Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I have entusiastically reviewed the paper by Dragu R. Here, author synthesizes current evidence supporting a lung–kidney interorgan crosstalk framework in COPD, whereby chronic and acute pulmonary pathophysiology generates systemic disturbances that progressively impair renal structure and function. The heart is incorporated as a physiological intermediary, modulating hemodynamic transmission and venous congestion, without constituting the primary disease axis. Recognizing the role of kidney complications in COPD is crucial, as it influences how we diagnose, predict outcomes, and treat patients—especially when there are sudden flare-ups. 

Following my suggestions: 

-) There is a lack of a discussion about the role of sarcopenia in the definition of renal function in patients with COPD. Please, edit a section dedicated to the limitation in use of serum creatinine formulas in sarcopenic patients and discuss the usefulness of alternative biomarker ( cystatin C ) independent of muscle mass. 

-) Please, describe in more details the clinical phenotypes of COPD patients with increased renal risk (sarcopenic, congestive bronchitis, hypercapnic, with PH/RV dysfunction), because renal vulnerability is not the same. After that, please explain the mechanisms of AKI and CKD in COPD related with hypoxia/hypercapnia, systemic inflammation and venous congestion.

-) Please, describe the role of renal functional reserve (RFR), useful for define renal fragility in patients with COPD. The manuscript should include a section dedicated to RFR as a functional determinant of renal fragility in COPD, to explain that RFR is often reduced despite a normal eGFR, representing a kidney at risk, sensitive to the hemodynamic and inflammatory stresses. 

-) Please, discuss in more details  pathophysiology of AKI‑CKD transition. This is important to understand why patients with COPD develop progressive loss of renal function after episodes of AKI. Try to explain the role of emerging biomarkers for early identification of AKI (NGAL, TIMP2, KIM1..). 

-) Expand in the discussion the role of heart as a co-driver of kidney damage, not a simple "intermediary". 

-) Evaluate to edit a practical section discussing how to monitor kidney function in COPD, when to use cystatin C, how to manage fluids, which drugs increase AKI risk and when to involve a nephrologist.

-) Enrich section Future directions calling Take home messages and future directions and insert 2-3 take-home messages (useful for readers in my opinion). 

-) A little reduction of molecular part may be useful, summarizing relevant pathways (HIF/TGF-β, ADMA-RhoA, NF-κB, RAAS/SNS), avoiding more specialized details

-) Fig 1: Transform in a circular circuit: in my opinion in example: 

Lung → Heart → Kidney → Systemic inflammation → Lung

Congestion → Hypoxia → Fibrosis → Reduced reserve → AKI → CKD → More inflammation

Giving a relevant role to heart. 

In conclusion, here author explain that uniquely integrates molecular hypoxia signalling, endothelial dysfunction, and venous congestion into a unified lung–kidney crosstalk framework specific to COPD. Renal dysfunction is a common yet underrecognized and prognostically relevant component of COPD. Both chronic and acute kidney injury arise from lung–kidney inter
organ crosstalk driven by pulmonary pathophysiology, with cardiac involvement modulating hemodynamic transmission rather than defining the primary disease axis. Integrating kidney-aware strategies into COPD management offers a pragmatic route to improved outcomes and reflects a broader transition toward systems-based care in chronic respiratory disease. I hope that, after my suggestions and revisions of other reviewers, the paper may be re-evaluated, I congratulate myself with author for the work and I thank Editor for the opportunity to do the review of this interesting paper.

Best regards

 

Author Response

We thank the reviewer for the thorough and constructive evaluation and for recognizing the conceptual framework of the manuscript. All comments have been carefully addressed, and the manuscript has been substantially revised accordingly.

Comment 1

Lack of discussion on sarcopenia and limitations of creatinine-based renal function; include cystatin C.

Response:
We agree with this important point. A dedicated discussion on sarcopenia-related bias in creatinine-based eGFR and the role of cystatin C has been incorporated and integrated into the diagnostic framework.

Location in manuscript:

• Section 3.1 (new paragraph on sarcopenia and creatinine limitation)
• Section 3.3 (expanded and unified discussion on cystatin C and alternative biomarkers)

 

Comment 2

Describe COPD phenotypes with increased renal risk and link to mechanisms.

Response:
We added a new structured subsection defining clinically relevant COPD phenotypes associated with renal vulnerability, including congestive, hypercapnic, sarcopenic, and PH/RV dysfunction phenotypes. Mechanistic links to hypoxia, inflammation, and congestion were explicitly integrated.

Location in manuscript:

• New Section 3.4 “Phenotypic Clusters of Increased Renal Risk”

 

Comment 3

Include renal functional reserve (RFR) as determinant of renal fragility.

Response:
A dedicated subsection on renal functional reserve (RFR) has been added, emphasizing its role as a dynamic marker of renal vulnerability despite preserved eGFR and its relevance in COPD-related stress states.

Location in manuscript:

• New Section 3.5 “Renal Functional Reserve and Renal Fragility”

Comment 4

Expand AKI–CKD transition and include biomarkers.

Response:
The AKI–CKD transition section was substantially expanded to include mechanistic pathways of maladaptive repair and integration of emerging biomarkers (NGAL, KIM-1, TIMP-2, IGFBP7) for early detection.

Location in manuscript:

• Section 4.1 “AKI-to-CKD Transition” (expanded)

 

Comment 5

Expand role of heart as co-driver rather than intermediary.

Response:
We carefully refined the conceptual framework. The heart is now described as a physiological amplifier with conditional co-driving effects, particularly in the presence of pulmonary hypertension and venous congestion, while preserving the lung-centric model to avoid conceptual overlap with cardiorenal syndrome.

Location in manuscript:

• Section 2 (Conceptual Framework; revised wording)

 

Comment 6

Add practical clinical section (monitoring, cystatin C, fluids, nephrology referral).

Response:
A clinically oriented section was expanded to include renal monitoring strategies, indications for cystatin C use, AKI prevention principles, and criteria for nephrology referral.

Location in manuscript:

• Section 5 “Clinical Implications” (expanded)

 

Comment 7

Include take-home messages.

Response:
A dedicated “Take-Home Messages and Future Directions” section has been introduced to summarize key clinical and mechanistic insights.

Location in manuscript:

• Section 6 (new structure)

 

Comment 8

Reduce excessive molecular detail.

Response:
The molecular sections were streamlined to emphasize key signaling axes (HIF/TGF-β, NF-κB, ADMA–RhoA, RAAS/SNS) while reducing excessive mechanistic granularity. Redundant details were removed to improve readability.

Location in manuscript:

• Section 3.2 (refined throughout)

 

Comment 9

Modify Figure 1 to circular model and emphasize heart.

Response:
Figure 1 has been revised to reflect a circular interorgan loop (lung–heart–kidney–systemic inflammation) and to better represent bidirectional interactions and cardiac amplification.

Location in manuscript:

• Figure 1 (revised)
• Figure legend updated accordingly

Reviewer 2 Report

Comments and Suggestions for Authors

Specific comments/recommendations for the revision:

• At many places, the author has provided sentences without any associated references. It is highly recommended to cite appropriate references for such texts. Such as 1) Chronic airflow limitation, ventilation–perfusion mismatch ………………, 2) Renal injury is conceptualized as a downstream………………….., 3) Hypoxia- and hypercapnia-mediated chemoreflex…………………., 4) Angiotensin II–mediated efferent arteriolar constriction ……………….., 5) Renal venous congestion directly reduces…………………..

• In the introduction section: ONLY the discussion of COPD and kidney disease is mentioned. It is better to provide some information in the context of cardiac involvement, as it is incorporated as an intermediary organ, as per the abstract.
• In the Table 1: It is recommended to incorporate one column mentioning the specific animal model (in vivo) or cell model (in vitro) or patients used to study the mentioned Signaling Pathway and associated Renal Impact.
• In the Figure 1: the author has represented the effects of Zone-1-Lung and Zone-2-Heart on Zone-3-Kidney. As per the discussion (in 3.2), it is also noted that Zone-1 and Zone-2 are also interconnected and affect each other. So, it would be better to interconnect Lung and Heart in the figure.

Author Response

We thank the reviewer for the precise and helpful comments, which improved the scientific rigor and clarity of the manuscript.

Comment 1

Missing references in several mechanistic statements.

Response:
Appropriate references have been added to all indicated statements, particularly those related to:

• Pulmonary pathophysiology
• Hemodynamic and neurohormonal mechanisms
• Venous congestion physiology

No unsupported statements remain.

Location in manuscript:

• Sections 2 and 3.2 (multiple additions throughout)

 

Comment 2

Include cardiac context in the Introduction.

Response:
The Introduction has been revised to explicitly introduce cardiac mediation within the lung–kidney axis, aligning it with the conceptual framework described in the abstract.

Location in manuscript:

• Introduction (final paragraph revised)

 

Comment 3

Add experimental/model context to Table 1.

Response:
After careful consideration, we elected not to add a model-specific column in order to preserve the conceptual clarity and narrative-review nature of the table. Instead, the table legend was refined to explicitly state that pathways summarize evidence derived from experimental and clinical studies.

Location in manuscript:

• Table 1 legend (revised)

 

Comment 4

Improve Figure 1 by interconnecting lung and heart.

Response:
The figure has been revised to include bidirectional interaction between lung and heart, consistent with the described physiology and reviewer suggestion.

Location in manuscript:

• Figure 1 (updated schematic)

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors

Thank you for your new version of this interesting topic. Please, re-evaluate for the last time syntaxes  I hope that, after my suggestions and evaluation of other potential reviewers, the paper may be able to be published. 

Congratulation for your hard work to edit the manuscript. I thank Editor for the oppotunity to do the review of your interesting paper. 

Best Regards. 

Author Response

We sincerely thank the reviewer for the careful re-evaluation of the revised manuscript and for the positive and encouraging comments.

Comment:
Please re-evaluate syntax.

Response:
We have performed a comprehensive final revision of the manuscript focusing on language, syntax, and formatting. Minor grammatical refinements, punctuation corrections, and consistency adjustments (including spacing, hyphenation, and terminology) were implemented throughout the text to improve clarity and readability.

Location in manuscript:

• Revisions applied throughout the manuscript (global language and formatting editing)

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript is more compelling.

Author Response

We thank the reviewer for the positive assessment of the revised manuscript.

Comment:
The revised manuscript is more compelling.

Response:
We appreciate the reviewer’s encouraging feedback and are pleased that the revisions have improved the clarity and overall impact of the manuscript.