Time-Zero Kidney Biopsy and Deceased-Donor Transplant Outcomes: A Systematic Review and Meta-Analysis of Prognostic Value, Prediction, and Clinical Utility

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

Please accept my congratulations on your work.

This is an unusually rigorous, transparent and well-documented review, exceeding what is typical for the field. The central conclusion is appropriately conservative: both the biopsy-based accept and discard rules are appropriately cautious and well supported by the presented data.

Comment 1:

One of the most significant contributions of this review is the establishment of a distinction between prognostic association and incremental prediction. While the Results provide limited numerical data on the prediction studies, the Supplementary Material offers clinically informative comparisons.

In order to reinforce the message that 'biopsies may show an association with outcome without adding valuable predictive information to clinical variables', please include one or two numerical examples in the Results or Discussion.

Comment 2:

The manuscript suggests that vascular injury could influence future decisions regarding perioperative or machine perfusion. However, the current evidence does not show that changes in management based on biopsy findings improve outcomes. I would therefore propose presenting this as an area for future prospective investigation rather than as a current clinical application.

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The systematic meta-analysis presented by Sainz-Bravo et al. examines statistical associations between time-zero biopsies and various outcome parameters (DGF / death-censored graft failure), but also attempts to shed light on questions regarding the incremental predictive value and the clinical utility based on the available data. In my opinion, this — along with the methodological rigor and precision with which the review was conducted — is where its true significance and strength lie.

From a clinical perspective, I have only two comments:

Delayed graft function ( DGF) is rather an ambiguous outcome measure. Its interpretability is further complicated by variations in how it is defined and diagnosed. Formally, DGF is defined as the need for at least one dialysis session during the first week after transplantation. Currently, however, there are no generally accepted criteria for determining when dialysis is necessary, and the decision to initiate dialysis depends largely on the judgement of the nephrologist involved in the patient‘s care. Furthermore, in many cases, the indication depends exclusively on the recipient‘s current post-operative condition — for example, when hyperkalemia or volume overload must be corrected immediately. It should therefore come as no surprise that the pre-transplant biopsy has only a limited predictive value for the clinically defined, multi-causal endpoint of DGF. Even a well-designed clinical trial with strictly pre-defined outcome measure will therefore do little to improve the diagnostic specificity of the time-zero biopsy.

The seemingly unambiguous endpoint of death-censored graft failure and/or definition-unclear graft failure is strongly influenced, in terms of causality, by the timing of its occurrence after transplantation. Surgical complications that impair graft survival — such as problems with vascular or ureteral anastomosis, infectious complications, and acute rejection episodes — typically occur in the early post-operative phase and are hardly related to the graft‘s histology. In contrast, factors such as long-term impairment of kidney function, the development of high blood pressure, and drug-induced nephrotoxicity — factors that determine the ultimate prognosis of a kidney transplant — are more likely causally linked to pre-existing histological damage that can be detected in a biopsy prior to the transplant.

For the reasons mentioned above, I am somewhat reluctant when the authors suggest to conduct well-designed, standardized, and adequately powered studies with pre-defined adjustments for confounders. As a result, the internal validity of such a study, and subsequently the certainty of biopsy-guided decisions could, in theory, be improved to some extent. However, an equally significant drawback would arise with regard to the external validity of such an analysis for its utility in real-world scenarios. Personally, I believe that the present quantitative meta-analysis — which was conducted with great accuracy and a high methodological standard — has sufficiently answered the most important question: The decision as to whether a kidney should be considered suitable for transplantation or be discarded cannot be made on basis of a time-zero biopsy.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This is a comprehensive and complex meta-analysis regarding donor kidney biopsy in relation to the graft survival and outcome in kidney transplant recipients. The study provides a novel analysis to an old problem and it is relatively well designed, covering all the actual scientific literature on the topic.

The statistical methods used are suitable and the results are relatively well presented. However, the conclusions and the discussions do not have a proper structure and are somehow convoluted and confusing, limiting the predictive and conclusive power of this study.

In order to improve the quality of the manuscript and empower the results of the meta-analysis the "Discussion" section needs to be re-written, in a more synthetic and concise manner. Also a special section regarding the limitations of the study should be outlined.

Author Response

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Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

This systematic review summarizes data concerning prognostic vale of time-zero biopsy prior KTx. The methodology is fine. I have no concern regarding the analysis. Introduction is well-written. The weakest part is discussion. In my opinion there is enough data to close the discussion on prognostic value and we don't need next studies. The most important is the question whether the biopsy findings add more than the age of graft. We already have the programs old-to-old. Perhaps this aspect could be discussed. 

In addition the conclusion should be modified. Especially this part ' Standardized, adequately 
powered studies with prespecified confounder adjustment and external validation are needed to determine whether these signals improve prediction beyond established clinical variables and ultimately benefit biopsy-guided decisions.'

We just need national registries and standardization for assessment of kidney biopsies to improve the analysis concerning the prediction significance of time-zero biopsy.

 

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have properly addressed all the recommendations made during the first round of manuscript review.

Author Response

Dear Reviewer,

Thank you for your careful reassessment of our revised manuscript and for confirming that the recommendations from the first review round have been addressed. We appreciate your constructive feedback and the time you have devoted to reviewing our work.

Sincerely,
Jaime Briseno-Ramirez
Corresponding author, on behalf of all authors

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you for collaboration. no further comments.

Author Response

Dear Reviewer,

Thank you for reviewing our revised manuscript and for confirming that you have no further comments. We appreciate your time and helpful feedback throughout the review process.

Sincerely,
Jaime Briseno-Ramirez
Corresponding author, on behalf of all authors