Association of T cell-derived Inflammatory Cytokines with Acute Kidney Injury and Mortality after Cardiac Surgery

ABSTRACT INTRODUCTION Animal models of renal ischemia-reperfusion injury demonstrate that interferon-γ producing T-helper (Th)-1 cells worsen acute kidney injury (AKI), whereas IL-4 and IL-13-producing Th2 cells lead to repair. We tested the association of these cytokines with AKI and mortality in patients who underwent cardiac surgery. METHODS In 1,444 participants of a multicenter, prospective, observational cohort, we measured ten plasma biomarkers before and after cardiac surgery (interferon-γ, IL-4, IL-13, TNF-α, IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-12p70) and combined these biomarkers using principal component analysis (PCA). We also tested independent associations of Th1 (interferon-γ) and Th2 (IL-4, IL-13) biomarkers with clinical outcomes of post-operative AKI and 1-year mortality. RESULTS AKI occurred in 492 (34%) participants and 1-year mortality in 81 (6%). Within six hours after surgery, interferon-γ, IL-4 and IL-13 increased 2.1-, 6.0-, and 4.6-fold, respectively, from their preoperative levels. Patients with higher interferon-γ had higher odds of AKI [adjusted odds ratio per log change, 1.35 (1.13, 1.6)] and mortality [1.51 (1.17, 1.94)]. Patients with higher IL-4 and IL-13 also had higher odds of AKI [1.26 (1.09, 1.46), 1.4 (1.16, 1.69)] and mortality [1.46 (1.18, 1.82), 1.71 (1.27, 2.31)]. Adding biomarkers to the clinical variables using PCA improved the AUC by 0.01 for AKI and 0.04 for mortality resulting in final AUCs of 0.85 (0.83-0.87) and 0.76 (0.70-0.81), respectively. CONCLUSION Both Th1 and Th2 cytokines increased immediately after cardiac surgery and were associated with AKI and 1-year mortality. Our findings indicate activation of both Th1 and Th2 pathways after cardiac surgery rather than predominance of either pathway.