Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This study investigated the influence of body position on diuretic response in patients with acutely decompensated heart failure. It has prospective, randomized design with a protocol for position allocation, precise urine output measurement via catheterization, and comprehensive biochemical and neurohormonal assessments, allowing for comparisons of natriuresis, urine dilution, and adrenergic/renin-aldosterone activity.

On the other hand, small sample size (n=12) renders it underpowered, with trends in urine concentration and adrenaline excretion unlikely to achieve statistical significance and prone to type II errors. Absence of significant differences in primary outcomes despite detailed data indicates a descriptive rather than conclusive design, with the unblinded, short-duration protocol inadequate for capturing long-term positional hemodynamic effects.

There are several major concerns that the authors are invited to address in a revision:

1. The Methods section has no information about control for 24-hour circadian rhythms in measured parameters, that constitutes a methodological gap that could confound findings. Circadian variations are well-documented in heart failure processes, including diurnal urine output peaks, morning renin/aldosterone elevations, nocturnal catecholamine surges (e.g., adrenaline, noradrenaline), and fluctuations in creatinine clearance and electrolyte excretion. These surges can modulated by both time of day and posture transitions. With the protocol spanning hours (e.g., baseline to 6 hours post-diuretic) without specified daily timing, unaccounted circadian influences may obscure positional effects on natriuresis, urine dilution, and adrenergic activity.

2. The protocol lacks specification of synchronized administration of interventions (e.g., diuretic dosing, positional changes) and measurements (urine output, neurohormonal markers, renal parameters) across participants. This omission, again, allows circadian confounding, as diurnal rhythms vary in patients, affecting renal perfusion, natriuretic response, and catecholamine values. Without cross-synchronization (e.g., matched times relative to circadian cycles or standardized windows), inter-patient variability biases interpretations of positional diuretic efficacy.

3. The heterogeneous population (ages 60–88 years, mean 74±14; 83% male) features unadjusted analyses for age (as a continuous covariate) or sex (as a categorical variable), despite their potential to confound natriuresis, urine dilution, and neurohormonal responses. In this small cohort, such omissions may obscure or exaggerate positional effects, given age-related renal declines and sex-specific hormonal profiles (e.g., androgenic adrenergic influences) in heart failure pathophysiology. Reliance on descriptive statistics without covariate adjustment undermines generalizability and robustness.

Author Response

I sincerely thank for the thorough and insightful evaluation of our manuscript. Your valuable comments and constructive suggestions have undoubtedly contributed to enhancing the quality and clarity of our work. Responses for each remark were attached in the separate file.

Yours sincerely,

Mateusz Guzik

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript by Guzik and Tymków presents a randomized study examining the impact of body position (supine vs. upright) on diuretic response and neurohormonal activation in 12 patients with acutely decompensated HFrEF. The work addresses a clinically important question of renal perfusion physiology, based on prior observations in non-HFrEF cohorts. The obtained results are important and deserve publication.

Specific comments:

1). Urine dilution definition (baseline creatinine ratio) is unconventional; clarify its validation beyond the cited prior work.

2). Expand limitations to discuss unmeasured confounders like intravascular volume (e.g., via IVC ultrasound).

3). The abstract states “renin concentration tended to be higher in upright than in supine individuals,” but the Results section describes the opposite trend (higher in supine) in lines 164-165. Please clarify. Check also the sentence in lines 192-194.

4). Several typographical errors exist (e.g., “Potasium” in Table 1). Please check carefully.

Summarizing, I recommend minor revision of the manuscript prior to acceptance.

Author Response

I sincerely thank the You for the careful and insightful evaluation of our manuscript. Your thoughtful comments and constructive suggestions have greatly contributed to enhancing the quality and clarity of our work. I also greatly appreciate your positive reception of our study, which we find very encouraging and motivating.

The responses for each remark were attached in separate file.

Yours sincerely,

Mateusz Guzik

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors present a prospective, randomized pilot study evaluating the association between body position and diuretic response as well as neurohormonal activation in patients with acutely decompensated HFrEF treated with contemporary guideline-directed medical therapy. The topic is clinically relevant and physiologically well motivated. The manuscript is clearly written and methodologically transparent.

However, several issues should be addressed to strengthen the scientific rigor and interpretability of the findings:

• Given the very small sample size (n = 12), the study should be more explicitly framed as hypothesis-generating. Interpretations based on non-significant trends (e.g., renin and catecholamine patterns) should be clearly described as descriptive observations rather than mechanistic conclusions.
• The absence of statistically significant differences between groups should not be interpreted as equivalence of body positions. The authors are encouraged to explicitly state that the study is underpowered to detect modest but potentially clinically meaningful effects.
• All patients remained in the supine position for 4 hours prior to randomization and diuretic administration. This design choice may have attenuated physiological differences between groups, particularly with respect to neurohormonal activation. The rationale for this approach and its potential impact on the results should be discussed in greater detail.
• Significant baseline differences in urea and creatinine concentrations between the supine and upright groups are present. As renal function is a key determinant of diuretic response and neurohormonal activation, this imbalance should be more thoroughly discussed as a potential confounder.
• There appears to be inconsistency between the Abstract, Results section, and figures regarding adrenaline/epinephrine findings in supine versus upright patients. These discrepancies should be carefully reviewed and corrected to ensure internal consistency.
• The rationale for assessing urinary catecholamines instead of plasma concentrations should be clarified. Additionally, the interpretation of creatinine-adjusted catecholamine values should be better explained, particularly in the context of variable renal function.
• The Conclusions section should be softened to reflect the descriptive and exploratory nature of the study. Emphasis should be placed on the need for larger, adequately powered studies to validate the observed trends.

Author Response

I would like to express our sincere gratitude for the thorough, insightful, and constructive review of our manuscript. Yours detailed comments and thoughtful suggestions have provided substantial value and have significantly contributed to improving the scientific quality, clarity, and overall rigor of the manuscript. We sincerely hope that all comments and concerns have been adequately addressed and that the revisions satisfactorily reflect Yours valuable input.

Responses for each remark and comment were attached in a separate file.

Yours sincerely,

Mateusz Guzik

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The revised version is a clear improvement. I still suggest a few areas to be corrected:

• Significant differences in baseline urea and creatinine between the supine and upright groups persist. This imbalance should be more explicitly discussed as a potential confounder.
• The potential dilution of positional effects should be more explicitly acknowledged in the Discussion.

Author Response

I would like to thank for Your thoughtful evaluation, as well as for the valuable suggestions that have substantially enhanced the quality and scientific merit of the manuscript. I sincerely hope that the current revisions and responses are thorough and satisfactory. All responses to the remarks and comments were included in the attached file.

Yours sincerely,
Mateusz Guzik

Author Response File: Author Response.docx