Sepsis involves lethal organ dysfunction due to the activation of both pro- and anti-inflammatory responses [20], and is modified by non-immunologic pathways, including cardiovascular, neuronal, autonomic, hormonal, bioenergetic, metabolic, and coagulation pathways [21–23]. Severe sepsis is associated with a mortality rate of > 50% [24], and the most common cause of AKI among critically ill patients is sepsis [3]. PCT has the highest specificity among diagnostic markers for sepsis, but can yield false positive results since its levels increase in various non-sepsis contexts (e.g., severe trauma, invasive surgical procedure, critical burn injuries) [8–10]. Presepsin, another diagnostic marker for sepsis, is secreted from granulocytes in response to infectious stimuli in an animal sepsis model [25]. According to Liu et al., presepsin was the best predictor of early stage sepsis in emergency department patients [26]. Presepsin values have also been reported to be associated with organ dysfunction, coagulation disorders, and ICU mortality [27].
In the present study, presepsin cut-off values for predicting septic AKI, RRTi in sepsis patients, and prognosis in septic AKI patients were higher than those previously reported as predicting severe sepsis and septic shock [18, 19] (Tables 3, 4 ). Moreover, presepsin values for predicting RRTi had a higher cut-off value and specificity relative to those for predicting septic AKI. A significant negative correlation was previously reported between presepsin levels and estimated glomerular filtration rate in both non-sepsis and sepsis patients [28]. Increases in presepsin levels in hemodialysis (HD) patients may not be related to renal dysfunction, but rather the activation of neutrophils and/or monocytes, since HD activates monocytes and/or neutrophils, which in turn leads to presepsin release from monocytes [29]. Presepsin levels in HD patients without infection were reported to be 783–2,360 pg/ml [30]. Nakamura et al. retrospectively examined presepsin values in ICU patients with or without sepsis, and reported that presepsin values were markedly high in patients with renal failure and end-stage kidney disease. Presepsin values in those with sepsis ranged from 2,632 to 20,000 pg/ml, while patients without sepsis had presepsin values of 2,134 to 19,633 pg/ml [28]. In the present study, presepsin cut-off values for predicting RRTi were similar to these previously reported levels. Our results suggest the need to adopt a higher presepsin cut-off value for predicting septic AKI, RRTi in sepsis patients, and prognosis in septic AKI patients.
Cut-off values for predicting septic AKI, RRTi in sepsis patients, and prognosis in septic AKI patients on Day 2 or later after ICU entry were higher than those on Day 1 (Tables 3, 4). Multivariate logistic regression analyses identified presepsin on Day 2 to be a predictor of prognosis in septic AKI patients (Table 7). Presepsin levels measured at the time of ICU admission may not be at an optimal level for predicting septic AKI, RRTi in sepsis patients, and prognosis in septic AKI patients. Indeed, several studies have reported that presepsin levels increase as the severity of sepsis increases [31–33]. For instance, Masson et al. reported that an increase in presepsin levels from Day 1 to Day 2 after ICU admission can predict higher ICU and 90-day mortality [34]. Our findings suggest the importance of not only measuring presepsin levels at the time of ICU admission, but also monitoring its temporal changes after ICU admission in order to better predict the onset of septic AKI, RRTi in sepsis patients, and prognosis in septic AKI patients.
The AUC, sensitivity, and specificity of PNI for predicting RRTi were 0.72, 66.7%, and 93.5%, respectively, with a higher specificity than that for presepsin alone on Days 1, 2, and 5. The corresponding median PNI values (inter-quartile range) were 18.4 (14.6–30.0) in RRTi patients and 28.9 (22.7–34.1) in non-RRTi patients. These findings suggest that a lower PNI can predict RRTi in sepsis patients and may serve as an easy “rule in” test at the time of ICU admission. PNI can be obtained at low cost and rapidly in clinical settings where presepsin values cannot be easily measured, and provides information necessary for interventions in sepsis patients within the first few hours of ICU admission. Our findings also suggest that hypoalbuminemia and lymphocytopenia (albumin and lymphocyte counts are used to calculate PNI) are important variables for predicting RRTi in sepsis patients. Serum albumin levels are significantly correlated with presepsin levels [30]. Zahorec et al. found a correlation between severity of the clinical course and extent of lymphocytopenia in oncological ICU patients following major surgery, sepsis, and septic shock [35].
This study has several limitations. First, the present study was conducted at a single center with a small sample size. Second, we used a single biomarker, and no comparisons were made with other biomarkers.