Early Endothelial Injury in Pancreas Transplantation: Insights from a Prospective Cohort Largely Composed of Simultaneous Pancreas-Kidney Recipients

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

The authors addressed the points raised by the reviewer adequately. 

Author Response

Responses to Reviewer 1 Comments

Summary:

We would like to thank the reviewer for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in fluorescent yellow in the re-submitted files.

Questions for general evaluation:

Quality of English Language

( ) The English could be improved to more clearly express the research.

(x) The English is fine and does not require any improvement.

Yes      Can be improved          Must be improved         Not applicable

Does the introduction provide sufficient background and include all relevant references?

(x)                    ( )                                ( )                                ( )

Is the research design appropriate?

(x)                    ( )                                ( )                                ( )

Are the methods adequately described?

(x)                    ( )                                ( )                                ( )

Are the results clearly presented?

(x)                    ( )                                ( )                                ( )

Are the conclusions supported by the results?

( )                    (x)                               ( )                                ( )

Are all figures and tables clear and well-presented?

(x)                    ( )                                ( )                                ( )

We agree with the reviewer that the Conclusions could be more closely aligned with the scope of the results and stated with greater precision. In response, we have revised them to ensure that they more accurately reflect the findings of the study and avoid overinterpretation.

 

Point-by-point response to Comments and Suggestions for Authors:

Comments 1: The authors addressed the points raised by the reviewer adequately.

Response 1: We sincerely thank the reviewer for this positive assessment and for acknowledging that the points raised have been adequately addressed.

Author Response File: Author Response.pdf

Reviewer 2 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

The authors improved the paper.  The title reflects the study content. Conclusions are acceptable. The authors clearly stated that the study generates a hypothesis that requires verification in the next larger study.

Perhaps it would be important to stress more the lack of translation into clinical practice, as no cut-off for suitable markers that increase the risk of post-transplant complications has been established. 

Author Response

Responses to Reviewer 2 Comments

Summary

We would like to thank the reviewer for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in fluorescent yellow in the re-submitted files.

Questions for general evaluation:

Quality of English Language

( ) The English could be improved to more clearly express the research.

(x) The English is fine and does not require any improvement.

Yes      Can be improved          Must be improved         Not applicable

Does the introduction provide sufficient background and include all relevant references?

(x)                    ( )                                ( )                                 ( )

Is the research design appropriate?

(x)                    ( )                                ( )                                 ( )

Are the methods adequately described?

(x)                    ( )                                ( )                                 ( )

Are the results clearly presented?

(x)                    ( )                                ( )                                 ( )

Are the conclusions supported by the results?

(x)                    ( )                                ( )                                 ( )

Are all figures and tables clear and well-presented?

(x)                    ( )                                ( )                                 ( )

Point-by-point response to Comments and Suggestions for Authors:

Comments 1: The authors improved the paper.  The title reflects the study content. Conclusions are acceptable. The authors clearly stated that the study generates a hypothesis that requires verification in the next larger study.

Perhaps it would be important to stress more the lack of translation into clinical practice, as no cut-off for suitable markers that increase the risk of post-transplant complications has been established.

Response 1: We sincerely thank the reviewer for this helpful comment, as well as for the positive overall assessment of the revised manuscript. We agree that the potential clinical translation of these biomarkers into clinical practice should be stated more explicitly and interpreted with caution.

Although our findings suggest that circulating endothelial biomarkers may be relevant for perioperative risk assessment in pancreas transplantation, the present study did not establish clinically applicable cut-off values or validated thresholds for identifying recipients at increased risk of post-transplant complications. Given the exploratory design, the relatively small sample size, and the limited number of clinical events, our results should not be interpreted as supporting immediate implementation in routine clinical decision-making. Rather, they identify biologically relevant associations and perioperative biomarker patterns that may inform future validation studies. 

In response to the reviewer’s suggestion, we have revised the manuscript to emphasize this point more clearly. Specifically, we have added text to the Discussion and Conclusions stating that the current clinical applicability of these biomarkers remains limited by the absence of clinically applicable cut-off values and by the lack of predictive performance assessment in larger cohorts. We now also state more explicitly that future studies will be needed to define clinically relevant thresholds and determine whether these biomarkers can be integrated into perioperative management after pancreas transplantation.

Author Response File: Author Response.pdf

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study primarily analyses SPK; therefore, the results show ischemia-reperfusion injury in both the kidney and the pancreas. The study lacks a KTx control group to support the final conclusion.

The increase of endothelial injury markers is expected after KTx, In my opinion, the authors should collect an additional group of KTx before publishing the study. If the pattern is different, the difference can be attributed to the injury of pancreas.

The description of the results is misleading, addressing only the pancreas transplantation (not SPK).

The number of complications (7 graft losses) is too low for analysis. The reasons are heterogenous, that complicate the analysis.

Acute rejection episodes are expected at least for kidney grafts. How many ATN has occurred? The paper omit this important issue.

Title is misleading - omite the aspect of kidney transplantation (SPK) and kidney endothelial injury.

The abstract is not informative. There is no information about inclusion of patients after SPK (47 of 52). The number of studied patients is missing. There is no information of graft losses.

The results section omit presentation of kidney complication, and did not analyse them.

The interpretation of described data can change after inclusion of kidney complication data. 

The description of the results is misleading, addressing only the pancreas transplantation (not SPK).

The number of complications is too low for analysis.

 

 

Author Response

Editor in Chief

Medical Sciences

Manuscript ID:  medsci-4123035

Barcelona, April 10, 2026

Dear Editor,

Thank you for the opportunity to submit a revised version of our manuscript entitled “Early endothelial injury in pancreas transplantation: Insights from a prospective cohort largely composed of simultaneous pancreas-kidney recipients” for reconsideration in Medical Sciences.

We are grateful to you and to the reviewers for the careful evaluation of our work and for the thoughtful and constructive comments provided. These suggestions have helped us improve the scientific precision, clarity and clinical framing of the manuscript.

In response to the reviewers’ comments, we have extensively revised the manuscript. Specifically, we refined the interpretation of endothelial biomarker dynamics within the transplantation context of our cohort, strengthened the presentation of kidney-related outcomes, further elaborated on the clinical implications of the endothelial injury patterns identified and revised the Discussion and Conclusions to ensure that all interpretations are fully supported by the reported results.

All modifications in the revised manuscript are highlighted in red. Below, we provide a detailed point-by-point response to each reviewer’s comments.

We hope that the revised manuscript is now suitable for further consideration in Medical Sciences.

 

Sincerely,

 

Dr. Emma Folch-Puy, PhD

Experimental Pathology Department, IIBB-CSIC

c/ Rosellón 161, 7º, 08036 Barcelona, Spain    

Tel: +34 93 363 83 00 ext 357

Fax +34 93 363 83 01

E-mail: emma.folch@iibb.csic.es

 

 

Review Report Form 1

Quality of English Language

( ) The English could be improved to more clearly express the research.

(x) The English is fine and does not require any improvement.

 

Yes      Can be improved          Must be improved        Not applicable

Does the introduction provide sufficient background and include all relevant references?

(x)       ( )        ( )         ( )

Is the research design appropriate?

(x)       ( )        ( )         ( )

Are the methods adequately described?

(x)       ( )        ( )         ( )

Are the results clearly presented?

(x)       ( )        ( )         ( )

Are the conclusions supported by the results?

( )        ( )        (x)        ( )

Are all figures and tables clear and well-presented?

(x)       ( )        ( )         ( )

 

Quality of English and overall presentation:

We sincerely thank the reviewer for the careful and insightful evaluation of our manuscript. The comments were highly valuable and helped us to improve the precision and clinical framing of the revised version. In particular, they prompted us to better contextualize our findings within the predominant simultaneous pancreas-kidney (SPK) transplantation setting of our cohort, to clarify the interpretation of the different perioperative sampling time points and to more explicitly acknowledge the limitations inherent to the study design.

 

Comments and Suggestions for Authors:

Comments 1: The study primarily analyses SPK; therefore, the results show ischemia-reperfusion injury in both the kidney and the pancreas. The study lacks a KTx control group to support the final conclusion.

Response 1: We appreciate the reviewer for raising this important point. We agree that, in the context of simultaneous pancreas-kidney transplantation (SPK), endothelial injury measured at later postoperative time points may reflect a systemic response to ischemia-reperfusion injury (IRI) involving both the pancreas and kidney grafts. We have therefore revised the manuscript to avoid over-attribution of these later biomarker changes to the pancreas alone.

At the same time, one of the main strengths of our study is the inclusion of a very early sampling time point obtained 10 minutes after pancreas graft reperfusion and before kidney implantation. This sampling window is particularly informative because it captures the immediate endothelial response predominantly attributable to pancreas reperfusion while minimizing the influence of the kidney graft. We believe that this aspect provides novel information that is not currently available in clinical SPK studies.

We fully agree that the inclusion of a kidney-only transplant cohort could provide useful contextual information regarding endothelial injury associated with renal ischemia-reperfusion. However, in the specific context of SPK, such a comparator would not allow a direct quantitative separation of pancreas- and kidney-derived endothelial injury, because renal reperfusion occurs after pancreas implantation within a perioperative inflammatory and hemodynamic environment that has already been influenced by pancreas reperfusion. For this reason, biomarker patterns observed after implantation of both grafts cannot be interpreted as the sum of two independent organ-specific signals.  

As this prospective study was originally designed to investigate pancreas-containing transplants using predefined perioperative sampling time points, a contemporaneous kidney-only transplant cohort was not included into the current protocol. We concur that incorporating such a comparator would benefit future research. Accordingly, we now explicitly address its absence in the Discussion section.

In response to the reviewer’s comment, we have revised the manuscript accordingly, including the Abstract, Introduction, Methods (subsection 2.7.), Results (Subsection 3.4. and 3.6.), Discussion and Conclusions, to more accurately frame the findings within the clinical context of SPK transplantation and to distinguish immediate pancreas-specific reperfusion injury from later systemic endothelial responses. We are grateful to the reviewer for prompting us to sharpen this important aspect of the manuscript and to present the interpretation of our findings with greater precision and in a clinically meaningful way.

Comments 2: The increase of endothelial injury markers is expected after KTx, In my opinion, the authors should collect an additional group of KTx before publishing the study. If the pattern is different, the difference can be attributed to the injury of pancreas.

Response 2: We thank the reviewer for this constructive suggestion. As noted above, we agree that the inclusion of a kidney-only transplant cohort could be informative as an external comparator and would help contextualize the endothelial response associated with renal IRI. However, in the SPK setting, a direct comparison with kidney-only transplantation would not permit a simple subtraction-based attribution of the observed biomarker patterns to one graft or the other. In SPK, the pancreas is reperfused first, and the kidney graft is subsequently implanted into a recipient who has already undergone pancreas reperfusion and early systemic inflammatory activation. Therefore, the endothelial response observed after both grafts are implanted reflects integrated perioperative biology of SPK rather than the isolated and directly separable organ-specific events.

Importantly, our study design includes a 10-minute post-reperfusion sampling point obtained before kidney implantation, which provides a unique opportunity to assess the immediate endothelial response predominantly attributable to pancreas reperfusion. We believe that this early time point is a key strength of the present study and partially mitigates the absence of a kidney-only comparator.  

As this prospective study was originally designed to focus on pancreas-containing transplants, with predefined perioperative sampling time points, a contemporaneous kidney-only transplant cohort was not included into the current protocol. We appreciate the reviewer’s thoughtful suggestion that the inclusion of such a comparator would benefit future research. Accordingly, we have now explicitly acknowledged this point in the Discussion section.

In response to the reviewer’s comment, we have revised the manuscript and refined the description and interpretation of endothelial biomarker dynamics within the clinical context of SPK transplantation across all sections.

 Comments 3: The description of the results is misleading, addressing only the pancreas transplantation (not SPK).

Response 3: We thank the reviewer for this important observation. We agree that the original wording did not sufficiently emphasize that the cohort was predominantly composed of simultaneous pancreas-kidney (SPK) transplant recipients (47/52), and this clinical context is essential for interpretation of the findings.

In the revised manuscript, we have therefore adjusted the terminology throughout the text to more accurately reflect the main study population, emphasizing the SPK setting, while preserving the relevance of the five pancreas retransplantations cases included in the cohort. In addition, the term PTx (pancreas transplantation) was originally used as a general designation encompassing all pancreas transplant procedures, including SPK transplantation. To avoid potential confusion, we have reduced the use of the term pancreas transplantation when the intended meaning was broader and, where appropriate, replace it with the more general term transplantation or with explicit reference to SPK. 

We have also made kidney-related outcomes more visible in the Results. Specifically, in Subsection 3.4 we now clearly report the association between endothelial injury markers and the development of kidney acute tubular necrosis (ATN), including a detailed description of the ATN cases and their temporal relationship with transplantation. Pancreas-specific are also now clearly distinguished from kidney-related complications. In Subsection 3.6, we have emphasized that kidney-related events, such as DGF, contribute to overall outcomes and are considered in the interpretation of endothelial biomarker dynamics.

In addition, the Discussion section has been broadened to explicitly address kidney functional complications in the context of SPK transplantation. In particular, we now highlight how kidney injury markers such as ATN and DGF may reflect systemic microvascular stress and how endothelial biomarker alterations observed at later postoperative time points may represent the combined IRI affecting both pancreas and kidney grafts. These revisions ensure that the manuscript accurately reflects the dual-graft context of SPK transplantation.

 Comments 4: The number of complications (7 graft losses) is too low for analysis. The reasons are heterogenous, that complicate the analysis.

Response 4: We thank the reviewer for this pertinent comment and fully agree that the number of pancreas graft loss events in our cohort is limited and that the underlying causes are heterogeneous. For this reason, these analyses were performed and are now presented in an exploratory and descriptive manner, rather than as evidence of independent predictors or causal associations.

To make this clearer, we have revised both the Statistical analysis subsection, Results and the Discussion to explicitly state that the low number of events precluded multivariate analyses and that these findings should be interpreted as hypothesis-generating. Importantly, this reflects the low annual volume of pancreas transplantation worldwide and the inherent difficulty of assembling large single-center cohorts, which further underscores the need for validation in larger multicenter studies.

In addition, to improve the clarity and structure of the manuscript, the detailed description of the pancreas graft loss events and their underlying causes has been moved from the Discussion to the Results section (Subsection 3.4), where postoperative complications are now presented more appropriately alongside other clinical outcomes.

 Comments 5: Acute rejection episodes are expected at least for kidney grafts. How many ATN has occurred? The paper omit this important issue.

Response 5: We thank the reviewer for highlighting this important issue. Kidney acute tubular necrosis (ATN) was prospectively recorded in our study and is now more explicitly reported in the revised manuscript. In total, four recipients developed ATN during the early postoperative period. Importantly, three of these recipients subsequently developed an episode of acute kidney rejection 19, 26 and 71 days after transplantation. This temporal sequence suggests that ATN represented an early postoperative event most likely related to IRI, whereas the rejection episodes occurred later during follow-up. In parallel, the endothelial biomarkers analyzed in this study showed their most pronounced changes immediately after reperfusion or at 24 hours and generally returned toward baseline by discharge, supporting the interpretation that the early biomarker signal primarily reflects IRI rather than later immune-mediated injury.

To address the reviewer’s concern, this information has now been incorporated into the Results (Subsection 3.4) and Discussion sections, and number of ATN cases is summarized in Table 4.

 Comments 6: Title is misleading - omite the aspect of kidney transplantation (SPK) and kidney endothelial injury.

Response 6: We thank the reviewer for this thoughtful comment and agree that the predominant clinical context of our cohort is simultaneous pancreas-kidney (SPK) transplantation, which is highly relevant for the interpretation of the findings.

In response to the reviewer’s comment, we have revised the title to better reflect both the main clinical setting of the cohort and the scope of the study. Specifically, the title has been changed from:

“Evolution of endothelial injury in pancreas transplantation: Insights from a prospective study”

to:

“Early endothelial injury in pancreas transplantation: Insights from a prospective cohort largely composed of simultaneous pancreas-kidney recipients”

In addition, we have revised the keywords, to better reflect the study population and clinical context. We have replaced the keyword “pancreas transplantation” with “simultaneous pancreas and kidney transplantation” and added pancreas retransplantation.

 Comments 7: The abstract is not informative. There is no information about inclusion of patients after SPK (47 of 52). The number of studied patients is missing. There is no information of graft losses.

Response 7: We thank the reviewer for this valuable comment. In response, the Abstract has been revised to provide a more complete and informative summary of the study design and key outcomes. Specifically, the revised abstract now includes the total number of recipients studied (N=52), the number undergoing SPK transplantation (n=47), the number of pancreas graft losses observed during follow-up (n=7), a clearer description of the temporal pattern of endothelial biomarker changes following graft reperfusion, and conclusions that are better aligned with the reported results.

We believe these additions improve the clarity of the Abstract and more accurately represent the clinical context and relevance of the study.

 Comments 8: The results section omit presentation of kidney complication, and did not analyse them.

Response 8: We thank the reviewer for this important observation. We agree that, although kidney-related complications were prospectively recorded in the study, the original version of the manuscript did not sufficiently detail the spectrum of postoperative kidney events beyond the functional complications most directly related to IRI, namely ATN and DGF. We also agree that, in a predominantly SPK cohort, a clearer presentation of kidney complications improves the clinical interpretation of the results.

In response, we have revisited the kidney complication dataset and now distinguish more clearly between functional kidney complications linked to IRI and kidney surgical and urological complications. Because the main objective of the study was to characterize endothelial injury in relation to perioperative IRI, ATN and DGF remain the kidney-related outcomes specifically explored in relation to endothelial biomarker dynamics. In addition to these functional IRI-related events, the postoperative kidney complication dataset showed that kidney surgical/urological complications included hematuria (n=5), perirenal hematoma (n=5), renal artery thrombosis (n=2), and urinary leakage (n=2).

We have therefore revised the Results (Subsection 3.6) to make kidney surgical and urological complications more visible and to describe them in grouped form according to their clinical type and management. At the same time, because these complications were heterogeneous and the number of cases in each individual category was small, we considered that a separate biomarker-based analysis for each surgical subtype would not be statistically robust and could lead to overinterpretation. For this reason, these events are now presented descriptively, whereas ATN and DGF remain the kidney-related complications specifically analyzed in relation to endothelial biomarker dynamics, in keeping with the IRI-focused scope of the study.

We believe that these revisions provide a more complete and clinically meaningful presentation of postoperative kidney morbidity in our cohort, while preserving the main mechanistic focus of the manuscript on endothelial injury associated with ischemia-reperfusion in pancreas transplantation, predominantly in the SPK setting.

 Comments 9: The interpretation of described data can change after inclusion of kidney complication data.

Response 9: We appreciate the reviewer’s comment and agree that a clearer and more complete presentation of kidney-related complications are relevant for the interpretation of endothelial biomarker dynamics in the SPK setting.

As detailed above, the revised manuscript now integrates kidney complications more explicitly at two levels. First, we retain ATN and DGF as the kidney-related outcomes specifically assessed in relation to endothelial biomarkers, because these events are pathophysiologically linked to IRI and early kidney graft dysfunction, which constitute the main objective of the present study. Second, we now also describe the spectrum of kidney surgical and urological complications recorded after transplantation. Importantly, inclusion of these kidney complication data does not change the main interpretation of the biomarker results, but rather helps to contextualize them more appropriately within the SPK setting.

Specifically, in the revised manuscript, we now emphasize more clearly that biomarker changes observed at later postoperative time points should be interpreted as part of the broader systemic response occurring after implantation of both grafts. In parallel, the 10 min post-reperfusion sampling point remains particularly informative because it was obtained after pancreas reperfusion and before kidney implantation, thereby predominantly reflecting the immediate endothelial response to pancreas reperfusion.

We also note that the most severe kidney surgical events were two cases of renal artery thrombosis, both of which ultimately led to kidney nephrectomy. However, because surgical/urological complication categories were heterogeneous and individually infrequent, including only two such major vascular events, we considered that a separate biomarker-based analysis for each subtype would not be statistically robust and could lead to overinterpretation. We have therefore presented these complications descriptively and avoided drawing unsupported mechanistic conclusions from these small subgroups.

We believe that this revised presentation provides a more balanced and clinically meaningful interpretation of the data. At the same time, it also supports further evaluation in larger multicenter studies, which may enable a more detailed assessment of less frequent kidney complication subtypes in future work.

 Comments 10: The description of the results is misleading, addressing only the pancreas transplantation (not SPK).

Response 10: We thank the reviewer for this additional comment We believe, this point overlaps with a concern raised earlier, which has been addressed in detail above.

 Comments 11: The number of complications is too low for analysis.

Response 11: We thank the reviewer for this additional comment. We believe, this point overlaps with a concern raised earlier, which has been addressed in detail above.

 

We are grateful to the reviewer for this constructive perspective, which helped us refine the SPK-specific framing of the study, clarify the interpretation of immediate versus later endothelial injury signals and improve the overall scientific precision and clinical relevance of the manuscript.

 

 

Author Response File: Author Response.doc

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review the manuscript entitled “Evolution of endothelial injury in pancreas transplantation: Insights from a prospective study” by Ferrer-Fàbrega et al.

The manuscript addresses an important topic in pancreas transplantation, focusing on IRI and its impact on endothelial and glycocalyx integrity. The prospective design and inclusion of 52 patients provide valuable clinical data and strengthen the study’s relevance.

However, the manuscript remains largely descriptive. The authors are encouraged to discuss their findings more thoroughly in the context of potential therapeutic interventions or clinical consequences that may arise from the observed endothelial changes. A more explicit link between the described injury patterns, possible strategies to mitigate endothelial damage, and how these findings might inform preservation strategies or perioperative management to protect the microvasculature should be included.

Minor comment:

Figure 1: Baseline values appear to be missing in panels 1A and 1B and should be added for completeness.

Author Response

Editor in Chief

Medical Sciences

Manuscript ID:  medsci-4123035

              Barcelona, April 10, 2026

Dear Editor,

Thank you for the opportunity to submit a revised version of our manuscript entitled “Early endothelial injury in pancreas transplantation: Insights from a prospective cohort largely composed of simultaneous pancreas-kidney recipients” for reconsideration in Medical Sciences.

We are grateful to you and to the reviewers for the careful evaluation of our work and for the thoughtful and constructive comments provided. These suggestions have helped us improve the scientific precision, clarity and clinical framing of the manuscript.

In response to the reviewers’ comments, we have extensively revised the manuscript. Specifically, we refined the interpretation of endothelial biomarker dynamics within the transplantation context of our cohort, strengthened the presentation of kidney-related outcomes, further elaborated on the clinical implications of the endothelial injury patterns identified and revised the Discussion and Conclusions to ensure that all interpretations are fully supported by the reported results.

All modifications in the revised manuscript are highlighted in red. Below, we provide a detailed point-by-point response to each reviewer’s comments.

We hope that the revised manuscript is now suitable for further consideration in Medical Sciences.

Sincerely,

Dr. Emma Folch-Puy, PhD

Experimental Pathology Department, IIBB-CSIC

c/ Rosellón 161, 7º, 08036 Barcelona, Spain    

Tel: +34 93 363 83 00 ext 357

Fax +34 93 363 83 01

E-mail: emma.folch@iibb.csic.es

 

Review Report Form 2

Quality of English Language

( ) The English could be improved to more clearly express the research.

(x) The English is fine and does not require any improvement.

Yes      Can be improved          Must be improved        Not applicable

Does the introduction provide sufficient background and include all relevant references?

(x)       ( )        ( )         ( )

Is the research design appropriate?

(x)       ( )        ( )         ( )

Are the methods adequately described?

(x)       ( )        ( )         ( )

Are the results clearly presented?

( )        (x)       ( )         ( )

Are the conclusions supported by the results?

( )        (x)       ( )         ( )

Are all figures and tables clear and well-presented?

( )        (x)       ( )         ( )

 

We sincerely thank the reviewer for the careful and constructive evaluation of our manuscript. We greatly appreciate the recognition of the clinical relevance of the study and the positive assessment of its prospective design and patient cohort. The reviewer’s comments were particularly helpful in encouraging us to improve the clarity of the Results section, to better align the conclusions with the reported results and to strengthen the translational interpretation of the endothelial injury patterns identified in our cohort. We also revised the figures and tables to improve consistency and facilitate interpretation.

 

Comments and Suggestions for Authors

Comments 1: Thank you for the opportunity to review the manuscript entitled “Evolution of endothelial injury in pancreas transplantation: Insights from a prospective study” by Ferrer-Fàbrega et al.

The manuscript addresses an important topic in pancreas transplantation, focusing on IRI and its impact on endothelial and glycocalyx integrity. The prospective design and inclusion of 52 patients provide valuable clinical data and strengthen the study’s relevance.

However, the manuscript remains largely descriptive. The authors are encouraged to discuss their findings more thoroughly in the context of potential therapeutic interventions or clinical consequences that may arise from the observed endothelial changes. A more explicit link between the described injury patterns, possible strategies to mitigate endothelial damage, and how these findings might inform preservation strategies or perioperative management to protect the microvasculature should be included.

Response 1: We thank the reviewer for this insightful and constructive comment. We agree that, beyond the descriptive characterization of biomarker changes, it is important to discuss the potential clinical and translational implications of the endothelial injury patterns identified in this study.

In response, we have revised and expanded the Discussion to better connect our findings with the broader context of graft protection. Specifically, we now emphasize that glycocalyx shedding and alterations in the VEGF-sVEGFR1 axis are consistent with early microvascular dysfunction and may represent biologically relevant pathways for future strategies aimed at attenuating IRI and preserving graft endothelial integrity. We have also strengthened the discussion of how perioperative biomarker patterns may contribute to early risk stratification and may help inform future preservation strategies and perioperative management approaches designed to protect the graft microvasculature.  

In addition, to improve clarity and ensure that the Discussion more accurately reflects the results obtained, we streamlined this section and removed a paragraph focused on speculative mechanistic explanations for the differential timing of glycocalyx component shedding, along with the corresponding references. The following paragraph was removed:

“Given that syndecans are transmembrane proteoglycans bearing HS chains [24], and that enzymatic HS degradation accelerates syndecan-1 shedding [25], the concomitant in-crease in both markers at 10 min after graft reperfusion are mechanistically coherent. In contrast, changes in hyaluronan levels emerged at 24 h PR. This delayed shedding time-line may be attributed to the fact that larger molecules such as hyaluronan typically re-quire more extensive enzymatic processing and exhibit a slower release into the circulation than smaller proteoglycans such as syndecan-1 [26].”

This paragraph has been replaced with the following text which better reflects the study design and the temporal interpretation of the biomarker data in our cohort:

“This immediate post-reperfusion window predominantly reflects pancreas-specific injury, as the kidney graft had not yet been implanted. By contrast, biomarker changes observed at 24 h, including the elevation of hyaluronan, should be interpreted within the broader SPK context, as both grafts had been implanted by then and may contribute to the systemic endothelial response.”

Moreover, because the majority of recipients underwent simultaneous pancreas-kidney (SPK) transplantation, this clarification was particularly important to ensure an accurate interpretation of perioperative biomarker dynamics. We believe that these revisions improve the scientific precision, clarity, and translational relevance of the manuscript.

Minor comment:

Comments 2: Figure 1: Baseline values appear to be missing in panels 1A and 1B and should be added for completeness.

Response 2: We thank the reviewer for noting this point. In the original version of Figure 1, baseline preoperative values were not displayed for amylase (panel 1A) and lipase (panel 1B), as our primary interest was the postoperative evolution of these markers. However, we agree that consistency across panels improves interpretability. Accordingly, preoperative baseline values for amylase and lipase have now been added to panels 1A and 1B so that all markers are presented across the same set of time points.

In addition, the corresponding revisions have also been incorporated into Subsection 3.2 (Circulating tissue injury markers), where the text has been updated accordingly to reflect the inclusion of baseline amylase and lipase values in Figure 1.

 

We are grateful to the reviewer for this valuable perspective, which encouraged us to strengthen the translational interpretation of our findings and to improve the clarity and consistency of the revised manuscript.

 

 

 

 

Author Response File: Author Response.doc