Serum interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study

Abstract

Introduction: Acute kidney injury (AKI) is associated with high mortality rates. New biomarkers that can identify subjects with early AKI (before the increase in serum creatinine) are needed to facilitate appropriate treatment. The purpose of this study was to test the role of serum cytokines as biomarkers for AKI and prolonged mechanical ventilation.

Methods: This was a case-control study of children undergoing cardiac surgery. AKI was defined as a 50% increase in serum creatinine from baseline within 3 days. Levels of serum interleukin (IL)-1beta, IL-5, IL-6, IL-8, IL-10, IL-17, interferon (IFN)-gamma, tumor necrosis factor-alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using a bead-based multiplex cytokine kit in conjunction with flow-based protein detection and the Luminex LabMAP multiplex system in 18 cases and 21 controls. Levels of IL-6 and IL-8 were confirmed with single-analyte ELISA; IL-18 was also measured with single-analyte ELISA.

Results: IL-6 levels at 2 and 12 hours after cardiopulmonary bypass (CPB) and IL-8 levels at 2, 12 and 24 hours were associated with the development of AKI using the Wilcoxon rank-sum test and after adjustment for age, gender, race, and prior cardiac surgery in multivariate logistic regression analysis. In patients with AKI, IL-6 levels at 2 hours had excellent predictive value for prolonged mechanical ventilation (defined as mechanical ventilation for more than 24 hours postoperatively) by receiver operator curve (ROC) analysis, with an area under the ROC curve of 0.95. IL-8 levels at 2 hours had excellent predictive value for prolonged mechanical ventilation in all patients. Serum IL-18 levels were not different between those with and without AKI.

Conclusions: Serum IL-6 and IL-8 values identify AKI early in patients undergoing CPB surgery. Furthermore, among patients with AKI, high IL-6 levels are associated with prolonged mechanical ventilation, suggesting that circulating cytokines in patients with AKI may have deleterious effects on other organs, including the lungs.

Figure 1

Serum IL-6 and IL-8 are increased in patients with acute kidney injury (AKI) following cardiopulmonary bypass (CPB). (a) Serum IL-6 was determined at 0, 2, 12, and 24 hours after cardiopulmonary bypass, and median levels were significantly increased 2 and 12 hours after CPB in patients with AKI versus patients without AKI. *P < 0.01; **P < 0.05. (b) Serum IL-8 was determined at 0, 2, 12, and 24 hours after cardiopulmonary bypass, and median levels were significantly increased at 2, 12, and 24 hours in patients with AKI versus patients without AKI. *P < 0.05; **P < 0.001.

Figure 2

Serum IL-6 and IL-8 are increased in patients who required prolonged mechanical ventilation after cardiopulmonary bypass (CPB). (a) Serum IL-6 levels at 2 hours after CPB were significantly increased in patients who required mechanical ventilation at 24 hours after CPB, compared with those who were extubated; P = 0.005. (The horizontal line represents the median; box encompasses the 25th through 75th percentiles; and whiskers encompass the 10th through 90th percentiles). (b) Serum IL-8 levels at 2 hours after CPB were significantly increased in patients who required mechanical ventilation at 24 hours after CPB, compared with those who were extubated; P = 0.0001.

Figure 3

Receiver-operator characteristic (ROC) curve for the ability of serum IL-6 to predict prolonged mechanical ventilation in patients with acute kidney injury (AKI) after cardiopulmonary bypass (CPB). Prolonged mechanical ventilation was defined as more than 24 hours of ventilation. Interleukin-6 levels were log transformed because they were abnormally distributed. The area under the ROC curve is 0.95, with a Hosmer-Lemeshow goodness-of-fit P value of 0.85, demonstrating that increased IL-6 at 2 hours is an excellent predictor of prolonged mechanical ventilation in patients with AKI after CPB.

Figure 4

Receiver-operator characteristic (ROC) curve for the ability of IL-8 to predict prolonged mechanical ventilation after cardiopulmonary bypass (CPB). Prolonged mechanical ventilation was defined as more than 24 hours of ventilation. Interleukin-8 levels were log-transformed because they were abnormally distributed. The area under the ROC curve is 0.89, with a Hosmer-Lemeshow goodness-of-fit P value of 0.75, demonstrating that increased serum IL-8 at 2 hours is an excellent predictor of prolonged mechanical ventilation in patients after CPB.