This study prospectively assessed uCXCL10 in a typical heterogeneous PICU population. Our dada revealed that elevated uCXCL10 was independently associated with AKI and sepsis after adjustment for confounding factors, and uCXCL10 could be a potential indicator of septic AKI and PICU mortality in critically ill children.
In normal condition, CXCL10 is expressed at low levels in the kidney, but their expression levels are upregulated in renal tubular cells after insult, involving in the pathogenesis of AKI [11, 12, 27]. Higher uCXCL10 levels were found among the critically ill children with AKI in our study, which was in consistent with a prospective nested case-control study performed by Ho J et al . They compared urinary proteomes of adults before, during, and after cardiopulmonary bypass surgery, discovering that uCXCL10 levels were upgraded in patients with AKI postoperatively . In a recent study on urinary biomarkers of AKI, uCXCL10 was discovered and validated to be associated with AKI in children after HCT . However, these data are limited to small studies originally designed for AKI prediction in a specific setting. Our results confirmed the significant association of uCXCL10 with AKI regardless of illness severity and the presence of sepsis, in critically ill children.
The discriminative power of uCXCL10 for AKI in our study was less well comparing with the study of Vaidya et al . Our result suggested that uCXCL10 may not be a good predictor of AKI in critically ill children. Different from the patients without AKI in the present study, 102 individuals without AKI in previous study were from 3 types: 50 healthy volunteers, 39 patients undergoing cardiac catheterization and 13 patients admitted to the intensive care unit . The healthy volunteers accounted for half of those who were non-AKI, which may partly explain the discrepancy. In critically ill patients, AKI development is characterized with heterogeneity, and the predictive value of AKI is highly dependent on the underlying conditions. Our study indicates that although it is undisputed that uCXCL10 is associated with kidney injury, similar association has been identified between uCXCL10 and sepsis, which makes uCXCL10 measurements generally a poor diagnostic tool in complex contexts in critically ill children. Moreover, the levels of uCXCL10 were influenced by age and body weight, which might be another explanation for the poor performance in the clinical utility of uCXCL10 as an AKI biomarker in PICU population.
Sepsis is a well-known main cause of AKI in critically ill patients [5, 28]. The CXCL10 has been reported to regulate the pathogenesis of sepsis [29, 30]. In our present study, uCXCL10 levels were higher in critically ill children with sepsis, suggesting that the levels of uCXCL10 were influenced by inflammation and infection. Urinary CXCL10 remained independently associated with both sepsis and AKI, indicating that the increases of uCXCL10 due to AKI and sepsis are additive. These results were supported by animal research in which a marked upregulation of CXCL10 was detected within kidney in septic acute renal failure model .
In this study, uCXCL10 had an ability to discriminate septic AKI in all critically ill children and in children with sepsis. These findings suggested that uCXCL10 could be diagnostic of septic AKI. Considering that septic AKI is a frequent complication in critically ill patients, and associated with higher risk of in-hospital mortality [28, 32], the identification of early biomarkers of septic AKI is extremely important. Urinary biomarker neutrophil gelatinase-associated lipocalin and cell cycle biomarkers of tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 are the frequently investigated and have been proved to predict septic AKI in patients with sepsis [32–34]. Our finding emphasizes that uCXCL10, as any other biomarker, must be interpreted in the specific clinical context. Although, to our knowledge, this is the first report about the relationship of uCXCL10 and septic AKI, this was a single cohort study and 22 (6.4%) critically ill children were septic AKI, a multi-center study with more cases would be needed to confirm our findings. Additional studies are also required to delineate the specific mechanism of CXCL10 in septic and non-septic AKI.
As uCXCL10 has been related to different conditions of inflammation and injury and proven as a reliable marker for septic AKI, it has been consequentially evaluated as a prognostic marker. Our study firstly proved that uCXCL10 levels had independent associations with PICU mortality in critically ill patients. Clinical studies about the association between CXCL10 and mortality have been limited and predominantly investigated in blood rather than in urine of adult patients [21, 35, 36]. As regards to CXCL10 in urine, a pilot study conducted in patients with ischemic AKI suggested that uCXCL10 might predict renal functional outcome at various times along the course of ischemic AKI and predict mortality of AKI patients within 3 months . However, in adult patients with established AKI, uCXCL10 was a good biomarker of AKI as mentioned earlier, but it was not predictive of in-hospital mortality . Both AKI and sepsis are established risk factors for mortality, and AKI and sepsis increase mortality synergistically [2, 38]. In our study, patients with septic AKI had a similar mortality compared to non-septic AKI, suggesting that non-septic etiologies may also contribute to the high mortality rate in AKI patients. The relationship between elevated uCXCL10 levels and increased risk of all-cause PICU death in our cohort was independent of the presence of sepsis and/or AKI and illness severity assessed by the PRISM III score, indicating that uCXCL10 is not simply associated with AKI and sepsis, but also a potential indicator of PICU mortality in critically ill children. Thus, elevated uCXCL10 levels in ICU patients should not be simply viewed as a risk indicator for AKI but rather should prompt a thorough investigation for coexisting conditions, which will ultimately determine the prognosis of the ICU patients. Furthermore, the predictive abilities of the peak uCXCL10 for PICU mortality was better than the initial uCXCL10. These results suggest that dynamic monitoring of uCXCL10 levels upon PICU admission is valuable for clinicians in guiding preventive strategies and improving prognosis.
There are some limitations in this study. First, the AKI incidence may be underestimated when SCr at PICU admission was considered as a baseline, given that the majority of critically ill children did not have baseline SCr prior to PICU admission. In consistent with our previous studies [23, 25], the lowest SCr value within 2 weeks during the PICU stay was used as a baseline for patients with elevated SCr ≥ 106.1 µmol/L at PICU admission, which, however, has not been validated in critically ill children. Nevertheless, a previous study suggests that the lowest SCr within the first week in the ICU better approximates the true baseline distribution and leads to more accurate diagnosis of AKI, as compared with the estimation methods of back-calculating baseline SCr . Second, although it is a challenge to evaluate the performance of biological indicators on the diagnosis of septic AKI based on the recommendations applying to children [26, 32] and the relevance of this finding of uCXCL10 in predicting septic AKI is limited by the small sample size, the diagnostic accuracy of uCXCL10 persisted in all critically ill children and in a subgroup analysis of children with sepsis. Third, we did not perform an etiological analysis for developing AKI. Since our study was carried out in a general and mixed PICU population, it was difficult to distinguish the exact causes of AKI from the existence of complex comorbidities. Fourth, it is unclear whether uCXCL10 is truly causatively involved in pathophysiologic mechanisms of underlying conditions resulting in high mortality or whether it reflects general inflammation and injury in critical illness. Further studies are required for understanding of the biochemical properties and regulatory mechanisms of uCXCL10 in critical illness. Fifth, the single-center study design represents a main limitation. Although we add novel insights to the literature, we did not compare other kidney injury biomarkers, and could not prove the statistical superiority of initial uCXCL10 value overall other standard parameters in early predicting adverse outcome. A multi-center study with a larger quantity of samples is necessary for further validation.