In this retrospective cohort study, we investigated the association between preoperative Se levels and CSA-AKI development amongst patients undergoing cardiac surgery. We observed a relatively high incidence of CSA-AKI in patents with low Se levels, and found that a higher serum Se level was significantly associated with decreased risk of incident CSA-AKI even after adjusting for confounding variables.

Benefiting from the increasing epidemiological knowledge, the role of Se (including organic or inorganic forms) has been related to a number of clinical diseases [18]. Different from observational findings, interestingly, current intervention studies with Se supplements in population all failed to prove the preventive effect of Se to reduce the risk of type 2 diabetes or cancers [19, 20]. These controversial results suggest the complexity pathophysiological effects of Se in vivo and potential threshold effects. Several studies have reported the associations between serum Se and morbidity and mortality of kidney disorders, mainly focusing on CKD. Patients with CKD are always characterized by active inflammation and oxidative stress, as well as abnormal metabolisms of microelements. Previous observational studies demonstrated that patients with CKD had a lower serum Se levels than those of healthy adults [16, 21]. Xie et al. found that Se intake seemed to have an inverse relationship on CKD development [15]. Zhu et al. analyzing 3,063 CKD adults from NHANES database reported that a higher serum selenium concentration could attenuate the risk of all-cause and CVD mortality in patients with CKD, albeit without estimated adequate dose recommendation [22].

In contrast, the evidence regarding the relationship between serum Se level or Se supplementation and CSA-AKI development after cardiac surgery is still scarce. A joint supplement intervention trial comprising Se supplements found that Se 600 mg twice a day did not reduce the risk of AKI in patients with elective off-pump CABG [23]. In our study, we firstly reported that a higher serum Se level could significantly reduce the risk of CSA-AKI. We conjecture that heterogeneity in study designs, including patients, serum Se levels, and surgery (CABG and valve surgery in our study) have contributed to differences between the two studies. Serum Se concentration largely varies among different population partially due to the differential geographical distribution of Se in soil. The main sources of dietary Se are meat and eggs, followed by grains such as flour and rice [24]. Se deficiency is common globally especially in China, while some countries such as Venezuela, Canada, the United States and Japan have high intakes of Se (> 100 µg/day) [25]. Considering potential differences in dietary habits, selenium distribution, and genetic background, a note of caution must be introduced about the generalizability of our findings to other populations.

Our findings supported the role of preoperative Se levels in identifying high-risk patients with CSA-AKI, and suggested that comprehensive perioperative management should be implemented to reduce the risk of AKI in patients with low serum Se levels or selenium deficiency. In this study, we also observed a nearly L-shaped correlation between serum Se levels and incident CSA-AKI. This finding is similar to previous studies focusing on populations with heart failure and CKD [22, 26], despite with different baseline serum Se concentration. As reported, however, the serum Se level associated with minimal mortality risk is 130–150 µg/L in the general population [27]. These results suggest that the health benefits of Se have a potential threshold effect, and only appropriate serum Se levels can exert organ protective benefits. Limited by highly selective population and sample size, our study failed to identify Se concentrations with the lowest risk of AKI. Additionally, we did not observe interactions between Se and age, sex, hypertension, diabetes, heart failure and atrial fibrillation for the AKI odds. Although diabetes status possibly affect the Se metabolism [28], consistently protective effects of the higher Se level existed in patients with or without diabetes. These preliminary evidence calling for future large-sample research to clarify the possible association between Se and prevention of CSA-AKI.

Regarding the definition of AKI, we adopt the diagnostic criteria of KIDGO rather than the Risk, Injury, Failure, Loss, End-Stage (RIFLE), or Acute Kidney Injury Network (AKIN) criteria. Compared to its predecessors (the RIFLE and AKIN scales), the KIDGO criteria has showed the greater sensitivity to identify earlier kidney injury and better ability of predicting mortality [29, 30]. Notably, The KDIGO scale is also based on the one-fits-all, single measurement of plasma creatinine concentration. This criteria failed to define those AKI not detected by plasma creatinine changing when undamaged nephrons provided recruitment of renal functional reserve [31]. Considering potential multi-etiopathological nature of AKI, future diagnostic algorithms which accounting for injury biomarkers, renal blood flow, and etiopathological features may help to accurately identify AKI.

Several underlying mechanisms of Se involvement in kidney health have been discussed. The most noteworthy aspect is the antioxidant effect of Se by acting as a cofactor of antioxidant GPx enzymes [9]. Se nanoparticles may alleviate AKI induced by ischemia reperfusion injury by upregulated the (GPx)-1 levels and suppressed NLRP3 inflammasome [32]. When selenoprotein expression are saturated, however, excessive serum Se will bind to nonspecific selenium-containing proteins and exert harmful effects through selenomethionine (SeMet) in place of methionine [33]. The metabolites of SeMet including selenols/selenates can product superoxide radicals and selenyl sulphides/disulphides, causing protein aggregation, endoplasmic reticulum stress, and inactivation of transcription factors [34]. This could to some extent explain the negative results in the Se supplementation trails [19, 20, 23]. In addition, Se is involved in the synthesis and activity of deiodinases, and then through regulating thyroid hormone influences renal hemodynamics [35]. Moreover, Se has been found related to cellular immunity and humoral immunity, and Se depletion could impaired lymphocytic proliferation, macrophage activation, cytokine generation, and neutrophil chemotaxis [36, 37].

Several limitations should be considered when interpreting our findings. First, like other observational studies, we cannot derive a causal relationship between Se level and AKI after cardiac surgery especially due to single center and small sample size. And the generalization of our findings should be with caution because of selective population. Second, residual confounders or unmeasured factors may interfere the results due to observational nature. However, multivariate analyses and subgroup analyses showed robust and consistent results. And we have further validated the step-wise associations by Se quartile and a dose-response curve, which lowers the chances of bias. Third, we exclude patients without Se measurement, which causing potential selection bias. Finally, we only assessed the serum Se concentration at baseline because of the design of a short-term exposure-outcome study. Future research should take the dynamic changes of Se concentration into account.