The Switch from Ferric Gluconate to Ferric Carboxymaltose in Hemodialysis Patients Acts on Iron Metabolism, Erythropoietin, and Costs: A Retrospective Analysis

Round 1

Reviewer 1 Report

This manuscript entitled” Strategies in the treatment of anemia in hemodialysis patients: from iron choice to erythropoietin dose” was a single center study to investigate the efficacy using two different iron formula, FCM/FG, on iron status and erythropoiesis. There are several flaws in the study design and data expression. My critiques are in below.

Major concerns

1.        Authors stated that study design was a retrospective, however, it was more likely a prospective design from the statement in the “ Materials and Methods”,  two-stage shifting and a wash-out period for one month, sign consent in participants before study initiation. The definition should be clarified.

2.        It will be easily understand the possible effects of FG and FCM on iron status and erythropoiesis showing the data of elemental iron supplement in the study participants among two groups. 

3.        FG dose was fixed in the participants, however, FCM dose was adjusted according to iron status in the participants. What is the reasons? 

4.        Protocol for epoetin zeta administration, how to stratify according to Hb levels?

5.        How to explain the decline ERI beginning from time 6 in FCM treatment, Table 1? Similar question in Table 2 for Hb elevation in time 7?

6.        A flow chart for participants’ deposition is suggested.

7.        What is the HD-related data in the participants, such as vascular access, components of dialysate, category of dialyzers, and range of blood flow rate. These components could influence the effects on iron status and erythropoiesis in HD patients. 

Minor concerns

1.        How to explain serum iron and ferritin were higher in FCM group, however, transferrin was lower in FCM group when compared to those in FG group?

2.        Fig 3,  I cannot find the curve expression in the text.

3.        I would like to suggest a table to show the iron status in patients without EPO use in the follow-up period. Accordingly, readers could easily understand the effect of FCM on erythropoiesis.  

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

I would like to begin by greeting the authors and congratulating them for having decided to investigate an area where there is still so much to discover, but also for having decided to share this article with the rest of the scientific community, so that science can evolve.

This is a study on strategies in the treatment of anemia in hemodialysis patients. It is a very important and current topic, in permanent evolution and which it never hurts to have more information.

All comments, doubts and suggestions made are constructive and try to improve the article, after several attentive readings.

Title

I believe that the title is presented in a simple, clear and concise way. However, there are doubts about what type of study is presented by reading the title.

Abstract

The abstract should be clear about the type of study.

To what extent can this study change the practices of nephrologists around the world?

Key words:

Repetitions with expressions that are in the title should be avoided. Whenever possible keywords should be Mesh. Authors should review the keywords.

Introduction

References 2 and 5 are presented in the text together with references 1 and 4. References 2 and 5 refer to studies published by this group of authors. Authors must clearly present a justification as to whether this constitutes a case of improper self-citation or not.

Reference 11 is displayed with references 10, 12 and 13. I request clarification as above.

The objective of the end of the Introduction must be exactly the same as that of the Abstract and vice versa.

The introduction contains 13 bibliographical references. On such an up-to-date topic, I believe that the authors should make an effort to improve this component of the article, especially in the up-to-dateness of the references. Of these 13 references, 5 are from 2018 or earlier and the remaining 7 from 2019 (4), 2020 (2), 2021 (1) and 2022 (1). I get the feeling that this part of the article was written and was submitted like this, in 2023, without any revision. The introduction deserves a little more effort on the part of the authors so that their work is enriched.

Also in the introduction, the authors must make clear reference to the reason why this article should be published in a journal as important as Medicina. What data from this article can change the practice of nephrologists around the world? What does this article bring to scientific knowledge? Are there clinical practices that should be changed? What kind of studies are still needed?

Materials and methods

The type of study is clearly indicated. It remains to do so in the abstract and consider including this information in the title.

Do the data refer to the years between 2015 and 2017? What justifies the time gap for submission of this article in 2023? This issue deserves clarification from the authors.

It is not clear why the authors define the study as retrospective.

Results

Figure 3 is completely illegible.

Review text on page 8, lines 279-281.

Discussion

Sometimes confused. Authors should review this component of the article.

Did the authors had patient safety issues? Were there complications?

Conclusions

Authors should avoid abbreviations in the conclusion.

The conclusion must take into account the defined limitations of the study.

Bibliographic references

Bibliographic references do not follow the rules defined by the journal.

General Comments

The formal formatting of the article does not follow the rules defined by the journal. Spacing, tabs, table formatting: there are several formatting inconsistencies.

The use of the pronoun “we” should be avoided. This language is not admissible in a scientific article.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Although authors’ response to previous critiques, there are a few points in the text that should be clarified.

Previous critiques

1.     It will be easily understand the possible effects of FG and FCM on iron status and erythropoiesis showing the data of elemental iron supplement in the study participants among two groups. 

Author response: We clarify these differences in the results section, as also described below about the differences between a “not-treated” group and an “EPO-treated” group. 

Q: I did not find elemental iron data in both groups in the result section. I focus on “elemental iron amount” in individual group.

2.      I would like to suggest a table to show the iron status in patients without EPO use in the follow-up period. Accordingly, readers could easily understand the effect of FCM on erythropoiesis.  

Author response: We thank the reviewer for this observation, because we better highlighted this difference. We analyzed our data, distinguishing patients who were not treated with EPO during FCM and, the same time, patients who receive EPO during the FG period. We described the differences on iron markers in the result section. In particular, the “not treated” patients were characterized by an improved iron metabolism. We also reported this observation in the discussion section. If the reviewer approves, we prefer to report these data in the text and not in a table.  

Q: I prefer to describe in the text.

New critiques

1.     Abstract: The iron switch induced a reduction of ESA administered dose of 1,610.500 UI (31% of reduction; p< 0.001) 

Q: ESA 1,610.500 UI was weekly or total doses in the study period? 

2.     Ref 11. It seems that similar study results have been published in Kidney Res Clin Pract 39: 334-43, 2020. 

Q: A duplicated manuscript? Or any difference between two studies?

3.     KDIGO has published an executive conclusions on optimal anemia management (Kidney Int 99: 1280-95, 2021). There are statements in the text (p1287) in below: For HDCKD patients, PIVOTAL showed that proactive i.v. iron administered unless serum ferritin >700 ug/l or TSAT > 40% was superior to a reactive strategy triggered only for TSAT <20% and ferritin <200 ug/l, indicating that the latter strategy should be avoided.

Q: I would like to suggest citing this reference and write the differences between recent KDIGO conclusion and this study protocol on iron status decision.     

Author Response

Reviewer 1

Although authors’ response to previous critiques, there are a few points in the text that should be clarified.

Previous critiques

1. It will be easily understand the possible effects of FG and FCM on iron status and erythropoiesis showing the data of elemental iron supplement in the study participants among two groups. 

Author response: We clarify these differences in the results section, as also described below about the differences between a “not-treated” group and an “EPO-treated” group. 

Q: I did not find elemental iron data in both groups in the result section. I focus on “elemental iron amount” in individual group.

In the results section, we described the total elemental iron administered in the FG and FCM group during the entire study period.

2. I would like to suggest a table to show the iron status in patients without EPO use in the follow-up period. Accordingly, readers could easily understand the effect of FCM on erythropoiesis.  

Author response: We thank the reviewer for this observation, because we better highlighted this difference. We analyzed our data, distinguishing patients who were not treated with EPO during FCM and, the same time, patients who receive EPO during the FG period. We described the differences on iron markers in the result section. In particular, the “not treated” patients were characterized by an improved iron metabolism. We also reported this observation in the discussion section. If the reviewer approves, we prefer to report these data in the text and not in a table.  

Q: I prefer to describe in the text.

We agree. We did not create a Table and we reported the data in the Results section, as commented in the previous revision.

New critiques

1. Abstract: The iron switch induced a reduction of ESA administered dose of 1,610.500 UI (31% of reduction; p< 0.001) 

Q: ESA 1,610.500 UI was weekly or total doses in the study period? 

It refers to the entire study period. This concept was underlined in the abstract and in the results section

2. Ref 11. It seems that similar study results have been published in Kidney Res Clin Pract 39: 334-43, 2020. 

Q: A duplicated manuscript? Or any difference between two studies?

They are not duplicated data. The data published in 2020 refer to a follow-up period of 48 months with a clinical evaluation of the results. In this study we analyzed the relations between the correction of iron status and pharmacoeconomic consequences.   

3. KDIGO has published an executive conclusions on optimal anemia management (Kidney Int 99: 1280-95, 2021). There are statements in the text (p1287) in below: For HDCKD patients, PIVOTAL showed that proactive i.v. iron administered unless serum ferritin >700 ug/l or TSAT > 40% was superior to a reactive strategy triggered only for TSAT <20% and ferritin <200 ug/l, indicating that the latter strategy should be avoided.

Q: I would like to suggest citing this reference and write the differences between recent KDIGO conclusion and this study protocol on iron status decision.     

We agree with this criticism and we added some references in the introduction section.

Reviewer 2 Report

The authors made an effort to try to improve the quality of the article. However, I was not fully satisfied, especially with regard to figure 4, which is illegible. If the quality of this figure does not improve, I believe that the article cannot be published under these conditions.

Author Response

Reviewer 2

The authors made an effort to try to improve the quality of the article. However, I was not fully satisfied, especially with regard to figure 4, which is illegible. If the quality of this figure does not improve, I believe that the article cannot be published under these conditions.

We deleted the Figure N 4 from the text and we created another figure.