was mention about the mechanism and such not being well understood about uremia or how to eliminate the buildup from hemodialysis, possibly expanding in the clinical side of what has been attempted to reduce these toxins - whether it is different manipulations with the dialysate composition, the filter, etc or medications/diet, etc would have been instrumental to know what further work needs to be done.  

There were a few areas within this report, especially within the first two paragraphs about non-scientific language that comes across as more opinion-based. 

Author Response

We would like to express our gratitude to the reviewer for his/ her valuable comments and overall positive appraisal of the manuscript. We have included a section discussing the therapeutic aspects of removing residual uremic toxins. It is important to emphasize that there is still a significant amount of work that has to be done in this area. Although we have evidence that our therapies can reduce the levels of certain toxins, there is a lack of substantial evidence on the actual clinical outcomes. Finally, we looked at the wording used in the article and removed multiple instances of subjective language.

Reviewer 3 Report

Well organized and thought provoking review of complex topic.  The number of potential uremic toxins continues to evolve and a summary table of current toxins might be appropriate.  Highlighting IS and p-cresol would be an appropriate example of a class of protein bound toxins.  The summary of IS/p-cresol toxicity is reviewed well in this manuscript.

specific issues: page 2/102  national coordinated dialysis study should be national cooperative dialysis study

page 3/134,  add area to low surface area

page 5/226,  i am not sure if the average reader know what epuration means,  probably could reword this first sentence

Author Response

We express our gratitude to the reviewer for his/ her meticulous reading of the content. We have considered and included these recommendations. We acknowledge the existence of multiple potential uremic toxins and recognize that this idea is constantly developing. However, we would want to express our disagreement with the inclusion of an overview table of uremic toxins. This is not an exhaustive list of all individual metabolites, as there are already multiple high-quality articles available on this subject. Reproducing these works would be redundant on our part. We have included reference to a notable review in the topic (Rosner et al) for anyone who wishes to further look into this topic and hope the reviewer agrees that this is sufficient

Round 2

Reviewer 1 Report

The effects of uremic toxins on kidney and associated mechanisms, the clearance methods of uremic toxins were described more clearer by the authors in the revised review. I suggest adding some information about the injury of organs beyond the kidney caused by the uremic toxins before publication because uremic toxins also affect the cardiovascular, nervous, immune systems and other systems, in addition to direct attacking on the kidneys, which was not mentioned in the review.

Author Response

We appreciate the reviewer's examination and concur that this revised version of the text provides an in-depth overview of the transport processes associated with protein-bound uremic toxins.

The inclusion of additional tissue-specific effects in the second sentence is challenging, as section 3 already covers the impact on several tissue types including endothelium, hepatocytes, intestinal epithelium, and macrophages. Once again, we concur that this article does not encompass all the clinical effects of uremia. However, its primary objective is not to delineate the clinical symptoms, but rather to elucidate the concept and underlying physiology. Consequently, we incorporated a concise paragraph addressing the blood-brain barrier, as there are compelling in vivo and in vitro discoveries in that domain. However, we abstain from exploring further into clinical specifics.

If the reviewer or journal deems it necessary to include this perspective, we would recommend referencing individual reviews pertaining to this topic, rather than attempting to incorporate it into the already comprehensive overview we provide.