Is Chronic Kidney Disease Affecting the Postoperative Complications of Vitrectomy for Proliferative Diabetic Retinopathy?

Round 1

Reviewer 1 Report

Dear Authors The clinical question raised in this manuscript is very appropriate and essential since DR and DN has a very high correlation and incidence.I would suggest the authors to elaborate more on the results. Thank you

Author Response

Response to Reviewer 1

We would like to thank you for this review and your comments on how the manuscript might be improved. We have made some changes in the document according to your suggestions. Every point has been discussed. The changes and additions in the revised document are in red font and the responses to your questions are in blue font in this file. We hope that our responses are satisfactory.

 

Dear Authors The clinical question raised in this manuscript is very appropriate and essential since DR and DN has a very high correlation and incidence. I would suggest the authors to elaborate more on the results. Thank you

 

Response: Thank you for the suggestion, and we agree with your points. In accordance with the comment, we have added the following text in the Result section to support the Conclusion section: “In post-vitrectomy NVG cases, one eye in the stage 1-2 CKD group and eight eyes in the Stage 3-5 CKD group had post-vitrectomy VH events before the onset of NVG’.

 

We have also changed the following text in the Discussion section to make it easier for readers to understand [line 300]:

 

“ Moreover, previous studies have also shown that vitreous hemorrhage following vitrectomy is a risk factor for neovascular glaucoma. Our observational data confirmed these findings because post-vitrectomy vitreous hemorrhage had been followed by the onset of neovascular glaucoma in some recent cases. Thus, postoperative vitreous hemorrhage might have affected the outcomes as a prognostic factor for the development of neovascular glaucoma after vitrectomy.”

to

“Regarding post-vitrectomy NVG, Takayama et al. reported that post-vitrectomy VH was a risk factor for the onset of NVG since it might increase VEGF and inflammatory cytokine levels in the aqueous humor, resulting in the development of NVG [4]. In the current study, most (9 of 13 eyes) of the patients with post-vitrectomy NVG had post-vitrectomy VH events before the onset of NVG. Thus, we speculate that the development of post-vitrectomy NVG might be somewhat affected by post-vitrectomy VH.”

 

Reviewer 2 Report

Brief summary:

The manuscript entitled “Is Chronic Kidney Disease Affecting the Postoperative Complications of Vitrectomy for Proliferative Diabetic Retinopathy?” by Kameda and colleagues attempts to find the correlation between different stages of chronic kidney disease (CKD) and the risk of post-vitrectomy vitreous hemorrhage (VH) and neovascular glaucoma (NVG) in patients with proliferative diabetic retinopathy (PDR). Using a retrospective observational study, the authors found significantly increased incidence of post-vitrectomy VH and NVG in the group with stage 3-4 CKD without hemodialysis, compared to the group with stage 1-2 CKD without hemodialysis and the group receiving hemodialysis. While the topic is very interesting, there were several issues that could be addressed to improve the quality of the manuscript. These are outlined below:

 

Overall:

1. After initial definition of vitreous hemorrhage (VH) and neovascular glaucoma (NVG), the abbreviations should be used throughout the text.
2. Post-vitrectomy VH and NVG are rephrased in general terms throughout the text as “post-surgery outcomes”, “postoperative events”, “vitreous hemorrhage event” “event-free group”. As post-vitrectomy VH and NVG are specific outcomes in your study, the same, specific terminology should be used consistently throughout the text.
3. Is dialysis and hemodialysis the same? Please use the term consistently

 

Abstract:

1. The group names, Non-CKD, CKD group, HD, are confusing and do not capture the disease features accurately. For instance, it is contradictive to name the group “Non-CKD”, when it is defined by “stage 1-2 CKD” and in the definition saying “normal renal function” when in fact renal disease is present. The authors might find it more beneficial to name the groups as early CKD, moderate CKD, and late CKD instead, which captures the idea of disease progression.
2. Line 19-20: The sentence, “risk factors for these complications were determined in non-dialysis patients” appears incomplete.

 

Introduction:

1. The overall focus of the introduction could be improved to focus on the relationship between CKD and RD and why it is important to explore this relationship.
2. Line 3: VH is briefly mentioned in second sentence and NVG is never discussed. Then in the last sentence the authors mentioned that these are “often used to estimate the outcome of vitrectomy as the primary end point”. Given that these are the main outcomes of the study, they should be discussed in greater depth and much earlier in the introduction (eg. how they are formed, how do they affect the patient, why are they considered primary end points?).
3. Line 44-45 and 48-50: More references are required that show that PDR and CKD are co-morbidities with a particular focus on studies that have looked at their progression rates together.

 

Methods:

1. Line 64-65: It seems unusual that consent was waived due to use of retrospective data. Usually ethical approval is required when working patient’s biological data either retrospectively or prospectively. Could the authors clarify this?
2. Line 65: The use of the word “consecutive” appears inappropriate here. The authors could consider specifying if these are Type1 or Type 2 DM patients instead.
3. Line 69-71: Could the authors clarify on the alternative laser treatment and number of patients involved if they did not have PRP? Please specify why some people are seen “more frequently” and whether that affects the results.
4. Line 72-74: Was there a time limit eg. use of VEGF inhibitor within 3 months (which patients who had had anti-VEGF 10yrs ago are included)
5. Line 76: Why is it better to include the “one that had undergone a prior surgery”? Would it not be better to use eyes without prior surgeries because of reduced confounding variables?
6. Line 83: Could the authors please clarify the significance of having the female sex included in their equation?
7. Line 110-112: The phrase, “… surgical procedures (combined cataract surgery; endolaser photocoagulation, including the total number of shots; and removal of fibrovascular proliferation)” should be stated much earlier under the inclusion criteria of participants.
8. Line 119: Are fibrovascular membranes and epiretinal membranes the same?

 

Results:

1. Line 142-144: the phrase “…showing a significant difference among the three groups” does not tell us where the difference is (between which groups).
2. Line 146-149: While there was a statistically significant difference, the difference was only 2%. Could the authors comment on the biological/clinical significance of such small level of change?
3. Line 146-149: Results for NVG should be written in a similar format as used for VH. Furthermore, the authors should not include implications eg. “more likely to develop” as this belongs in the discussion section.
4. Results for Table 2 should be described in a separate paragraph.
5. For Table 2, it is confusing that the group names are (I) CKD, (II) CKD+ (III)HD, and the grades are also I, II, III, because in the significant difference column I comparisons are made between the groups or between the grades. Changing the group names as previously suggested might help with this.
6. Table 3 and 4, the authors should add asterisks next to p values to indicate the statistical significance, then add these to the footnote defining what the number of asterisks represent.

 

Discussion:

Overall the discussion was difficult to follow.   

1. Line 178: What are the strong association between DR and CKD? The authors should explain that they are both diabetic vascular diseases that progress to worse stages with longer duration of diabetes, the fact that DR is often seen in patients with CKD or vice versa.

• Line 179: The second sentence is hard to understand. The authors should delete “no” as the word “discrepancy” means disagreement or differences, so “no discrepancy” = agreement.
• Line 179: What are the “epidemiologic findings”? I think you are trying to say “Clinically, it is likely that diabetic patients with PDR requiring vitrectomy, already have CKD, as both develop after long duration of diabetes. This sentence also requires a reference.

2. Line 182: The sentence “the impact of CKD on vitrectomy related complications” as it currently reads suggest a cause and effect which is a strong assumption to make. The authors should consider changing this to “correlation between CKD and post-vitrectomy complications”.
3. Line 188-198: It is unclear why the authors now discuss a relationship between VH and NVG which doesn’t really relate to their research question.

• Line 199-221: The order of sentences and the argument here confusing. For instance, more background is required on hemodialysis and systemic anti-coagulation using heparin.
• Line 219: The term “pathogenesis” means development of disease therefore, “severity of retinopathy and macular edema” are not examples of pathogenesis of VH and NVG.

4. Line 237: What is a priori power and what is the benefit of performing it?
5. In the discussion, the authors mentioned systemic anti-coagulation agent (blood thinner) is used in dialysis, which increases risk of VH. This is useful to know in the introduction, so readers understand the rationale and you can even use this to write a hypothesis, which is not present in the current manuscript.

Author Response

Response to Reviewer 2

 

We would like to thank you for this review and your comments on how the manuscript might be improved. We have made some changes in the document according to your suggestions. Every point has been discussed. The changes and additions in the revised document are in red font and the responses to your questions are in blue font in this file. We hope that our responses are satisfactory.

 

Brief summary:

The manuscript entitled “Is Chronic Kidney Disease Affecting the Postoperative Complications of Vitrectomy for Proliferative Diabetic Retinopathy?” by Kameda and colleagues attempts to find the correlation between different stages of chronic kidney disease (CKD) and the risk of post-vitrectomy vitreous hemorrhage (VH) and neovascular glaucoma (NVG) in patients with proliferative diabetic retinopathy (PDR). Using a retrospective observational study, the authors found significantly increased incidence of post-vitrectomy VH and NVG in the group with stage 3-4 CKD without hemodialysis, compared to the group with stage 1-2 CKD without hemodialysis and the group receiving hemodialysis. While the topic is very interesting, there were several issues that could be addressed to improve the quality of the manuscript. These are outlined below:

 

Overall:

After initial definition of vitreous hemorrhage (VH) and neovascular glaucoma (NVG), the abbreviations should be used throughout the text.

 

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have abbreviated vitreous hemorrhage and neovascular glaucoma to VH and NVG, after defining at the first mention, throughout the text.

 

Post-vitrectomy VH and NVG are rephrased in general terms throughout the text as “post-surgery outcomes”, “postoperative events”, “vitreous hemorrhage event” “event-free group”. As post-vitrectomy VH and NVG are specific outcomes in your study, the same, specific terminology should be used consistently throughout the text.

 

Response: Thank you for the suggestion. We agree that the phrase〝post-vitrectomy VH and NVG” is more appropriate in some settings and have made changes. However, the phrases “postoperative events,” “postsurgical outcomes,” and “vitrectomy-related complications” include other complications in addition to post-vitrectomy VH and NVG. We therefore wish to retain the original words in some sentences.

 

Is dialysis and hemodialysis the same? Please use the term consistently

 

Response: Thank you for the suggestion. We have changed dialysis to hemodialysis throughout the text.

 

Abstract:

The group names, Non-CKD, CKD group, HD, are confusing and do not capture the disease features accurately. For instance, it is contradictive to name the group “Non-CKD”, when it is defined by “stage 1-2 CKD” and in the definition saying “normal renal function” when in fact renal disease is present. The authors might find it more beneficial to name the groups as early CKD, moderate CKD, and late CKD instead, which captures the idea of disease progression.

 

Response: We thank the reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have changed the non-CKD group and the CKD group to the stage 1-2 CKD group and the stage 3-5 CKD group, consistent with the phrasing used in many studies.

 

Line 19-20: The sentence, “risk factors for these complications were determined in non-dialysis patients” appears incomplete.

 

Response：We appreciate the reviewer’s concerns on this point. We speculate that the decline in eGFR may be associated with a higher risk of post-vitrectomy VH and NVG. To prove this, only patients from whom we could take accurate measurement of renal function (i.e., non-hemodialysis patients) were identified. However, we agree that the sentence appears incomplete. We therefore have changed the following text in the abstract section [line 19]:

 

“Risk factors for these complications were determined in the non-dialysis patients.”

to

“We also determined whether the deterioration of the estimated glomerular filtration rate (eGFR) was associated with post-vitrectomy events .”

 

 

Introduction:

The overall focus of the introduction could be improved to focus on the relationship between CKD and RD and why it is important to explore this relationship.

  

Response: We appreciate the reviewer’s concerns on this point; We also understand the importance of focusing on the relationship between CKD and DR. However, we wish to make the study interesting not only for ophthalmologists, but also for diabetologists and nephrologists. Therefore, we introduced severity and treatment of vitreous hemorrhage due to PDR, and major complications following vitrectomy. For these reasons, we do not wish to change the introduction section to focus on the relationship.

 

Line 3: VH is briefly mentioned in second sentence and NVG is never discussed. Then in the last sentence the authors mentioned that these are “often used to estimate the outcome of vitrectomy as the primary end point”. Given that these are the main outcomes of the study, they should be discussed in greater depth and much earlier in the introduction (eg. how they are formed, how do they affect the patient, why are they considered primary end points?).

 

Response：Thank you for the suggestion. We agree that this point requires clarification and have added the following text in the introduction section: “Among these complications, recurrent VH is the most common postoperative event, and has been reported in 7-63% of patients [1]. Similarly, the incidence of NVG, which is regarded as a terminal severe complication, was also present at a higher rate (9.3-11.8%) than other complications, except for VH [1, 4].”

 

Line 44-45 and 48-50: More references are required that show that PDR and CKD are co-morbidities with a particular focus on studies that have looked at their progression rates together.

 

Response：We appreciate the reviewer’s concerns on this point. We have added the following three references that show an association between CKD and PDR.

 

• Boelter MC.; Gross JL.; Canani LH.; Costa LA.; Lisboa HR.; Três, GS.; Lavinsky J.; Azevedo MA. Proliferative diabetic retinopathy is associated with microalbuminuria in patients with type 2 diabetes. Brazilian Journal of Medical and Biological Research 2006, 39, 1033-1039
• Song YS .; Nagaoka T.; Omae T.; Yokota H.; Takahashi A.; Yoshida A. SYSTEMIC RISK FACTORS IN BILATERAL PROLIFERATIVE DIABETIC RETINOPATHY REQUIRING VITRECTOMY. Retina 2016, 36, 1309-1313
• Deva R.; Alias MA.; Colville D.; Tow FKNFH.; Ooi QL.; Chew S.; Mohamad N.; Hutchinson A.; Koukouras I.; Power DA.; Savige J. Vision-Threatening Retinal Abnormalities in Chronic Kidney Disease Stages 3 to 5. Clin J Am Soc Nephrol 2011, 6, 1866 –1871

 

 

Methods:

Line 64-65: It seems unusual that consent was waived due to use of retrospective data. Usually ethical approval is required when working patient’s biological data either retrospectively or prospectively. Could the authors clarify this?

 

Response：Thank you for the suggestion. We confirm that the Institutional Review Board of Tokyo Women’s Medical University approved the study protocol and waived the requirement for informed consent because of the retrospective study design. If necessary, we can submit the Japanese document and approval of the ethics committee.

 

Line 65: The use of the word “consecutive” appears inappropriate here. The authors could consider specifying if these are Type1 or Type 2 DM patients instead.

 

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have deleted the title “consecutive.”

 

Line 69-71: Could the authors clarify on the alternative laser treatment and number of patients involved if they did not have PRP? Please specify why some people are seen “more frequently” and whether that affects the results.

 

Response：We thank the Reviewer for this pertinent comment. All cases seemed to have PRP scarring. However, there is no clinically clear definition of PRP (e.g., more than 1200 shots) and it is a somewhat ambiguous expression. However, to clarify whether laser treatment affected the results, the total number of laser shots at vitrectomy were compared in the three groups. Concerning “more frequently,” patients who had post-vitrectomy complications, including VH or NVG, were examined more frequently, as is medically ethical and essential. Moreover, we think that the examination intervals in the current study did not affect the result. However, we agree with the need to clarify the meaning of “more frequently.” Therefore, we have changed the following text in the Result section [line 76]:

“more frequently ”

to

“or more frequently if patients had postoperative events”

 

Line 72-74: Was there a time limit eg. use of VEGF inhibitor within 3 months (which patients who had had anti-VEGF 10yrs ago are included)

 

Response：Thank you for the suggestion. Not all cases had a history of anti-VEGF injection.

 

Line 76: Why is it better to include the “one that had undergone a prior surgery”? Would it not be

better to use eyes without prior surgeries because of reduced confounding variables?

 

Response: We appreciate the reviewer’s concerns on this point. The nature of ocular or systemic measurements of paired eyes poses a long-standing question to ophthalmologists regarding the correlation between the two eyes of the same patient. In the current study, we analyzed data from one eye of one patient to maintain the assumption of independence required by the statistical analysis as used in many ophthalmic research studies.

 

Line 83: Could the authors please clarify the significance of having the female sex included in their equation?

 

Response: Thank you for the suggestion. We apologize for not clarifying this point. In general, the value of serum creatinine, which is an indicator of renal function, depends on muscle mass. Therefore, serum creatinine must be corrected by sex, age, race etc., for an accurate measurement of renal function

 

Line 110-112: The phrase, “… surgical procedures (combined cataract surgery; endolaser photocoagulation, including the total number of shots; and removal of fibrovascular proliferation)” should be stated much earlier under the inclusion criteria of participants.

 

Response：Thank you for the suggestion. We wished to determine whether different surgical procedures affected post-vitrectomy events. Therefore, we wished not to include those factors in the inclusion criteria.

 

Line 119: Are fibrovascular membranes and epiretinal membranes the same?

 

Response：Thank you for the question. These terms have the same meaning. We used different phrases to avoid the using same expression in one sentence.

 

 

Results:

Line 142-144: the phrase “…showing a significant difference among the three groups” does not tell us where the difference is (between which groups).

 

Response：Thank you for the suggestion. In this sentence, there was no need to show where the difference was between groups because the analysis procedure was the Kruskal-Wallis test. The outcome of the Kruskal-Wallis test only showed that there were differences among the three groups, but not about which groups differed from the other groups. Therefore, the subsequent sentence showed which group were differed from the other groups using Bonferroni post-hoc analysis.

 

Line 146-149: While there was a statistically significant difference, the difference was only 2%. Could the authors comment on the biological/clinical significance of such small level of change?

and

Line 146-149: Results for NVG should be written in a similar format as used for VH. Furthermore, the authors should not include implications eg. “more likely to develop” as this belongs in the discussion section.

 

  

Response：Thank you for the suggestion. This means that there were significant differences in the incidence of NVG between the stages 3-5 CKD (17%) and stages 1-2 CKD groups (2%), and between the stage-5 CKD (17%) and HD groups (0%,). However, we understand that that this may be a misleading expression for readers. In accordance with the comment, we have changed the following text in the Result section [line 151]:

“Particularly, patients in the CKD group (17%, 12/70 eyes) were more likely to develop postoperative neovascular glaucoma than those in the non-CKD (2%, 1/60 eyes) and HD (0%, 0/30 eyes) groups (P = 0.006 and P = 0.016, respectively)”

to

“Particularly, post-vitrectomy NVG events were significantly higher in the stages 3-5 CKD group (17%, 12/70 eyes) than in the stages 1-2 CKD group (2%, 1/60 eyes) and HD group (0%, 0/30 eyes) (P = 0.006 and P = 0.016, respectively)”

 

Results for Table 2 should be described in a separate paragraph.

 

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have separated the VH category (Table 2) and the NVG category (Table 3)

 

For Table 2, it is confusing that the group names are (I) CKD, (II) CKD+ (III)HD, and the grades are also I, II, III, because in the significant difference column I comparisons are made between the groups or between the grades. Changing the group names as previously suggested might help with this.

 

Response: Thank you for the suggestion. We have changed (I) CKD(-), (II) CKD(+), (III) HD to stages 1-2 CKD, stages 3-5 CKD, HD in Tables 1 and 2.

 

Table 3 and 4, the authors should add asterisks next to p values to indicate the statistical significance, then add these to the footnote defining what the number of asterisks represent.

 

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have added asterisks next to P values and the footnote in all tables.

 

 

Discussion

Overall the discussion was difficult to follow.  

Line 178: What are the strong association between DR and CKD? The authors should explain that they are both diabetic vascular diseases that progress to worse stages with longer duration of diabetes, the fact that DR is often seen in patients with CKD or vice versa.

and

Line 179: The second sentence is hard to understand. The authors should delete “no” as the word “discrepancy” means disagreement or differences, so “no discrepancy” = agreement.

and

Line 179: What are the “epidemiologic findings”? I think you are trying to say “Clinically, it is likely that diabetic patients with PDR requiring vitrectomy, already have CKD, as both develop after long duration of diabetes. This sentence also requires a reference.

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have changed the following text in the Discussion section [line 188]:

“Numerous studies have reported a strong association between the severity of diabetic retinopathy and CKD. There was no discrepancy between their epidemiologic findings and the real world and the real world since patients with diabetes and severe PDR who crucially need vitrectomy are likely to have CKD in clinical settings.”

to

“Several clinical studies have shown that PDR is associated with an increased risk for CKD [20–23]. We realize that patients with diabetes and severe PDR who crucially need vitrectomy are likely to have CKD in real-world settings.”

 

 

Line 182: The sentence “the impact of CKD on vitrectomy related complications” as it currently reads suggest a cause and effect which is a strong assumption to make. The authors should consider changing this to “correlation between CKD and post-vitrectomy complications”.

 

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have changed the following text in the Discussion section [line 191]:

“the impact of CKD on vitrectomy-related complications”

to

“ the correlation between CKD and post-vitrectomy complications”

 

Line 188-198: It is unclear why the authors now discuss a relationship between VH and NVG which doesn’t really relate to their research question.

 

Response：Thank you for the suggestion. This sentence tries to express our thoughts about the occurrence of post-vitrectomy NVG in the current study. However, we also agree that it is difficult to understand. Therefore, we agree with your suggestion and have added the following text in the result section [line 153] to support the conclusion section: “In post-vitrectomy NVG cases, one eye in the stages 1-2 CKD group and eight eyes in the stages 3-5 CKD group had post-vitrectomy VH events before the onset of NVG ”, and changed the following text in the discussion section [line 198]:

 

“Similarly, in the current study, recurrent vitreous hemorrhage after vitrectomy was significantly higher in the CKD group (43%) than in the non-CKD (10%) and HD (10%) groups. Moreover, previous studies have also shown that vitreous hemorrhage following vitrectomy is a risk factor for neovascular glaucoma. Our observational data confirmed these findings because post-vitrectomy vitreous hemorrhage had been followed by the onset of neovascular glaucoma in some recent cases. Thus, postoperative vitreous hemorrhage might have affected the outcomes as a prognostic factor for the development of neovascular glaucoma after vitrectomy.”

to

“ Our observational data confirmed these findings, as post-vitrectomy VH was significantly higher in the stages 3-5 CKD group (43%) than in the stages 1-2 CKD (10%) and HD (10%) groups. Regarding post-vitrectomy NVG, Takayama et al. reported that post-vitrectomy VH was a risk factor for the onset of NVG since it might increase VEGF and inflammatory cytokines in the aqueous humor, resulting in the development of NVG [4]. In the current study, most (9 of 13 eyes) of the patients with post-vitrectomy NVG had post-vitrectomy VH events before the onset of NVG. Thus, we speculate that the development of post-vitrectomy NVG might be somewhat affected by post-vitrectomy VH.”

 

Line 199-221: The order of sentences and the argument here confusing. For instance, more background is required on hemodialysis and systemic anti-coagulation using heparin.

and

In the discussion, the authors mentioned systemic anti-coagulation agent (blood thinner) is used in dialysis, which increases risk of VH. This is useful to know in the introduction, so readers understand the rationale and you can even use this to write a hypothesis, which is not present in the current manuscript.

 

Response：Thank you for the suggestion. We agree with your suggestion and have added the following text to the introduction section [line 54] to support the conclusion section: “Moreover, many physicians are concerned that patients with PDR and CKD who are on hemodialysis (HD) and undergo vitrectomy may have a higher risk of post-vitrectomy VH, since HD requires systemic anticoagulation using unfractionated heparin.”

 

Line 219: The term “pathogenesis” means development of disease therefore, “severity of retinopathy and macular edema” are not examples of pathogenesis of VH and NVG.

 

Response：We thank the Reviewer for this pertinent comment. We agree with your suggestion. In accordance with the comment, we have deleted the phrase, “such as the severity of retinopathy and macular edema.”

 

Line 237: What is a priori power and what is the benefit of performing it?

 

Response：We appreciate the reviewer’s concerns on this point. After discussing the reviewer’s comment, we concluded that this sentence about a priori power analysis was not absolutely necessary. Therefore, we have deleted the sentence. Thank you for your constructive suggestion.

Author Response File: Author Response.docx

Reviewer 3 Report

This study is interesting and quite original. Evaluates the correlation between eGFR, particularly the presence or absence of chronic renal failure or dialysis, and the risk of ocular complications after vitrectomy in individuals with proliferative diabetic retinopathy.

The work is well written, and the authors point out the limitations of the study. This review raises few comments to try to make the study interesting not only for an ophthalmologist, but also for a diabetologist, a nephrologist or a cardiologist.

1- The authors noted that CKD significantly increases the risk of post-vitrectomy ocular complications in patients with proliferative diabetic retinopathy. Therefore, close follow-up for at least 6 months after vitrectomy in these patients would be helpful. This observation further extends the clinical importance of identifying the simultaneous presence of these two microangiopathies in the diabetic patient. In fact, it is known that the association between diabetic kidney disease (DKD) and diabetic retinopathy not only identifies a population with a high CV risk (Diabetes Care 2006 Mar; 29 (3): 498-503. doi: 10.2337/diacare. 29.03.06.dc05-1776), but also allows the identification of diabetic subjects who can benefit from a multifactorial treatment that rapidly and in durably reduces MACEs and mortality, as recently observed in the randomized multicenter study NID-2 (Cardiovasc Diabetol (2021) 20:145. doi: 10.1186/s12933-021-01343-1). This important issue and the references above should be added and commented on in the discussion.

2- Subjects in both the CKD and non-CKD groups have a mean HbA1c> 7% (7.4 and 7.5%, respectively). It is therefore not possible to exclude that better glycemic control may have reduced the risk of post-vitrectomy complications

3- An important limitation of the study is that the population with CKD, and also that with post-vitrectomy ocular complications is overwhelmingly male. Therefore, the study results cannot be generalized to the female gender.

Author Response

Response to Reviewer 3

 

We would like to thank you for this review and your comments on how the manuscript might be improved. We have made some changes in the document according to your suggestions. Every point has been discussed. The changes and additions in the revised document are in red font and the responses to your questions are in blue font in this file. We hope that our responses are satisfactory.

 

This study is interesting and quite original. Evaluates the correlation between eGFR, particularly the presence or absence of chronic renal failure or dialysis, and the risk of ocular complications after vitrectomy in individuals with proliferative diabetic retinopathy. The work is well written, and the authors point out the limitations of the study. This review raises few comments to try to make the study interesting not only for an ophthalmologist, but also for a diabetologist, a nephrologist or a cardiologist.

• The authors noted that CKD significantly increases the risk of post-vitrectomy ocular complications in patients with proliferative diabetic retinopathy. Therefore, close follow-up for at least 6 months after vitrectomy in these patients would be helpful. This observation further extends the clinical importance of identifying the simultaneous presence of these two microangiopathies in the diabetic patient. In fact, it is known that the association between diabetic kidney disease (DKD) and diabetic retinopathy not only identifies a population with a high CV risk (Diabetes Care 2006 Mar; 29 (3): 498-503. doi: 10.2337/diacare. 29.03.06.dc05-1776), but also allows the identification of diabetic subjects who can benefit from a multifactorial treatment that rapidly and in durably reduces MACEs and mortality, as recently observed in the randomized multicenter study NID-2 (Cardiovasc Diabetol (2021) 20:145. doi: 10.1186/s12933-021-01343-1). This important issue and the references above should be added and commented on in the discussion.

Response: We appreciate the reviewer’s concerns on this point. We agree with your suggestion. In accordance with the comment, we have added the above recommended references and the following text to the discussion section [line 239]: “The beneficial effects of an intensive multifactorial therapy on renal outcomes are well documented [43, 44]. Moreover, Sasso et al. reported that patients with both diabetic kidney disease and severe diabetic retinopathy were likely to have cardiovascular risk, but that intensive multifactorial therapy for such patients provided a remarkable benefit with regard to this risk [45, 46]. In the current study, we could not determine whether this therapy was associated with a decreased risk of post-vitrectomy complications; thus, further investigation is required to clarify this issue.”

.

• Subjects in both the CKD and non-CKD groups have a mean HbA1c> 7% (7.4 and 7.5%, respectively). It is therefore not possible to exclude that better glycemic control may have reduced the risk of post-vitrectomy complications

Response: We appreciate the reviewer’s concerns on this point. We also understand the importance of clarifying the relationship between glycemic control and post-vitrectomy complications. However, the data available to us regarding HbA1c were limited, and thus, we cannot address your question. This issue needs to be investigated in a future study. Therefore, to clarify this point, we are currently investigating the association between glycemic control and post-vitrectomy complications in diabetic patients with proliferative diabetic retinopathy. Thank you for your constructive suggestion.

 

• An important limitation of the study is that the population with CKD, and also that with post-vitrectomy ocular complications is overwhelmingly male. Therefore, the study results cannot be generalized to the female gender.

Response: We appreciate the reviewer’s concerns on this point. Actually, a few clinical studies have shown that male sex itself is associated with an increased risk for post-vitrectomy complications, as mentioned in the Introduction section. Therefore, we could not assess whether the trend of more men developing post-vitrectomy complications in the current study resulted from subject selection bias or was a natural consequence. This issue also needs to be investigated in a future study. Thank you for your constructive suggestion.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

No additional comments