Recurrent Immunoglobulin A Nephropathy after Kidney Transplant—An Updated Review

Round 1

Reviewer 1 Report

The review by Lee B et al. reviews the Recurrent Immunoglobulin A Nephropathy after Kidney Transplant. This update is interesting, nicely written, and well-organized. I appreciate the authors' efforts in providing this comprehensive review, however, some paragraphs are too brief and it may be taken into consideration for publication after the following major revisions:

1-  I recommend dividing the paragraph epidemiology into 2 subsections: epidemiology in the native kidney and epidemiology in transplantation.

2- In the paragraph "epidemiology" the authors highlighted that some immunosuppressive regimens are associated with risk of recurrence. It is advisable to specify in the text which treatments (e.g. induction with ATG)

3-  It is recommended to add a summary table of the main risk factors highlighting the risk factors (e.g. recipient-related risk factors and transplant-related risk factors)

4- It is recommended to make the paragraph "pathogenesis" less synthetic by describing all the mechanisms of development of the disease (e.g. role of complement, B lymphocytes with APRIL and BAFF, Spleen tyrosine kinase (SYK)...) in order to introduce the therapeutic targets described in the "treatment" paragraph 

In the paragraph "treatment" the authors have synthesized the evidence on the treatment of IgAN, however some modifications are necessary because the evidence described very often are not referred to the context of the transplantation and some types of treatment have not been cited. Therefore, I recommend:

5- Line 182: Cite and summarize evidence from studies on corticosteroid treatment in posttransplant IgAN recurrence

6- Cite and summarize evidence from studies on the treatment with mycophenolate/azathioprine in IgAN recurrence post-transplant.

7- Cite and summarize evidence from studies on the rituximab treatment in IgAN recurrence post-transplant.

8- Cite and summarize evidence from studies on the bortezomib treatment in IgAN recurrence post-transplant.

9- Cite and summarize evidence from studies on treatment with SYK inhibitor (fostamatinib) in IgAN recurrence post-transplant.

10- add a summary table of the evidence on IgAN recurrence treatment highlighting the effectiveness of the various therapies in the context of native kidneys and transplantation (e.g. column 1: drug; column 2: type of study; column 3: native or recurrent kidney; column 4: synthetic evidence from the study; column 5 references)

Author Response

Thank you very much for your kind review and invaluable suggestions on the manuscript. Below you will find a point-by-point reply to all comments: 

1-  I recommend dividing the paragraph epidemiology into 2 subsections: epidemiology in the native kidney and epidemiology in transplantation.

Thank you for the invaluable suggestion, we have now split the Epidemiology section into 1) Native Disease and 2) Recurrent Disease Post-Renal Transplant

2- In the paragraph "epidemiology" the authors highlighted that some immunosuppressive regimens are associated with risk of recurrence. It is advisable to specify in the text which treatments (e.g. induction with ATG)

Within the Recurrent Disease subsection of Epidemiology, we have included a discussion regarding the possible influence of induction (specifically rATG), and maintenance immunosuppression on the risk of IgAN recurrence, starting on line 86 “Immunosuppressive regimen may play a part in the risk of IgAN recurrence…”.

3-  It is recommended to add a summary table of the main risk factors highlighting the risk factors (e.g. recipient-related risk factors and transplant-related risk factors)

We have added Table 1. that specifically addresses recipient- and donor-related, in addition to transplant associated risk factors for recurrent IgA nephropathy post-transplant. 

4- It is recommended to make the paragraph "pathogenesis" less synthetic by describing all the mechanisms of development of the disease (e.g. role of complement, B lymphocytes with APRIL and BAFF, Spleen tyrosine kinase (SYK)...) in order to introduce the therapeutic targets described in the "treatment" paragraph 

Thank you for the invaluable suggestion. We have greatly expanded the Pathogenesis section to include the recommended items, starting on line 119 with “Complement activation has been shown to play a large role in glomerular injury in IgAN…”.

In the paragraph "treatment" the authors have synthesized the evidence on the treatment of IgAN, however some modifications are necessary because the evidence described very often are not referred to the context of the transplantation and some types of treatment have not been cited. Therefore, I recommend:

5- Line 182: Cite and summarize evidence from studies on corticosteroid treatment in posttransplant IgAN recurrence

We have now included a section under Treatment to address the utility of corticosteroid maintenance in transplant recipients and its association with recurrent IgA nephropathy, starting on line 256 “Corticosteroid withdrawal regimens gained popularity in the mid 2000’s…”.

6- Cite and summarize evidence from studies on the treatment with mycophenolate/azathioprine in IgAN recurrence post-transplant.

We have now included two paragraphs that address the utility of mycophenolic acid derivatives and azathioprine in treatment of IgA nephropathy and stated the current lack of evidence of their use in recurrent disease starting on line 278, “In terms of antimetabolite use…”. Based on the persistent risk of recurrent IgAN despite the majority of transplant recipients being on a maintenance immunosuppressive regimen that includes MMF, our hypothesis is that its efficacy at treating the condition is muted.  

7- Cite and summarize evidence from studies on the rituximab treatment in IgAN recurrence post-transplant.

We have now added a paragraph to address the evidence of using rituximab in recurrent IgA nephropathy along with corresponding studies in native IgAN, starting on line 347 “The use of B cell targeted therapy …”.

8- Cite and summarize evidence from studies on the bortezomib treatment in IgAN recurrence post-transplant.

We have now added a paragraph detailing the utility of proteosome inhibitors, specifically bortezomib, in IgA nephropathy, starting on line 367 “Anti-CD20 agents detailed above are ineffective in terminally differentiated plasmablasts …”. Despite the off-label applications and investigations of proteosome inhibitors in antibody mediated rejection following kidney transplantation, there are no studies of its use in recurrent IgAN.

9- Cite and summarize evidence from studies on treatment with SYK inhibitor (fostamatinib) in IgAN recurrence post-transplant.

We have now added a paragraph describing the evidence for using SYK inhibitors (fostamatinib) in native IgA nephropathy. Given the novelty of this agent, there are currently no published studies on its use in recurrent IgAN. This starts on line 377 “As previously explored in the pathogenesis section, Syk is an immunoreceptor …”.

10- add a summary table of the evidence on IgAN recurrence treatment highlighting the effectiveness of the various therapies in the context of native kidneys and transplantation (e.g. column 1: drug; column 2: type of study; column 3: native or recurrent kidney; column 4: synthetic evidence from the study; column 5 references)

Thank you for the suggestion. We have now included Table 2. To the manuscript that summarizes the treatment options for IgAN, including the specific details recommended, linked to references listed at the end of the manuscript.

Reviewer 2 Report

I appreciate the well written review of rec IgAN by authors. I only have a few minor suggestions. Firstly, there are some grammatical corrections. Secondly, while the authors made reference to effect of different induction and maintenance immunosuppression regimens on risk of recurrence, I do feel that in a review this could be fleshed out a little better, since it is a topic of some interest to transplant and general nephrologists.

Some scattered grammatical and punctuation errors. 

Author Response

Thank you for your kind review of the manuscript and for your invaluable suggestions. Below you will see a point-by-point reply to the comments : 

I appreciate the well written review of rec IgAN by authors. I only have a few minor suggestions. Firstly, there are some grammatical corrections.

Thank you for outlining them, we have revised the grammatical errors in the revised manuscript.

Secondly, while the authors made reference to effect of different induction and maintenance immunosuppression regimens on risk of recurrence, I do feel that in a review this could be fleshed out a little better, since it is a topic of some interest to transplant and general nephrologists.

We have added a section under the Epidemiology section on the potential role of induction and maintenance immunosuppression on recurrent IgAN risk, starting on line 86 “Immunosuppressive regimen may play a part in the risk of IgAN recurrence…”.

Reviewer 3 Report

Dear Editor and Associated Editor,

       I would like to thank you for the opportunity to evaluate this manuscript. The aim of this study is to provide a review about the recurrent IgA nephropathy after kidney transplantation.

The paper mainly focuses on the epidemiology, pathogenesis and therapy of IgAN, with little emphasis on the recurrence of IgAN in transplant patients. The Authors don’t describe possible risk factors related to the development of the recurrence (e.g donor age, human leukocyte antigen effect, serum IgA concentration, recipient age etc.).

Author Response

Thank you for your kind review of the manuscript and for your invaluable suggestions. Below you will see a point-by-point reply to the comments : 

       I would like to thank you for the opportunity to evaluate this manuscript. The aim of this study is to provide a review about the recurrent IgA nephropathy after kidney transplantation.

The paper mainly focuses on the epidemiology, pathogenesis and therapy of IgAN, with little emphasis on the recurrence of IgAN in transplant patients. The Authors don’t describe possible risk factors related to the development of the recurrence (e.g donor age, human leukocyte antigen effect, serum IgA concentration, recipient age etc.).

Thank you for your suggestion. We have added Table 1. that specifically addresses recipient- and donor-related, in addition to transplant associated risk factors for recurrent IgA nephropathy post-transplant.  There is also an added paragraph under the Epidemiology section that addresses this topic starting on line 97 “Risk factors for recurrent IgAN can be broken into three categories…”.

Round 2

Reviewer 1 Report

The authors addressed all of the comments and revised the content of the manuscript accordingly. In light of this, I recommend that it may be considered for publication in Transplantology Journal in its present form.