Xavier Rogiers

In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool.

OBJECTIVE The authors evaluate the safety, applicability, and effectiveness of a new technique for split-liver transplantation. SUMMARY BACKGROUND DATA Split-liver transplantation offers an attractive way to increase the donor pool for cadaveric liver transplantation. The application of this concept has been hampered by inferior patient and graft survivals and higher complication rates. Without supportive data, the concern about increasing biliary leakage and poor initial graft function persisted. The authors focused on the causes of these complications by presenting a new technique to eliminate these problems. METHODS Liver splitting was performed in the heart-beating cadaveric organ donor, using the technique described for procurement of the left lateral lobe of a live donor. A detailed description of the technique is presented. A retrospective review of the first 14 transplantations resulting from 7 in situ splitting procedures was collected. The results were compared with 19 conventional split-liver transplants performed during the same period. RESULTS Six-month patient and graft survivals after in situ split-liver transplantation were 92.8% and 85.7%, respectively. Biliary complications were absent. Postoperative courses were mostly uneventful and characterized by lower peak transaminase levels compared with standard techniques. Early graft function of extrahepatic organs procured simultaneously was excellent. CONCLUSIONS In situ split-liver transplantation provides superior results, related mainly to reduction of cold ischemic damage of the grafts and avoidance of biliary complications. In situ split-liver transplantation renders graft reduction alone obsolete and opens a donor pool for adults to receive right lobes safely. It allows for long-distance sharing between pediatric and adult liver transplant units because the procedure abolishes ex situ benching and prolonged ischemia time and provides two anatomically perfect grafts with hemostasis accomplished.

3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome

BACKGROUND Mortality after liver transplantation depends on heterogeneous recipient and donor factors. Our aim was to assess risk of death and to develop models to help predict mortality after liver transplantation. METHODS We analysed data from 34,664 first adult liver transplants from the European Liver Transplant Registry to identify factors associated with mortality at 3-months (n=21,605 in training dataset) and 12-months (n=18,852 in training dataset) after transplantation. We used multivariable logistic regression models to generate mortality scores for each individual, and assessed model discrimination and calibration on an independent validation dataset (n=9489 for 3-month model and n=8313 for 12-month model). FINDINGS 2540 of 21,605 (12%) individuals in the 3-month training sample had died by 3 months. Compared with those transplanted in 2000-03, those transplanted earlier had a higher risk of death. Increased mortality at 3-months post-transplantation was associated with acute liver failure (adjusted odds ratio 1.61), donor age older than 60 years (1.16), compatible (1.22) or incompatible (2.07) donor-recipient blood group, older recipient age (1.12 per 5 years), split or reduced graft (1.96), total ischaemia time of longer than 13 h (1.38), and low United Network for Organ Sharing score (score 1: 2.43; score 2: 1.67). However, cirrhosis with hepatocellular carcinoma, alcohol cirrhosis, hepatitis C or primary biliary cirrhosis, donor age 40 years or younger, or less, hepatitis B, and larger size of transplant centre (> or = 70 transplants per year) were associated with improved early outcomes. The 3-month mortality score discriminated well between those who did and did not die in the validation sample (C statistic=0.688). We noted similar findings for 12-month mortality, although deaths were generally underestimated at this timepoint. INTERPRETATION The 3-month and 12-month mortality models can be effectively used to assess outcomes both within and between centres. Furthermore, the models provide a means of assessing the risk of post-transplantation mortality, giving clinicians important data on which to base strategic decisions about transplant policy in particular individuals or groups.

Portal Vein Embolization vs. Portal Vein Ligation for Induction of Hypertrophy of the Future Liver Remnant

The objective of this study was to assess the efficacy of right portal vein embolization (PVE) vs. right portal vein ligation (PVL) for induction of hypertrophy of the left lateral liver lobe before extended right hepatectomy. Thirty-four patients with primary or secondary liver tumors and estimated remnant functional liver parenchyma of less than 0.5% of body weight underwent either right PVE (transcutaneous, n= 10; transileocolic, n =7) or right PVL (n=17). Liver volume was assessed by CT scan before occlusion of the right portal vein and prior to resection. There were no deaths. The morbidity rate in each group was 5.8% (PVE, 1 abscess; PVL, 1 bile leak). The increase in liver volume was significantly higher after PVE compared with PVL (188±81 ml vs. 123±58 ml) (P= 0.012). Postoperative hospital stay was significantly shorter after PVE in comparison to PVL (4±2.9 days vs. 8.1±5.1 days;P<0.01). Curative liver resection was performed in 10 of 17 patients after PVE and 11 of 17 patients after PVL. PVE and PVL were found to be feasible and safe methods of increasing the remnant functional liver volume and achieving resectability for extended liver tumors. PVE results in a significantly more efficient increase in liver volume and a shorter hospital stay.

Evolution of Donor Morbidity in Living Related Liver Transplantation: A Single-Center Analysis of 165 Cases

Objective:During the last 14 years, living donor liver transplantation (LDLT) has evolved to an indispensable surgical strategy to minimize mortality of adult and pediatric patients awaiting transplantation. The crucial prerequisite to performing this procedure is a minimal morbidity and mortality risk to the healthy living donor. Little is known about the learning curve involved with this type of surgery. Patients and Methods:From January 1991 to August 2003, a total of 165 LDLTs were performed in our center. Of these, 135 were donations of the left-lateral lobe (LL, segments II and III), 3 were of the left lobe (L, segments II–IV), 3 were full-left lobes (FL, segments I–IV), and 24 were of the full-right lobe (FR, segments V–VIII). We divided the procedures into 3 periods: period 1 included the years 1991 to 1995 (LL, n = 49; L, n = 2; FR, n = 1), period 2 covered 1996 to 2000 (LL, n = 47), and period 3 covered 2001 to August 2003 (LL, n = 39; FR, n = 23; FL, n = 3; L, n = 1). Perioperative mortality and morbidity were assessed using a standardized classification. Length of stay in intensive care unit, postoperative hospital stay, laboratory results (bilirubin, INR, and LFTs), morbidity, and the different types of grafts in the 3 different periods were compared. Results:One early donor death was observed in period 1 (03/07/93, case 30; total mortality, 0.61.%). Since 1991, the perioperative morbidity has continually declined (53.8% vs. 23.4% vs. 9.2%). In period 1, 28 patients had 40 complications. In period 2, 11 patients had 12 complications, and in period 3, 6 patients had 9 complications. Within the first period, 1 donor underwent relaparotomy because of bile leakage. Postoperative hospital stay was 10 days, 7 days, and 6 days, respectively. Donation of the full right lobe, in comparison with that of the left lateral lobe, resulted in a significantly diminished liver function (bilirubin and INR) during the first 5 days after donation but did not increase morbidity. One donor from period 1 experienced late death caused by amyotrophic lateral sclerosis. Conclusions:In a single center, morbidity after living liver donation strongly correlates to center experience. Despite the additional risks associated with temporary reduction of liver function, this experience enabled the team to bypass part of the learning curve when starting right lobe donation. Specific training of the surgical team and coaching by an experienced center should be implemented for centers offering this procedure to avoid the learning curve.

In Situ Splitting Of The Liver In The Heart-beating Cadaveric Organ Donor For Transplantation In Two Recipients

SLT presents an interesting concept to alleviate the organ shortage for children with end-stage liver disease. The procedure has, however, not gained wide acceptance. This is not only related to the complexity of the procedure, but also to the poorer results and the complications reported on the right side graft. We report on a first case in which we applied a new concept for splitting. The liver was split in situ in the heart-beating cadaveric donor with the aim of reducing the problems with the right side graft. This procedure makes splitting of the liver possible without submitting the recipient of the right side to increased risk. Therefore, in situ splitting of the liver has the potential of making splitting of liver grafts the rule rather than the exception, thus increasing the organ pool for small children presently carrying a high risk of dying on the waiting list.

RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-α and NF-κB

The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-κB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-α and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death–promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.

Living donor for liver transplantation

Since living related liver transplantation was first performed in 1989, more than 150 cases have been performed worldwide, mostly in the United States and Japan. This paper reports the first series of living related liver transplantation in Europe. Twenty living related liver transplantation surgeries were performed over a 13‐mo period, with an overall patient survival of 85%. For patients who underwent elective transplantation (n=13), the survival rate was 100%. Technical complications included one arterial thrombosis necessitating retransplantation and five bile leaks requiring surgical revision. The technical improvements that permit avoidance of these complications are discussed. A detailed description of the living related liver procurement is given. All procurements yielded grafts of excellent quality. No intraoperative complications occurred, and no reoperations were necessary. No heterologous blood transfusion was needed. In two patients, incisional hernias developed after wound infection. Living related liver transplantation does not absolve the transplant community of efforts to promote cadaveric organ procurement. Nevertheless, living related liver transplantation does have the advantage of a readily available graft of excellent quality, permitting transplantation with optimal timing under elective conditions. Several centers are now preparing living related segmental liver transplants, following the model of our protocol, for three reasons: (a) to obtain superior results compared with cadaveric liver transplantation; (b) to overcome cadaveric organ shortage and further reduce pretransplantation mortality and (c) to provide viable organs in countries where cadaveric organ procurement is not established. When performed by a team experienced in pediatric liver transplantation and in adult liver resection, living related liver transplantation is an excellent modality for the treatment of end‐stage liver disease in children. (Hepatology 1994;20:49S‐55S.)

Selection of the living liver donor.

Living related liver transplantation offers several advantages in comparison to transplantation of cadaver organs. To achieve maximal donor safety evaluation, selection criteria and complications of the donor operation were retrospectively analyzed in living donors of segmental liver transplants. Seventy-three liver donor candidates were evaluated between October 1991 and June 1994. The median age of 42 mothers and 31 fathers was 31 years (range, 19-50 years). The median volume of the left lateral liver lobe comprised 230 ml (100-350 ml). Twenty-four of 73 (33%) donor candidates were not accepted for living donation. Rejection was due to unsuitability of the donors liver as a graft (n = 13) or due to an increased risk for living donation (n = 11). Of 35 living donations performed so far, one was a full left hemihepatectomy and 34 were left lateral segmentectomies. The length of the donor operation was, on average, 4.3 hr. No heterologous blood was needed. Postoperative complications included death due to pulmonary embolism (n = 1), seizure due to a previously undiagnosed ependymoma (n = 1), bile duct injury (n = 1), incisional hernia necessitating late revision (n = 2), and duodenal ulcer (n = 2). Long-term follow-up revealed no persistent complications. Using our standardized protocol, 33% of young, presumably healthy donor candidates were rejected for living donation.

Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12‐ and 36‐month results

Everolimus is a macrolide immunosuppressive agent with known consistent absorption. In this double‐blind study, we examined the safety and tolerability of everolimus vs. placebo in de novo liver transplant recipients. One hundred and nineteen liver allograft recipients were randomized to 1 of 4 groups: everolimus 0.5 mg bid, everolimus 1.0 mg bid, everolimus 2 mg bid, or placebo. Patients received oral cyclosporine to achieve a target trough level of 150‐400 ng/mL in combination with prednisone. Primary and secondary endpoints of safety, tolerability, and efficacy were determined at 12 months, and patients were followed through 36 months. There was a trend toward fewer treated acute rejections in the everolimus group than in the placebo group: everolimus 0.5 mg: 39.3%; everolimus 1.0 mg: 30.0%; everolimus 2 mg: 29.0%; placebo: 40.0% (P = not significant). Adverse events were higher in everolimus‐treated patients especially at the 4‐mg/day dose, but there was no difference in the incidence of thrombocytopenia or leukopenia between all groups and renal function as determined by serum creatinine, and creatinine clearance remained stable to 36 months in everolimus‐treated patients. Mean cholesterol and triglycerides increased from baseline in all treatment groups, and maximum levels were seen at 6 months. In conclusion, this study demonstrates that everolimus in combination with oral cyclosporine had an acceptable safety and tolerability profile, paving the way for additional studies in this transplant indication. Liver Transpl, 2006.

Long-term differentiated function of heterotopically transplanted hepatocytes on three-dimensional polymer matrices.

Hepatocyte transplantation using porous matrices is under investigation as an alternative therapy for certain liver diseases. For this purpose, long-term function of transplanted hepatocytes is mandatory. This problem has not been sufficiently investigated yet. In this study Lewis rats were used as donors and recipients. Stimulated (group A, portocaval shunt) or unstimulated (group B) hepatocytes were transplanted into prevascularized polyvinyl-alcohol matrices. Cell-free matrices served as controls (group C). Matrices were harvested between 1 h and 1 year after implantation and analyzed by morphometry; albumin RNA in situ hybridization; and cytokeratin-, actin-, desmin-, and macrophage-specific antigen immunohistology. The hepatocyte number significantly decreased within the first week following implantation. Between 1 month and 1 year after transplantation a significant increase in hepatocyte number was noted in groups A and B. Albumin transcripts of transplanted hepatocytes were at normal levels at all times except for group B after 1 year. The immunohistology suggested engraftment of nonparenchymal liver cells. We conclude that 3-dimensional matrices provide a sufficient environment for long-term engraftment of transplanted liver cells. The hepatocytes are able, despite suboptimal initial engraftment, to repopulate the scaffold for at least half of the recipients life span and maintain cell-specific function after sufficient stimulation.