Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial

Abstract

The increased use of older and/or marginal donor organs in liver transplantation over the last decade calls for strategies to minimize ischaemic reperfusion (I/R) injury to prevent early graft failure. Tacrolimus, a very potent and effective calcineurin inhibitor, was selected because of its ability to ameliorate I/R injury. A randomized, blinded, controlled single-centre trial of 26 liver transplant recipients was performed between February 2008 and December 2009. Donor organs were randomized to be perfused intraportally during liver transplantation with 1.5 l 5% albumin infusion containing either 20 ng/ml tacrolimus or placebo. The primary end point was liver function as assessed by aspartate transaminase (AST) or alanine transaminase (ALT) levels 6 days after transplantation. Treatment effectiveness was tested by transcriptome-wide analysis of biopsies. There was no difference in the primary end point, i.e. AST (IU/l) and ALT (IU/l) at day 6 after transplantation between groups. Furthermore, choleastatic parameters as well as parameters of liver synthesis were not different between groups. However, tacrolimus treatment suppressed inflammation and immune response in the transplanted liver on a genome-wide basis. Intrahepatic administration of tacrolimus did not result in a reduction of AST and ALT within the first week after transplantation.

Trial registration: ClinicalTrials.gov NCT00609388.

Figure 1

CONSORT flow chart of organ donor and liver graft recipients.

Figure 2

Dendrogram derived by hierarchical clustering of gene expression profiles characterizing the tacrolimus group (black bar) and the placebo group (blue bar).Pearson correlation was used as distance metric and complete linkage as linkage method. Red spots indicate up-regulated transcripts, whereas green spots indicate down-regulated transcripts relative to the mean overall samples.

Figure 3

Protein–protein interaction network of significant DEGs with a fold change over 1.2, respectively. Blue nodes (10 DEGs) indicate down-regulated genes and red nodes (11 DEGs) indicate up-regulated genes with tacrolimus use. Grey nodes represent proteins/complexes identified by the nearest neighbour expansion method.

Figure 4

Trajectories of aspartate transaminase (AST) (a) and alanine transaminase (ALT) (b) concentrations in the first 6 days after transplantation stratified by therapy. Solid line: placebo, dashed line: tacrolimus. Vertical bars represent standard deviation; the P-value was derived from the mixed linear model for longitudinal data (treatment effect).