Cardiorenal and Metabolic Convergence in Acute Heart Failure: Severe Cardiorenometabolic Syndrome as a High-Risk Phenotype

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this retrospective monocentric study, Dr. Raquel López-Vilella and colleagues aimed to investigate the impact of severe cardio-reno-metabolic syndrome (CRMS), defined as estimated glomerular filtration rate <45 mL/min/1.73 m² associated with type 2 diabetes mellitus and/or obesity, in acute phase of heart failure (HF).

The authors conducted a retrospective study enrolling 2,228 patients admitted for acute HF between 2015 and 2025.

They found that severe CRMS was present in 486 patients (21,8%) who were older, had worse functional class, and a higher burden of cardiovascular comorbidities but, noteworthy, during follow-up, severe CRMS was associated with significantly higher mortality, HF readmissions, and the composite endpoint of the single components.

Furthermore, in multivariable analysis, severe CRMS remained an independent predictor of mortality, HF readmissions, and overall morbidity and mortality.

The study research topic warrants careful consideration, due to strong interest about cardio-reno metabolic impact on HF patients, even more in patients admitted for acute HF. These findings could be useful to intensify the medical therapy since the last phases of admission in patients with overlapped CRMS and HF.

Overall, this is a quite nicely written article with good figures.

However, it has some limitations that should be addressed from the authors:

• The paper focuses on a CRMS phenotype using simple, admission-based variables (eGFR <45 mL/min/1.73 m² plus diabetes and/or obesity) and this enhances real-world applicability. However, numerous prior studies and registries have already demonstrated the adverse prognostic impact of CKD in acute HF, the negative influence of diabetes on HF outcomes and the compounded risk associated with multimorbidity. The proposed severe CRMS phenotype does not clearly outperform existing risk stratification approaches or even simpler markers (eGFR alone, NT-proBNP, prior hospitalizations) and is not convincingly demonstrated that severe CRMS provides incremental prognostic information beyond its individual components or beyond established clinical models. The authors should add incremental value analyses (C-statistics, net reclassification improvement, integrated discrimination improvement). Furthermore, they should compare severe CRMS against CKD alone (eGFR <45), diabetes alone, a simple comorbidity count or validated HF risk scores. Finally, they should explicitly clarify whether severe CRMS is a syndromic construct or merely a composite marker of disease severity.
  
  
• The definition of severe CRMS is pragmatic and reproducible, but has several issues. The chosen cutoff (eGFR <45) is arbitrary and not justified by sensitivity analyses. Obesity is treated dichotomously, without accounting for body composition, cachexia, and sarcopenic obesity. Diabetes also is defined categorically, without considering disease duration, glycemic control and insulin use. For improving the strength of the definition, it could be useful to provide sensitivity analyses using alternative eGFR thresholds (such as <60), diabetes-only vs obesity-only subgroups, continuous rather than dichotomous variables.
  
  
• The introduction section should be expanded briefly mentioning diagnostic and therapeutic strategies for acute HF. In this respect, please cite relevant paper.
  
  
• In the study there is a potential collinearity: eGFR, NT-proBNP, anemia, and diuretic use likely overlap in prognostic information.
  
  
• Residual confounding is highly likely. Indeed, severe CRMS patients are older, more comorbid, more congested, and more frequently hospitalized. Adjustment does not fully account for HF severity (right ventricular function, frailty, congestion burden).
  
  
• Recently, several drugs emerged in the cardio-reno-metabolic field (SGLT2-I, GLP1RA ecc). These drugs showed a clear benefit in both coronary artery disease and in the HF scenario (doi:10.3390/jcm15031108). The authors should summarize this evidence and cite this relevant paper.
  
  
• Effect sizes are modest. Adjusted HRs for mortality and readmissions (1.20–1.25) suggest limited independent impact. This weakens the claim of a distinct “high-risk phenotype.”

Author Response

We have attached a separate document with detailed, point-by-point responses to the Reviewer’s valuable and constructive comments, which have been instrumental in improving the quality and clarity of the manuscript.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors propose the concept of a “severe cardiorenometabolic syndrome” as a distinct, high-risk phenotype characterized by the convergence of these three organ systems. This manuscript addresses a timely and clinically significant issue. The overlap between heart failure, chronic kidney disease, and metabolic disorders (such as diabetes and obesity) is well-recognized, and the American Heart Association’s recent focus on Cardiovascular-Kidney-Metabolic (CKM) syndrome makes this topic highly relevant. 

1. Novelty
While the authors attempt to define a specific “severe” phenotype, the findings largely confirm the established understanding that multi-morbidity drives poor prognosis in AHF, rather than providing a fundamentally new paradigm or a novel therapeutic target. The authors should more explicitly delineate how their definition or findings differ from or add to the current CKM framework. 

2. Support of the statement
Statements regarding pathophysiology and prevalence are insufficiently supported by the results or the cited references. For example, assertions about the mechanistic drivers of “convergence” or specific prevalence rates in different demographics should be cross-checked against the provided bibliography. Please revise the manuscript to ensure that all claims are rigorously backed. 

3. Clinical Implications
- The metabolic component of the triad is complex. The references list works on the “obesity paradox”. Discuss whether the presence of obesity or diabetes confers a linear increase in risk within this phenotype or if there are non-linear relationships, as suggested by some of the cited literature.
- Also, consider strengthening the Discussion section by addressing how identifying “Severe Cardiorenometabolic Syndrome” should change management. Does it call for specific SGLT2 inhibitor use, more aggressive diuresis, or multidisciplinary care? Linking the findings to therapeutic implications would enhance the study’s impact.

Author Response

We have attached a separate document with detailed, point-by-point responses to the Reviewer’s valuable and constructive comments, which have been instrumental in improving the quality and clarity of the manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

This is a second revision of a well written study aimed to investigate the impact of severe cardio-reno-metabolic syndrome (CRMS), defined as estimated glomerular filtration rate <45 mL/min/1.73 m² associated with type 2 diabetes mellitus and/or obesity, in acute phase of heart failure (HF).

The topic is of clinical relevance.

The paper is well revised, and the authors provided satisfactory comments to this reviewer’s suggestions.

There are no concerns about ethical issues, conflict of interest and plagiarism/publication ethics.