Cardiovascular Comorbidities and Advanced Chronic Kidney Disease in Hospitalized Patients with Multiple Myeloma: A Single-Center Retrospective Cohort Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor, I carefully read the manuscript “Cardiovascular Comorbidities and Advanced Chronic Kidney Disease in Hospitalized Patients with Multiple Myeloma: A Single-Center Retrospective Cohort Study”.

Even if the topic is clinically relevant, I believe that the manuscript required to be carefully revised before it can be considered for publication.

• The main limitation concerns the definition of advanced chronic kidney disease: it is defined as eGFR or creatinine clearance <30 mL/min, but it is not clear whether renal dysfunction was chronic, documented for at least three months, or partly related to acute kidney injury during hospitalization. This distinction is particularly important in multiple myeloma, where acute renal impairment may be common. In addition, the exact prevalence of advanced CKD, which is the primary outcome, should be clearly reported in the abstract, results, and baseline characteristics.
• The very high prevalence of diabetes and hypertension also requires clarification, since the denominators appear to vary substantially across comorbidities, and these variables were excluded from the adjusted model because of missing data. All comorbidities should therefore be reported as n/N (%) rather than as simple percentages.
• The multivariable model also needs further detail, including the number of patients included in the complete-case analysis, the number of events, and whether model stability was assessed. The finding that atrial fibrillation and myocardial ischemia were significant only in univariate analysis, but not after adjustment, should be interpreted more cautiously and framed as exploratory rather than confirmatory.
• I would also ask the authors to specify the formula used for eGFR or creatinine clearance, to better define “myocardial ischemia”, and to clarify the apparent chronological inconsistency between a 2025 manuscript, inclusion of patients until February 2026, and ethics approval dated March 2026.
• Finally, several minor language and formatting issues should be corrected, and some references not directly related to multiple myeloma, CKD, or cardiovascular comorbidity should be reconsidered.

Comments on the Quality of English Language

Several minor language and formatting issues should be corrected.

Author Response

Dear Editorial Team,

We sincerely thank you for giving us the opportunity to submit a revised draft of our manuscript. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on our paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 1

Dear Editor, I carefully read the manuscript “Cardiovascular Comorbidities and Advanced Chronic Kidney Disease in Hospitalized Patients with Multiple Myeloma: A Single-Center Retrospective Cohort Study”.

Even if the topic is clinically relevant, I believe that the manuscript required to be carefully revised before it can be considered for publication.

• The main limitation concerns the definition of advanced chronic kidney disease: it is defined as eGFR or creatinine clearance <30 mL/min, but it is not clear whether renal dysfunction was chronic, documented for at least three months, or partly related to acute kidney injury during hospitalization. This distinction is particularly important in multiple myeloma, where acute renal impairment may be common. In addition, the exact prevalence of advanced CKD, which is the primary outcome, should be clearly reported in the abstract, results, and baseline characteristics.

We thank the reviewer for this important observation. We agree that distinguishing chronic kidney disease from acute kidney injury is particularly important in patients with multiple myeloma. Accordingly, we revised the manuscript to clarify the definition of advanced CKD throughout the Methods, Abstract, Results, and Discussion sections.

Advanced CKD was defined exclusively as an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², automatically reported by the institutional laboratory using the CKD-EPI 2021 equation. CKD classification was based on both a documented pre-existing diagnosis of CKD in the medical record and renal function assessment during hospitalization. Patients with isolated acute kidney injury were excluded. In patients without previously documented CKD, serial serum creatinine measurements during hospitalization, renal function at discharge, and available previous medical records were reviewed to confirm the chronic nature of renal impairment and minimize misclassification of transient renal dysfunction.

We have also clarified this definition in the Abstract and Methods sections and emphasized that the reported findings refer to advanced CKD rather than acute kidney injury. In addition, the exact prevalence of advanced CKD is now explicitly reported in the Abstract, Results, and baseline characteristics table as 94/116 patients (81.0%) among those with available renal function data.

 

• The very high prevalence of diabetes and hypertension also requires clarification, since the denominators appear to vary substantially across comorbidities, and these variables were excluded from the adjusted model because of missing data. All comorbidities should therefore be reported as n/N (%) rather than as simple percentages.

 

We thank the reviewer for this important observation. We agree that reporting percentages alone may be misleading when the denominator differs between variables because of missing data. Comorbidity frequencies have been revised and are now reported as absolute numbers and percentages [n (%)]. Diabetes mellitus was present in 31/32 patients (96.9%), hypertension in 86/91 patients (94.5%), and CKD in 94/116 patients (81.0%) among those with available data.

 

• The multivariable model also needs further detail, including the number of patients included in the complete-case analysis, the number of events, and whether model stability was assessed. The finding that atrial fibrillation and myocardial ischemia were significant only in univariate analysis, but not after adjustment, should be interpreted more cautiously and framed as exploratory rather than confirmatory.

 

We thank the reviewer for this important comment. Additional details regarding the multivariable model have been added to the Methods and Results sections. Specifically, we now report the number of patients included in the complete-case analysis and the number of advanced CKD events available for modeling. Because of the relatively small sample size, limited number of events, substantial missing data, and the high prevalence of certain comorbidities, the adjusted model was intended as an exploratory analysis rather than a confirmatory model. We have revised the Discussion accordingly and emphasize that the multivariable findings should be interpreted cautiously and should not be considered evidence of independent associations.

 

• I would also ask the authors to specify the formula used for eGFR or creatinine clearance, to better define “myocardial ischemia”, and to clarify the apparent chronological inconsistency between a 2025 manuscript, inclusion of patients until February 2026, and ethics approval dated March 2026.

We thank the reviewer for this observation.

Estimated glomerular filtration rate (eGFR) was automatically reported by the institutional laboratory using the CKD-EPI 2021 equation and was used throughout the study for the definition and classification of chronic kidney disease. The manuscript has also been revised to clarify the definition of myocardial ischemia, which was based on a documented clinical diagnosis recorded in the medical record, including a history of ischemic heart disease, prior myocardial infarction, or documented coronary artery disease.

The study included consecutive hospitalizations between January 2015 and February 2026, and the final dataset was completed after the end of the inclusion period. Ethical approval for the retrospective analysis of anonymized data was obtained from the Ethics Committee of “Sf. Ioan” Clinical Emergency Hospital on 31 March 2026 (Approval No. R4166/31.03.2026) prior to data analysis and manuscript submission. The study was retrospective and based on anonymized medical records. Written informed consent, including consent for medical research and publication, was available in the hospital records of all included patients.

We also note that the “Diseases 2025” designation visible in the manuscript corresponds to the journal template provided by MDPI and does not reflect the study period or submission date.

 

 

• Finally, several minor language and formatting issues should be corrected, and some references not directly related to multiple myeloma, CKD, or cardiovascular comorbidity should be reconsidered.

 

 

We thank the reviewer for this suggestion. The manuscript was carefully revised to correct minor language, formatting, and stylistic inconsistencies. In addition, the reference list was reviewed and streamlined by removing citations that were not directly relevant to the primary focus of the study, namely multiple myeloma, advanced chronic kidney disease, and cardiovascular comorbidities. These revisions improved the clarity and focus of the manuscript.

 

 

 

 

Comments on the Quality of English Language

Several minor language and formatting issues should be corrected.

We thank the reviewer for this suggestion. A thorough language and formatting review of the manuscript was performed. Minor grammatical, stylistic, and typographical issues were corrected, terminology and abbreviations were standardized throughout the manuscript, and formatting inconsistencies were addressed to improve overall clarity and readability. 

We are looking forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have.

Sincerely,

Dr. Beatrice Bălăceanu-Gurău

Corresponding Author

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses a clinically relevant topic exploring the coexistence of cardiovascular comorbidities and advanced chronic kidney disease in hospitalized patients with multiple myeloma. The topic is potentially interesting, particularly given the growing recognition of cardio-renal interactions and cardiac amyloidosis in hematologic malignancies. The manuscript is generally well structured and the authors have attempted to contextualize the findings within the current literature. However, despite some strengths, several important methodological and interpretative concerns remain. In particular, the extremely high prevalence of cardiovascular comorbidities reported in the cohort raises concerns regarding data definition, patient selection, and possible overestimation of comorbidity burden. Overall, the manuscript requires substantial clarification before it can be adequately interpreted. 

 

Major comments

 

#1. The most important concern relates to the extremely high prevalence of cardiovascular and metabolic comorbidities reported in the cohort. Diabetes mellitus is reported in 96.9% of patients and hypertension in 94.5%, which are extraordinarily high values even for elderly hospitalized multiple myeloma populations. Although the authors partially acknowledge possible overestimation, the explanation remains insufficient. The manuscript should provide much greater clarity regarding how these diagnoses were ascertained, whether diagnoses were active, historical, treatment-based, or extracted automatically from administrative records. The possibility of coding bias or duplication of comorbidity extraction should also be discussed more explicitly.

 

#2. The study design remains essentially cross-sectional despite being described as a “retrospective cohort study.” Cardiovascular comorbidities and advanced CKD were assessed contemporaneously during hospitalization, and no longitudinal renal or cardiovascular outcomes were evaluated. Therefore, several statements implying clinical “association with advanced CKD burden” should be interpreted cautiously, as temporality and causality cannot be established. The manuscript should more consistently frame the findings as descriptive associations within a hospitalized cohort.

 

#3. The definition of advanced CKD remains somewhat problematic. The manuscript combines eGFR <30 mL/min/1.73 m² and creatinine clearance <30 mL/min, but it is unclear:

• whether eGFR was systematically available in all patients;
• which equation was used for eGFR calculation;
• whether creatinine clearance was estimated or directly measured;
• whether acute kidney injury at hospitalization may have influenced classification.

This is particularly important in multiple myeloma, where acute kidney injury, dehydration, and paraprotein-related renal dysfunction may transiently alter renal indices. The manuscript should better clarify how chronic versus acute renal dysfunction was distinguished.

 

#4. The multivariable analysis should be interpreted very cautiously. The adjusted model includes only four covariates in a relatively small cohort, while diabetes mellitus and hypertension were excluded due to missing data and model instability. However, these are the dominant comorbidities in the cohort and likely major confounders of the observed cardio-renal associations. Therefore, the adjusted analysis is probably under-adjusted and should not be interpreted as demonstrating independent associations.

 

#5. The Discussion repeatedly refers to integrated cardio-renal assessment and cardiac amyloidosis. While clinically relevant, these aspects are largely speculative in the current dataset because systematic echocardiography, cardiac biomarkers, cardiac MRI, and standardized amyloidosis evaluation were not available. Consequently, some paragraphs become disproportionately broad relative to the actual data generated by the study. The Discussion should remain more closely aligned with the observational findings.

 

#6. Several analyses appear somewhat redundant and do not substantially contribute to the main objective of the manuscript. For example:

• extensive histogram presentation of biological variables;
• repeated sex comparisons;
• age-group boxplots without significant findings;
• broad correlation analyses with weak or expected correlations.

These sections make the manuscript unnecessarily long relative to the simplicity of the main findings and could be substantially streamlined.

 

#7. The manuscript occasionally overstates the clinical implications of statistically fragile findings. For example: atrial fibrillation loses statistical significance after adjustment (p = 0.076); myocardial ischemia reverses directionality in multivariable analysis; confidence intervals are wide throughout. Therefore, statements suggesting clinically meaningful associations should be tempered more carefully.

 

Minor comments

 

• Several grammatical and stylistic inconsistencies remain throughout the manuscript. Examples include: “advanced CKD and cardiovascular disease frequently coexist” followed by repetitive wording later in the same paragraph; “The usefullness of immunohistochemistry” in reference 33 should be corrected to “usefulness”; inconsistent spacing around percentages and p-values; inconsistent abbreviation formatting (e.g., NTproBNP instead of NT-proBNP).
• The references should be revised carefully. Several citations appear only loosely related to the specific objective of the manuscript, and the bibliography is disproportionately extensive for a relatively small retrospective study. 
• Table 3 should specify more clearly whether odds ratios derive from crude univariate logistic regression or simple contingency analysis. 
• Authors repeatedly use terms such as “advanced CKD burden” and “clinical impact” despite the absence of outcome analyses (mortality, dialysis, cardiovascular events, hospitalization duration). More neutral wording would improve scientific precision. 

Author Response

Dear Editorial Team,

We sincerely thank you for giving us the opportunity to submit a revised draft of our manuscript. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on our paper. We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers. Here is a point-by-point response to the reviewers’ comments and concerns.

 

Reviewer 2

The manuscript addresses a clinically relevant topic exploring the coexistence of cardiovascular comorbidities and advanced chronic kidney disease in hospitalized patients with multiple myeloma. The topic is potentially interesting, particularly given the growing recognition of cardio-renal interactions and cardiac amyloidosis in hematologic malignancies. The manuscript is generally well structured and the authors have attempted to contextualize the findings within the current literature. However, despite some strengths, several important methodological and interpretative concerns remain. In particular, the extremely high prevalence of cardiovascular comorbidities reported in the cohort raises concerns regarding data definition, patient selection, and possible overestimation of comorbidity burden. Overall, the manuscript requires substantial clarification before it can be adequately interpreted. 

 

Major comments

 

1. The most important concern relates to the extremely high prevalence of cardiovascular and metabolic comorbidities reported in the cohort. Diabetes mellitus is reported in 96.9% of patients and hypertension in 94.5%, which are extraordinarily high values even for elderly hospitalized multiple myeloma populations. Although the authors partially acknowledge possible overestimation, the explanation remains insufficient. The manuscript should provide much greater clarity regarding how these diagnoses were ascertained, whether diagnoses were active, historical, treatment-based, or extracted automatically from administrative records. The possibility of coding bias or duplication of comorbidity extraction should also be discussed more explicitly.

We thank the reviewer for this important comment. We agree that the prevalence of diabetes mellitus (96.9%) and hypertension (94.5%) appears considerably higher than that reported in most multiple myeloma cohorts. After re-evaluating the original database and source records, we confirmed that these values accurately reflect the available data extracted from the study population. To improve transparency, comorbidity frequencies are now reported as absolute numbers and percentages [n (%)] throughout the manuscript.

Several factors may explain these findings. First, our institution is a tertiary emergency referral hospital that predominantly manages elderly patients with advanced disease and multiple chronic comorbidities. Second, the study included only hospitalized patients rather than ambulatory or population-based multiple myeloma cohorts. Therefore, the cohort is enriched for patients with a high burden of cardiovascular and metabolic disease and is not intended to be representative of the overall multiple myeloma population.

We agree that the retrospective identification of comorbidities from administrative and clinical records may introduce documentation and coding-related limitations. To address the reviewer’s concern, we have expanded both the Methods and Discussion sections to provide a more detailed description of the comorbidity ascertainment process and to explicitly acknowledge the potential influence of coding practices, referral-center case mix, and selection bias on the observed prevalence estimates.

 

2. The study design remains essentially cross-sectional despite being described as a “retrospective cohort study.” Cardiovascular comorbidities and advanced CKD were assessed contemporaneously during hospitalization, and no longitudinal renal or cardiovascular outcomes were evaluated. Therefore, several statements implying clinical “association with advanced CKD burden” should be interpreted cautiously, as temporality and causality cannot be established. The manuscript should more consistently frame the findings as descriptive associations within a hospitalized cohort.

 We thank the reviewer for this important methodological observation. We agree that the retrospective design and the use of contemporaneously collected hospitalization data do not allow determination of temporal relationships between cardiovascular comorbidities and advanced CKD.

Our intention was to describe the coexistence of cardiovascular and renal disease within a hospitalized multiple myeloma cohort rather than to imply causality or directionality. In response to the reviewer's suggestion, we have revised the manuscript throughout to avoid language suggesting prediction, causation, or temporal association. Terms such as "factors associated with advanced CKD", "determinants", and similar expressions have been replaced with wording emphasizing descriptive and cross-sectional associations.

We have also expanded the Discussion section to explicitly acknowledge that cardiovascular comorbidities and advanced CKD were assessed contemporaneously and that causal relationships cannot be inferred from the present study design.

We agree that the present analysis is cross-sectional in nature because cardiovascular comorbidities and renal status were assessed contemporaneously during hospitalization. However, the study was conducted within a retrospectively assembled cohort of hospitalized patients with multiple myeloma. To avoid confusion, we have emphasized throughout the manuscript that the reported findings represent descriptive cross-sectional associations observed within this retrospective cohort.

3. The definition of advanced CKD remains somewhat problematic. The manuscript combines eGFR <30 mL/min/1.73 m² and creatinine clearance <30 mL/min, but it is unclear:

• whether eGFR was systematically available in all patients;
• which equation was used for eGFR calculation;
• whether creatinine clearance was estimated or directly measured;
• whether acute kidney injury at hospitalization may have influenced classification.

This is particularly important in multiple myeloma, where acute kidney injury, dehydration, and paraprotein-related renal dysfunction may transiently alter renal indices. The manuscript should better clarify how chronic versus acute renal dysfunction was distinguished.

We thank the reviewer for this important comment and agree that further clarification regarding renal function assessment is warranted.

Estimated glomerular filtration rate (eGFR) was routinely available in the hospital electronic medical record system and was automatically reported by the institutional laboratory using the CKD-EPI 2021 equation. This parameter was available for all patients included in the study.

Classification of chronic kidney disease was not based solely on a single creatinine measurement obtained at admission. CKD status was established using both documented pre-existing CKD diagnoses recorded in the patients’ medical history and renal function parameters available during hospitalization. Advanced CKD was defined as CKD stages 4–5, corresponding to an eGFR <30 mL/min/1.73 m².

Patients with isolated acute kidney injury were excluded from the study. For patients presenting with elevated serum creatinine without a previously documented diagnosis of CKD, renal function was reassessed throughout hospitalization, including serial serum creatinine measurements and evaluation at discharge following treatment of reversible contributing factors. Previous medical records available in the electronic health system were also reviewed to identify documented CKD before the index hospitalization. This approach was used to minimize misclassification of transient renal dysfunction as chronic kidney disease.

We have revised the Methods section to clarify the renal function assessment, the use of the CKD-EPI 2021 equation, and the procedures used to distinguish chronic kidney disease from isolated acute kidney injury.

 

4. The multivariable analysis should be interpreted very cautiously. The adjusted model includes only four covariates in a relatively small cohort, while diabetes mellitus and hypertension were excluded due to missing data and model instability. However, these are the dominant comorbidities in the cohort and likely major confounders of the observed cardio-renal associations. Therefore, the adjusted analysis is probably under-adjusted and should not be interpreted as demonstrating independent associations.

 We thank the reviewer for this important observation and agree that the adjusted model should be interpreted with caution.

The multivariable analysis was performed as an exploratory analysis within a relatively small cohort. Diabetes mellitus and hypertension were initially considered for inclusion; however, their extremely high prevalence, limited variability, and substantial missing data resulted in model instability and unreliable coefficient estimates. For this reason, they were not retained in the final adjusted model.

We agree that diabetes mellitus and hypertension are important cardio-renal comorbidities and may act as major confounders of the observed associations. Therefore, the adjusted model should not be interpreted as demonstrating independent associations or causal relationships. Rather, it should be viewed as an exploratory assessment of cross-sectional associations within a hospitalized cohort of patients with multiple myeloma.

To address the reviewer's concern, we have revised the Results, Discussion, and Conclusions sections to further emphasize the exploratory nature of the multivariable analysis and the possibility of residual confounding.

 

5. The Discussion repeatedly refers to integrated cardio-renal assessment and cardiac amyloidosis. While clinically relevant, these aspects are largely speculative in the current dataset because systematic echocardiography, cardiac biomarkers, cardiac MRI, and standardized amyloidosis evaluation were not available. Consequently, some paragraphs become disproportionately broad relative to the actual data generated by the study. The Discussion should remain more closely aligned with the observational findings.

 We thank the reviewer for this thoughtful comment and agree that some sections of the Discussion extended beyond the data directly available in the present study.

Our intention was to place the observed cardio-renal burden in the broader clinical context of multiple myeloma, where cardiac amyloidosis represents an important but frequently underrecognized complication. However, we acknowledge that systematic assessment for cardiac amyloidosis, including standardized cardiac biomarkers, cardiac magnetic resonance imaging, and dedicated diagnostic protocols, was not available in our cohort.

In response to the reviewer's suggestion, we have revised and shortened the relevant Discussion sections, reduced speculative statements regarding cardiac amyloidosis, and more clearly emphasized that these considerations are provided as contextual background rather than findings derived from our dataset. The revised Discussion now focuses more closely on the observed coexistence of advanced CKD and cardiovascular comorbidities within the study population.

 

6. Several analyses appear somewhat redundant and do not substantially contribute to the main objective of the manuscript. For example:

• extensive histogram presentation of biological variables;
• repeated sex comparisons;
• age-group boxplots without significant findings;
• broad correlation analyses with weak or expected correlations.

These sections make the manuscript unnecessarily long relative to the simplicity of the main findings and could be substantially streamlined.

We thank the reviewer for this valuable suggestion. In response, we substantially streamlined the Results section by reducing analyses that were not directly related to the primary study objective.

The detailed correlation analysis and corresponding table were removed. Age-group analyses were condensed to a brief summary statement because no statistically significant differences were identified. Sex-based comparisons were shortened, and graphical presentation of these findings was removed. These revisions allowed the manuscript to focus more directly on the coexistence of advanced CKD and cardiovascular comorbidities in hospitalized patients with multiple myeloma.

 

7. The manuscript occasionally overstates the clinical implications of statistically fragile findings. For example: atrial fibrillation loses statistical significance after adjustment (p = 0.076); myocardial ischemia reverses directionality in multivariable analysis; confidence intervals are wide throughout. Therefore, statements suggesting clinically meaningful associations should be tempered more carefully.

 We thank the reviewer for this important observation and agree that the clinical interpretation of the statistical findings should be appropriately tempered.

The primary purpose of the study was to describe the coexistence of cardiovascular comorbidities and advanced CKD within a hospitalized multiple myeloma cohort. As noted by the reviewer, the associations observed in univariate analyses were attenuated after multivariable adjustment, and atrial fibrillation no longer reached conventional statistical significance. Furthermore, the confidence intervals were relatively wide, reflecting the limited sample size and uncertainty of the estimates.

In response to the reviewer's comment, we have revised the Abstract, Results, Discussion, and Conclusions sections to avoid overinterpretation of the findings and to emphasize the exploratory and descriptive nature of the observed associations. The revised manuscript no longer implies clinically meaningful independent associations and instead highlights that the findings describe patterns of coexistence that require confirmation in larger prospective studies.

 

Minor comments

 

• Several grammatical and stylistic inconsistencies remain throughout the manuscript. Examples include: “advanced CKD and cardiovascular disease frequently coexist” followed by repetitive wording later in the same paragraph; “The usefullness of immunohistochemistry” in reference 33 should be corrected to “usefulness”; inconsistent spacing around percentages and p-values; inconsistent abbreviation formatting (e.g., NTproBNP instead of NT-proBNP).

 

We thank the reviewer for this careful reading of the manuscript and for identifying several grammatical, stylistic, and formatting inconsistencies.

We have thoroughly revised the manuscript to improve language quality, consistency, and readability. Specifically, repetitive wording has been corrected, terminology has been standardized throughout the text, and grammatical errors have been addressed. We have also revised reference 33 ("usefullness" corrected to "usefulness"), standardized abbreviation formatting (including NT-proBNP), and corrected spacing and punctuation inconsistencies around reported statistical values and p-values.

In addition, the entire manuscript has undergone a comprehensive language and style review to ensure consistency with scientific writing standards.

 

• The references should be revised carefully. Several citations appear only loosely related to the specific objective of the manuscript, and the bibliography is disproportionately extensive for a relatively small retrospective study. 

We thank the reviewer for this suggestion. The bibliography was carefully reviewed and streamlined. Several references that were only indirectly related to the study objectives were removed, particularly those not directly addressing multiple myeloma, chronic kidney disease, or cardiovascular comorbidities. The Discussion section was also condensed to maintain closer alignment with the study findings and dataset. These revisions reduced the overall length of the bibliography while preserving the references considered essential for contextualizing the results.

 

• Table 3 should specify more clearly whether odds ratios derive from crude univariate logistic regression or simple contingency analysis. 

 

We thank the reviewer for this helpful comment.

To improve clarity, we have revised the manuscript and Table 3 to explicitly indicate that the reported odds ratios were derived from univariate logistic regression analyses. The table title and corresponding Methods section have been updated accordingly.

 

• Authors repeatedly use terms such as “advanced CKD burden” and “clinical impact” despite the absence of outcome analyses (mortality, dialysis, cardiovascular events, hospitalization duration). More neutral wording would improve scientific precision. 

 

We thank the reviewer for this important observation and agree that certain expressions could imply clinical consequences that were not directly assessed in the present study.

The study was designed to describe the coexistence of advanced CKD and cardiovascular comorbidities in a hospitalized multiple myeloma cohort and did not evaluate clinical outcomes such as mortality, cardiovascular events, rehospitalization, or length of hospital stay.

In response to the reviewer's comment, we have carefully revised the manuscript and replaced terms such as "clinical impact", "advanced CKD burden", and similar expressions with more neutral wording focused on prevalence, coexistence, and descriptive associations. The revised text more accurately reflects the scope of the data and avoids implying outcome-related effects that were not directly assessed.

 

We are looking forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have.

Sincerely,

Dr. Beatrice Bălăceanu-Gurău

Corresponding Author

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor,

I thank the authors for their revised manuscript and for their detailed response to my previous comments. Several requested changes have been implemented, particularly the more cautious interpretation of the findings, the clarification that the analysis is exploratory, and the additional description of the CKD definition and multivariable model.

However, I still have some concerns before acceptance.

1. First, there appears to be an important inconsistency regarding the prevalence of advanced CKD. In the response letter, the authors state that advanced CKD is reported as 94/116 patients (81.0%). However, in the manuscript this figure appears to refer to CKD overall, whereas advanced CKD is reported as 55/116 patients in the Abstract and as 55/94 patients among those with CKD in the Results. This should be corrected and reported consistently throughout the Abstract, Results, Tables, and Discussion.
2. Second, although the authors now report comorbidities with denominators, the very different denominators across variables remain a major limitation. The authors should make this even clearer, especially in Figure 2 and in the interpretation of diabetes, hypertension, atrial fibrillation, myocardial ischemia, and heart failure prevalence.
3. Third, the multivariable model still requires clarification. The authors state that the complete-case model included 116 patients, but some cardiovascular comorbidity variables appear to have lower denominators. The authors should clarify how missing comorbidity data were handled and whether missing values were treated as absent diagnoses or excluded from the model.

Comments on the Quality of English Language

Several minor language and formatting issues should be corrected.

Author Response

Dear Editorial Team,

We sincerely thank you for giving us the opportunity to resubmit a revised draft of our manuscript. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on our paper. We have been able to incorporate changes to reflect all of the suggestions provided by the reviewers. Here is a point-by-point response to the reviewers’ comments and concerns.

Reviewer 1

Dear Editor,

I thank the authors for their revised manuscript and for their detailed response to my previous comments. Several requested changes have been implemented, particularly the more cautious interpretation of the findings, the clarification that the analysis is exploratory, and the additional description of the CKD definition and multivariable model.However, I still have some concerns before acceptance.

1. First, there appears to be an important inconsistency regarding the prevalence of advanced CKD. In the response letter, the authors state that advanced CKD is reported as 94/116 patients (81.0%). However, in the manuscript this figure appears to refer to CKD overall, whereas advanced CKD is reported as 55/116 patients in the Abstract and as 55/94 patients among those with CKD in the Results. This should be corrected and reported consistently throughout the Abstract, Results, Tables, and Discussion.

 

We thank the reviewer for this important observation. We agree that CKD and advanced CKD should be clearly distinguished throughout the manuscript. CKD (all stages) was present in 94 of 116 patients (81.0%) with available renal data, whereas advanced CKD, defined as eGFR <30 mL/min/1.73 m², was present in 55 of 116 patients (47.4%). We carefully revised the manuscript to ensure that advanced CKD is reported consistently according to its predefined definition in the Abstract, Results, Discussion, and Conclusions. Any instances in which the prevalence of CKD (all stages) was inadvertently described as advanced CKD have been corrected.

CKD classification was available for 116 patients, whereas quantitative eGFR measurements were available for 112 patients. In four patients, CKD status was determined from documented medical history and clinical records despite the absence of a recorded eGFR value in the study database.

 

2. Second, although the authors now report comorbidities with denominators, the very different denominators across variables remain a major limitation. The authors should make this even clearer, especially in Figure 2 and in the interpretation of diabetes, hypertension, atrial fibrillation, myocardial ischemia, and heart failure prevalence.

 

We thank the reviewer for this important observation. We agree that the varying denominators across comorbidity variables represent a major limitation of retrospective data collection. We have expanded the Figure 2 legend, Results, and Discussion sections to emphasize that prevalence estimates were calculated using available-case denominators and that data completeness differed substantially across variables. We additionally report prevalence estimates using the entire cohort as the denominator and clarify that the very high percentages observed for diabetes mellitus, hypertension, atrial fibrillation, myocardial ischemia, and heart failure should not be interpreted as population-level prevalence estimates. To facilitate interpretation, we additionally calculated prevalence estimates using the entire cohort (n = 137) as the denominator. These analyses confirmed that the very high prevalence values reported using available-case denominators were influenced by variable data completeness across comorbidity variables.

 

3. Third, the multivariable model still requires clarification. The authors state that the complete-case model included 116 patients, but some cardiovascular comorbidity variables appear to have lower denominators. The authors should clarify how missing comorbidity data were handled and whether missing values were treated as absent diagnoses or excluded from the model.

 

We thank the reviewer for this important comment. The multivariable logistic regression analysis was performed using a complete-case approach. The outcome variable was advanced CKD, defined as eGFR <30 mL/min/1.73 m². The analysis was restricted to the subset of 116 patients with sufficient renal data available for CKD classification. Among these patients, 55 met the definition of advanced CKD. Missing values were not imputed and were not treated as absence of a diagnosis. Variables with a substantial proportion of missing data, including diabetes mellitus and hypertension, were excluded from the final adjusted model because their inclusion would have substantially reduced the analyzable sample size and compromised model stability. The final multivariable model therefore included age, sex, atrial fibrillation, and myocardial ischemia. We have revised the Methods and Results sections to clarify the study population included in the adjusted analysis and the handling of missing data.

 

Comments on the Quality of English Language

Several minor language and formatting issues should be corrected.

 

We thank the reviewer for this observation. The manuscript has been carefully revised for language, grammar, style, and formatting. Minor linguistic inconsistencies and typographical errors were corrected throughout the text, and the manuscript was reviewed to improve clarity and readability.

 

We are looking forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have.

Sincerely,

Dr. Beatrice Bălăceanu-Gurău

Corresponding Author

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have carefully addressed the reviewer comments and substantially improved the manuscript. The revised version provides a clearer definition of advanced CKD, a more transparent description of comorbidity ascertainment, and a more balanced interpretation of the observed associations.Importantly, the authors now appropriately acknowledge the cross-sectional nature of the analyses, the limitations related to retrospective data collection, the potential impact of coding and misclassification bias, and the exploratory nature of the multivariable model. The Discussion and Conclusions have been revised accordingly and are now much more consistent with the study design and the available data.

I have no further major concerns. The remaining issues are minor and mainly editorial in nature.

Author Response

Dear Editorial Team,

We sincerely thank you for giving us the opportunity to resubmit a revised draft of our manuscript. We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments on our paper. We have been able to incorporate changes to reflect all of the suggestions provided by the reviewers. Here is a point-by-point response to the reviewers’ comments and concerns.

 

Reviewer 2

The authors have carefully addressed the reviewer comments and substantially improved the manuscript. The revised version provides a clearer definition of advanced CKD, a more transparent description of comorbidity ascertainment, and a more balanced interpretation of the observed associations. Importantly, the authors now appropriately acknowledge the cross-sectional nature of the analyses, the limitations related to retrospective data collection, the potential impact of coding and misclassification bias, and the exploratory nature of the multivariable model. The Discussion and Conclusions have been revised accordingly and are now much more consistent with the study design and the available data.

I have no further major concerns. The remaining issues are minor and mainly editorial in nature.

 

We highly appreciate the reviewer's careful evaluation of the revised manuscript and for the positive feedback. We appreciate the reviewer’s recognition of the efforts made to clarify the definition of advanced CKD, improve the description of comorbidity ascertainment, and provide a more cautious interpretation of the findings. We are pleased that the revisions have addressed the major concerns raised during the previous review round. We have carefully reviewed the manuscript once again and corrected minor language and formatting issues where appropriate.

 

We are looking forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have.

Sincerely,

Dr. Beatrice Bălăceanu-Gurău

Corresponding Author

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Editor, I have reviewed the revised version of the manuscript and the authors’ point-by-point response. Overall, the authors have made a substantial effort to address the previous comments, and the manuscript has improved considerably. However, they should perform a final language and formatting check, including consistency between the Abstract, Results, tables/figures, and Discussion.

Comments on the Quality of English Language

Several minor language and formatting issues should be corrected.

Author Response

Please see the attachment. 

 

Author Response File: Author Response.pdf