Serum cytokine profiles associated with early allograft dysfunction in patients undergoing liver transplantation

Abstract

Early allograft dysfunction (EAD) occurring in the first week post-liver transplantation is associated with increased graft failure and mortality and is believed to be largely due to ischemia/reperfusion injury. We anticipated that the presence of EAD would be reflected by alterations in expression of serum proteins associated with an inflammatory response in the peri-operative period, and hypothesized that a specific pattern of expression might correlate with the development of EAD. The serum levels of 25 cytokines, chemokines, and immunoreceptors were measured by Luminex multiplex assays pre- and post-liver transplantation. Levels of each cytokine biomarker were compared in adult recipients with or without EAD at serial time points using samples collected pre-operatively and at 1, 7, 14, and 30 days post-transplant. EAD was defined according to standard criteria as maximum alanine transferase (ALT) or aspartate transferase (AST) levels on days 1-7 of >2000 U/ml, day 7 bilirubin level ≥10 mg/dl, or a day 7 international normalized ratio (INR) ≥1.7. Multivariable analyses showed that patients experiencing EAD had lower pre-operative IL-6 and higher IL-2R levels. Patients with EAD also showed higher MCP-1 (CCL2), IL-8 (CXCL8), and RANTES (CCL5) chemokine levels in the early post-operative period, suggesting up-regulation of the NF-kB pathway, in addition to higher levels of chemokines and cytokines associated with T cell immunity, including MIG (CXCL9), IP-10 (CXCL10) and IL-2R. These findings identify several possible biomarkers and pathways associated with EAD, that may guide future validation studies and investigation of specific cellular and molecular mechanisms of graft dysfunction. Furthermore, if validated, our findings may contribute to perioperative prediction of the occurrence of EAD and ultimately lead to identification of potential interventional therapies.

Copyright © 2011 American Association for the Study of Liver Diseases.

Figures

Figure 1. Box plots of serum levels of cytokines important to cellular immune responses, shown by day of study for EAD (blue) and non-EAD (yellow) subjects

(A) IL-2R, (B) IP-10 and (C) Mig. Black squares represent the median and the box is the interquartile range; circles represent outliers. P-values are displayed for p

Figure 2. Box plots of serum levels of NF-κB-stimulated chemokines that are higher in EAD patients in the early post-operative period, shown by day of study for EAD (blue) and non-EAD (yellow) subjects

(A) MCP-1, (B) RANTES, (C) IL-8 and (D) IL-6. Black squares represent the median and the box is the interquartile range; circles represent outliers. P-values are displayed for p

Figure 3. Box plots of serum levels of cytokines that have anti-inflammatory effects or are higher in control patients, shown by day of study for EAD (blue) and non-EAD (yellow) subjects

(A) IL-1Rα, (B) IL-10, (C) GM-CSF, and (D) TNFa. Black squares represent the median and the box is the interquartile range; circles represent outliers. P-values are displayed for p