SARS-CoV-2 Infection Is Associated with an Accelerated eGFR Decline in Kidney Transplant Recipients up to Four Years Post Infection

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review Report

5.04.2025

 

I was invited to review the manuscript submitted to Diagnostics-MDPI, entitled:
" SARS-CoV-2 infection is associated with an accelerated eGFR decline in kidney transplant recipients up to four years postinfection".

The topic of the manuscript is original and has some strengths: a large and diverse cohort of KTRs, and robust statistical analysis. The duration of the study was four years, but the follow-up period for patients was variable, depending on the year of the COVID-19 infection, with variations ranging from 30 days to 4 years. However, the time from transplant to study entry was significantly longer in the control group compared to the COVID-19 group, which could further influence the survival duration and the comparison between groups.

The limitations mentioned by the authors include the global analysis of cases without differentiating between pandemic waves or viral subtypes, as well as the lack of data regarding vaccination status, both for the COVID-19 and non-COVID groups.

The presentation of the study requires some clarifications:

1. What was the time duration from the moment of the transplant to the diagnosis of COVID-19?
2. How were the COVID-19 cases classified: asymptomatic, mild, moderate, severe, or critical?
3. How many patients with COVID-19 were treated with Remdesivir?
4. The duration of the study was four years, but the follow-up period for patients was variable, depending on the year of the COVID-19 infection, with variations ranging from 30 days to 4 years. However, the time from transplant to study entry was significantly longer in the control group compared to the COVID-19 group, which could further influence survival duration and the comparison between groups.
5. What were the causes of chronic kidney disease that led to kidney transplantation?

• The aim of the study should be clearly defined.
• The methodology should be further elaborated to explain more precisely how the results were obtained.
• The discussion should include a section regarding post-COVID-19 renal impairment, particularly in kidney transplant patients.

Comments for author File: Comments.pdf

Author Response

Reviewer 1

What was the time duration from the moment of the transplant to the diagnosis of COVID-19?

Dear reviewer, thank you for reviewing our manuscript and for your comment. The median time from transplant to diagnosis of COVID-19 was 4.61 years (IQR: 1.71, 9.67). This is shown in the fourth row of Table 1.

 

How were the COVID-19 cases classified: asymptomatic, mild, moderate, severe, or critical?

Thank you for your comment. The majority of COVID-19 patients (432/510, 83.68%) were hospitalized during acute infection, of which 15 experienced critical illness (ICU or IMV). The rest experienced mild or asymptomatic infection that did not require hospitalization. We have added this information to Table 1.

 

How many patients with COVID-19 were treated with Remdesivir?

Thank you for your comment. Approximately 37% of COVID-19 patients were treated with Remdesivir (this is now added to Table 1).

 

The duration of the study was four years, but the follow-up period for patients was variable, depending on the year of the COVID-19 infection, with variations ranging from 30 days to 4 years. However, the time from transplant to study entry was significantly longer in the control group compared to the COVID-19 group, which could further influence survival duration and the comparison between groups.

Thank you for your comment. We agree that this could bias our results. Multivariate analysis showed that recency of transplant (time from transplant to index date) was not significantly associated with all-cause mortality (third row of Table 2). For analysis of eGFR and UPCR, time zero was defined as the transplant date, which accounts for variations in transplant to index date time. This variable was adjusted for all outcomes. We now mention in discussion:

The COVID-19 group consisted of more recent transplant recipients than the control group by approximately two years on average. It is possible that the elevated level of immunosuppression in recent KTRs increased susceptibility to infection. It is also possible that the elevated level of immunosuppression in recently KTRs contributed to worse long-term outcomes. However, multivariate analysis showed that recency of transplant (time from transplant to index date) was not significantly associated with all-cause mortality or eGFR and UPCR as the generalized estimating equations modeling of eGFR and UPCR treated transplant date as time zero.

 

What were the causes of chronic kidney disease that led to kidney transplantation?

Thank you for your comment. Causes of CKD were not consistently documented in the EMR. However, most patients had diabetes and hypertension and we added the percentage of patients with polycystic kidney disease and glomerulonephritis diagnosed before transplant to Table 1.

 

The aim of the study should be clearly defined.

Thank you for your comment. We have added the following sentences to the abstract and introduction respectively:

            We aimed to compare long-term outcomes of KTRs with and without exposure to SARS-CoV-2.

            We thus investigated the long-term outcomes of KTRs with and without SARS-CoV-2 infection up to four years post-infection.

 

The methodology should be further elaborated to explain more precisely how the results were obtained.

Thank you for your comment. We have enhanced our description of the methods.

 

The discussion should include a section regarding post-COVID-19 renal impairment, particularly in kidney transplant patients.

Thank you for your comment. We have added a paragraph above the limitations addressing post-COVID renal impairment:

Post-COVID-19 renal impairment is an emerging concern, particularly in KTRs, who are already at increased risk for renal dysfunction due to chronic immunosup-pression and pre-existing comorbidities like T2DM and HTN [53-56]. Acute kidney in-jury during acute SARS-CoV-2 infection has been frequently reported among KTRs [26]. Our findings span four years, demonstrating that even after recovery and survival from acute infection, long-term declines in renal filtration capacity occur in the following years. Further research is warranted to determine whether specific therapeutic strate-gies, such as early anti-inflammatory treatment or adjustments in immunosuppression, may mitigate this decline and preserve long-term graft filtration function [26,57].

Reviewer 2 Report

Comments and Suggestions for Authors

The work by Shawn Qiu and co-authors is devoted to studying the long-term consequences of COVID-19 in kidney transplant recipients. Despite the large number of studies analyzing kidney function in COVID-19, there is still limited data on delayed effects. Therefore, this study is highly relevant and has significant scientific and practical value. The manuscript provides a detailed and well-structured description of a retrospective single-center study involving a large patient cohort divided into two groups: kidney transplant recipients with a history of COVID-19 and those without prior infection. The study demonstrates that even four years after COVID-19, there is a significant decline in eGFR, suggesting substantial long-term implications for graft health.

Overall, the study is well-conducted, but several questions and remarks remain:

1. The use of eGFR as the sole parameter for diagnosing CKD is considered insufficient. The diagnosis based on eGFR has several limitations: (1) The kidney is a multifunctional organ, and eGFR reflects only one of its functions; (2) eGFR has inherent variability depending on cardiovascular status and blood pressure, particularly in cases of impaired autoregulation or medication use; (3) It changes with age, nonlinearly and individually for each person; (4) eGFR may not correlate with actual GFR in certain conditions and diseases. Thus, eGFR can serve as an initial screening tool but should not be used for CKD diagnosis without a thorough assessment of the full clinical profile. This limitation should be explicitly mentioned in the Limitations of the Study section. Why was UCPR only chosen as the only marker for kidney status assessment? There are various other markers of CKD progression, such as urinary collagen fragments (endotrophin, procollagen III, endostatin), among others. Could these have been included for a more comprehensive analysis?

2. Is there an opportunity to compare sex-specific differences in the presented parameters? For example, how do UCPR and eGFR differ between male and female patients? Such an analysis could provide additional insights into potential sex-related variations in kidney function post-COVID-19.

           

Author Response

Reviewer 2

The use of eGFR as the sole parameter for diagnosing CKD is considered insufficient. The diagnosis based on eGFR has several limitations: (1) The kidney is a multifunctional organ, and eGFR reflects only one of its functions; (2) eGFR has inherent variability depending on cardiovascular status and blood pressure, particularly in cases of impaired autoregulation or medication use; (3) It changes with age, nonlinearly and individually for each person; (4) eGFR may not correlate with actual GFR in certain conditions and diseases. Thus, eGFR can serve as an initial screening tool but should not be used for CKD diagnosis without a thorough assessment of the full clinical profile. This limitation should be explicitly mentioned in the Limitations of the Study section.

Dear reviewer, thank you for reviewing our manuscript and for your comment. We agree that eGFR is insufficient to capture all dimensions of kidney function and health and now state this explicitly in our limitations:

Additionally, the use of eGFR to assess kidney function has limitations as it may be influenced by cardiovascular status, blood pressure variability, and medications, and changes nonlinearly with age and disease states. Furthermore, in certain individuals and conditions, eGFR may not correlate well with actual GFR.

 

Why was UCPR only chosen as the only marker for kidney status assessment? There are various other markers of CKD progression, such as urinary collagen fragments (endotrophin, procollagen III, endostatin), among others. Could these have been included for a more comprehensive analysis?

Thank you for your comment. We would like to analyze these biomarkers as you suggest but unfortunately, they are not standardized for routine clinical use at our and most other institutions. We also mention this in our limitations:

Although other markers such as urinary collagen fragments (endotrophin, procollagen III, endostatin) could offer additional insights into fibrotic or structural kidney changes, they are not yet standardized for routine clinical use and were not available at our institution during the study period.

 

Is there an opportunity to compare sex-specific differences in the presented parameters? For example, how do UCPR and eGFR differ between male and female patients? Such an analysis could provide additional insights into potential sex-related variations in kidney function post-COVID-19.

Thank you for your comment. We have provided results of this sex-stratified analysis in Supplementary Table 1. Your suggestion led to an interesting finding. Among males, those with COVID-19 had faster decline in eGFR over time (-1.12 [-1.65, -0.59] units/year). This association was not seen in females. COVID-19 was also not associated with changes in UPCR among male or female kidney transplant recipients.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors

congratulations for your study.The objetive of your study is very interesting. I am worried about the selection of the groups ,because they are not similar in comorbilities, As a matter of fact, the percentage of comorbilities is significatively superior in the covid group and this event could handicap the conclusion. I do not underestand why with such an important group of controls, you have not been able to perform a better  match between the groups.

Author Response

Reviewer 3

congratulations for your study.The objetive of your study is very interesting. I am worried about the selection of the groups ,because they are not similar in comorbilities, As a matter of fact, the percentage of comorbilities is significatively superior in the covid group and this event could handicap the conclusion. I do not underestand why with such an important group of controls, you have not been able to perform a better  match between the groups.

Dear reviewer, thank you for reviewing our manuscript and for your comment. We adjusted for baseline comorbidities in our multivariate regression models to mitigate confounding and isolate the association of COVID-19 with the outcomes of interest. We now mention this in the limitations. 

Reviewer 4 Report

Comments and Suggestions for Authors

I have read with interest and ease this study investigating the long-term outcomes of KTR with a history of SARS-17 CoV-2 infection- the topic with important implications on future health of our transplanted patients that is not jet sufficiently covered in the published literature.

There was respectable number of patients and authors have addressed the strengths and limitations to the study.

I do not have any mayor concerns. I have one suggestion. Under Results, I like the fact that there is concise and clear explanation to every table, but I would just suggest that this text should be placed before or after table, and not above table where usually the title (or short explanation) of the table stands (I specially refer to Table 2 and 3).

Best regards.

 

Author Response

Reviewer 4

I do not have any mayor concerns. I have one suggestion. Under Results, I like the fact that there is concise and clear explanation to every table, but I would just suggest that this text should be placed before or after table, and not above table where usually the title (or short explanation) of the table stands (I specially refer to Table 2 and 3).

Dear reviewer, thank you for reviewing our manuscript. As you correctly suggested, the interpretative portion of the table description is already present in the results text, and we have now removed it from the table description.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

I have think about the author's commentaries and I agree about publishing it