Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Abstract

Inflammation has an integral role in the pathophysiology of AKI. We investigated the associations of two biomarkers of inflammation, plasma IL-6 and IL-10, with AKI and mortality in adults undergoing cardiac surgery. Patients were enrolled at six academic centers (n = 960). AKI was defined as a ≥ 50% or ≥ 0.3-mg/dl increase in serum creatinine from baseline. Pre- and postoperative IL-6 and IL-10 concentrations were categorized into tertiles and evaluated for associations with outcomes of in-hospital AKI or postdischarge all-cause mortality at a median of 3 years after surgery. Preoperative concentrations of IL-6 and IL-10 were not significantly associated with AKI or mortality. Elevated first postoperative IL-6 concentration was significantly associated with higher risk of AKI, and the risk increased in a dose-dependent manner (second tertile adjusted odds ratio [OR], 1.61 [95% confidence interval (95% CI), 1.10 to 2.36]; third tertile adjusted OR, 2.13 [95% CI, 1.45 to 3.13]). First postoperative IL-6 concentration was not associated with risk of mortality; however, the second tertile of peak IL-6 concentration was significantly associated with lower risk of mortality (adjusted hazard ratio, 0.75 [95% CI, 0.57 to 0.99]). Elevated first postoperative IL-10 concentration was significantly associated with higher risk of AKI (adjusted OR, 1.57 [95% CI, 1.04 to 2.38]) and lower risk of mortality (adjusted HR, 0.72 [95% CI, 0.56 to 0.93]). There was a significant interaction between the concentration of neutrophil gelatinase-associated lipocalin, an established AKI biomarker, and the association of IL-10 concentration with mortality (P = 0.01). These findings suggest plasma IL-6 and IL-10 may serve as biomarkers for perioperative outcomes.

Keywords: Epidemiology and outcomes; clinical epidemiology; cytokines; mortality.

Figure 1.

Inflammatory biomarkers, plasma IL-6 and IL-10, significantly increase in AKI patients after cardiac surgery. In patients with AKI, plasma IL-6 levels (A) were significantly increased both pre- and postoperatively, while plasma IL-10 levels (B) were significantly increased only at all postoperative time points. Each bar represents the interquartile range (25th percentile to 75th percentile), and the horizontal black line represents the median. *P<0.05. Day 1 refers to postoperative time 0–6 hours after surgery, day 2 corresponds to 48 hours after surgery, and day 3 corresponds to 72 hours after surgery.

Figure 2.

High plasma IL-6 and IL-10 are associated with increased risk of AKI, and high plasma IL-10 is associated with decreased 3-year mortality after cardiac surgery. Adjusted for age (per year), sex, white race, cardiopulmonary bypass time >120 minutes, nonelective surgery, preoperative eGFR, diabetes, hypertension, site, congestive heart failure, myocardial infarction, preoperative urinary albumin-to-creatinine ratio, increase in serum creatinine, and type of surgery. *P<0.05. Mortality rate per 1000 patient-years adjusted for site.

Figure 3.

NGAL modulates the protective effects of IL-10. The protective effect of those with the highest levels of postoperative IL-10 was observed only with NGAL levels above the mean (P=0.01 for both plasma and urine NGAL). High NGAL levels were defined as greater than the median value, and low NGAL was defined as less than or equal to the median value. Adjusted for age (per year), sex, white race, cardiopulmonary bypass time >120 minutes, nonelective surgery, preoperative eGFR, diabetes, hypertension, site, congestive heart failure, myocardial infarction, preoperative urinary albumin-to-creatinine ratio, increase in serum creatinine, and type of surgery. *P value for the interaction between the third tertile of IL-10 and NGAL (high/low).