How to Estimate the Probability of Tolerance Long-Term in Liver Transplant Recipients.

BACKGROUND: Operational tolerance as the ability to accept the liver transplant without pharmacological immunosuppression is a common phenomenon in the long-term course. However, it is currently underutilized due to a lack of simple diagnostic support and fear of rejection despite its recognized benefits. In the present work, we present a simple score based on clinical parameters to estimate the probability of tolerance. PATIENTS AND METHODS: In order to estimate the probability of tolerance, clinical parameters from 82 patients after LT who underwent weaning from the IS for various reasons at our transplant center were extracted from a prospectively organized database and analyzed retrospectively. Univariate testing as well as multivariable logistic regression analysis were performed to assess the association of clinical variables with tolerance in the real-world setting. RESULTS: The most important factors associated with tolerance after multivariable logistic regression were IS monotherapy, male sex, history of hepatocellular carcinoma pretransplant, time since LT, and lack of rejection. These five predictors were retained in an approximate model that could be presented as a simple scoring system to estimate the clinical probability of tolerance or IS dispensability with good predictive performance (AUC = 0.89). CONCLUSION: In parallel with the existence of a tremendous need for further research on tolerance mechanisms, the presented score, after validation in a larger collective preferably in a multicenter setting, could be easily and safely applied in the real world and already now address all three levels of prevention in LT patients over the long-term course.

Liver Transplantation for Metamizole induced Acute Liver Failure.

Metamizole, or dipyrone, is a frequently prescribed analgetic drug that can cause drug-induced liver injury (DILI). Still, there are only a few metamizole-associated DILI cases (n = 61, including our study) described in the literature. So far liver transplantation has been reported in 6 patients with metamizole-induced acute liver failure. In 2020, a German group described a bigger cohort (n = 23) of metamizole-related DILI. Shortly thereafter, this issue gained wider attention as the German Federal Institute for Drugs and Medical Devices published a Direct Healthcare Professional Communication, emphasizing DILI as a potential adverse event caused by metamizole. We herein report 2 patients that were admitted to our liver transplant center due to acute liver failure (ALF) in April and May 2021. Both patients reported intake of metamizole as pain medication over a few weeks. After ruling out alternative reasons for ALF and fulfilling the King's College criteria both patients received emergency liver transplantations in our center. Pathology assessment of both explants were consistent with metamizole-associated DILI. As illustrated by our 2 cases of metamizole-induced liver failure with subsequent liver transplantation, this rare but presumably often overlooked adverse drug effect of metamizole should be considered as differential diagnosis in cases of cryptogenic liver failure.

Self-limited HBV infection of the recipient does not reactivate after liver transplantation: Observations from a 30-year liver transplant program.

BACKGROUND: A self-limited hepatitis B infection can reactivate in patients under immunosuppression or chemotherapy (reappearance of hepatitis B surface antigen (HBsAg) or HBV-DNA). Exact circumstances of HBV reactivation in patients undergoing liver transplantation (LT) for end-stage liver diseases (ESLD) unrelated to HBV are unknown, and recommendations on HBV prophylaxis remain unclear. PATIENTS AND METHODS: Among 1273 liver transplants, 168 patients with a self-limited HBV hepatitis B infection prior to LT were identified from our prospective liver transplant database. Patients with underlying chronic HBV infection and recipients of an anti-HBc-positive liver were not included in the analysis. Demographic, laboratory, serological, and virological data were analyzed retrospectively. Appearance of HBsAg or HBV-DNA was defined as reactivation. RESULTS: The median follow-up after LT was 12.0 years (0.6-30.7 years). The rate of HBV reactivation was 0% independent of antiviral prophylaxis (n = 7; 4.2%), the etiology of ESLD, hepatitis C treatment, or the anti-HBs concentration. The overall patient survival with a history of a self-limited HBV infection before LT did not significantly differ from the rest of the cohort. CONCLUSION: Antiviral treatment with nucleos(t)ide analogues post-liver transplantation in order to prevent HBV reactivation in patients with a resolved self-limited hepatitis B infection prior to LT seems to be omittable since the main viral reservoir is removed by the hepatectomy. These findings may clarify the current uncertainty in the recommendations regarding the risk of HBV reactivation in patients with self-limited hepatitis B prior to LT.

Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial.

OBJECTIVE: To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model. DESIGN: Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13). SETTING: Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union). PARTICIPANTS: Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9). INTERVENTIONS: CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48. MAIN OUTCOME MEASURES: The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio. RESULTS: For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire. CONCLUSIONS: The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies. TRIAL REGISTRATION: NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).

Living-Donor Liver Transplant: An Analysis of Postoperative Outcome and Health-Related Quality of Life in Liver Donors.

OBJECTIVES: Living-donor liver transplant represents an established alternative to deceased-donor liver transplant. The procedure is considered safe for donors; however, concerns about the donors' health-related quality of life and health status have not been fully addressed. Here, we aimed to assess the health-related quality of life and postoperative and 1-year clinical outcomes in living liver transplant donors. MATERIALS AND METHODS: All patients undergoing liver resection for adult-to-adult living-donor liver transplant at our center between December 1999 and March 2013 were evaluated retrospectively. Health-related quality of life was evaluated in a second assessment through written health-related quality of life questionnaires (the Short Form 36 assessment tool) sent to all patients who underwent liver resection for living-donor liver transplant between 1989 and 2012. RESULTS: We identified 104 patients who underwent liver resection for living-donor liver donation between December 1999 and March 2013. Postoperative morbidity was 35.9%, with 56.8% of patients having minor complications. No postoperative, 30-day, or 90-day mortality was evident. At year 1 after transplant, 30 patients (28.8%) had (ongoing) complications, of which 80% were considered minor according to Clavien-Dindo classification. Regarding health-related quality of life, liver donors were characterized as having significantly higher scores in the general health perception component in the Short Form 36 assessment tool (P < .001). We found no significant results in other assessment components (all P > .05). CONCLUSIONS: Liver donors are characterized by an excellent health-related quality of life that is comparable to the general population. Because some donors tend to have concerns regarding their employment status after the procedure, a comprehensive and critical evaluation of potential donors is needed.

The 28-year incidence of de novo malignancies after liver transplantation: A single-center analysis of risk factors and mortality in 1616 patients.

De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow-up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow-up. The median follow-up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3-81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A-treated compared with tacrolimus-treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow-up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404-1414 2017 AASLD.

Impact of abdominal drainage systems on postoperative complication rates following liver transplantation.

BACKGROUND: Depending on the extent of surgery, coagulation status and the number of anastomoses, drains are routinely used during liver transplantation. The aim of this study was to compare different drain types with regard to abdominal complication rates. METHODS: All consecutive full-size orthotopic liver transplantations (LTX) performed over a 7-year period were included in this retrospective analysis. Abdominal drain groups were divided into open-circuit drains and closed-circuit drains. Data are reported as total number (%) or median (range); for all comparisons a p value <0.05 was considered statistically significant. RESULTS: A total of 256 LTX [age 56.89 (0.30-75.21) years; MELD 14.5 (7-40)] was included; 56 (21.8 %) patients received an open-circuit Easy Flow Drain (Group 1) and 200 (78.2 %) a closed-circuit Robinson Drainage System (Group 2). For Groups 1 and 2, overall infection rates were 78.6 and 56 % (p = 0.001), abdominal infection rates 50.82 and 21.92 % (p = 0.001), yeast infection rates 37 and 23 % (p = 0.02), abdominal bleeding rates 26.78 and 17 % (p = 0.07), biliary complication rates 14.28 and 13.5 % (p = 0.51), respectively. CONCLUSIONS: In this retrospective series, open-circuit drains were associated with more abdominal complications, mainly due to intraabdominal infections, than were closed-circuit drains.

Outcome analysis of laparoscopic incisional hernia repair and risk factors for hernia recurrence in liver transplant patients.

INTRODUCTION: Incisional hernia is a common complication after liver transplantation (LT). Immunosuppression, obesity, and use of steroids are known risk factors. The purpose of the retrospective study was to summarize and evaluate experiences and results of laparoscopic intraperitoneal onlay mesh (IPOM) hernia repair. METHODS: We reviewed our liver transplant patients over a seven-yr period with laparoscopic incisional hernia repair (LIHR) to direct our attention on risk factors for hernia recurrence after hernia repair. RESULTS: Fifty-four patients after LT with incisional hernia were treated with laparoscopic repair, 42 male and 12 female patients of overall mean age of 58 ± 9 yr and body mass index (BMI) of 25 ± 4 kg/m(2) . A total of 755 LTs were performed at our institution in this time period, resulting in 7.15% of patients undergoing laparoscopic hernia repair. The mean postoperative hospital stay after was nine d. During the follow-up, nine recurrent hernias were noted (17%). BMI (p = 0.001) and sirolimus as immunosuppressive therapy were significantly associated with hernia recurrence (p = 0.014). CONCLUSION: LIHR is a safe and feasible method to treat hernias after LT. BMI and sirolimus as immunosuppressive therapy are risk factors for recurrence of hernia after laparoscopic hernia repair.

Murine cervical heart transplantation model using a modified cuff technique.

Mouse models are of special interest in research since a wide variety of monoclonal antibodies and commercially defined inbred and knockout strains are available to perform mechanistic in vivo studies. While heart transplantation models using a suture technique were first successfully developed in rats, the translation into an equally widespread used murine equivalent was never achieved due the technical complexity of the microsurgical procedure. In contrast, non-suture cuff techniques, also developed initially in rats, were successfully adapted for use in mice(1-3). This technique for revascularization involves two major steps I) everting the recipient vessel over a polyethylene cuff; II) pulling the donor vessel over the formerly everted recipient vessel and holding it in place with a circumferential tie. This ensures a continuity of the endothelial layer, short operating time and very high patency rates(4). Using this technique for vascular anastomosis we performed more than 1,000 cervical heart transplants with an overall success rate of 95%. For arterial inflow the common carotid artery and the proximal aortic arch were anastomosed resulting in a retrograde perfusion of the transplanted heart. For venous drainage the pulmonary artery of the graft was anastomosed with the external jugular vein of the recipient(5). Herein, we provide additional details of this technique to supplement the video.

Long-term outcome in kidney transplant recipients over 70 years in the Eurotransplant Senior Kidney Transplant Program: a single center experience.

BACKGROUND: Kidney transplantation in the elderly is complicated by comorbidities and a higher incidence of death. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys from older donors to the increasing number of older recipients. In this retrospective, single center data analysis, we compare the outcome of recipients older than 70 years with younger recipients transplanted under the ESP protocol. METHODS: Between 1999 and 2009, a total of 83 kidneys were transplanted under the ESP protocol in Innsbruck and 19 of the recipients were older than 70 years (mean, 72.7 years). Cold ischemia time was kept short in both groups by giving preference to regional donor organs. RESULTS: Patient survival at 1 and 5 years were 95% and 67% in the 70+ group and 94.4% and 82.6% in the 70- group. Graft survival was 95% and 52% at 1 and 5 years in the 70+ group and 94.4% and 79.0% in the 70- group. When censored for death, graft survival at year 1 and 5 were 100% and 82% in the 70+ group and 98.1% and 92.7% in the 70- group. The delayed graft function rate was high in both groups (36.8% and 41.1%, respectively). Morbidities were largely related to hemodynamic, oncologic, and infectious events. Cardiac failure was the major cause of death. CONCLUSION: Relatively good results can be achieved with renal transplantation in patients older than 70 years under careful pretransplant evaluation and postoperative management of comorbidities.

Alemtuzumab in solid organ transplantation and in composite tissue allotransplantation.

Alemtuzumab (Campath®, Genzyme Corporation, MA, USA) is a potent monoclonal antilymphocyte, anti-CD52 antibody. Since the 1980s, alemtuzumab has been used extensively in organ transplantation as an induction agent - also with the aim of avoiding or reducing maintenance immunosuppression. We herein review the literature on alemtuzumab in solid organ and composite tissue allotransplantation with an emphasis on clinical and mechanistic aspects of alemtuzumab. In summary, the use of alemtuzumab in solid organ and composite tissue allotransplantation shows excellent early results and holds potential for wider use in conjunction with immunosuppression minimization protocols.