Acute Kidney Injury in the Context of COVID-19: An Analysis in Hospitalized Mexican Patients

Round 1

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

Thanks for allowing me to review the paper from Mexico. Hola

This is a retrospective analysis of the patients with COVID19 in 2020 with and without AKI and the association analysis of various parameters including death. It become difficult to consider that "all patients gave informaed consent" with reasonable mortality in the group. 

In the definition of AKI, increase in BUN and S Creatinine is a expected and marker of diagnosis, and the severity of the AKI is better correlate to study, rather than just random numbers. 

Increase in AKI is rather a surragte marker of the severity of infections and inflammatory response, and no data is presented to claim "effective management of AKI with alleviate the negative consequences of COVID". It is rather a subset of patients with worse disease COVID and association with AKI as one of the complication.

If valid estimates of the parameters of a finite population are to be produced, the finite population needs to be defined very precisely and the sampling method needs to be carefully designed and implemented. This entry focuses on the estimation of such finite population parameters using what is known as the randomization or design-based approach. This is lacking in the description. 

Use of AKIN Criteria should elaborate AKIN Classification (Stage 1 to 3) to assess the outcomes. This is unclear from the data presented. 

 

Introduction be succint and be relevant to the population in the study. It is also worth noting that incidence of Covid mortality has significantly reduced all over the world since 2020, and thus the comparison should be only to the group in 2020 in other studies. 

The study population is small to make strong conclusions, where selection process seems less clear and then the data collection that is not predefined. There is no data on the recovery of AKI, peak effect of AKIand characteristics of patients with high grade complications including mortality. 

Presentation of the data to the point would be more helpful to understand the point to be delivered. 

The outcomes studied are of limited utility to change the clinical practice. I suggest review following rephrasing in a clear and consice manner. 

 

 

Comments on the Quality of English Language

It is winded way of presentation with repetition of obvious. 

Author Response

Thanks for allowing me to review the paper from Mexico. Hola

This is a retrospective analysis of the patients with COVID19 in 2020 with and without AKI and the association analysis of various parameters including death. It become difficult to consider that "all patients gave informaed consent" with reasonable mortality in the group. 

In the definition of AKI, increase in BUN and S Creatinine is a expected and marker of diagnosis, and the severity of the AKI is better correlate to study, rather than just random numbers. 

Increase in AKI is rather a surragte marker of the severity of infections and inflammatory response, and no data is presented to claim "effective management of AKI with alleviate the negative consequences of COVID". It is rather a subset of patients with worse disease COVID and association with AKI as one of the complication.

If valid estimates of the parameters of a finite population are to be produced, the finite population needs to be defined very precisely and the sampling method needs to be carefully designed and implemented. This entry focuses on the estimation of such finite population parameters using what is known as the randomization or design-based approach. This is lacking in the description. 

Use of AKIN Criteria should elaborate AKIN Classification (Stage 1 to 3) to assess the outcomes. This is unclear from the data presented. 

Introduction be succint and be relevant to the population in the study. It is also worth noting that incidence of Covid mortality has significantly reduced all over the world since 2020, and thus the comparison should be only to the group in 2020 in other studies. 

The study population is small to make strong conclusions, where selection process seems less clear and then the data collection that is not predefined. There is no data on the recovery of AKI, peak effect of AKI and characteristics of patients with high grade complications including mortality. 

Presentation of the data to the point would be more helpful to understand the point to be delivered. 

The outcomes studied are of limited utility to change the clinical practice. I suggest review following rephrasing in a clear and consice manner. 

Reply: Thank you for your comments. Hola. We have added a graph about the selection and calculation of the population (Figure 1). We have also added AKI works on COVID-19 in Mexico (citations 26-29). We have added the AKIN Classification to our analyzes.

We have compared our work with studies from 2020 or with work on patient samples from this year. Finally, we have highlighted the contribution of this article, such as the prevalence of AKI in 25.3% of patients with COVID-19, the factors associated with it, such as advanced age (>65 years), high blood pressure, higher leukocyte count at admission and during the hospital stay, and elevated levels of C-reactive protein, serum creatinine, and blood urea nitrogen (BUN). The clinical consequences associated with signs of prostration, pneumonia, and the need for ventilatory assistance. Additionally, patients with AKI had a mortality rate of 74%.

Reviewer 2 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

The revised manuscript is significantly improved.  I note that only 25% of the patients (with a high proportion of elderly and multiple comorbidities) were vaccinated against COVID.  It would be appropriate to emphasize the importance of vaccination in this high risk group.  The authors should consider shortening the manuscript.

Author Response

Reviewer 2

The revised manuscript is significantly improved.  I note that only 25% of the patients (with a high proportion of elderly and multiple comorbidities) were vaccinated against COVID.  It would be appropriate to emphasize the importance of vaccination in this high risk group.  The authors should consider shortening the manuscript.

Reply: Thanks for your comments. We have synthesized the content of the article and added new statistical analyses.

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

I read with interest the article on AKI in COVID -19 patients in Mexican patient by Juan Carlos Borrego Moreno, et al. They wanted to investigate the occurrence and consequences of AKI in Mexican patients with COVID-19 and at the same time identify the factors associated with AKI in Mexican individuals with COVID-19. The manuscript addresses an interesting topic for daily medicine. However, the article suffers from major shortcomings that severely limit its value. The biggest shortcoming is that it does not provide any new insights.   I have some comments on the concept of the analysis, the statistics, the discussion and the conclusions.   Comments:

1.    Authors should follow the STROBE checklist for conducting an observational analysis.

2.    The number of patients included is small. Why were not all available patients included in the study? The patient population consisted of 1019 patients. Why were only 313 patients included in the study although data from more patients were available? Please also indicate the inclusion and exclusion criteria. It is difficult to understand why not all patients were included in the study, which would certainly have led to a better representativeness of the results.

3.    Make a figure of the patient selection flow chart.

4.    The authors did not examine the relationship between some variables and AKI. The authors only reported the differences between the groups and did not attempt to assess the relationship between specific parameters and AKI.

5.    The statistics are insufficient. Please use appropriate statistical analysis to assess the relationship between specific variables and AKI, which was one of the aims of the study. In addition, the authors should describe how they selected the variables included in the model.

6.    Line 173-176:« Furthermore, the male gender was predominant, representing 57.83% (n=181) of the total sample size. Additionally, 16.29% (n=51) of the patients are retired. It was discovered that a majority, 86.9% (n=272) of the patients reside in the central region of the state of Zacatecas (Table 1«. There was no difference between the groups in terms of gender and obesity. Please reformulate. It is logical that older patients in the AKI group were more likely to be retired. Please state the reason for including occupational engagement in the analysis.

7.    Please indicate in the text only the summary of the differences between the groups. Otherwise, the tables are of no additional value. As it is now, the text only duplicates the data already mentioned in the tables.

8.    The authors found that patients who were sicker were more likely to suffer AKI. It is generally known that sicker patients are more likely to suffer from AKI. In addition, It is generally known that patients with AKI (regardless of the underlying disease) have a higher mortality rate. There is nothing new in the analysis. The aim of the article was to identify likely predictors of AKI, but this was not done.

9.    The authors should define their endpoints. They need to decide what they want to evaluate and which groups they want to compare. They should also explain why they are looking at the 20-day mortality rate and not the in- hospital or 30-day mortality rate, which is usually the case.

10.  Please provide the data on COVID-19 antiviral drugs in both groups.

11.  Abbreviations should be explained the first time they are used.

12.  The article contains many inconsistencies. In the text, the authors compare the 20-day mortality. However, in the Kaplan-Meier analysis, they observed patients for up to 45 days. Please correct.

 

This article contains many inconsistencies, ambiguities and sometimes contradictions.
It should be written more carefully and describe the facts more accurately and consistently.
The authors should decide what they wanted to study and which patient groups they wanted
to compare and how. They should define the end-points. Also, these data should be presented
and analyzed in an appropriate way, with correct definitions, correct statistics and an
appropriate conclusion. As it stands, the study does not add value to the field of internal
medicine. They should consider performing the proposed statistical analyzes and then
adjusting and rewriting the discussion accordingly. However, a lot of work has been put
into the study, a lot of data has been collected and it has some potential.

 

Author Response

Reviewer 3

I read with interest the article on AKI in COVID -19 patients in Mexican patient by Juan Carlos Borrego Moreno, et al. They wanted to investigate the occurrence and consequences of AKI in Mexican patients with COVID-19 and at the same time identify the factors associated with AKI in Mexican individuals with COVID-19. The manuscript addresses an interesting topic for daily medicine. However, the article suffers from major shortcomings that severely limit its value. The biggest shortcoming is that it does not provide any new insights.   I have some comments on the concept of the analysis, the statistics, the discussion and the conclusions.   

 

Comments:

1. Authors should follow the STROBE checklist for conducting an observational analysis.
2. The number of patients included is small. Why were not all available patients included in the study? The patient population consisted of 1019 patients. Why were only 313 patients included in the study although data from more patients were available? Please also indicate the inclusion and exclusion criteria. It is difficult to understand why not all patients were included in the study, which would certainly have led to a better representativeness of the results.
3. Make a figure of the patient selection flow chart.

 

Reply: Thank you for your comments. Despite the medical records of the 1019 patients being available, our institution tells us that we must take a population sample to guarantee the anonymity of the patient data. We have added a Flow chart about the inclusion criteria and sample calculation in the methods section.

 

4. The authors did not examine the relationship between some variables and AKI. The authors only reported the differences between the groups and did not attempt to assess the relationship between specific parameters and AKI.
5. The statistics are insufficient. Please use appropriate statistical analysis to assess the relationship between specific variables and AKI, which was one of the aims of the study. In addition, the authors should describe how they selected the variables included in the model.

 

Reply: Thank you for your comments. We added new statistical analyses to our study and used the AKIN classification. The variables were chosen in accordance with other similar studies analyzing the prevalence of AKI in COVID-19. However, one limitation of this retrospective study is the homogeneity in the availability of data, an issue that was also related to the choice of variables.

 

6. Line 173-176:« Furthermore, the male gender was predominant, representing 57.83% (n=181) of the total sample size. Additionally, 16.29% (n=51) of the patients are retired. It was discovered that a majority, 86.9% (n=272) of the patients reside in the central region of the state of Zacatecas (Table 1«. There was no difference between the groups in terms of gender and obesity. Please reformulate. It is logical that older patients in the AKI group were more likely to be retired. Please state the reason for including occupational engagement in the analysis.
7. Please indicate in the text only the summary of the differences between the groups. Otherwise, the tables are of no additional value. As it is now, the text only duplicates the data already mentioned in the tables.

 

Reply: Thank you for your comments. We have rephrased the sentence.

8. The authors found that patients who were sicker were more likely to suffer AKI. It is generally known that sicker patients are more likely to suffer from AKI. In addition, It is generally known that patients with AKI (regardless of the underlying disease) have a higher mortality rate. There is nothing new in the analysis. The aim of the article was to identify likely predictors of AKI, but this was not done.

 

9. The authors should define their endpoints. They need to decide what they want to evaluate and which groups they want to compare. They should also explain why they are looking at the 20-day mortality rate and not the in- hospital or 30-day mortality rate, which is usually the case.

 

Reply: Thanks for your comments. We have made the changes to the patient mortality data. We have also carried out a relative risk analysis between our variables. Finding that age (>65 years), arterial hypertension, high creatinine levels, endotracheal intubation, and pneumonia are associated with the development of AKI. On the other hand, among the protective factors against AKI, high hemoglobin levels and the consumption of statins during COVID-19 were found.

 

10. Please provide the data on COVID-19 antiviral drugs in both groups.

Reply: Thank you for your comments. During the study period, no antivirals were approved for use in COVID-19, hence the absence of this data.

 

11. Abbreviations should be explained the first time they are used.

Reply: Thank you for your comments. We have corrected the paper.

 

12. The article contains many inconsistencies. In the text, the authors compare the 20-day mortality. However, in the Kaplan-Meier analysis, they observed patients for up to 45 days. Please correct.

Reply: Thank you for your comments. We have corrected the sentence. “The examination of the Kaplan-Meier curve revealed an apparent elevated death rate among patients who developed AKI during the first 20 days of hospital stay compared to those who did not have AKI, a distinction that continued until 45 days of stay”.

Reviewer 4 Report (New Reviewer)

Comments and Suggestions for Authors

Borrego Moreno JC retrospectively investigated the occurrence and consequences of AKI in 1,019 Mexican patients diagnosed with COVID-19 at the IMSS Zacatecas General Hospital

After the selection of 313 cases by a finite population technique to ensure representativeness, they found 54 cases of AKI (25.30%prevalence), with a 74% mortality rate. The patients with AKI exhibited an advanced age (>65 years), high blood pressure, a higher number of white blood cells during admission and the hospital stay, and elevated levels of C-reactive protein serum creatinine, and blood urea nitrogen (BUN). Clinically, patients with AKI presented signs of prostration, and pneumonia, and required a higher rate of ventilator assistance.

The Authors concluded that prompt identification and management of AKI could potentially alleviate the negative consequences of this complication within the Mexican population during COVID-19.

 

General comment

Thanks for allowing me to review this paper. This is an epidemiological study, that examined the risk factors for AKI and in-hospital mortality in a cohort of Mexican patients with Covid-19. This paper has the novelty of exploring the Mexican population. However, data on Covid-19 are growing and updates on this topic are welcome.

 

Major comments
1) The Authors wrote in lines 167-168 “A prevalence of AKI amounting to 25.30% (n=54) was identified throughout the entire cohort of cases under evaluation”. However, 54/313=0.172. Please check the correct % of AKI prevalence.

2) In tab. 3 please separately provide creatinine and C-reactive protein of patients with COVID-19 upon admission and during hospitalization

3) The Authors showed that the patients with COVID + and AKI died at a higher rate and that the patients with AKI presented a higher WBC count and C-reactive protein upon admission and a higher rate of pneumonia. As higher WBC count and C-reactive protein upon admission are risk factors for mortality too (or they could indicate a picture of sepsis-associated AKI), AKI could have been an epiphenomenon present in the last days before the fatal outcome due to pneumonia, or expression of an AKI stage III needing CKRT.  I suggest analyzing the peak of creatinine and the stage reached upon the death of the AKI group  

Based on the results, please discuss the suggested meaning of AKI for the mortality risk.

Comments on the Quality of English Language

good

Author Response

Reviewer 4

Borrego Moreno JC retrospectively investigated the occurrence and consequences of AKI in 1,019 Mexican patients diagnosed with COVID-19 at the IMSS Zacatecas General Hospital

After the selection of 313 cases by a finite population technique to ensure representativeness, they found 54 cases of AKI (25.30%prevalence), with a 74% mortality rate. The patients with AKI exhibited an advanced age (>65 years), high blood pressure, a higher number of white blood cells during admission and the hospital stay, and elevated levels of C-reactive protein serum creatinine, and blood urea nitrogen (BUN). Clinically, patients with AKI presented signs of prostration, and pneumonia, and required a higher rate of ventilator assistance.

The Authors concluded that prompt identification and management of AKI could potentially alleviate the negative consequences of this complication within the Mexican population during COVID-19.

 

General comment

Thanks for allowing me to review this paper. This is an epidemiological study, that examined the risk factors for AKI and in-hospital mortality in a cohort of Mexican patients with Covid-19. This paper has the novelty of exploring the Mexican population. However, data on Covid-19 are growing and updates on this topic are welcome.

 

Major comments
1) The Authors wrote in lines 167-168 “A prevalence of AKI amounting to 25.30% (n=54) was identified throughout the entire cohort of cases under evaluation”. However, 54/313=0.172. Please check the correct % of AKI prevalence.

Reply: Thank you for your comments. We have corrected the data.

2) In tab. 3 please separately provide creatinine and C-reactive protein of patients with COVID-19 upon admission and during hospitalization

Reply: Thank you for your comments. Unfortunately, one of the limitations of our retrospective study is access to data. Sadly, we have no data on creatinine and CRP during hospitalization.

3) The Authors showed that the patients with COVID + and AKI died at a higher rate and that the patients with AKI presented a higher WBC count and C-reactive protein upon admission and a higher rate of pneumonia. As higher WBC count and C-reactive protein upon admission are risk factors for mortality too (or they could indicate a picture of sepsis-associated AKI), AKI could have been an epiphenomenon present in the last days before the fatal outcome due to pneumonia, or expression of an AKI stage III needing CKRT.  I suggest analyzing the peak of creatinine and the stage reached upon the death of the AKI group  

Based on the results, please discuss the suggested meaning of AKI for the mortality risk.

Reply: Thanks for your comments. We added new information to the discussion, including new analyses of risk and protective factors for the development of AKI during COVID-19.

 

Round 2

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

Thanks for allowing me to review the paper. Modifications are appropriate.

 

I may suggest "Finally, statin consumption seem to be/ associated with  a protective factor for the development of AKI (RR 268 0.824, CI 0.783, 95% 0.868)."

Comments on the Quality of English Language

Minor corrections to reflect association rather than definitive causation effect

Author Response

Reply: Thank you for your comments. We have made the suggested changes!

Reviewer 4 Report (New Reviewer)

Comments and Suggestions for Authors

I have no further comments

Comments on the Quality of English Language

good

Author Response

Reply: Thank you for your comments. We made changes to the English grammar to make the text clearer.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Reviewing for :

« Acute Kidney Injury in the Context of COVID-19: An Analysis 2 in Hospitalized Mexican Patients »

 

 

Major comments:

Abstract:

-          It is not clearly explained what you are comparing in the sentance : « Moreover, the individuals under study exhibited other distinguishing factors, including 38 being above the age of 65,… blood urea nitrogen (BUN) ». Furthermore comparing plasma creatinine between two groups of AKIN defined AKI present or not is really not relevant.

Methods:

-          Why does this study focus only on 313 patients and not 1019 ? This is a major issue. At least describe your finite population technique.

-          Why did you choose the AKIN definition and not the KDIGO criteria ?

Results:

-          Table 5, so some patients have AKI and COVID-19 but no pneumonia ? To what is their AKI related ? It seems really confiousing to compare patients with COVID-19 as the primary problem in hospitalisation and patients with probably others primary problems and also with a mild or indolent COVID-19 (given that these patients do not have COVID-19 pneumonia).

 

 

Minor comments:

Introduction:

-          Sentance from line 52 to 55 should be removed « It is imperative … circumstances ».

-          Line 65 to 82, it should be more relevant to talk about severe COVID-19, with ARDS definition or at least in the intensive care unit, because comparing incidence of COVID-19 associated AKI between studies everywhere in the world during the first wave is not relevant, the patients selected in these studies are not comparable in terms of severity.

Results:

-          Both table 1 and 2 are named « patients with COVID-19 », it’s either confusing or obvious

Author Response

Reviewer #1

Major comments:

Abstract:

-          It is not clearly explained what you are comparing in the sentance : « Moreover, the individuals under study exhibited other distinguishing factors, including 38 being above the age of 65,… blood urea nitrogen (BUN) ». Furthermore comparing plasma creatinine between two groups of AKIN defined AKI present or not is really not relevant.

Reply: Thanks for your comments. The abstract has been restructured for clarity.

Results: “The data showed a 25.30% prevalence of AKI among patients infected with severe COVID-19. Remarkably, these patients with AKI exhibited an advanced age (>65 years), high blood pressure, a higher number of white blood cells during admission and the hospital stay, and elevated levels of C-reactive protein, serum creatinine, and blood urea nitrogen (BUN). Clinically, patients with AKI had signs of prostration, pneumonia, and the requirement for ventilatory assistance when compared to those without AKI. Finally, those diagnosed with AKI and COVID-19 had a 74% death rate”

Methods:

-          Why does this study focus only on 313 patients and not 1019? This is a major issue. At least describe your finite population technique.

Reply: Thank you for your query on the cohort size in our study. The selection of 313 patients from a larger cohort was a statistically driven decision to ensure data completeness and robustness of our analysis, as per the AKIN criteria for AKI. This approach is consistent with the finite population correction principle, allowing for accurate extrapolation of our results to the broader population.

 

-          Why did you choose the AKIN definition and not the KDIGO criteria ?

Reply: Thanks for your comments. In this study was used the AKIN definition because KDIGO criteria removes the threshold of a 0.5 mg/dl increment for SCr >4 mg/dl in the criteria of stage 3 AKI. (REFERENCE: Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury Kidney Int Suppl, 2 (2012), pp. 1-138).

Results

-          Table 5, so some patients have AKI and COVID-19 but no pneumonia ? To what is their AKI related ? It seems really confiousing to compare patients with COVID-19 as the primary problem in hospitalisation and patients with probably others primary problems and also with a mild or indolent COVID-19 (given that these patients do not have COVID-19 pneumonia).

Reply: We agree with the reviewer. Some patients have AKI and COVID-19 but no pneumonia. However, the objective of this study was to determine the association between AKI and SARS-CoV-2 infection regardless of the presence of pneumonia, due to that SARS-CoV-2 could directly damage the kidney tubules through virus entry using the ACE2 receptor which is strongly expressed along the apical membrane of proximal tubule cells. (REFERENCE: https://doi.org/10.3390/ijms21093275)

 

Minor comments:

Introduction:

-          Sentance from line 52 to 55 should be removed « It is imperative … circumstances ».

Reply: Thanks for your comments. We consider relevant your comments and changes in the final version of the manuscript.

 

-          Line 65 to 82, it should be more relevant to talk about severe COVID-19, with ARDS definition or at least in the intensive care unit, because comparing incidence of COVID-19 associated AKI between studies everywhere in the world during the first wave is not relevant, the patients selected in these studies are not comparable in terms of severity.

Reply: We appreciate your comments. Effectively, the prevalence and incidence of AKI are not comparable because these values vary in different populations around the world. We, therefore, restructured the introduction based on the high mortality rates associated with AKI in patients with COVID-19, which are consistent in several studies and show the impact of AKI in severe cases.

Results:-    Both table 1 and 2 are named « patients with COVID-19 », it’s either confusing or obvious

Reply: Thanks for your comments. We consider relevant your comments, and changes in the final version of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Borrego Moreno et al. present a retrospective cohort study examining the relationships of various variables with AKI associated with hospitalised COVID 19 patients. Through examining  a representative cohort approximately 300 patients, they noted a prevalence of AKI and COVID19 in around 26% of the cohort. Through additional analysis they also noted an statistically significant associations with the following: age >65 years, arterial hypertension and various blood-based biomarkers including WBC and CRP. They also noted a significantly increased mortaility in patients with both pathologies with a rate of 74%. I have the following comments to make:

 

Line 60 – replace “damage” with “injury”. I would recommend this is replaced throughout the document. Keep consistent with the term “acute kidney injury”.

 

Lines 65-82 – this section fails to discuss the influence of co-morbidity in patients with AKI and COVID19. Often, such patients have other significant disease states which themselves can become decompensated and influence mortality in this cohort.

 

Lines 89-95 – I feel stronger justification for the study needs to be given e.g. why is this study specifically important for Mexican patients? How could the results shape practice and policy in Mexico?

 

Line 108 – can you please provide more description of how the 313 patients were selected using a finite population method? This could be added in an appendix if required. Moreover, do you think the number of patients sufficiently powered to look for differences? If you did power the study, did you consider post-hoc power analyses?

 

Line 111 – what PCR test was used specifically to diagnose COVID19. Did this change in the period examined too? 

 

Line 122-125 – I think there needs to be more justification why you chose the variables to be examined? How did you define the variables too? This needs more explanation e.g. how did you define arterial hypertension or obesity?

 

Table 1 – what proportion of patients exhibited CKD and how many had acute-on-chronic CKD? CKD itself would be a risk factor for a poorer prognosis in those with AKI+COVID19. Previous population studies have examined this.

 

Discussion section  - overall, I feel this is poor and the weakest part of the manuscript. The discussion only goes as far to compare with other group's results. This is not sufficient. There is little explanation given for the findings of the present study nor are there any suggestions for further work or possible practice changes based on the results. Also, little focus has been given to the Kaplan-Meier curve. I think this is important to discuss further e.g. why was there a divergence between both groups at d10? Furthermore, the strengths and limitations of the study have not been discussed. In your paragraph regarding ACEi/ARB, what would be your stance in stopping these agents in AKI with COVID19? I would personally stop them, temporarily at least. 

Comments on the Quality of English Language

English is a little convoluted in placed. Simpler language should be used. Especially in the introduction.

Author Response

Reviewer #2

Borrego Moreno et al. present a retrospective cohort study examining the relationships of various variables with AKI associated with hospitalised COVID 19 patients. Through examining  a representative cohort approximately 300 patients, they noted a prevalence of AKI and COVID19 in around 26% of the cohort. Through additional analysis they also noted an statistically significant associations with the following: age >65 years, arterial hypertension and various blood-based biomarkers including WBC and CRP. They also noted a significantly increased mortaility in patients with both pathologies with a rate of 74%. I have the following comments to make:

Line 60 – replace “damage” with “injury”. I would recommend this is replaced throughout the document. Keep consistent with the term “acute kidney injury”.

Reply: The suggested changes were made throughout the text. Thanks for your comments.

 

Lines 65-82 – this section fails to discuss the influence of co-morbidity in patients with AKI and COVID19. Often, such patients have other significant disease states which themselves can become decompensated and influence mortality in this cohort.

Reply: In the introduction, we only mentioned some of the factors that influence the development of AKI during COVID-19 disease, including comorbidities. However, in this new submission version, we have added the following paragraph (Line 80):

“It has been reported that the most common comorbidities conferring renal vulnerability to AKI are diabetes mellitus and hypertension, in addition to hyperlipidemia and chronic kidney disease (CKD), present in 40%, 61.4%, 57.1% and 22.2% of patients with COVID-19 and AKI, respectively [21,22]. However, these data are not comparable because the comorbidities and factors influencing the development of AKI are different for each population. Hence the necessity to carry out studies in several geographical regions to improve comparability”.

 

Lines 89-95 – I feel stronger justification for the study needs to be given e.g. why is this study specifically important for Mexican patients? How could the results shape practice and policy in Mexico?

Reply: Thanks for your comments. We appreciate the observation, we corroborated that in the manuscript a sentence related to this comment, this change can be noted in the final version of manuscript.

Line 96: “Clinical studies in Mexico have reported the lack of a national registry of AKI cases in the country, demonstrating the epidemiological precision of this disease. Additionally, clinical follow-up of individuals who presented episodes of AKI rarely occurs, thus limiting data regarding the outcome of the disease. The 23% of mortality associated with AKI is recorded by the health sector in Mexico, which is why it is important to identify additional factors that trigger AKI, such as COVID-19, which can generate public health efforts such as national nephrology programs that actively participate in the generation of or departments specializing in kidney diseases (PMID: 35721615)”

 

Line 108 – can you please provide more description of how the 313 patients were selected using a finite population method? This could be added in an appendix if required. Moreover, do you think the number of patients sufficiently powered to look for differences? If you did power the study, did you consider post-hoc power analyses?

Reply: In response to the request for a more detailed description of our patient selection using a finite population method and the statistical power of our study, we have prepared an appendix. This appendix will elucidate the selection methodology and the statistical considerations that underpin our analysis.

To address your query on the prevalence of AKI in our cohort, the 25.30% prevalence observed aligns with findings from various geographical regions. For instance, Bashir et al. (2022) reported a 12.7% prevalence in a Mogadishu cohort, while Morosini et al. (2021) observed a higher prevalence of 37.14% in a hospital in Italy. Moreover, Wen et al. (2020) found a 41% prevalence in severe and critical patients in Wuhan. These studies corroborate the prevalence rate we report, underscoring the variability of AKI incidence in COVID-19 patients across different settings.

We believe the sample size of 313 patients was adequately powered to detect differences in AKI prevalence, as substantiated by our initial power analysis. The detailed methodology and statistical analysis will be provided in the appendix of our manuscript.

“Appendix: Methodological Details on Patient Selection and Statistical Power

Patient Selection Methodology: The selection of 313 patients from a larger cohort was conducted with a focus on data completeness and adherence to AKIN criteria for AKI diagnosis. This was in accordance with finite population correction principles to ensure a representative sample.

Statistical Power Analysis: Our initial power analysis, based on expected AKI prevalence and effect size, indicated that our sample size was sufficient. This is supported by the prevalence rates reported in the literature, which vary significantly:

Bashir et al. (2022) found a 12.7% prevalence in their study, highlighting the lower end of the spectrum.

Morosini et al. (2021) observed a prevalence of 37.14%, demonstrating the higher variability in different patient populations.

Wen et al. (2020) reported a 41% prevalence in a subset of severe and critical patients, which is particularly relevant to our study's focus on hospitalized patients.

Conclusion: The appendix will conclude by affirming the methodological soundness of our approach and the statistical power of our study, with detailed references to the literature that supports our prevalence findings and sample size determination.”

References:

Bashir, A., et al. (2022). Prevalence of Acute Kidney Injury in Covid-19 Patients- Retrospective Single-Center Study. Link to article.

Morosini, U., et al. (2021). MO380INCREASED PREVALENCE OF ACUTE KIDNEY INJURY AND MORTALITY IN COVID-19 HOSPITALIZED PATIENTS. Link to article.

Wen, C., et al. (2020). Prevalence of Acute Kidney Injury in Severe and Critical COVID-19 Patients in Wuhan, China.

 

Line 111 – what PCR test was used specifically to diagnose COVID19. Did this change in the period examined too? 

Reply: Thanks for your comments. In 2020-2023, the General Hospital of Zone No. 1 of the IMSS Zacatecas, for the diagnosis of COVID-19, used the Logix Smart ABC (Influenza A/B, SARS-CoV-2) Test Kit. This information was added in the methods section.

 

Line 122-125 – I think there needs to be more justification why you chose the variables to be examined? How did you define the variables too? This needs more explanation e.g. how did you define arterial hypertension or obesity?

Reply: Thanks for your comments. All variables were based on clinically relevant and validated criteria, which are widely accepted in the medical community (WHO, JNC-8, AKIN, etc). In addition to the appropriate variables described in other studies of the severity of COVID-19 biomarkers or the context of AKI and COVID-19. This information was added to the variables section.

“Variables

The primary dependent variable in this study was the incidence of acute renal damage, as determined by the AKIN criteria, using the serum creatinine (SCr) criteria [24]. Independent variables were selected for their clinical relevance and their previously documented association with AKI in the context of severe respiratory infections, including COVID-19 [11,13,25–28]. These variables include demographic parameters, medical history, comorbidities, laboratory findings, clinical progression, and evaluation of AKI”

 

Table 1 – what proportion of patients exhibited CKD and how many had acute-on-chronic CKD? CKD itself would be a risk factor for a poorer prognosis in those with AKI+COVID19. Previous population studies have examined this.

Reply: Thanks for your comments. In our study, the presence of CKD was an exclusion criterion. This was added to the methods section.

 

Discussion section  - overall, I feel this is poor and the weakest part of the manuscript. The discussion only goes as far to compare with other group's results. This is not sufficient. There is little explanation given for the findings of the present study nor are there any suggestions for further work or possible practice changes based on the results. Also, little focus has been given to the Kaplan-Meier curve. I think this is important to discuss further e.g. why was there a divergence between both groups at d10? Furthermore, the strengths and limitations of the study have not been discussed. In your paragraph regarding ACEi/ARB, what would be your stance in stopping these agents in AKI with COVID19? I would personally stop them, temporarily at least.

Reply: Thanks for your comments. A restructuring of the discussion has been implemented to enhance clarity and ensure that every point raised is adequately addressed.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors report the impact of development of AKI in patients with COVID-19.  The manuscript is excessively long and would benefit from being shortened.  In particular, the tables could be shortened.  In Table 1 the relevance of disease incidence by employment status is unclear. Table 2 is excessively long and details of absence of sertain diseases could be deleted. Table 4 could be completely deleted.  

The following references could be added: 

Aukland EA, Klepstad P, Aukland SM, Ghavidel FZ, Buanes EA. Acute kidney injury in patients with COVID-19 in the intensive care unit: evaluation of risk factors and mortality in a national cohort. BMJ Open. 2022 Jun 23;12(6):e059046. doi: 10.1136/bmjopen-2021-059046. PMID: 35738654; PMCID: PMC9226471.

 

Schaubroeck, H., Vandenberghe, W., Boer, W. et al. Acute kidney injury in critical COVID-19: a multicenter cohort analysis in seven large hospitals in Belgium. Crit Care 26, 225 (2022). https://doi.org/10.1186/s13054-022-04086-x

 

Lumlertgul, N., Pirondini, L., Cooney, E. et al. Acute kidney injury prevalence, progression and long-term outcomes in critically ill patients with COVID-19: a cohort study. Ann. Intensive Care 11, 123 (2021). https://doi.org/10.1186/s13613-021-00914-5.

Comments on the Quality of English Language

The English language requires editing for conciseness.

Author Response

Reviewer #3

The authors report the impact of development of AKI in patients with COVID-19.  The manuscript is excessively long and would benefit from being shortened.  In particular, the tables could be shortened.  In Table 1 the relevance of disease incidence by employment status is unclear. Table 2 is excessively long and details of absence of sertain diseases could be deleted. Table 4 could be completely deleted.  

Response: Thanks for your comments. Some of the variables in Tables 1 and 2 have been eliminated. Regarding Table 4, we believe some data could be important for readers, so we have added it as a supplementary table, eliminating it from the main text.

 

The following references could be added: 

Aukland EA, Klepstad P, Aukland SM, Ghavidel FZ, Buanes EA. Acute kidney injury in patients with COVID-19 in the intensive care unit: evaluation of risk factors and mortality in a national cohort. BMJ Open. 2022 Jun 23;12(6):e059046. doi: 10.1136/bmjopen-2021-059046. PMID: 35738654; PMCID: PMC9226471.

Schaubroeck, H., Vandenberghe, W., Boer, W. et al. Acute kidney injury in critical COVID-19: a multicenter cohort analysis in seven large hospitals in Belgium. Crit Care 26, 225 (2022). https://doi.org/10.1186/s13054-022-04086-x

 

Lumlertgul, N., Pirondini, L., Cooney, E. et al. Acute kidney injury prevalence, progression and long-term outcomes in critically ill patients with COVID-19: a cohort study. Ann. Intensive Care 11, 123 (2021). https://doi.org/10.1186/s13613-021-00914-5.

 

Response: Thanks for your comments. This information has been added to the introduction and discussion sections.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Comments for author File: Comments.pdf

Author Response

Reviewer 1: Methods: - Why does this study focus only on 313 patients and not 1019? This is a major issue. At least describe your finite population technique.

Reply: Thank you for your query on the cohort size in our study. The selection of 313 patients from a larger cohort was a statistically driven decision to ensure data completeness and robustness of our analysis, as per the AKIN criteria for AKI. This approach is consistent with the finite population correction principle, allowing for accurate extrapolation of our results to the broader population.

Reviewer’s reply : This is a weakness of the study even if it’s is statistically correct, you loose statistical power.

Reply: Thank you for your comments. We agree with your statement. However, our institution (IMSS) requires us to guarantee the confidentiality of the data, which is why we are required to take a sample of the total population.

However, the sample size is similar to other AKI and COVID-19 studies.

https://doi.org/10.3390/healthcare11212903

https://doi.org/10.3390/healthcare11172402

https://doi.org/10.3390/jcm12134412

 

Why did you choose the AKIN definition and not the KDIGO criteria ?

Reply: Thanks for your comments. In this study was used the AKIN definition because KDIGO criteria removes the threshold of a 0.5 mg/dl increment for SCr >4 mg/dl in the criteria of stage 3 AKI. (REFERENCE: Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury Kidney Int Suppl, 2 (2012), pp. 1-138).

Reviewer’s reply : KDIGO definition is better than AKIN, recommanded by all the nephrology societies and more correlated to mortality

Reply: Thanks for your comments. We agree with you. However, in addition to the previous response, we can add that our institution's COVID-19 Protocol dictates the use of the AKIN criteria. One of the main limitations of our study is that it is a retrospective study, which is why we cannot adjust it to the criteria KDIGO.

 

Reviewer 1: - Table 5, so some patients have AKI and COVID-19 but no pneumonia ? To what is their AKI related ? It seems really confiousing to compare patients with COVID-19 as the primary problem in hospitalisation and patients with probably others primary problems and also with a mild or indolent COVID-19 (given that these patients do not have COVID-19 pneumonia).

Reply: We agree with the reviewer. Some patients have AKI and COVID-19 but no pneumonia. However, the objective of this study was to determine the association between AKI and SARS-CoV-2 infection regardless of the presence of pneumonia, due to that SARS-CoV-2 could directly damage the kidney tubules through virus entry using the ACE2 receptor which is strongly expressed along the apical membrane of proximal tubule cells. (REFERENCE: https://doi.org/10.3390/ijms21093275)

Reviewer’s reply : okay, proximal tubule cells express ACE2 receptor, but if a patient has a non severe upper airway infection by SARS-CoV-2, it is unlikely the virus will circulate in the blood, be filtred by the glomerulus and infect enough proximal tubular cells to be responsible of a significant kidney injury. The right design of the hypothesis you propose is to match patients with the same diseases or the same hospitalisation motif with and without covid-19 and to compare the incidence of AKI.

 

Reply:

Thanks for your comments. It must be clear that during COVID-19, various factors intervene in developing complications resulting from it. In this context, not only the viral load interferes.

Some studies have reported an association between glomerular disease and the development of AKI during COVID-19; remarkably, these patients had mild COVID-19 and did not require respiratory assistance. One of these factors is the predisposition of the APOL1 gene (DOI: 10.1681/ASN.2020060804). Although genetic predisposition predominantly affects Africans (DOI: 10.2215/CJN.15161219), it is also present in Latin Americans of African descent (DOI: 10.1681/ASN.2016030357).

There are even reports of COVID-19-associated nephropathy (COVAN), which is related to immune deregulation in patients with COVID-19 and is associated with the development of AKI. Remarkably, cytokines such as interleukin-1β, -6, -10, and IFN-γ are upregulated in SARS-CoV-2 infection (DOI: 10.1038/s41581-020-0332-3).

On the other hand, similar cases have been reported in infections with HIV-1 (HIVAN), and when comparing HIVAN and COVAN, viral detection in the kidneys seems to be more common in HIVAN than in COVAN (DOI: 10.1159/000312882).

Other biomarkers that have been observed to be related to the development of glomerular disease during COVID-19 are eGFR and TFGe, where levels below normal before COVID-19 have been associated with the development of AKI post-COVID-19 (DOI: 10.34067/KID.0006612021).

Given this diversity of uncontrollable previous factors in a population as diverse as the Mexican population, we set to analyze patients with similar diseases or the same reason for hospitalization with and without COVID-19 and compare the incidence of AKI.

Reviewer 2 Report

Comments and Suggestions for Authors

I am satisfied with the revisions made to the manuscript. In particular, the discussion now reads better.

Author Response

Thanks for your comments.