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Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR)

2012; Elsevier BV; Volume: 57; Issue: 3 Linguagem: Inglês

10.1016/j.jhep.2012.04.015

1600-0641

René Adam, Vincent Karam, V. Delvart, John O’Grady, Darius F. Mirza, Jürgen Klempnauer, Denis Castaing, P. Neuhaus, Neville V. Jamieson, Mauro Salizzoni, Stephen Pollard, Jan Lerut, Andreas Paul, Juan Carlos García‐Valdecasas, Fernando San Juan Rodríguez, Andrew K. Burroughs,

Renal Transplantation Outcomes and Treatments

Since 1968 the European Liver Transplant Registry (ELTR) collects prospectively the data of liver transplantation (LT) in 145 centers all over Europe. It represents more than 95% of the overall European data compared to the published official figures [[1]International figures on organ donation and transplantation activities 2009. http://www.transplant-observatory.org.Google Scholar]. This collection is made prospectively through a standardized questionnaire. The first part of the questionnaire includes items regarding date and indication for LT, donor and recipient data, surgical technique of LT, and the immediate postoperative immunosuppression therapy. The second part concerns graft and patient outcome, and immunosuppressive regimen follow-up. Participation in the ELTR is voluntary and a standard computerized database is provided to contributing centers with detailed instructions for the collection of accurate and uniform information [[2]Adam R. McMaster P. O'Grady J.G. Castaing D. Klempnauer J.L. Jamieson N. et al.Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.Liver Transpl. 2003; 9: 1231-1243Crossref PubMed Scopus (492) Google Scholar]. Along with reports concerning LT for specific hepatic diseases [3Mentha G. Giostra E. Majno P.E. Bechstein W.O. Neuhaus P. O'Grady J. et al.Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 Centres.J Hepatol. 2006; 44: 520-528Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 4Lerut J. Orlando G. Adam R. Sabbà C. Pfitzmann R. Klempnauer J. et al.Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European Liver Transplant Registry.Ann Surg. 2006; 244: 854-862Crossref PubMed Scopus (2) Google Scholar, 5Mutimer D.J. Gunson B. Chen J. Berenguer J. Neuhaus P. Castaing D. et al.Impact of donor age and year of transplantation on graft and patient survival following liver transplantation for hepatitis C virus.Transplantation. 2006; 81: 7-14Crossref PubMed Scopus (142) Google Scholar, 6De Kerckhove L. De Meyer M. Verbaandert C. Mourad M. Sokal E. Goffette P. et al.The place of liver transplantation in Caroli's disease and syndrome.Transpl Int. 2006; 19: 381-388Crossref PubMed Scopus (83) Google Scholar, 7Melzi M.L. Kelly D.A. Colombo C. Jara P. Manzanares J. Colledan M. et al.Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry.Transpl Int. 2006; 19: 726-731Crossref PubMed Scopus (56) Google Scholar, 8Lerut J.P. Orlando G. Adam R. Schiavo M. Klempnauer J. Mirza D. et al.The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: Report of the European Liver Transplant Registry.Ann Surg. 2007; 246: 949-957Crossref PubMed Scopus (146) Google Scholar, 9Burra P. Senzolo M. Adam R. Delvart V. Karam V. Germani G. et al.Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).Am J Transplant. 2010; 10: 138-148Crossref PubMed Scopus (254) Google Scholar, 10Schramm C. Bubenheim M. Adam R. Karam V. Buckels J. O'Grady J.G. et al.Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.Liver Transpl. 2010; 16: 461-469PubMed Google Scholar, 11Mergental H. Porte R.J. Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis.Transpl Int. 2010; 23: 662-667Crossref PubMed Scopus (25) Google Scholar, 12Wahlin S. Stål P. Adam R. Karam V. Porte R. Seehofer D. et al.Liver transplantation for erythropoietic protoporphyria in Europe.Liver Transpl. 2011; 17: 1021-1026PubMed Google Scholar], ELTR has allowed the development of risk models for liver-transplantation mortality according to the characteristics of the donor and recipient, and of the transplant procedure [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. Quality of the data is assessed routinely. A regular auditing process is conducted each year to ensure the reliability of the scientific analysis of the data, a control of the good adequacy between ELTR questionnaire and patient charts is performed by randomly conducted audit visits. Results of these audit visits have indicated that ELTR data were reliable and the scientific results of ELTR can be considered credible and representative of LT in Europe [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. In addition, a control quality program has been developed internally. The data are subjected to checks for completeness, consistency, and range. Comprehensive logical intra- and inter-updates are performed. Moreover, the ELTR has established agreements with the European Organ Sharing Organizations (OSO): United Kingdom Transplant Service Support Authority (UKTransplant), Spanish Organizaciòn Nacional de Transplantes (ONT), Scandinavian Scanditransplant (SKT), Dutch Transplant Foundation (NTS), Eurotransplant (ET), French Agence de la Biomédecine (ABM) to exchange data collected from European Centers and to cross check common data between OSO and ELTR. We have first considered all data since 1968 to show the evolution of results of LT in Europe since its initial development. The rest of the analysis has been undertaken during two different periods: (a) from January 1988 to December 2009 (89,865 LT – 80,347 patients), where the date from January 1988 was chosen as corresponding to the diffusion of cyclosporine-based immunosuppression and to the standardization of the surgical procedure, (b) the last 10-year period data from January 2000 to December 2009 (54,088 LT – 48,218 patients) to give a more recent evaluation of LT results in Europe. Data were analyzed as a whole without distinction of pediatric transplants that represent 10% of LTs in Europe. Data are analyzed with Statistical Analysis System (SAS). The dynamics of data control are continued during the statistical analyzes. Calculation of survival rates are determined by the actuarial method. From May 1968 to December 2009, the ELTR collected data concerning 93,634 liver transplantations (LTs) in 83,816 patients from 145 centers of 26 countries (Fig. 1). These data give a comprehensive overview of the status and evolution of LT in Europe. Both the number of transplant centers and the annual number of LTs performed in Europe have gradually increased since the creation of ELTR (Fig. 2). However, after an exponential increase from the eighties, a plateau has become to be reached in recent years with about 5800 LTs performed all over Europe.Fig. 2Evolution of 93,634 LTs performed in Europe since May 1968. Arrows indicate the year the first LT was performed in indicated countries. ∗This decrease is owed to the fact that some centers did not yet send their updating further to the recent changes of the questionnaire.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Main indications for LT in Europe with the corresponding graft and patient survival rates at 1, 5 and 10 years are listed in Table 1. Cirrhosis is the most frequent indication (52%), mainly related to either viral infection (21% with 13% of hepatitis C virus infection (HCV) and 7% of hepatitis B virus infection (HBV)), or alcohol abuse (19%). Combined viral and alcoholic (ALD) cirrhosis represents 3% of cases, with 2% of HCV–ALD. Cirrhosis is followed by three major indications: primary liver tumors (14% with 12.1% of hepatocellular carcinoma), cholestatic disease (11%), and acute hepatic failure (8%, 2% of which are virus-related). Cholestatic disease includes primary biliary cirrhosis (6%) and extra-hepatic biliary atresia (4%). Primary sclerosing cholangitis represents 4% of cases. Biliary atresia is the most frequent indication (57%) in the pediatric population, followed by metabolic disease (19%). Metabolic disease represents 6% of indications with familial amyloïdotic polyneuropathy as the major indication (2%), followed by three indications of equal frequency (1%): Wilson disease, alpha-1-antitrypsin deficiency and hemochromatosis. Secondary tumors (mainly carcinoid), Budd Chiari and benign liver tumors (mainly polycystic disease) represent only 1% of indications in Europe.Table 1Primary indications for LT in Europe and the corresponding survival. Open table in a new tab The percentage of main indications for LT has significantly changed with time. While cancers represented 50% of indications before 1980, they dramatically decreased during the nineties (10%) before resuming a linear increase since 2000, to currently represent more than 20%. Conversely, acute hepatic failure that led anecdotally to LT before 1986 has since become a recognized indication for LT. (Fig. 3). In the 10 recent years, two groups of indication have shown an increase: primary liver tumors (16%), mainly related to HCC, and cirrhosis (53%), mainly alcoholic (20%). Drug-related fulminant hepatitis is henceforth the leading disease in the group of acute hepatic failures. In the same way, primary sclerosing cholangitis is the main indication in the group of cholestatic diseases. Patient and graft survival of this 10-recent-year population are summarized in Table 1. One, 3 and 6-month patient's survivals were 90%, 85% and 82% before 2000. Survival rates dramatically increased to reach 94%, 91% and 88%, respectively. The critical period for post-LT outcome is the first 6 months: 46% of deaths and 65% of re-LT occurs within 6 months after LT (Fig. 4). In 49% of cases, re-LT is indicated in the month after primary LT, and one quarter of deaths occurs within the first month after LT. Data represented in Table 2, Table 3 correspond to main cause of death or graft failure. Main causes of death in the 18,186 patients (about 23%) who died after primary LT or re-LT were, by decreasing order: (1) general causes as multiple organ failure and cerebrovascular, cardiovascular, pulmonary, and renal complications (29%); (2) recurrence of primary disease (20%), mostly cancer (11%); (3) sepsis (18%) mostly bacterial (9%); (4) technical complications (5%), mostly hemorrhage and vascular (3%); and (5) rejection (4%) mostly chronic (3%) (Table 2). Intra-operative deaths and primary non-function represented 3% of all deaths. When we consider only the patients who survive beyond 6 months (Fig. 5), there are less technical complications, infection and general complications (cerebrovascular, cardiovascular, pulmonary, and renal), but more tumoral and non-tumoral recurrences, de novo tumor and rejection.Table 2Post-LT mortality after first LT in Europe. Complications correspond to first declared cause of death according to date of occurrence. Open table in a new tab Table 3Recipient graft survival according to the type of LT in Europe. Open table in a new tab The data of the last 10 years show a decrease in overall mortality (16%) with the same distribution of the causes of death observed in the population from 1988. When all indications are considered during the entire study period, patient survival rates are 82% at 1 year, 71% at 5 years, 61% at 10 years, 51% at 15 years and 43% at 20 years. When we consider only the patients who survive beyond 6 months, patient survival rates are dramatically higher (96% at 1 year, 83% at 5 years, 71% at 10 years, 61% at 15 years and 52% at 20 years). After an improvement between 1988 and 2000, the survival of these patients appears to be relatively steady since 2000 (Fig. 6). Survival has improved regularly year after year, reaching 85% at 1 year after 2004 compared with 76% in 1990–1994 and only 33% before 1985 (Fig. 7). The improvement concerns all the indications but particularly LT for cancers (Fig. 8).Fig. 8Patient survival according to indication for and year of LT.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, survival of patients transplanted in the recent 10 years has improved to reach 85% at 1 year and 73% at 5 years. Ten percent of LTs have been performed in pediatric patients (<15 years), with 3.4% of children younger than 2 years. Five-year survival in children is significantly better than in adults (79% vs. 70%, p <0.0001). In the pediatric population, 5-year survival rate is identical for children under 2 years and for those aged 3 to 15 years (79%). In the 10 last years, the rate of pediatric LT has decreased to 8% and the corresponding 5 year-survival is still better than in adults (82% vs. 72%, p <0.0001). The 5-year patient survival rate is significantly better for cirrhosis (72%) than for primary liver tumors (52%, p <0.001) and acute hepatic failure (64%, p <0.001). In viral cirrhosis, HBV and HCV co-infection have a better 5-year survival (82%) than mono-infection with HCV (65%) or HBV (74%). The greater survival rates obtained in metabolic diseases (78%), cholestatic disease (78%) and congenital biliary disease (83%), occur partly because of the high percentage of children in these groups. Details of survival rates at 1, 5 and 10, 15 and 20 years according to the primary indication are listed in Table 1. Although 5-year survival in the last 10-year population was improved in all indications, the most important gain in survival was observed in LTs for primary liver tumors, which is presently 64%, liver metastases (55%) and acute hepatic failure (69%). The majority of donors were male (59%). Seventy-six percent were younger than 55 years, whereas 11% were older than 65 years. An increasing percentage of livers are coming from donors older than 60 years (1% in 1989, 15% in 1999 and 29% in 2009), in relation to the increasing gap between a growing waiting list and a relatively stable donor pool (Fig. 9). Graft survival when organs were procured from donors younger than 55 years was significantly higher than that with organs from donors older than 65 years (65% vs. 57% at 5 years, p <0.0001). With 71% at 1-year and 50% 5-year graft survival, there is no argument to discard octogenarian grafts among aged subjects without associated risk factors (Fig. 10).Fig. 10Recipient graft survival according to donor age.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, 5-year graft survival was 69% with donors younger than 55 years and 59% with donor older than 65 years. However, aged grafts are more frequently transplanted to aged recipients (33% of grafts older than 60 years were used in recipients older than 70 years, and only 21% were used in recipients younger than 70 years, p <0.0001), explaining at least in part, the difference in survival. In addition to the already mentioned better 5-year survival of pediatric vs. adult LT recipients, an influence of recipient age is observed for adults. Survival rates are 74% for adults aged 16–45 years, 70% for those aged 46–60 years, and 64% for those older than 60 years. However, average age of transplanted recipients has increased steadily during the last decade, and patients older than 60 years, who represented less than 5% in the 1980s, represented approximately 25% of transplant recipients in 2009 (Fig. 11). When we consider the last 10-year period, 5-year survival has increased in all the subgroups of adult recipients to reach 77% for adults of 16–45 years, 73% for 46–60 years and 66% over 60 years. Ninety-two percent of LTs were isogroup, and 7.6% were compatible. Only 0.6% were incompatible and restricted to urgent procedures. In emergencies, isogroup and compatible LTs have similar survival. In elective conditions, isogroup LTs have a better 5-year survival than compatible LTs (66% vs. 60%, p <0.0001). Incompatible LTs have a decreased 5-year graft survival rate as compared to isogroup and compatible LTs (27% vs. 53%, p <0.0001). However, use of these incompatible grafts in emergency indications allows around 50% survival rate in patients otherwise destined to a fatal outcome. Although 5 year-survival in the last 10-year population was improved in all the groups of type matching, the most important gain in survival was observed in incompatible matching (+41%). However, only 0.3% of LTs were incompatible. More than 99% LTs were done orthotopically, and 87% of grafts were full size. Alternative procedures to full size LTs have been used increasingly in recent years (9% before 2000 vs. 16% after 2000). In the 2000s, alternative procedures were represented by reduced livers (2%), split livers (6%) living donors (6%), and domino transplants (1%). 1, 5, 10, 15 and 20-year graft survivals of each type of graft are summarized in Table 3. Survival at 5 years was similar between split liver and cadaveric full size grafts (65%), but lower than that of living donors (69%) and higher than that of reduced and domino grafts (62% and 59%, respectively). Auxiliary grafts represented 0.8% of overall LTs with a lower graft survival as compared to non-auxiliary grafts in urgent indications (5-year survival rates: 45% vs. 52%), and in elective indications (60% vs. 66%, p <0.0001). Graft survival was better when cold ischemia time was less than 12 h and University of Wisconsin solution was used for preservation (p <0.001). When we consider the last 10-year period, 5-year graft survival has increased in all types of graft to reach 68% for reduced grafts, 67% for split and 62% for domino. The ELTR has cumulated data concerning 3622 living related LTs (LRLTs) performed in 78 centers from 20 countries from October 1991 to December 2009 (Fig. 1). The results of this technique will be published elsewhere. In summary, adults represented 65% of LRLTs. Since 2001 adult LRLTs largely exceeded pediatric LTs. The donor surgical mortality rate was 0.18%. Overall 5-year graft survival of LRLT was 69%, better for children than for adults (78% vs. 63%, p<0.001). Whereas graft survival of LRLT was better than cadaveric LT for children (78% vs. 72%, p<0.001), it was similar for adults (64% vs. 63%). Overall, graft loss included more technical complications (26% vs. 14%), more infection (23% vs. 18%), more rejection (8% vs. 4%), more tumor recurrence (12% vs. 9%), but less general complications (20% vs. 27%) and less non-tumor disease recurrence (4% vs.12%) after LRLT than after cadaveric LT (all p <0.05). Re-LT was indicated in 5596 cases (7%) mainly for technical complications (37%) (mostly vascular (27%) and biliary (10%)), for primary non-function (25%) and for rejection (19%), mainly chronic (14%). Recurrence of primary disease (mostly non-tumoral) was concerned in only 11% of cases (Table 4).Table 4Cause of re-LT after the first LT in Europe. The complications correspond to the first cause of failure declared according to time of occurrence. Open table in a new tab Five-year graft survival rates for the second and third LTs were 42% and 37%, respectively, significantly lower than those for primary LT (65% – p 55 has been demonstrated as an independent risk factor of post-transplant outcome [[13]Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar], the evolution shows that older donors are increasingly used to augment the donor pool. Similarly, recipient age has been considered as independently associated with higher post-transplant mortality, the but older recipients increasingly undergo LT owing to improved results and better selection of patients. What has not changed with time is the critical period of the first 6 months and, more generally, the first year to determine the final outcome of the transplanted recipients. More than a half of the deaths and three quarters of re-LTs occurred within the first year after LT. That means that when patients have successfully reached the first year after LT, they have an optimal chance to survive at long-term. When required (in approximately 7% of patients), re-LT is associated with much less optimal results than the first LT. However, there is no team that would consider this result a reason to exclude a new LT suggesting that a sort of moral contract exists with the patient, in addition to strict consideration of the optimal use of organs. Interestingly, the gap of survival is observed between first and second LT while third and fourth LTs are not associated with results much worse than those of second LTs. One of the prominent features of recent years has been the development of LRLT, performed by almost half of the centers. As with split LT, LRLT aims to provide more patients with transplants, but with special attention to decrease as much as possible risks for the donor, now estimated to be of 0.18% for mortality and 23% for postoperative morbidity. However, LRLT has tended to decrease in recent years in Europe mirroring the trend in the US, where it has actually decreased [[21]Brown Jr., R.S. Live donors in liver transplantation.Gastroenterology. 2008; 134: 1802-1813Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar]. Potential living liver donors are best served by accurate information about donor mortality. Access to such data is difficult and these individuals benefit from living liver donor registries and peer-reviewed publication of donor mortality. That may provide an impetus for centers with unreported deaths to submit these outcomes to the liver transplantation community [22Bramstedt K.A. Living liver donor mortality: where do we stand?.Am J Gastroenterol. 2006; 101: 755-759Crossref PubMed Scopus (40) Google Scholar, 23Trotter J.F. Adam R. Lo C.M. Kenison J. Documented deaths of hepatic lobe donors for living donor liver transplantation.Liver Transpl. 2006; 12: 1485-1488Crossref PubMed Scopus (190) Google Scholar]. In conclusion, LT is definitely a validated therapy of end-stage liver disease, acute liver failure and HCC. It is becoming relatively safe as compared to the initial years. Indications are oriented to more optimal use of the limited donor pool. Survival is increasing gradually in relation to greater expertise in the surgical procedure and management of immunosuppressive therapy. Alternatives to conventional use of cadaveric full size liver grafts are expanding to palliate the organ shortage. This latter development including the increasing use of non-heart beating donors, the long-term evaluation of the MELD allocation policy now used in the majority of countries will probably represent a key issue in the near future. To increase the donor pool, to avoid patient death on the waiting list, and to offer equal access to good indications of LT have become the main challenges of a treatment that presently allows 70–80% of patients to survive at 5 years. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The authors are indebted to all the 145 contributing centers listed at the following link www.eltr.org/spip.php?page=centers-tous. The registry is supported by a grant from Astellas, Novartis and a logistic support of the Paul Brousse Hospital (Assistance Publique – Hôpitaux de Paris). ELTR is a service of the European Liver and Intestine Transplant Association (ELITA).