Long-Term Preoperative Atorvastatin or Rosuvastatin Use in Adult Patients before CABG Does Not Increase Incidence of Postoperative Acute Kidney Injury: A Propensity Score-Matched Analysis

Round 1

Reviewer 1 Report

In this paper, the authors have demonstrated the effect of long-term use of statins before CABG towards the incidence of postoperative AKI. The study is well designed, and the manuscript is written well, methods explained clearly and limitations explained.  However, in my opinion the paper has few minor shortcomings regarding data analyses as mentioned below.

Considering numerous previous publications reporting the effect of statins on postoperative AKI which are contradictory (Line 60-69). Authors might want to explain the reason of these inconsistent conclusions due to different settings, heterogenous population, and different inclusion and exclusion criteria. And most importantly how this study is unique as compared to other studies. The novelty of the study is not highlighted through out the manuscript.

In Introduction, a brief introduction of statins and their potential towards cardiovascular disorders is missing. This is important to lay a frame for the readers to follow the rationality of the study. Following which they can extrapolate the benefits of statins beyond cardiovascular diseases, towards the renoprotective effects against AKI.

Line 132. “Secondary endpoints were not studied”. Authors might want to explain why they have not considered important outcomes like onset of major adverse cardiovascular events during the post-operative hospital care in their analysis.

Discussion needs a major overhaul.

Line 240-243. “statin use did not have a significant positive effect …. with some cohort and randomized clinical trials”. The authors need to explain all the possible reasoning and conflicts, why their interpretation is same or different from previous studies.

Line 245-256. The scientific basis for statin therapy and its association to postoperative AKI needs to be explored here with emphasis on their mechanistic role and pharmacokinetic parameters. “background of the intake of statins ….. background of cardiac surgery” Please explain and revise this section.

The manuscript may be accepted following minor revision.

Author Response

Response to Reviewer 1

We are grateful to our reviewer for his or her very important comments to our work. We tried to correct all shortcomings according to these comments. All changes in the text are highlighted in green.

In this paper, the authors have demonstrated the effect of long-term use of statins before CABG towards the incidence of postoperative AKI. The study is well designed, and the manuscript is written well, methods explained clearly and limitations explained.  However, in my opinion the paper has few minor shortcomings regarding data analyses as mentioned below.

Considering numerous previous publications reporting the effect of statins on postoperative AKI which are contradictory (Line 60-69). Authors might want to explain the reason of these inconsistent conclusions due to different settings, heterogenous population, and different inclusion and exclusion criteria. And most importantly how this study is unique as compared to other studies. The novelty of the study is not highlighted through out the manuscript.

We have added this information to the article.

As we have already said, there are currently contradictory data on the effect of statins on kidney function in cardiac surgery. Initially considering statins as a preventive agent for the development of nephropathy after artificial circulation, they turned into "harmful" and "not recommended" medications. However, given the different research conditions, heterogenous population, different inclusion and exclusion criteria, not everything is so clear today.

Moreover, the ECTS manual emphasizes that no data are available on whether patients already taking statins should continue or discontinue therapy preoperatively, although in common practice statins are continued perioperatively.

The hypothesis of our study is precisely to prove that long-term use of statins before heart surgery "does not increase the frequency of AKI."

In Introduction, a brief introduction of statins and their potential towards cardiovascular disorders is missing. This is important to lay a frame for the readers to follow the rationality of the study. Following which they can extrapolate the benefits of statins beyond cardiovascular diseases, towards the renoprotective effects against AKI.

Thank you for advice. We have added this information to the article.

Line 132. “Secondary endpoints were not studied”. Authors might want to explain why they have not considered important outcomes like onset of major adverse cardiovascular events during the post-operative hospital care in their analysis.

Indeed, it was a completely erroneous proposal. We revised it.

Line 240-243. “statin use did not have a significant positive effect …. with some cohort and randomized clinical trials”. The authors need to explain all the possible reasoning and conflicts, why their interpretation is same or different from previous studies.

Line 245-256. The scientific basis for statin therapy and its association to postoperative AKI needs to be explored here with emphasis on their mechanistic role and pharmacokinetic parameters. “background of the intake of statins ….. background of cardiac surgery” Please explain and revise this section.

We tried to redo this section in the article.

Reviewer 2 Report

Major

1. As the authors themselves point out, numerous factors have been associated with risk for cardiothoracic surgery-associated AKI. Th authors include some of these factors in Table 1 and in the supplement. Other factors should be compared between the groups and included in Table 1. These factors include but are not limited to emergency vs. elective surgery, transfusion requirement, need for IABP or mechanical ventilation, etc. (see Thakar risk model).

Minor 

1. The authors conclude in line 36 and in multiple other places throughout the manuscript that "statin use before surgery does not increase the incidence of postoperative AKI". I suggest that the word "increase" be changed to "influence" since most studies suggest that statins either decrease or have no influence on the risk of AKI rather than increase risk.

Author Response

Response to Reviewer 2

We are grateful to our reviewer for his or her very important comments to our work. We tried to correct all shortcomings according to these comments. All changes in the text are highlighted in green.

Major

As the authors themselves point out, numerous factors have been associated with risk for cardiothoracic surgery-associated AKI. Th authors include some of these factors in Table 1 and in the supplement. Other factors should be compared between the groups and included in Table 1. These factors include but are not limited to emergency vs. elective surgery, transfusion requirement, need for IABP or mechanical ventilation, etc. (see Thakar risk model).

Thanks to the reviewer for mentioning the Thakar risk model. We didn't use it in our study. This will be very useful for us in the future.

We have studied all the parameters used in this model: Gender, Heart Failure, Ejection Fraction, COPD Requiring Medical Therapy, Diabetes Requiring Insulin and other parameters.

It turned out that in our analysis we evaluated almost all of these parameters. And even more covariates were taken into account in our PSM (line 168-171). Accordingly, we did not add those covariates that did not differ initially to the PSM.

It turns out that only the "emergency surgery" mentioned in the Thakar risk model was not taken into account by us. But in our department there are only planned cardiac surgery procedures, so we did not even consider this factor initially.

We are grateful to the reviewer for this information, but I think we compared the patients as much as possible according to important parameters, and it was legitimate to compare them.

Minor 

The authors conclude in line 36 and in multiple other places throughout the manuscript that "statin use before surgery does not increase the incidence of postoperative AKI". I suggest that the word "increase" be changed to "influence" since most studies suggest that statins either decrease or have no influence on the risk of AKI rather than increase risk.

The hypothesis of our study is precisely to prove that long-term use of statins before open heart surgery "does not increase the frequency of AKI." We have specifically planned our study in such a way as to focus on this. This is due to the fact that currently in the EACTS manual on perioperative management of adult cardiac surgery patients [32], the wording sounds exactly like this: "It is not recommended to initiate statin therapy shortly before cardiac surgery" (class III, level A). And the links point to the articles where statins just increase the incidence of AKI.

https://doi.org/10.1056/nejmoa1507750

https://doi.org/10.1001/jama.2016.0548

In addition, in the introduction section, we mentioned the inconsistency of the data and cited several studies where there was an increase in the frequency of AKI when taking statins before surgery.

https://doi.org/10.2147/tcrm.s160298

https://doi.org/10.1186/s13054-016-1560-6

Therefore, if the reviewer does not mind, we would like to leave exactly this wording.