Frequency and Risk Factors for Diuretic Resistance in Patients with Decompensated Heart Failure: A Retrospective Single-Center Study in Western Mexico

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript describes “Frequency and Risk Factors for Diuretic Resistance in Patients with Decompensated Heart Failure: A Retrospective Single-Center Study in Western Mexico. The authros aimed to determine how common diuretic resistance is among hospitalized heart failure patients and to identify the factors associated with it. The authors conducted a retrospective study by reviewing hospital records of patients admitted with decompensated heart failure between 2020 and 2022 at a hospital in western Mexico. Patients older than 18 years who met diagnostic criteria for heart failure and had complete clinical data were included. The authors divided the patients into two groups based on whether they developed diuretic resistance, which was defined by poor urine output despite high doses of diuretic medication. Statistical analyses, including bivariate and multivariate logistic regression, were used to evaluate clinical and biochemical variables associated with resistance. 

The authors found that 35.5% of the 76 patients analyzed had diuretic resistance, showing that it is a frequent complication in patients with decompensated heart failure. Several factors such as type 2 diabetes mellitus, chronic kidney disease, elevated creatinine and BUN levels, low albumin levels, and prior use of NSAIDs or ACEI/AARII medications were associated with diuretic resistance. However, multivariate analysis showed that diabetes mellitus, higher BUN levels, low serum albumin, and previous ACEI/AARII treatment were the strongest independent predictors. The authors concluded that recognizing these risk factors may help healthcare providers identify high-risk patients earlier and improve treatment strategies. Although the study provides valuable preliminary data for the Mexican population, the authors acknowledged limitations such as the small sample size and retrospective design, recommending larger prospective studies to confirm their findings. I recommend publish this article in Medical Sciences Journal.

Author Response

We sincerely thank the reviewer for the careful evaluation of our manuscript and for the positive assessment of our work. We greatly appreciate the reviewer’s recognition of the clinical relevance of this study and its contribution as preliminary evidence regarding diuretic resistance in hospitalized patients with decompensated heart failure in a Mexican population.

Reviewer 2 Report

Comments and Suggestions for Authors

This is a well written manuscript, providing important clinical information. While this particular study used a small number of patients, this is indicated as limitations and the results from this study may serve as a basis for larger prospective studies.

Minor comment: Please define "BUN" in the Abstract.

Author Response

Minor comment: Please define "BUN" in the Abstract.

We thank the reviewer for this helpful comment. Following the reviewer’s suggestion, we have defined BUN as “blood urea nitrogen” at its first mention in the Abstract. The corresponding change has been incorporated into the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors address a clinically relevant topic by evaluating the frequency of diuretic resistance and associated risk factors in patients hospitalized with decompensated heart failure. The study provides useful preliminary data from a Mexican patient population, where information on this topic remains limited. The manuscript is generally well organized and appropriate for the Brief Report format.

I have several suggestions that may strengthen the manuscript:

1. The exclusion of 141 out of 220 identified patient records due to incomplete data is substantial and may introduce selection bias. This limitation should be discussed more explicitly.
2. Because there is no universally accepted definition of diuretic resistance, the authors should briefly justify their choice of definition and discuss how this may affect comparisons with other studies.
3. The association between prior ACEI/AARII therapy and diuretic resistance deserves additional discussion. While ACEI/AARII therapy reduces RAAS activity, chronic treatment may trigger counter-regulatory responses that contribute to reduced diuretic responsiveness. Additionally, ACEI/AARII use may simply reflect more advanced cardiovascular or renal disease. A brief discussion would provide a useful physiological context for this finding.
4. The multivariate analysis should be reviewed carefully. Some reported odds ratios appear inconsistent with the direction of the associations described in the text. Clarification of variable coding and interpretation of the odds ratios would strengthen the manuscript.
5. A brief limitations paragraph would be helpful and should acknowledge the retrospective design, single-center setting, relatively small sample size, high proportion of excluded records, and lack of long-term follow-up.
6. Minor editorial revisions are recommended. The units reported for serum albumin in Table 2 should be verified, as the reported values appear more consistent with g/dL than mg/dL. A general review of laboratory units, abbreviations, and formatting is also recommended.

Overall, this Brief Report provides useful preliminary data regarding diuretic resistance in hospitalized heart failure patients and supports the need for larger prospective studies.

Author Response

1. The exclusion of 141 out of 220 identified patient records due to incomplete data is substantial and may introduce selection bias. This limitation should be discussed more explicitly.
   1. Answer: We thank the reviewer for this important observation. We agree that the exclusion of a substantial number of records due to incomplete information may have introduced selection bias and may limit the representativeness of the analyzed cohort. Accordingly, we have expanded the limitations paragraph in the Discussion section to explicitly acknowledge this issue, together with the retrospective design, single-center setting, relatively small sample size, and lack of long-term follow-up.
2. Because there is no universally accepted definition of diuretic resistance, the authors should briefly justify their choice of definition and discuss how this may affect comparisons with other studies.
   1. Answer: We thank the reviewer for this valuable comment. We agree that the lack of a universally accepted operational definition of diuretic resistance may affect comparisons across studies. Accordingly, we have revised the Methods section to clarify the rationale for using the definition proposed by Lu et al., which provides a reproducible criterion based on both diuretic dose and urinary output, is supported by previous literature on diuretic response and diuretic resistance, and has been previously applied in a predictive model. We have also expanded the Discussion section to acknowledge that differences in operational definitions may contribute to variability in the reported frequency of diuretic resistance and that direct comparisons between studies should therefore be made with caution.
3. The association between prior ACEI/AARII therapy and diuretic resistance deserves additional discussion. While ACEI/AARII therapy reduces RAAS activity, chronic treatment may trigger counter-regulatory responses that contribute to reduced diuretic responsiveness. Additionally, ACEI/AARII use may simply reflect more advanced cardiovascular or renal disease. A brief discussion would provide a useful physiological context for this finding.
   1. Answer: We thank the reviewer for this important suggestion. We agree that the association between prior ACEI/AARII therapy and diuretic resistance requires additional physiological and clinical context. Accordingly, we have expanded the Discussion section to acknowledge that the relationship between RAAS activity, RAAS-modifying therapy, and diuretic response is complex. We also clarified that prior ACEI/AARII use may have reflected more advanced cardiovascular or renal disease, rather than a direct causal effect of these therapies. Given the retrospective design and limited sample size, we have emphasized that this finding should be interpreted cautiously and considered hypothesis-generating.
4. The multivariate analysis should be reviewed carefully. Some reported odds ratios appear inconsistent with the direction of the associations described in the text. Clarification of variable coding and interpretation of the odds ratios would strengthen the manuscript.
   1. Answer: We thank the reviewer for this important observation. We carefully reviewed the coding and interpretation of the multivariate logistic regression model and agree that the direction of the reported odds ratios required clearer explanation. In the binary logistic regression model, the absence of diuretic resistance was used as the modeled outcome. Therefore, the reported odds ratios represent the odds of belonging to the non-resistant group. Accordingly, ORs below 1 for T2DM and prior ACEI/AARII treatment indicate lower odds of belonging to the non-resistant group, which is consistent with the higher frequency of these variables among patients with diuretic resistance in the bivariate analysis. Similarly, the OR for BUN represents the change in the odds of the non-resistant outcome for each 1 mg/dL increase in BUN, whereas the OR for serum albumin represents the change in the odds of the non-resistant outcome for each 1 g/dL increase in albumin. To avoid misinterpretation, we have revised the Methods, Results, Table 3, and Discussion sections to explicitly clarify the modeled outcome and the interpretation of the odds ratios. The underlying data and the estimates obtained from the multivariate model were unchanged.
5. A brief limitations paragraph would be helpful and should acknowledge the retrospective design, single-center setting, relatively small sample size, high proportion of excluded records, and lack of long-term follow-up.
   1. Answer: We thank the reviewer for this helpful suggestion. We have expanded the limitations paragraph in the Discussion section to explicitly acknowledge the retrospective design, single-center setting, relatively small sample size, substantial proportion of excluded records due to incomplete information, potential selection bias, and lack of long-term follow-up.
6. Minor editorial revisions are recommended. The units reported for serum albumin in Table 2 should be verified, as the reported values appear more consistent with g/dL than mg/dL. A general review of laboratory units, abbreviations, and formatting is also recommended.
   1. Answer: We thank the reviewer for this careful observation. We verified the laboratory units and corrected the unit for serum albumin in Table 2 from mg/dL to g/dL. We also performed a general review of laboratory units, abbreviations, capitalization, and formatting throughout the manuscript to improve consistency and clarity.

Overall, this Brief Report provides useful preliminary data regarding diuretic resistance in hospitalized heart failure patients and supports the need for larger prospective studies.

General Comment: We sincerely thank the reviewer for the careful evaluation of our manuscript and for the constructive comments provided. We have revised the manuscript accordingly to improve its methodological transparency, clarity, and scientific interpretation. Specifically, we clarified the rationale for the operational definition of diuretic resistance, expanded the Discussion regarding the potential association between prior ACEI/AARII therapy and diuretic resistance, clarified the coding and interpretation of the multivariate logistic regression model, strengthened the limitations section, and corrected laboratory units, abbreviations, capitalization, and formatting throughout the manuscript. All changes have been incorporated into the revised manuscript and are visible using track changes.