Jean-Bernard Otte

Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study

BACKGROUND No model exists for liver transplantation to estimate the mortality risk in a given patient, and no standard by which to assess performance in different centres. We investigated the intrinsic mortality risk in the absence of known mortality risk factors. METHODS We identified mortality risk factors and risk ratios quantified in data from the European Liver Transplant Registry (22,089 patients at 102 centres in 18 countries) registered from 1988 to 1997. To develop a model of the intrinsic risk and the risk ratios for specific factors, univariate and multivariate analyses were done separately for the overall population, for adults, and for children younger than 15 years, and the number of deaths were estimated. We validated the model by comparing mortality in patients without risk factors with the model-adjusted mortality in patients with risk factors. FINDINGS Overall 5-year and 8-year actuarial survival was 66% (95% CI 65-66) and 61% (60-62). 65% of deaths occurred within 6 months. Retransplantation, transplantation for cancer, acute liver failure, fewer than 20 split-liver grafts per year, and a centre workload of fewer than 25 transplants per year were the main risk factors of 12 identified factors. 1-year and 5-year death rates among adults with no risk factors were similar to model estimates (15 [13-16] vs 14% [13-15], and 22 (20-24) vs 23% [21-24]). Corresponding data for paediatric transplants were 9% (7-12) compared with 11% (9-12) and 13% (10-17) compared with 14% (11-16). The reduction of mortality risk in high-volume centres was even greater in patients without risk factors (48 vs 23%, p<0.001). INTERPRETATION The normalised intrinsic mortality risk can be combined with the relative risk ratios of known risk factors to better estimate the mortality risk of a given procedure in a given patient. Centres can assess performance by removing potential bias of donor and recipient selection.

Liver transplantation for hepatoblastoma: Indications and contraindications in the modern era

Abstract:  In the past 20 yr, a dramatic improvement has been achieved in the outcome of children with hepatoblastoma by combining cisplatin based chemotherapy and surgery. Treatment of patients in the USA is an exception to the rule that all patients should receive neoadjuvant chemotherapy. It is paramount that surgical resection be complete, both macro‐ and microscopically. Complete tumor resection can be achieved after chemotherapy with a partial hepatectomy when the intrahepatic extent is limited to 1–3 sectors. In multifocal (and solitary) hepatoblastomas invading all four liver sectors, and in centrally located tumors with close proximity to the major veins, the SIOPEL‐1 study and an extensive review of the world experience have shown that primary transplantation provides high, long term, disease‐free survival rate in the range of 80%. In contrast, the results of rescue transplants for incomplete tumor resection or disease recurrence after partial hepatectomy are disappointing (in the range of 30%). Hazardous attempts at partial hepatectomy in children with extensive hepatoblastoma should be discouraged. Guidelines are provided for early referral of children with extended hepatoblastoma to a transplant surgeon. There is a trend for a better patient survival after living related liver transplantation. Patients who will become candidates to liver transplantation should be treated with chemotherapy following the same protocols as for children undergoing a partial hepatectomy. There is a concern about cumulative nephrotoxicity of calcineurin inhibitors and chemotherapeutic drugs. Recent data suggest that these patients tolerate lower Tacrolimus trough blood levels than those transplanted for non‐malignant conditions, without increasing the risk of acute rejection. Due to the rarity of the disease, these children should be treated in specialized centers.

Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients

SummaryThe pharmacokinetics of intravenous and oral tacrolimus was assessed in paediatric liver transplant patients at two centers in Europe. Sixteen patients, age 0.7 to 13 years, participated in the study; 12 patients were evaluable for intravenous pharmacokinetics, and 16 for oral. Intravenous tacrolimus was given as a continuous 24 h infusion (mean 0.037±0.013 mg/kg/day), and oral tacrolimus was given in 2 doses per day (mean 0.152±0.015 mg/kg). Whole blood samples for the intravenous pharmacokinetic profile were taken before initiation of the first infusion, 4, 8, 12 and 24 h post-infusion, and every 24 h thereafter until intravenous administration was discontinued. During the 12 h wash-out period between intravenous and oral administration, samples were taken every 3 h. Samples for the oral pharmacokinetic profile were taken immediately before the first oral dose and 0.5, 0.75, 1, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-administration. Non-compartmental procedures were used to characterise the pharmacokinetic parameters. Mean estimates for clearance and terminal half-life were 2.3±1.2 ml/min/kg and 11.5±3.8 h, respectively, following intravenous tacrolimus. The mean bioavailability of oral tacrolimus was 25±20%. A strong correlation was observed between AUC and trough whole blood levels of tacrolimus (r=0.90). The clearance was approximately 2-fold higher than that previously observed in adults; this could explain the higher dosage requirements in children.

Is it right to develop living related liver transplantation? Do reduced and split livers not suffice to cover the needs?

The paper by Slooff [16], published in this issue of Transplant International, places the innovative techniques of liver transplantation in a very appropriate perspective regarding the currently nonreducible shortage of size-matched donors in pediatric liver transplantation. We have updated our own results obtained with reduced size liver and split liver transplantation in order to strengthen the argument very rightly made by the author. Received: 11 April 1994 Received after revision: 22 June 1994 Accepted: 28 June 1994

Characteristics of Epstein-Barr virus primary infection in pediatric liver transplant recipients.

BACKGROUND/AIM: Pediatric liver transplant recipients are at high risk of Epstein-Barr virus infection. However the incidence of clinical symptoms and the graft function at the time of acute infection remains poorly documented. The aim of this study was to monitor the clinical and biochemical events associated with primary Epstein-Barr virus infection. METHODS: Clinical and biological patterns associated with Epstein-Barr virus infection were prospectively searched in 38 liver transplanted children. Polymerase chain reaction and anti-Epstein-Barr virus IgM antibodies were used at regular intervals to detect the timing of primary infection. RESULTS: Five children (13%) had pretransplant immunity, 26 (68.5%) developed primary Epstein-Barr virus infection 15 to 90 days after transplantation and seven (18.5%) remained Epstein-Barr virus negative. The four patients with clinical symptoms at the time of infection subsequently developed post-transplant lymphoproliferative disease. A single post-transplant lymphoproliferative disease occurred in non-symptomatic patients (overall incidence 13%). No mortality was associated with post-transplant lymphoproliferative disease. Two asymptomatic patients had abnormal liver function tests possibly related to primary Epstein-Barr virus infection. CONCLUSION: Epstein-Barr virus primary infection occurs in 80% of seronegative patients within 3 months after OLT. Clinical symptoms are rare and closely associated with post-transplant lymphoproliferative disease. Outside post-transplant lymphoproliferative disease, the consequences of infection are marginal.

Liver retransplantation in children. A 21-year single-center experience*

In this study, the epidemiology and outcome of graft loss following primary pediatric liver transplantation (LT) were analysed, with the hypothesis that early retransplantation (reLT) might be associated with lower immunologic risks when compared with late reLT. Between March 1984 and December 2005, 745 liver grafts were transplanted to 638 children at Saint‐Luc University Hospital, Brussels. Among them, a total of 90 children (14%) underwent 107 reLT, and were categorized into two groups (early reLT, n = 58; late reLT, n = 32), according to the interval between either transplant procedures (< or >30 days). Ten‐year patient survival rate was 85% in recipients with a single LT, vs. 61% in recipients requiring reLT (P < 0.001). Ten‐year patient survival rates were 59% and 66% for early and late reLT, respectively (P = 0.423), the corresponding graft survival rates being 51% and 63% (P = 0.231). Along the successive eras, the rate of reLT decreased from 17% to 10%, whereas progressive improvement of outcome post‐reLT was observed. No recurrence of chronic rejection (CR) was observed after reLT for CR (0 of 19). Two children developed a positive cross‐match at reLT (two of 10, 20%), both retransplanted lately for CR secondary to immunosuppression withdrawal following a post‐transplant lymphoproliferative disease. In summary, the results presented could not evidence better results for late reLT when compared with early reLT. The former did not seem to be associated with higher immunologic risk, except for children having withdrawal of immunosuppression following the first graft.

Further refinements on splitting livers for transplantation

Anatomically speaking, the liver is a unique double organ. Precise knowledge of its anatomy and meticulous surgical techniques are required for its safe sharing, either between two recipients of a shared postmortem liver or between a live donor organ and a privileged recipient. Both approaches played a major role in the expansion of pediatric liver transplantation (1). In this issue of the journal, Jean de Ville de Goyet and colleagues of Bambino Gesu Hospital (Rome) compare the trans-hilar and the transumbilical division of a postmortem liver (2). They performed a five-yr retrospective analysis of 47 left split liver grafts procured with two different division techniques: through segment IV (“classical” group A, n = 28) or through the umbilical fissure (group B, n = 19). The techniques are precisely described and outcomes are analyzed. Procurement was performed by several surgical teams across Italy; the allocation to recipients was at random while all transplants were performed by the same team at Bambini Gesu. Trans-umbilical division procures a left lateral segment split graft containing Couinaud’s segments II and III, while the trans-hilar approach allows procurement of Couinaud’s segments II and III with a variable part of segment IV, by shifting the division line to the right of the falciform ligament, depending on the recipient size. Actuarial survival rates were outstanding, 96% for graft survival (35 months and 19 months follow-up in groups A and B, respectively) and 98% for patient survival. Grafts in group A were more often procured with one single bile duct than in group B (89% vs. 59%, respectively), without, however, a higher incidence of biliary complications in group B. The outcome of the corresponding right split grafts was also excellent with a 96% graft survival at three months. Five right grafts were lost due to thrombosis of the right hepatic artery when the celiac axis was retrieved with the left split graft. When a post-transplant biliary reconstruction is needed to repair an anastomotic stricture or when portal thrombosis requires a meso-Rex shunt, the authors draw attention to the more difficult and hazardous approach of the hilar region when the trans-umbilical technique is used because the vascular and biliary structures are brought to the surface. The peculiar and unique value of this paper is to compare the two division techniques, abundantly but separately described in the surgical literature (3). In conclusion, the authors synthesize the respective advantages and limitations of both division techniques. This paper is a very useful contribution to the field. A major issue in the field of liver division is the number of bile ducts transected when procuring a left split graft, from either a live donor or a postmortem organ. Although in the paper referenced above, Jean de Ville de Goyet and coworkers did not observe a higher rate of biliary complications when more than one single bile duct was transected, likely thanks to their meticulous technique, a higher incidence of this occurrence has been widely observed with multiple biliary anastomoses. The allocation of the celiac axis to the left split graft may add a risk on the right split graft. With this restriction, both liver division techniques are safe for the recipients of both split grafts. In the same issue of the journal, M. Kiss and coworkers from Semmelweis University, Budapest, Hungary, publish a valuable study about the best line of donor liver hepatotomy in living donor liver transplantation, according to the anatomical variations of the bile duct system (4). This study is important regarding the safety of both the donor and the recipient. Thirty cadaveric livers were recovered at autopsy. The biliary system was injected with a home-made resin mixture. Computed tomography