Impact of Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy on Renal Failures Requiring Dialysis in Adult Patients ≥ 40 Years
, Neeraj Mahajan 1, Deepak Chandramohan 3, Nihar Jena 4 and Hari Naga Garapati 5,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis retrospective study analyzes a large US database of patients undergoing HSCT. This analysis provides the important, yet fully expected, conclusion that renal dysfunction is a risk factor for further renal deterioration requiring dialysis after HSCT complicated by TMA. I have only a few minor comments: In the abstract, the authors are requested not to refer to specific studies, e.g., Farhadfar et al., without providing the full source. The conclusion should not end with the statement "emphasizing the need for therapy in the prevention and treatment of TA-TMA," as this is too general and adds no scientific value to the interpretation of the study results. The number of patients with eGFR <60 mL/min is significantly lower than that of patients with normal renal function, suggesting that additional criteria were applied in the former group. This may lead to selection bias, which should be addressed in the manuscript as a limitation of the study. The authors mention that the use of CNIs as preconditioning should cause transient impairment of renal function and may confound the results. I don't know why the authors didn't include this factor in their statistical model. This needs to be explained. The authors should have used the same eGFR calculation method (e.g., CKD-EPI equation) for the entire analyzed population. If serum creatinine values are available in the database, eGFR can be easily calculated using a single method.
Author Response
We truly appreciate you taking time to review our study and providing your valuable feedback. We sincerely hope we are able to answer your questions to your satisfaction. We have made our best effort to answer and have included the appropriate changes in yellow in the uploaded version. Please find the revised version of the manuscript attached.
Comment 1: This retrospective study analyzes a large US database of patients undergoing HSCT. This analysis provides the important, yet fully expected, conclusion that renal dysfunction is a risk factor for further renal deterioration requiring dialysis after HSCT complicated by TMA.
Response 1: We thank the reviewer for the comments supporting the importance of this study.
Comment 2: I have only a few minor comments: In the abstract, the authors are requested not to refer to specific studies, e.g., Farhadfar et al., without providing the full source.
Response 2: This is a very valid point and thank you. Abstract has been updated accordingly.
Comment 3: The conclusion should not end with the statement "emphasizing the need for therapy in the prevention and treatment of TA-TMA," as this is too general and adds no scientific value to the interpretation of the study results.
Response 3: We have updated and highlighted in yellow and change has been made. Our results demonstrate that patients with onset of TA-TMA, particularly those with pre-existing renal dysfunction, have a markedly higher risk of renal failure requiring dialysis, underscoring the importance of early recognition and risk-adapted management.
Comment 4: The number of patients with eGFR <60 mL/min is significantly lower than that of patients with normal renal function, suggesting that additional criteria were applied in the former group. This may lead to selection bias, which should be addressed in the manuscript as a limitation of the study.
Response 4: We have added the following in the limitations. Our study is observational, and inherent imbalances in baseline characteristics should be acknowledged. In particular, the number of patients with eGFR <60 mL/min was substantially lower than those with preserved renal function, reflecting the underlying distribution of our cohort. This smaller subgroup size may limit the precision of risk estimates and should be considered when interpreting the findings.
Comment 5: The authors mention that the use of CNIs as preconditioning should cause transient impairment of renal function and may confound the results. I don't know why the authors didn't include this factor in their statistical model. This needs to be explained.
Response 5: CNI use as acute GVHD prophylaxis was evaluated in the initial models. Because CNI assignment is often determined by patient performance status and underlying comorbidities, which were already included as covariates, and because CNI was not significantly associated with renal outcomes, it was not retained in the final Cox multivariable regression model.
Comment 6: The authors should have used the same eGFR calculation method (e.g., CKD-EPI equation) for the entire analyzed population. If serum creatinine values are available in the database, eGFR can be easily calculated using a single method.
Response 6: We agree that consistency in eGFR estimation is critical. In our dataset, eGFR was not calculated by us but was reported directly from the database. Importantly, the database uniformly estimated eGFR for all patients using the CKD-EPI equation.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe abstract needs to be readable and more concise. Introduction is long and not suited. We do not add references in the abstract! Keep one sentence and the aim and then proceed.
Introduction=Allogeneic hematopoietic cell transplantation (allo-HSCT) is a novel approach to cure malignant hematological disease= No it is not novel. Been going on for decades. Rephrase.
The 3rd paragraph very big. Split it two. Please write as where is the research gap that you want to fill? What is the novelty?
You also mention this study Farhadfar et al but you need to further analyze what you are doing with it…
Methods=
2.2= Specify and write a paragraph with inclusion/ exclusion criteria
Ethics section is missing
Statistics section is also missing
Karnofsky Performance Score (KPS= You must analyze the KPS and add reference
Results=
Many tables and a lot of text. Consider shortening the text only to the significant results. The rest the reader can see from the tables.
Also tables are very big. Consider some short of shortening.
Discussion=
Very small indeed. The first paragraph simply summarizes the results and it doesn’t fit. It looks like the conclusions section.
To our knowledge, our study is the largest in =Make it To date, our study..
You specify the limitations and the addition of your work. But the discussion lacks of comparative talk
Add heading on limitations
Make a section for future research
And also there is the heading of the conclusions section that is missing.
Overall an interesting study but not well written. Especially Introduction, Discussio, Conclusions..
Author Response
We truly appreciate you taking time to review our study and providing your valuable feedback. We sincerely hope we are able to answer your questions to your satisfaction. We have made our best effort to answer and have included the appropriate changes in green in the uploaded version. Please find the revised version of the manuscript attached.
Comment 1: The abstract needs to be readable and more concise. Introduction is long and not suited. We do not add references in the abstract! Keep one sentence and the aim and then proceed.
Response 1: We thank the reviewer for these constructive comments. We have revised the abstract to improve readability and conciseness.
Comment 2: Introduction=Allogeneic hematopoietic cell transplantation (allo-HSCT) is a novel approach to cure malignant hematological disease= No it is not novel. Been going on for decades. Rephrase.
Response 2: We have revised the Introduction. Allogeneic hematopoietic cell transplantation (allo-HSCT) is an established treatment modality with curative potential for malignant hematologic diseases.
Comment 3: The 3rd paragraph very big. Split it two. Please write as where is the research gap that you want to fill? What is the novelty? You also mention this study Farhadfar et al but you need to further analyze what you are doing with it…
Response 3: We cannot agree more. We have split it appropriately. also, revised according to this great suggestion.
Comment 4: Methods 2.2 specify and write a paragraph with inclusion/exclusion criteria
Response 4: We have included as suggested
Comment 5: Ethics section is missing
Response 5 : we have added this highlighted in yellow - This is an observational study with already available data and as such ethics approval was not required.
Comment 6: Statistics section is also missing, Section “Evaluation of Risk Factors” to be renamed as “Statistical Methods”
Response 6: We have added the statistical methods section as appropriately suggested.
Comment 7: Karnofsky Performance Score (KPS= You must analyze the KPS and add reference
Response 7: KPS was included in the analysis and reference 17 added
Comment 8: Results= Many tables and a lot of text. Consider shortening the text only to the significant results. The rest the reader can see from the tables. Also tables are very big. Consider some short of shortening.
Response 8: Great suggestion- We have revised the tables.
Comment 9: Discussion=Very small indeed. The first paragraph simply summarizes the results and it doesn’t fit. It looks like the conclusions section.
Response 9: We appreciate the input. We wanted to start the small discussion part with reiterating what we found and considering that has a small scope for larger discussion in this observational study.
Comment 10: To our knowledge, our study is the largest in =Make it To date, our study
Response 10: we have updated as suggested
Comment 11: You specify the limitations and the addition of your work. But the discussion lacks of comparative talk
Response 11: Unfortunately, this one comment, we did not have any comparative talk to add in discussion. Please accept our apology
Comment 12: Add heading on limitations
Response 12: Updated as per suggestion
Comment 13: Make a section for future research
Response 13: We have added :Use a shared frailty survival model to account for unobserved heterogeneity when estimating the impact of hematopoietic stem-cell transplantation–associated thrombotic microangiopathy (TA-TMA) on renal failure requiring dialysis among patients ≥40 years, characterized by pre-transplant kidney health. A frailty term (e.g., gamma or log-normal) will capture latent risk at the patient or center level that is not explained by measured covariates (e.g., VOD, GVHD grade, graft source, comorbidity.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsYou mentioned KPS and must analyze like this (for clarity):
The Karnofsky Performance Status scores range from 0 to 100. A higher score means the patient is better able to carry out daily activities.
And this is a pretty clear reference
Author Response
Thank you very much for taking time to review again and make this suggestion. We truly appreciate your expertise for helping us get this done a much better way.
Comment 1: You mentioned KPS and must analyze like this (for clarity):
Response 1: Karnofsky Performance Status (KPS) scores range from 0 to 100, with higher scores reflecting greater ability to perform daily activities. For analysis, KPS was dichotomized as 90–100 versus < 90, distinguishing patients with preserved versus impaired functional capacity. The reference is changed as suggested.
Author Response File: 
Author Response.pdf
