This study is the first to report associations of endothelial biomarkers with AKI in a large general medical/surgical ICU population. The results observed are consistent with previous studies, which have shown inflammatory markers to be associated with AKI events in various critically ill populations [40]. Several relatively smaller studies have recently explored associations of endothelial biomarkers and AKI. Recent case-control studies of cardiac surgery patients have found that plasma levels of Ang-2 increase post-surgically by a greater extent in patients who develop AKI than in controls [41, 42]. A cross-sectional study of critically ill patients at inception of renal replacement therapy in the ICU found that circulating Ang-2 was correlated with AKI stage and with 28-day mortality risk [43].
Accumulating evidence suggests that systemic inflammation and endothelial activation underlie the development of AKI [41, 43–46]. TNF is an inflammatory marker released by activated macrophages, monocytes, and neutrophils, and has been shown to have a major role in both sepsis and septic AKI [20, 47–49]. Renal endothelial cells are activated by TNF, further perpetuating the pro-inflammatory state and potentially sensitizing kidney tissue to subsequent damage [47, 48]. Recent efforts in animal models have demonstrated that Ang-1 may enhance the protective capacity of early endothelial outgrowth cells in murine AKI [50, 51]. Acute endothelial cell changes may lead to altered vascular reactivity, permeability, adherence of leukocytes, coagulation, and microvascular vasomotor autoregulation, perpetuating AKI.
Among a large cohort of critically ill patients admitted to the ICU, we found that circulating concentrations of inflammatory and endothelial biomarkers were significantly associated with a higher risk of AKI.
These biomarkers may highlight novel pathways of kidney injury in the setting of critical illness as well as the potential use of baseline biomarker profiles to identify individuals at risk of developing AKI. Our observations support the hypothesis that, before overt renal cellular injury has occurred, there may be alterations in microcirculation and tissue oxygenation that predispose individuals to renal damage [52]. This concept is especially relevant to the SIRS state, where inflammation and endothelial cell activation are prominent [16]. The microvasculature and endothelial cells in particular regulate blood flow to local tissue beds and modulate coagulation, inflammation, and vascular permeability. AKI has profound effects on the renal endothelium, resulting in microvascular dysfunction leading to ongoing ischemic conditions and further injury following the initial insult [53, 54].
While we highlight, for the first time, the independent association of endothelial biomarkers with AKI in critically ill patients, our study has some limitations. The most important limitation of this observational study is the potential for confounding, because characteristics such as illness severity are likely linked both with endothelial dysregulation and risk of AKI. Substantial efforts were made to adjust for potential confounding, but a causal association between the dysfunction of endothelial cells and AKI development cannot be established from our results. Second, this study was not designed with AKI as a primary endpoint and, as such, did not collect sufficiently detailed urine output data; AKI was only assessed retrospectively by changes in creatinine [34]. Data were not available on renal replacement therapy, which would have provided additional granularity to the severity of AKI definition. Moreover, sepsis decreases production of creatinine, limiting the use of changes in creatinine levels as a marker of AKI [55]. A small proportion of patients had insufficient sample volumes to measure all biomarkers simultaneously. These measurement issues may have resulted in non-differential misclassification, leading to an attenuation of associations toward the null. Third, we cannot exclude the possibility of reverse causality, wherein the damaged kidney itself may release endothelial markers before creatinine rises, and thus contributes to higher circulating levels of Ang-2 and lower circulating levels of Ang-1 [56]. Lastly, the subjects included in this study are all recruited from a single hospital and were all Caucasian, and this may limit the ability to more broadly interpret our results. We did, however, include subjects transferred from outside hospitals in the analyses and adjustment for this factor did not modify the associations with poor outcome.