Past and future approaches to ischemia-reperfusion lesion associated with liver transplantation

Abstract

Ischemia-reperfusion (I/R) injury associated with liver transplantation remains a serious complication in clinical practice, in spite of several attempts to solve the problem. The present review focuses on the complexity of I/R injury, summarizing conflicting results obtained from the literature about the mechanisms responsible for it. We also review the therapeutic strategies designed in past years to reduce I/R injury, attempting to explain why most of them have not been applied clinically. These strategies include improvements in pharmacological treatments, modifications of University of Wisconsin (UW) preservation solution based on a variety of additives, and gene therapy. Finally, we will consider new potential protective strategies using trimetazidine, 5-amino-4-imidazole carboxamide riboside (AICAR), melatonin, modulators of the renin-angiotensin system (RAS) and the phosphatidylinositol-3-OH kinase (PI3K)-Akt and the p42/p44 extracellular signal-regulated kinases (Erk 1/2) pathway. These strategies have shown promising results for I/R injury but have not been tested in experimental liver transplantation to date. Moreover, we will review ischemic preconditioning, taking into account the recent clinical studies that suggest that this surgical strategy could be appropriate for liver transplantation.

Introduction

Liver transplantation (LT) dates back to 1963, when Thomas Starzl carried out the first transplant on a child suffering from biliary atresia. Although LT provides effective therapy for most forms of acute and chronic liver failure, ischemia-reperfusion (I/R) injury, inherent in every LT, is the main cause of both initial poor function and primary non-function of liver allograft. The latter is responsible for 81% of re-transplantations during the first week after surgery (Clavien et al., 1992, Shaw, 1995, Jaeschke, 1996).

The shortage of organs has led centers to expand their criteria for the acceptance of marginal donors (Busuttil and Tanaka, 2003). Some of these include the use of organs from aged donors, non-heart-beating donors (NHBD), and grafts such as small-for-size or steatotic livers. However, I/R injury is the underpinning of graft dysfunction that is seen in the marginal organ (Busuttil and Tanaka, 2003). Donor age of more than 70 years was found to be associated with lower patient and graft survival. Additionally these donors also have an increased incidence of steatosis, which may potentiate cold preservation injury (Busuttil and Tanaka, 2003).

The fundamental problem with NHBD organs is the prolonged warm ischemia before cold preservation (Reddy et al., 2004). Controlled NHBDs provide organs that are far less prone to ischemic damage and tend to offer superior posttransplant function (Busuttil and Tanaka, 2003). The use of uncontrolled NHBDs is associated with a very high risk of primary nonfunction (Reddy et al., 2004).

One of the benefits of reduced-size grafts from living donors is a graft of good quality with a short ischemic time, this latter being possible because live donor procurements can be electively timed with recipient procedure (Farmer et al., 2001). On the other hand, the major concern over application of living-related liver transplantation (LRLT) for adults is graft-size disparity. The small graft needs posterior regeneration to restore the liver/body ratio. It is well known that I/R significantly reduces liver regeneration after hepatectomy (Franco-Gou et al., 2004). Moreover, increased rates of primary non-function have been reported when using donor livers with moderate steatosis compared with non-steatotic livers. As such, hepatic steatosis is the major cause of rejected grafts for LT and exacerbates the organ shortage problem (Selzner and Clavien, 2001). Therefore, minimizing the adverse effects of I/R injury could increase the number of both suitable transplantation grafts and of patients who successfully recover from LT. The first step towards achieving this objective is a full understanding of the mechanisms involved in I/R injury.