This study explored if pre-ICU statin use improves the clinical outcomes of patients with AKI based on the MIMIC-IV database. In this study, 14.2% of patients died in ICU within 30 days of ICU admission, 19.7% died in hospital within 30 days of ICU admission, and the median ICU LOS was 4.1 days. Our results demonstrated that pre-ICU statin may improve 30-day ICU mortality, 30-day in-hospital mortality, and ICU LOS. Moreover, the benefit of pre-ICU statin use was consistent across sex and AKI stage, except for 30-day ICU mortality in AKI stage 1. The association of pre-ICU statin use with mortality showed no sex differences but differed with AKI stages. Finally, sensitivity analyses confirmed the robustness of our results.
Chinaeke et al. showed that patients in ICU with sepsis who had pre-ICU statin use had decreased mortality and ICU LOS, demonstrating the pleiotropic effect of statin [21]. Our study was based on ICU patients with AKI, similar but different population with Chinaeke’s, also showed an association between pre-ICU statin use and outcomes. The present study further illustrates the pleiotropic effect of statins in critically ill patients. Although the pathophysiological mechanisms are not exactly the same, both AKI and sepsis are common in ICU patients [28]. Many critically ill patients simultaneously have both, namely septic AKI. Previous treatment guidelines for sepsis and AKI focused more on antibiotics, aggressive fluid-based therapy, vasoactive drugs [28]. However, these two studies provided a reference for the treatment of AKI and sepsis, which could be further verified in future randomized controlled trials to explore the optimal dose and type of statins.
Wu et al. showed that statin use reduced risks of 1-year and in-hospital mortality in 6091 hospitalized patients with dialysis-requiring AKI [14], and Li et al. showed that statin use reduced the occurrence of AKI and AKI-related mortality among patients undergone cardiac surgery [15]. These two studies were conducted on specific patients with AKI. AKI can occur for a variety of reasons in critically ill patients, and patients with AKI have a variety of manifestations and comorbidities. Therefore, we cannot exclude the possibility that the association of outcomes with statin use in patients with AKI is due to other factors. Our study included all patients with AKI in the MIMIC-IV database, regardless of etiology, manifestations, comorbidities, and AKI severity. Therefore, we cannot confirm whether the association is indirect, while the exact mechanism by which statins affect AKI remains obscure. However, the present study did show an association of positive outcomes with pre-ICU statin use in a complete population with AKI, not just in a specific group.
Statins have pleiotropic effects. Although the exact mechanism behind the effect of statins in AKI patients is not clear, some animal studies may provide clues. A rat study indicated that atorvastatin use could reduce endoplasmic reticulum stress and apoptosis [29], and another demonstrated that pravastatin reduced urinary protein excretion and retained the renal function and expression of nephrin in doxorubicin-induced nephropathy rats, concluding that pravastatin protects from and treats adriamycin-induced renal injury [30]. These studies suggest different mechanisms of action for statins in AKI, but this is a question which deserves further research.
Since this is an observational study, many variables were imbalance between the two groups, we utilized PS matching and weighting approaches, which ensure that patients were pseudo-randomized across two groups, as in a typical randomized controlled trial. Considering the possible interactions between variables, we also used the GBM model with PS weighting. GBM models can automatically find the relationships between covariates, such that we did not need to set the interaction between covariates. By PS methods, the conclusions were consistent with the multivariable model, proving that the results were robust.
Our study has some limitations: (1) The study is a retrospective observational study using existing data and not randomized. Although we extracted some related covariates and conducted three sensitivity analyses with PS methods, unobserved confounders may still exist that could lead to bias in the results. (2) Some individuals may have non-recorded pre-ICU statin use; which cannot be checked. (3) Some covariates in the data were missing, and multiple imputations were used for the missing values. This might have led to different results. For this reason, we conducted an analysis using the complete data set without missing values, obtaining consistent results (supplemental file Table S4). (4) We did not conduct a long-term effect analysis because the database did not have complete long-term follow-up, so we focused on 30-day mortality.