A. Pascher

Clinical extracorporeal hybrid liver support – phase I study with primary porcine liver cells

Abstract: The objective of this study was to evaluate the feasibility and safety of a hybrid liver support system with extracorporeal plasma separation and bioreactor perfusion in patients with acute liver failure (ALF) who had already fulfilled the criteria for high urgency liver transplantation (LTx). Eight patients (one male, seven female) were treated in terms of bridging to transplantation. The mean age was 36.5 yr (range 20 to 58). Etiology of liver failure was drug‐related in two patients, hepatitis B infection in three patients, and unknown for three patients. The bioreactors were charged with primary liver cells from specific pathogen‐free pigs. Cell viability varied between 91 and 98%. Continuous liver support treatment over a period of 8 to 46 h (mean 27.3 h) was safely performed and well‐tolerated by all patients. No complications associated with the therapy were observed during the follow‐up period. Thrombocytopenia was considered to be an effect of the plasma separation. Subsequently, all patients were transplanted successfully and were observed over at least 3 yr with an organ and patient survival rate of 100%. Screening of patients sera for antibodies specific for porcine endogenous retroviruses (PERVs) showed no reactivity – either prior to application of the system, or after extracorporeal treatment. The results encourage us to continue the development of the technology, and further studies appear to be justified. The bioreactor technology has been integrated into a modular extracorporeal liver support (MELS) system, combining biologic liver support with artificial detoxification technology.

In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD)

The detoxification capacities of single‐pass albumin dialysis (SPAD), the molecular adsorbents recirculation system, (MARS) and continuous veno‐venous hemodiafiltration (CVVHDF) were compared in vitro. In each experiment 4,100 mL of toxin‐loaded human plasma was processed for 6.5 hours. MARS treatment (n = 6) was undertaken in combination with CVVHDF. For SPAD (n = 6) and CVVHDF (n = 6) a high‐flux hollow fiber hemodiafilter (identical to the MARS filter) was used. Levels of ammonia, urea, creatinine, bilirubin, and bile acids were determined. Concentrations before and after application of detoxification procedures were expressed as differences and were compared using the Kruskal‐Wallis test. Post hoc comparisons for pairs of groups were adjusted according to Bonferroni‐Holm. Time, group, and interaction effects were tested using the nonparametric ANOVA model for repeated measurements. SPAD and CVVHDF induced a significantly greater reduction of ammonia levels than MARS. No significant differences were found among SPAD, MARS, and CVVHDF with respect to other water‐soluble substances. SPAD induced a significantly greater reduction in bilirubin levels than MARS. Reductions in bile acid levels were similar for SPAD and MARS. When operating MARS in continuous veno‐venous hemodialysis mode, as recommended by the manufacturer, no significant differences in the removal of bilirubin, bile acids, urea, and creatinine were found. However, MARS in continuous veno‐venous hemodialysis mode was significantly less efficient in removing ammonia than MARS in CVVHDF mode. In conclusion, the detoxification capacity of SPAD is similar to or even greater than that of MARS. (HEPATOLOGY 2004;39:1408–1414.)

Extracorporeal liver perfusion as hepatic assist in acute liver failure: a review of world experience

Background: There are almost no prospective, controlled and randomized clinical trials comparing different approaches towards hepatic assist. In order to create a basis for comparing the value of the existing different hepatic assist methods this article offers a systematic review of the world experience with allogeneic or xenogeneic extracorporeal liver perfusion (ECLP).

Psychosocial outcome of living donors after living donor liver transplantation: a pilot study

Walter M, Bronner E, Pascher A, Steinmüller T, Neuhaus P, Klapp BF, Danzer G: Psychosocial outcome of living donors after living donor liver transplantation: a pilot study. Clin Transplant 2002: 16: 339–344.

Technique of bile duct reconstruction and management of biliary complications in right lobe living donor liver transplantation

Abstract:  From December 1999 to January 2002, 50 right lobe living donor liver transplantations were performed. The donor operations included an intraoperative cholangiography to elicit variations in bile duct anatomy. The biliary reconstruction was done whenever possible as an end‐to‐end microanastomosis of the donor right hepatic duct with the recipients bile duct. As a result of the early segmental branching of the donor biliary tree, two segment bile ducts had to be anastomosed in 20 patients and three segment bile ducts in three patients. In 12 patients, a Roux‐en‐Y hepaticojejunostomy was performed. All anastomoses were drained externally. We observed two leakages at the resection surface which could be treated successfully by an external drainage. Six leaks occurred at the site of end‐to‐end biliary anastomoses. Twice the problem could be conservatively solved placing a stent percutaneously. In two patients a hepaticojejunostomy was performed after a bile duct necrosis. In two patients with an anastomotic leak, occurring 3 d, respectively, 3 month after the original transplantation, the bile duct could be directly reconstructed over a T‐tube. Two anastomotic stenoses were observed, one in combination with a leak treated by percutaneous stent implantation and the second, 3 month after transplantation which was treated surgically. Biliary reconstruction after living donor liver transplantation requires microsurgical techniques and can be performed as a direct end‐to‐end anastomosis in most cases. Biliary complications were treated by percutaneous drainage or surgical revision in all cases.

Psychosocial stress of living donors after living donor liver transplantation.

LIVING DONOR liver transplantation (LDLT) has emerged as an established treatment modality in the therapy of terminal liver disease in adults. Surgery-related complications and reports of fatalities among donors result in an ethical dilemma in the process of donor-recipient evaluation. Because the mortality rate among LDLT recipients is low, the surgery-related potential hazard primarily exists for donors. Initial results have shown an overall good psychosocial outcome for donors: all donors reported a willingness to donate on another occasion and no limitations of physical or social activities as of psychologic status. Little is known, however, about the factors that impinge on the psychosocial outcome following organ donation. For this reason, we evaluated the relationship between complications following LDLT surgery and stress perception among donors, and sought potential pre-surgery predictors of enhanced stress perception.

Analysis of allogeneic versus xenogeneic auxiliary organ perfusion in liver failure reveals superior efficacy of human livers.

Purpose: To compare the efficacy of allogeneic and xenogeneic extracorporeal liver perfusion (ECLP). Methods: An Internet-based keyword search was performed in the established online databases. Univariate and multivariate analysis of variance (general linear method) were performed. Results: Data from 198 patients were included in the statistical analysis, 142 of whom were treated by ECLP using porcine livers. Baboon livers were used in 29 patients, human livers in 14, and other or mixed species in 13 patients. Pig liver perfusions resulted in a 20% long-term-survival whereas the use of human livers was significantly more successful (survival rate (SVR) 43%, p<0.05). Baboon livers also revealed superior success (41%; p<0.05). Twenty-three patients were treated after 1991, 12 surviving long-term (52%). The latter all belonged to a group of 14 patients who received combined treatment consisting of ECLP and LTx (SVR-86% in this subgroup). Conclusion: Allogeneic ECLP was accompanied by significantly improved outcome compared with discordant xenogeneic ECLP. The role of hyperacute rejection in acute liver failure with reduced complement levels remains controversial. Physiologic disparity between pig and man may be the even more decisive determinant of outcome.

Clinical small bowel transplantation: Focus on mucosal barrier function

RECENTLY SMALL BOWEL transplantation has evolved to an established treatment for patients with short gut syndrome and intestinal failure. The introduction of new immunosuppressants offer the opportunity to minimize acute rejection episodes and associated problems. Nevertheless, good initial graft function with maintainance of the mucosal barrier function are of great importance. Preservation/reperfusion injury impairs mucosal barrier function and furthermore initiates the release of mediators. The release of specific and nonspecific inflammatory mediators may promote serious postoperative complications including the development of infection and acute rejection. Therefore, new strategies are required to decrease reperfusion injury and restore mucosal barrier function. Early postoperative enteral nutrition has been shown to restore mucosal barrier function and to decrease the incidence of infection including pneumonia, peritonitis, and sepsis. Enteral preparations containing glutamine, arginine, and omega-3 fatty acids, so called immunonutritions, are known to decrease the release of cytokines, reactive oxygen intermediates, and other mediators in critically ill patients. Lactobacilli, naturally found in the small intestine, have been shown to prevent bacterial overgrowth, to restore gut barrier function, and thereby, to reduce the occurrence of infection. To decrease infectious complications and possibly rejection, donors and recipients of small bowel grafts were treated with lactobacilli and immunonutrition.

Monitoring of immunosuppression after clinical small bowel transplantation

ACUTE REJECTION (AR) remains the most prominent risk factor following small bowel transplantation. Despite improved patient and organ survival rates from approximately 50% to 97% and 71%, respectively, by switching immunosuppression from cyclosporine (CsA)based protocols to tacrolimus (Tac)-based regimens, the rejection rate remains as high as 95% with 60% of rejection episodes occurring in the initial 3 months. New potent immunosuppressants, such as rapamycin (Rapa) and monoclonal antibodies against IL-2 receptor (daclizumab [Dac]), are believed to have the potential to further decrease rejection rates and improve outcomes after small bowel transplantation (SBTx). Pinna et al compared different induction protocols, including cyclophosphamide, mycophenolate mofetil, OKT3, and Dac, with Dac resulting in slightly decreased rejection rates and fewer infectious complications. Abu-Elmagd et al presented preliminary data suggesting the efficacy of Dac as induction therapy together with a Tac-based immunosuppressive regimen to reduce acute rejection (AR) rates (by 43%). The incidence rate of viral infection for and posttransplant lymphoproliferative disease was 7% for each. The impact of additional to Tac-based protocols of Rapa, steroids, and Dac induction therapy is undergoing evaluation in terms of whether they decrease the AR rate while increasing the risk for development of immunosuppression-associated infections, including CMV and EBV. However, monitoring of immunosuppression may facilitate individualized rather than fixed dosing of induction therapy with Dac.

Immunologisches und pharmakodynamisches Monitoring zur Abstossungsprävention und -behandlung nach Dünndarmtransplantation

Background: Severe acute rejections (AR) after intestinal transplantation (ITx) are associated with a mortality as high as 50 - 80%. Thus, various efforts were made to establish reliable and sensitive, noninvasive markers for acute rejection. Methods: 11 ITx were performed for irreversible short bowel syndrome. Pharmacodynamic and immunological monitoring comprised CD4 + CD25 + -T-cells, serum-IL2R, serum-TNFalpha, CD8 + HLA-DR-T-cells, LPS- binding protein (LBP), IL-6, IL8, and CRP. Results: 1-year-patient- and graft survival were 73% (9/11). The incidence of AR was 9% (1/11) within the first 6 month and 18% (2/11) within the first year. LBP was the only sensitive marker for protocol biopsy proven, otherwise not detectable indeterminate rejections (5/5; 100%). ARs were accompanied by a distinct rise of serum LBP and CRP (3/3), steroid-resistent AR by a significant increase of serum- TNF alpha (3/3). Pharmacodynamic monitoring of CD4 + CD25+ T-cells and serum IL2R allowed for individualized and reduced administration of daclizumab. Two patients experiencing OKT3-resistant AR received rescue treatment with infliximab (chimeric anti-TNF alpha mo Ab). According to pharmacodynamic monitoring of LBP and TNFa, four infusions (3 mg/kg KG body weight) were applied in each patient until complete recovery. Summary: LBP as marker for bacterial translocation revealed to be highly sensitive for indeterminate as well as acute rejections after ITx. Serum TNF alpha increase correlated with the onset of steroid- and OKT3-resistant AR. Pharmacodynamic monitoring allowed for individualized treatment regimens regarding daclizumab and infliximab. Infliximab turned out to be highly effective for the treatment of steroid- and OKT3-resistant rejections.