Perioperative Perfusion of Allografts with Anti-Human T-lymphocyte Globulin Does Not Improve Outcome Post Liver Transplantation-A Randomized Placebo-Controlled Trial

Abstract

Due to the lack of suitable organs transplant surgeons have to accept unfavorable extended criteria donor (ECD) organs. Recently, we demonstrated that the perfusion of kidney organs with anti-human T-lymphocyte globulin (ATLG) prior to transplantation ameliorates ischemia-reperfusion injury (IRI). Here, we report on the results of perioperative ATLG perfusion in a randomized, single-blinded, placebo-controlled, feasibility trial (RCT) involving 30 liver recipients (LTx). Organs were randomly assigned for perfusion with ATLG/Grafalon^® (AP) (n = 16) or saline only (control perfusion = CP) (n = 14) prior to implantation. The primary endpoint was defined as graft function reflected by aspartate transaminase (AST) values at day 7 post-transplantation (post-tx). With respect to the primary endpoint, no significant differences in AST levels were shown in the intervention group at day 7 (AP: 53.0 ± 21.3 mg/dL, CP: 59.7 ± 59.2 mg/dL, p = 0.686). Similarly, exploratory analysis of secondary clinical outcomes (e.g., patient survival) and treatment-specific adverse events revealed no differences between the study groups. Among liver transplant recipients, pre-operative organ perfusion with ATLG did not improve short-term outcomes, compared to those who received placebo perfusion. However, ATLG perfusion of liver grafts was proven to be a safe procedure without the occurrence of relevant adverse events.

Keywords: ATLG; liver transplantation; machine perfusion; organ perfusion; organ pretreatment; polyclonal antibody.

Figure 1

Participant flow diagram.

Figure 2

Functional liver parameter after liver transplantation. Results of routine blood analysis for the clinical parameters (a) alanine aminotransferase (ALT), (b) aspartate aminotransferase (AST), (c) Quick value, (d) bilirubin, (e) alkaline phosphatase, and (f) gamma-glutamyl transferase (GGT) are comparable for livers perioperatively perfused with ATLG as compared with control livers. ATLG: open circles; control: filled circles. data are presented as mean values ± SEM; *** p ≤ 0.001; ALP—alkaline phosphatase; ALT—alanine transaminase; AST—aspartate transaminase; ATLG—anti-human T-lymphocyte globulin; GGT—gamma-glutamyltransferase; POD—postoperative day.

Figure 3

Inflammation-related candidate gene expression in liver biopsies taken before ATLG perfusion, after ATLG perfusion, and one hour post-reperfusion. Real-time quantitative PCRs of mRNA of whole tissues were performed at different time points perioperatively. Selected candidate markers (a) HIF1a, (b) Lipocalin-2, (c) CCL21, (d) TGFβ, (e) CRP, (f) Caspase 3, (g) ICAM-1), which play major roles in the context of inflammation, and cell adhesion did not show significant differences before perfusion with ATLG (pre-flush), directly after perfusion with ATLG (post-flush), or following reperfusion (post-reperfusion) between ATLG-perfused livers and control livers. ATLG: open circles; control: filled circles. Data are presented as mean ± SEM; ATLG—anti-human T-lymphocyte globulin; CCL21—chemokine (C-C motif) ligand 21; CRP—C-reactive protein; HIF1a—hypoxia-inducible factor 1-alpha; ICAM-1—intercellular adhesion molecule 1; TGFβ—transforming growth factor-beta.

Figure 4

Patient and graft survival. No differences in (a) patient and (b) graft survival were detected between ATLG-perfused livers and control-perfused livers. The displayed p-values indicate 1- and 5-year survival. (AP: 93% 1-year patient survival vs. CP: 77% 1-year patient survival, p = 0.220; AP: 80% 5-year patient survival vs. CP: 77% 5-year patient survival, p = 0.718).