Current status of liver transplantation in Europe

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NATIONAL AND TRANSNATIONAL ORGAN EXCHANGE ORGANIZATIONS

Liver transplantation (LT) as life-saving procedure became a tremendous success story in medicine in Europe and worldwide. The first LT attempt in Europe was performed by Jean Demirleau in Paris in 1964. Although the procedure was performed in 4 hours, the patient expired 3 hours after LT presumably due to fibrinolysis. Since that time, LT in Europe and around the world benefited from many innovations and advancements including the introduction of cyclosporine and is today an established treatment for end-stage liver disease. According to the 2018 report of the European Liver Transplant Registry (ELTR), 146,762 LT have been performed in Europe until 2016. The wide acceptance of this procedure is not only reflected in the high numbers of performed LT but also in the fact that every European has today access to a national or transnational liver transplant program. In the most recent period, LT in Europe achieved respectable 1- and 5-year overall survival rates of 86% and 74%. The purpose of this review was to provide a global snapshot of the current regulation and clinical practice of LT in Europe in 2018.

Organ donation and transplantation is organized and executed by national transplant organization in many European countries. Examples are Agence de la Biomédecine in France, Centro Nazionale Trapianti in Italy, and Swisstransplant in Switzerland. Furthermore, transnational organ sharing organizations namely Eurotransplant and Scandiatransplant regulate and execute organ allocation among their country members. Other countries, mainly southern Europe, follow their national allocation systems but cooperate among each other at various levels organ exchange. Eurotransplant is an international non-profit organization founded in 1967 and coordinates the organ allocation of eight European countries including Austria, Belgium, Croatia, Germany, Hungary, Luxembourg, the Netherlands, and Slovenia. Eurotransplant acts as a transnational mediator between donor hospitals and transplant centers, serving a total population of around 137 million people. All transplant centers enter medical information of their patients into one central (inter)national waiting list, allowing the best match possible. The countries follow their own legislation (e.g. donor after circulatory death (DCD) legal policy) and donation policy (opt-in: Germany, the Netherlands; opt-out: all others) as shown in Table.

Prioritization in the Eurotransplant region is based on the Model for End-Stage Liver Disease (MELD). When no matched recipient is available on the national waiting list, the donor is registered at Eurotransplant. Based on an objective computer algorithm, Eurotransplant generates a matching list for each donor organ. According to their ranking on the matching list, organs are then offered to matched recipients. Due to the international collaboration, specific patient groups such as high-urgency patients, immunized patients, and children have a better chance of receiving a suitable organ in time. In 2018, over 1,700 LT were performed in the Eurotransplant region Scandiatransplant is another international organization founded in 1969 and coordinates the organ allocation of six northern European countries including Denmark, Finland, Iceland, Norway, Sweden, and Estonia.

It covers a population of around 28.8 million people. Other than most European countries, Scandiatransplant uses a center-driven organ allocation policy based on clinical waiting time. Similar to Eurotransplant, all transplant centers enter their patients into one central waiting list. In 2018, 377 livers were transplanted within the Scandiatransplant region, while at the end of the year there were 117 patients on the waiting list. South Alliance for Transplantation (SAT), which was founded in 2012 is a cooperative organization of the member countries Czech Republic, France, Italy, Portugal, Spain, and Switzerland. In contrast to Eurotransplant and Scandiatransplant, member countries of SAT follow their own national allocation and transplant rules but cooperate at various levels of organ exchange including surplus organ offers within their alliance.

DONATION AND ALLOCATION RULES IN EUROPEAN COUNTRIES

In general, organ donation either relies on the opt-in or opt-out consent type. In optin, agreement to organ donation needs to be given after death usually by the donor’s relatives when otherwise not declared by the donor before. In contrast, citizens in an optout system are automatically potential donors, but have the right to express their freewill by refusing organ donation. It has been shown, that opt-out consent leads to an increased number of transplanted livers. The majority of countries in the Eurotransplant region have an opt-out policy except Germany and the Netherlands, while member countries of Scandiatransplant have an equal distribution of opt-in and opt-out donation policy. Although there are exceptions, most other European countries with high donation rates have an opt-out policy including Belgium, Croatia, Czech Republic, France, Italy, and Portugal Donation rates largely vary among European countries ranging from 3.3 organ donations per million population (pmp) in Romania to 48 pmp in Spain. National donation rates and policies are presented in Table.

The majority of European countries including Eurotransplant follows the MELD-based liver allocation system, which was first introduced in the United States in 2002 and has been meanwhile implemented in many European countries. The MELD score, which includes serum bilirubin, serum creatinine and international normalized ratio for prothrombin time (INR), prioritizes the sickest patient. In most European countries as well as in the Eurotransplant region, prioritization for nonurgent LT is MELD-based, while taking into account the national allocation policies. On the other hand, Scandiatransplant, Italy, Spain, and Portugal use center-directed systems. Scandiatransplant has a short waiting list due to high donation rates in their member countries. Therefore, Scandiatransplant centers use center-driven allocation based on the waiting time. In contrast, prioritization in France is based on the 2007 implemented French Liver Allocation Score (FLAS), a MELD-based system taking into account several additional factors such as the distance between donor and recipient (for decompensated cirrhosis and hepatocellular carcinoma (HCC)), the tumor status, response to alternative therapies, and waiting time (patients with HCC). Allocation in the United Kingdom is based on the Transplant Benefit Score (TBS) since 2018. The TBS incorporates 7 donor and 21 recipient variables as shown in Table. Patients with the highest TBS and high urgent cases are prioritized in the United Kingdom.

CHANGE IN INDICATIONS FOR LIVER TRANSPLANTATION

During the past decade, the composition of the waiting list and the indications for LT have significantly changed in Europe and worldwide due to the development of effective anti-viral drugs and changes in life-style and nutritional behavior. The 2018 report of the European Transplant Registry (ELTR) revealed that cirrhosis regardless of the underlying disease was the most frequent indication for LT (50%), followed by primary liver tumors (17%), and cholestatic liver diseases (10%). Cirrhosis was mainly related to viral infection (22%) and alcohol abuse (19%), but this indication declined over the last years, mainly because of the decrease in hepatitis C virus (HCV)-related cirrhosis. Since the introduction of direct-acting antiviral drugs, the proportion of LT due to HCV-related disease has significantly decreased from 21% in 2014 to 11% in 2017 in the ELTR registry. Looking at the decrease of HCV in detail, both LT due to HCV-related cirrhosis as well as HCVrelated HCC decreased from 11 to 4.5% and 11 to 6.1% during the same period. On the other hand, cancer (mainly HCC) was the indication with the highest rise from 12% in 1997 to 24% between 2007-2016 according to the ELTR report. Similar observations were also reported by the Nordic Transplant Registry where HCC as primary indication for LT increased from 2.5% in 1994 to 20% in 2015. According to the United Network for Organ Sharing and Organ Procurement and Transplantation Network Transplant Registry the United States, where nonalcoholic steatohepatitis (NASH) became the second most common indication for LT, LT for NASH was increasingly performed in Europe accounting for 0.9% in 2014 and 5% in 2017. In addition, the Nordic Liver Transplant Registry also observed an increase of NASH as primary LT indication from 2.0% in 1994 to 6.2% in 2015.

EUROPEAN TRANSPLANT ACTIVITIES

In Europe, 174 transplant centers performed a total of 9,858 LT in 2018 which compares to 8,250 LT performed in the United States during the same year (Figure A). Among European countries, there is a large variation in liver transplant activities with high LT-rates in Croatia (32.4 pmp), Belgium (27.3 pmp), and Spain (26.3 pmp) and low rates in Romania (4.1 pmp), Bulgaria (2.2 pmp), and Greece (2.0 pmp) (Figure B). These differences are mainly attributed to large variations in donation rates with Spain (48.0 pmp) and Croatia (41.2 pmp) having by far the highest donation. The vast majority (86%) were deceased LT, while living donor liver transplantation (LDLT) was performed in 14% only. Donor-after-brain-death (DBD) grafts were most frequently used for deceased LT (91.6%), while only 8.4% of deceased LT used DCD grafts. Countries that significantlyexpanded their organ pool by DCD organs include Belgium, Spain, the Netherlands, and the United Kingdom (see section below). In contrast to deceased LT, LDLT programs are not well established in Europe and contributed to less than 5% of all types of LT in the past. However, Turkey is the only exception with an extraordinary high experience in LDLT performing 1,150 living donor cases in 2018, which accounts for 72.4% of all performed LT, due to religious and sociocultural reasons. With a steady rise of liver transplants in Turkey (1776 transplants 80.3% LDLT in 2019), Turkey is now performing more LDLTs than South Korea, and is the leading country in the world. Apart from Turkey, LDLT contributed to only 3.1% of all LT in Europe and was mainly practiced in Belgium (10.7%), Poland (7.5%), and Germany (6.5%). However, the example of Turkey demonstrates that LDLT can be a substantial strategy to increase the availability of donor organs.

Due to the organ shortage and waiting list mortality, “extended criteria” organs such as DCD organs are increasingly used for LT, although this type of donor organ is more prone to ischemia reperfusion injury, primary non-function, and biliary complications. In Europe, nine countries have active DCD liver programs including Austria, Belgium, Czech Republic, France, Italy, the Netherlands, Spain, Switzerland, and the United Kingdom. Of note, Norway had to put its DCD program temporarily on hold due to ethical and juridical concerns. In the other European countries, DCD LT is not practiced due to legal issues, absence of regulatory systems, or lack of experience. According to a recent report, a total of 2,500 DCD LTs have been performed in Europe in the period from 2008 to 2016. Uncontrolled DCD, which involves a suddenly unexpected cardio-pulmonary arrest with unsuccessful resuscitation, is only performed in significant numbers in France and Spain. In contrast, all other countries with DCD programs retrieve organs from controlled DCD donors. Controlled DCD refers to donation that follows an “anticipated” death occurring after planned removal of life-sustaining treatment such as mechanical ventilation and circulatory support. When short-term results of 1,497 controlled versus 66 uncontrolled DCD were compared, one-year graft (82 vs. 77%) and patient survival (90 vs. 85%) were similar for both DCD types.

To ensure that death after cardiac standstill has become irreversible, the Maastricht consensus recommended a “no-touch” period. According to national legislations, different lengths of “no-touch” periods have been implemented ranging from 5 to 20 minutes among European countries with DCD programs. This condition of normothermic non-perfusion contributes to the crucial donor warm ischemia time. In 2018, there was a large variance of DCD LT in terms of total numbers (range 1-257) and rates of DCD LT (0.5-41%) among European countries. A recent European study from Belgium and the Netherlands compared 126 DCD to 1,264 DBD LT. Although the 5-year graft survival rate was lower for the DCD group (66 vs. 54%), patient survival rates were comparable between both groups (71 vs. 68%). Of note, new developments in machine perfusion appear to have positive effects for the selection and quality of DCD organs considered for LT but we would like to refer this topic to the designated articles of this special edition.

Author: Philip C. Müller, Gokhan Kabacam, Eric Vibert, Giacomo Germani, Henrik Petrowsky