Association Between Predialysis Hypermagnesaemia and Morbidity

BMJ Open: first published as 10.1136/bmjopen-2018-027970 on 9 July 2019. Downloaded from PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Association between pre-dialysis hypermagnesemia and morbidity of uremic restless legs syndrome in maintenance hemodialysis patients: a retrospective observational study in Zhejiang, China AUTHORS Yang, Yi; Ye, Hongying; He, Qien; Zhang, Xiaohui; Yu, Biying; Yang, Jingjuan; Chen, Jianghua

VERSION 1 – REVIEW

REVIEWER Georgios Sakkas University of St Mark and St John, UK REVIEW RETURNED 29-Nov-2018

GENERAL COMMENTS This is a very interesting study with the potential to influence the amelioration of RLS symptoms in HD patients. Comments: it is not clear why the authors have been focused on intradialytic hypermagnesemia, and not on serum magnesium, during the off hemodialysis session days since RLS symptoms are taking place any time either during or after dialysis. http://bmjopen.bmj.com/ The authors should elaborate a bit more about the calcium– phosphorus metabolism mechanism via the PTH–FGF23 pathway and how this could affect the RLS symptoms. Authors need to include the new paper in RLS (J Physiol. 2018 Nov 14. doi: 10.1113/JP275341) motorneuron excitability and try to link it with their findings and hypothesis.

REVIEWER OLURANTI FAMILONI on September 27, 2021 by guest. Protected copyright. DEPT OF MEDICINE OLABISI ONABANJO UNIVERSITY SAGAGMU NIGERIA REVIEW RETURNED 21-Jan-2019

GENERAL COMMENTS ABSTRACT. Line 25, patients cannot be 'interviewed' in a retrospective study! line 30. use the word 'reviewed' rather than 'recruited'- it is retrospective DISCUSSION. The authors assumed that the intradialytic RLS was due to the dialysis, is it possible that they could be due to another aetiology? line 37. prevalence of 14.4 cannot be too 'low' if the range in the literature is (7 -45%) what is the relevance of Table 1?

REVIEWER Rosilene M Elias

BMJ Open: first published as 10.1136/bmjopen-2018-027970 on 9 July 2019. Downloaded from Universidade de Sao Paulo, Brazil REVIEW RETURNED 21-Jan-2019

GENERAL COMMENTS Dear authors,

I have read with interest the revised manuscript “Intradialytic hypermagnesemia is associated with morbidity of uremic restless legs syndrome in maintenance hemodialysis patients”. This retrospective study showed that RLS was present in 14.4% of patients and it was associated with hypermagnesemia, high levels of parathyroid hormone, hypercalcemia, hyperphosphatemia and longer time on dialysis. This is an interesting study and my comments are below:

Comments: 1. I understand that the main focus was the Mg. However, the results also should report other independent factors associated with RLS, such as high levels of PTH, hyperphosphatemia and longer time on dialysis. 2. I did not find hypermagnesemia among the independent variables in the logistic analysis illustrated in Table 4. The results in page 10 should be listed in Table 4 as is described in the manuscript. Please revise. 3. The authors should refrain from saying that “our data provide evidence that it is important to maintain magnesium stability in maintenance hemodialysis patients”. The conclusion is not supported by the data presented. You cannot affirm this unless you have an intervention. There is no cause-effect relationship prove based on the retrospective study. 4. Since the association between hypercalcemia and RLS is not usual, I was wondering if the hypercalcemia could be a result of secondary hyperparathyroidism (SHPT). If this is the case, high

levels of Ca, P and PTH are found in the context of http://bmjopen.bmj.com/ hyperparathyroidism. As a suggestion, I would categorize the PTH to define patients with and without SHPT and include this variable in the multivariate analysis instead of the hypercalcemia. The is a description in the literature in the association between RLS and SHPT, with improvement after the surgical treatment (Santos RS et all. Parathyroidectomy Improves Restless Leg Syndrome in Patients on Hemodialysis. PLoS One. 2016 May

19;11(5):e0155835.) on September 27, 2021 by guest. Protected copyright. 5. Is there any correlation between PTH and Mg? 6. Is there any difference among services using dialysate calcium concentration of 3.0 and 2.5 mEq/l in the prevalence of RLS?

Minor comments

1. Abstract. Setting. I would say patients on maintenance hemodialysis 3 times a week. 5. Introduction, please define HD when first appears in the text. 2. I believe that the authors are referring to pre-dialysis serum magnesium. If this is correct, please revise the entire manuscript, since “intradialytic” means that Mg was measured during the hemodialysis procedure, which it was not the case. There is also the word interdialysis, which is also incorrect unless the Mg was measured in the period between two hemodialysis procedures. 3. Please revise the sentence before the citations #2 and #7, since none of them refer to the association between RLS and calcium. If I may suggest other citation, please consider: Neves PD, et al. Effect of Mineral and Bone Metabolism on Restless Legs

BMJ Open: first published as 10.1136/bmjopen-2018-027970 on 9 July 2019. Downloaded from Syndrome in Hemodialysis Patients. J Clin Sleep Med. 2017 Jan 15;13(1):89-94 4. Please revise the sentence before the citations #13 and 14# since the authors mentioned hemodialysis patients and one study was experimental. 5. Discussion, page 13, line 14. Please revise the word hypophosphatemia. I think the authors were mean to say hyperphosphatemia. 6. I would delete the word “plus” before hemodiafiltration in the text and in the Table. 7. The name of the journals should be in short form in the citations. Please revise.

Thank you for the opportunity! Reviewer

VERSION 1 – AUTHOR RESPONSE

Answers to Reviewer #1: 1. We appreciated for your comments and the suggested reference which was really helpful for us. The purpose of our study was to determine whether the inter-dialysis serum magnesium level was associated with morbidity of uremic restless legs syndrome (RLS) in maintenance hemodialysis patients. Serum electrolyte level was tested before hemodialysis every 3 months. We added the measurement at Method section, paragraph 3. We did make mistake when we get help from the professional scientific editing service. It was “inter-dialysis”, not “intradialytic”. We revised all the words of “intradialytic” in our manuscript. 2. We added the calcium–phosphorus metabolism mechanism via the PTH–FGF23 pathway at Discussion section, paragraph 4.

3. We included the new paper in RLS (J Physiol. 2018 Nov 14. doi: 10.1113/JP275341) and linked it http://bmjopen.bmj.com/ with our findings and hypothesis at Discussion section, paragraph 3.

Answers to Reviewer #2: 1. We appreciated for your comments and the suggested reference which was really helpful for us. We revised the words “interviewed” and “recruited” at Abstract section. 2. The uremic RLS might be associated with hyperphosphatemia and PTH, which has been

added at Discussion section, paragraph 4. We did make mistake when we get help from the on September 27, 2021 by guest. Protected copyright. professional scientific editing service. It was “inter-dialysis”, not “intradialytic”. We revised all the words of “intradialytic” in our manuscript. 3. We deleted the sentences of “The prevalence of uremic RLS in the present study was relatively low” at Discussion section, paragraph 1. 4. Dialysate magnesium was associated with the inter-dialysis serum magnesium. Table 1 was used to illustrate the homogeneity of the dialysate magnesium in different dialysis centers.

Answers to Reviewer #3: 1. We appreciated for your comments and the suggested reference which was really helpful for us. We reported other independent factors associated with RLS in our previous articles. According to your suggestion, we have highlighted these factors at Results section, paragraph 3, and reported them at Discussion section, paragraph 4. We did not report other independent factors in order to fit the aim of our study. In addition, we cited the references you provided, which helped us a lot. 2. We revised the Table 4 and added the variable of hypermagnesemia. 3. We agree with you that there is no cause-effect relationship prove based on the retrospective study and revised the conclusions at Abstract section and Discussion section, paragraph 8.

BMJ Open: first published as 10.1136/bmjopen-2018-027970 on 9 July 2019. Downloaded from 4. According to your comment, we added the variable of premorbidity of secondary hyperparathyroidism in Table 2. In our cohort, we found no significant difference between the RLS patients and non-RLS patients. Therefore, we did not include this variable in the multivariate analysis. It might be due to the secondary hyperparathyroidism patients in our cohort did not reach the indication of parathyroidectomy. 5. We analyzed the correlation between PTH and Mg and found no correlation between them (r=0.064, p=0.125). Therefore, we did not include the result in the manuscript. 6. We added the variable of dialysate calcium concentration in Table 2. There was no significant difference between the RLS patients and non-RLS patients. 7. We revised the sentence at Abstract section and defined HD when first appeared in the text. 8. We sincerely appreciated for your comments about the word “intradialytic”. We did make mistake when we get help from the professional scientific editing service. It was “inter-dialysis”, not “intradialytic”. We revised all the words of “intradialytic” in our manuscript. 9. We revised the citation #7 according to your suggestion at Introduction section, paragraph 2. 10. We revised the sentence before the citations #13 and 14# at Introduction section, paragraph 3. 11. We revised the word hypophosphatemia at Discussion section, paragraph 6. 12. According to your suggestion, we deleted the word “plus” before hemodiafiltration in the text and in the Table. 13. We revised the name of the journals in short form in the citations.

VERSION 2 – REVIEW

REVIEWER Rosilene M Elias Universidade de Sao Paulo and Universidade Nove de Julho (UNINOVE) Brazil REVIEW RETURNED 09-Feb-2019 http://bmjopen.bmj.com/

GENERAL COMMENTS Dear authors,

I appreciate all the efforts to improve the manuscript and answer my comments point by point. The manuscript has improved a lot. My only remaining suggestion: please change "inter-dialysis" to "pre-dialysis". Inter-dialysis refers to a period of time between on September 27, 2021 by guest. Protected copyright. sessions, which can be anytime after the end of a session until the beginning of another. Pre-dialysis refers to a moment immediately before dialysis that it is your case. Sorry for the trouble in changing it again, but I think it would be more clear to the readers. I appreciate that you have included a citation based on my suggestion. I know this decision is up to you but I am sure that in this specific case, the reference changed what was written previously in the manuscript.

Best regards

BMJ Open: first published as 10.1136/bmjopen-2018-027970 on 9 July 2019. Downloaded from VERSION 2 – AUTHOR RESPONSE

Answers to Reviewer #3:

We appreciated for your comments and the suggested reference which was really helpful for us. We sincerely appreciated for your comments about the word “inter-dialysis”. We revised it by using the word “pre-dialysis”. In addition, we have revised competing interests statement.