Clinical efficacy of avatrombopag and recombinant human thrombopoietin in the treatment of chronic liver disease-associated severe thrombocytopenia: A real-world study.

Purpose: To investigate the clinical efficacy of avatrombopag, an oral thrombopoietin receptor agonist, versus subcutaneous recombinant human thrombopoietin (rh-TPO) in the treatment of severe thrombocytopenia (TCP) associated with chronic liver disease (CLD). Methods: Clinical data of 250 patients with severe TCP associated with CLD were collected in a single hospital from January 2019 to January 2022. The main parameters measured were the therapeutic response rate, changes in platelets (PLTs), and adverse events. Propensity score matching (PSM) was used to avoid possible selection bias. Results: After PSM, a total of 154 patients were enrolled in the study: 77 in the avatrombopag group and 77 in the rh-TPO group. There was no statistically significant difference between the two groups in the effect of increasing the PLT count (Waldχ 2 = 1.659, p = 0.198; Waldχ 2 = 0.220, p = 0.639). In addition, no interaction between time and different medications was found (Waldχ 2 = 0.540, p = 0.910; Waldχ 2 = 1.273, p = 0.736). Interestingly, in the subgroup analysis, both before and after PSM, avatrombopag showed better clinical efficacy than rh-TPO in the treatment of TCP associated with CLD in Child‒Pugh Class A (88.89% vs. 63.41%, p =0.003; 81.33% vs. 61.76%, p = 0.043). Fewer patients reported dizziness in the avatrombopag group than in the rh-TPO group both before and after PSM (7.8% vs. 25.0%; 7.8% vs. 24.7%, p < 0.05). Conclusion: Both before and after PSM, avatrombopag showed better clinical efficacy than rh-TPO in the treatment of TCP associated with CLD in Child‒Pugh Class A and showed a lower incidence of dizziness in all patients.

Is It Feasible to Standardize a Composite Postoperative Complication Reporting System for Liver Resection?

BACKGROUND: Although the Clavien-Dindo classification is well established in many fields of surgery, a conclusive severity grading system for liver surgery-specific complications has not yet been standardized. Post-hepatectomy liver Failure, Ascites, Bile leakage, Infection, and Bleeding were found to be the five most important components in an international survey. A score system with FABIB as the acronym was proposed by the authors to increase the feasibility of routine use. METHODS: The definition and grading of three components ("liver failure," "bile leakage," and "bleeding") were adopted from the International Study Group for Liver Surgery. The definition and grading for "ascites" as well as "infection" were proposed by the authors. The postoperative complications were documented prospectively. The data from 2012 to 2016 were reviewed and the correlations to other clinical parameters were analyzed retrospectively. RESULTS: Five hundred one consecutive liver resections were assessed. Two hundred twenty-four (44.7%) patients had at least one postoperative complication of the FABIB system. The FABIB score was found to correlate with the operation complexity (major vs minor liver resection, with or without biliodigestive anastomosis), underlying liver disease (normal liver parenchyma vs fibrosis vs cirrhotic liver), 90-day mortality (statistically significantly different within three predefined categories), and the length of hospital stay (the mean value increases proportionately to FABIB score). CONCLUSION: Using the FABIB reporting system, the five main complications after liver surgery can be documented in a standardized manner. Its clinical relevance might increase the feasibility and comparability of studies or trials in liver surgery.

De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans.

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.

Accuracy of Pretransplant Imaging Diagnostic for Hepatocellular Carcinoma: A Retrospective German Multicenter Study.

Selection and prioritization of patients with HCC for LT are based on pretransplant imaging diagnostic, taking the risk of incorrect diagnosis. According to the German waitlist guidelines, imaging has to be reported to the allocation organization (Eurotransplant) and pathology reports have to be submitted thereafter. In order to assess current procedures we performed a retrospective multicenter analysis in all German transplant centers with focus on accuracy of imaging diagnostic and tumor classification. 1168 primary LT for HCC were conducted between 2007 and 2013 in Germany. Patients inside the Milan, UCSF, and up-to-seven criteria were misclassified with definitive histologic results in 18%, 15%, and 11%, respectively. Patients pretransplant outside the Milan, UCSF, and up-to-seven criteria were otherwise misclassified in 34%, 43%, and 41%. Recurrence-free survival correlated with classification by posttransplant histological report, but not pretransplant imaging diagnostic. Univariate analysis revealed tumor size, vascular invasion, and grading as significant parameters for outcome, while tumor grading was the only parameter persisting by multivariate testing. Conclusion. There was a relevant percentage (15-40%) of patients misclassified by imaging diagnosis at a time prior to LI-RADS and guidelines to improve imaging of HCC. Outcome analysis showed a good correlation to histological, in contrast poor correlation to imaging diagnosis, suggesting an adjustment of the LT selection and prioritization criteria.

Dual antibody induction and de novo use of everolimus enable low-dose tacrolimus with early corticosteroid withdrawal in simultaneous pancreas-kidney transplantation.

BACKGROUND: To be an optimal immunosuppressive regimen after simultaneous pancreas kidney transplantation (SPK), low dose calcineurin inhibitor and early withdrawal of corticosteroids are desired. METHODS: Immunosuppressive regimen as such has been conducted consecutively in SPK recipients since 2009 in authors' institute. In addition to tacrolimus in low trough level and early corticosteroid withdraw, dual induction with basiliximab and low-dose thymoglobulin in combination with everolimus are the important components of the protocol. RESULTS: 25 consecutive primary SPK recipients were included in the study. Lymphocyte depletion by low dose thymoglobulin was limited to two weeks, and CD25 coating with basiliximab was detectable for 4 weeks. The BPAR within the first 12 months was 13%. During a median follow-up of 58 months, new-onset diabetes mellitus and renal function deterioration were rare events. No cytomegalovirus activation was encountered. The patients, pancreas and kidney graft survival at 1-year and 5-year was 100% and 94.4%, 95.8% and 95.8%, 100% and 100% respectively.

Long-term follow-up after full-split liver transplantation and its applicability in the recent transplant era.

INTRODUCTION: Full-split liver transplantation (LTX) offers the possibility to expand the donor pool by utilization of one liver for two adults. The aim of our study was to analyze the long-term outcome in a large series and its applicability in the recent transplant era. METHODS: We performed a retrospective analysis of all full-split LTX from deceased donors (1999-2015). Additionally, the potential of full-split LTX was retrospectively analyzed in all whole organ LTX recipients between 2006 and 2015 (after introduction of the MELD allocation). RESULTS: We performed 44 full-split LTX, thereof 82% before introduction of the MELD-based allocation system in Germany. Analysis showed highly selected recipients (median MELD score 8 points) and organ data (median donor age 30 years). 5- and 10-year patient survival rates after full-left and full-right LTX were 90.7%/90.7% and 85.2%/56.8% (P = .301), corresponding graft survival rates were 80.5%/80.5% in full-left grafts and 73.7%/36.8% in full-right graft (P = .198). CONCLUSION: In the past, in case of strict donor and recipient selection, full-split LTX was a feasible method with a good outcome. Due to introduction of the national waiting list with a patient-oriented allocation based on the MELD score in 2006, full-split LTX seems to be not any longer applicable.

Defining Benchmarks in Liver Transplantation: A Multicenter Outcome Analysis Determining Best Achievable Results.

: This multicentric study of 17 high-volume centers presents 12 benchmark values for liver transplantation. Those values, mostly targeting markers of morbidity, were gathered from 2024 "low risk" cases, and may serve as reference to assess outcome of single or any groups of patients. OBJECTIVE: To propose benchmark outcome values in liver transplantation, serving as reference for assessing individual patients or any other patient groups. BACKGROUND: Best achievable results in liver transplantation, that is, benchmarks, are unknown. Consequently, outcome comparisons within or across centers over time remain speculative. METHODS: Out of 7492 liver transplantation performed in 17 international centers from 3 continents, we identified 2024 low risk adult cases with a laboratory model for end-stage liver disease score ≤20 points, a balance of risk score ≤9, and receiving a primary graft by donation after brain death. We chose clinically relevant endpoints covering intra- and postoperative course, with a focus on complications graded by severity including the complication comprehensive index (CCI). Respective benchmarks were derived from the median value in each center, and the 75 percentile was considered the benchmark cutoff. RESULTS: Benchmark cases represented 8% to 49% of cases per center. One-year patient-survival was 91.6% with 3.5% retransplantations. Eighty-two percent of patients developed at least 1 complication during 1-year follow-up. Biliary complications occurred in one-fifth of the patients up to 6 months after surgery. Benchmark cutoffs were ≤4 days for ICU stay, ≤18 days for hospital stay, ≤59% for patients with severe complications (≥ Grade III) and ≤42.1 for 1-year CCI. Comparisons with the next higher risk group (model for end stage liver disease 21-30) disclosed an increase in morbidity but within benchmark cutoffs for most, but not all indicators, while in patients receiving a second graft from 1 center (n = 50) outcome values were all outside of benchmark values. CONCLUSIONS: Despite excellent 1-year survival, morbidity in benchmark cases remains high with half of patients developing severe complications during 1-year follow-up. Benchmark cutoffs targeting morbidity parameters offer a valid tool to assess higher risk groups.

Obstruction of peritoneal dialysis catheter is associated with catheter type and independent of omentectomy: A comparative data analysis from a transplant surgical and a pediatric surgical department.

BACKGROUND: Peritoneal dialysis (PD) catheter occlusion is a common complication with up to 36% of catheter obstructions described in the literature. We present a comparison of complications and outcome after implantation of PD catheters in a transplant surgical and a pediatric surgical department. METHODS: We retrospectively analyzed 154 PD catheters, which were implanted during 2009-2015 by transplant surgeons (TS, University Medical Center Hamburg-Eppendorf, Germany, n=85 catheters) and pediatric surgeons (PS, Charité University Medicine Berlin, Germany, n=69 catheters) in 122 children (median (range) age 3.0 (0.01-17.1) years) for acute (n=65) or chronic (n=89) renal failure. All catheters were one-cuffed or double-cuffed curled catheters, except that straight catheters were implanted into smaller children (n=19) by TS in Hamburg. RESULTS: Patient characteristics and operation technique did not differ between the departments. Peritonitis was the most common complication (33 catheters, 21.4%). Leakage (n=18 catheters, 11.7%) occurred more often in children weighing <10kg (p<0.001). The incidence of obstruction and dysfunction was significantly higher in catheters used in PS than catheters used in TS (30.4% vs. 11.8%, p=0.004). Omentectomy did not reduce the incidence of catheter obstruction (p=1.0). Perforation at the catheter tips was larger and appeared to be rougher in catheters used in PS than the catheters in TS. CONCLUSIONS: The type of catheter and presumably the type of perforation at the catheter tip may influence the incidence of peritoneal dialysis catheter obstruction.

The first case of domino-split-liver transplantation in maple syrup urine disease.

The enzymatic defect in MSUD results in accumulation of neurotoxic metabolites of BCAAs. LTX has shown to be a feasible strategy in patients non-responsive to diet. Because of sufficient enzyme activity in extrahepatic tissues in healthy people, the MSUD liver graft is a suitable domino organ. We present the first case of a technical challenging ex situ split of a MSUD domino organ transplanted into two pediatric recipients. The domino graft donor was a 21-year-old female (58 kg) suffering from MSUD with recurrent metabolic decompensation despite strict diet. The organ was allocated to a 14-year-old girl (55 kg) with primary sclerosing cholangitis. Due to excellent organ quality and suitable anatomy, a backward split for a girl of 3 months (5 kg) with decompensated liver cirrhosis due to biliary atresia was performed. The postoperative course was without relevant complications, and the three recipients were discharged on postoperative days 28, 29, and 45, respectively, with good organ function. BCAAs in plasma were normal in the two domino graft recipients, and the MSUD patient showed mildly elevated but stable BCAA concentrations despite an unrestricted diet. Split-domino LTX enabled successful transplantation of three patients of the waiting list with only one deceased donor graft.

Incidence of BK polyomavirus infection after kidney transplantation is independent of type of immunosuppressive therapy.

BACKGROUND: BK polyomavirus (BKV) infection and BKV nephropathy (BKVN) are risk factors for allograft function and survival. METHODS: We retrospectively analyzed BK viremia and BKVN in 348 patients who received a kidney transplantation donated after brain death (n=232) or living donation (n=116) between 2008 and 2013. A total of 266 patients were treated with standard immunosuppression consisting of basiliximab induction, calcineurin inhibitor (CNI), and mycophenolic acid (MPA, n=219) or everolimus (n=47); 82 patients received more intense immunosuppression with lymphocyte depletion, CNI and MPA (n=38) or everolimus (n=44). RESULTS: BK viremia occurred in 33 (9.5%) patients in the first year and in 7 (2.0%) recipients in the second year after transplantation. BKVN occurred in 4 (1.1%) patients in the first year. Donor and recipient age, diabetes, previous transplantation, and type of transplantation (donated after brain death vs living donation) were not risk factors (P>.05). BK incidence did not differ depending on induction or maintenance immunosuppression. CONCLUSION: Incidence of BK viremia is independent of recipient characteristics, type of transplantation as well as induction and maintenance immunosuppression.

Early Initiation of Everolimus After Liver Transplantation: A Single-Center Experience.

BACKGROUND: Evidence relating to early everolimus use after liver transplantation remains limited. MATERIAL AND METHODS: Ninety-one adult patients undergoing liver transplantation at our center during 2007-2012 in whom everolimus therapy was initiated <3 months post-transplant were analyzed retrospectively. Everolimus was started on days 1-5 in 50 patients (group 1) and after day 5 in 41 patients (group 2). Most patients continued to receive low-dose cyclosporine (59.3%, target 50-80 ng/ml) or low-dose tacrolimus (25.3%; target 3-5 ng/ml). Mean follow-up was 4.6 years. RESULTS: One-, three- and five-year patient survival rates were 80.5%, 74.2%, and 70.5%, respectively, and did not differ between groups 1 and 2. Six patients (6.6%) developed biopsy-proven acute rejection after a median of 47 days (range 27-356 days). Everolimus was discontinued due to adverse events in 21 patients (23.1%). Incisional hernia repair occurred in 14.0% and 9.4% of patients in group 1 and 2, respectively. Renal function remained stable during follow-up, despite poor baseline function. CONCLUSIONS: Everolimus with very low-dose calcineurin inhibitor given immediately after liver transplantation appears safe and effective, achieving a low rejection rate with well-preserved renal function.

Surgical complications after peritoneal dialysis catheter implantation depend on children's weight.

BACKGROUND: Surgical complications are estimated to be as high as 30%-40% during the first 8 weeks after implantation of peritoneal dialysis (PD) catheters. METHODS: 70 PD catheters which were implanted by transplant surgeons in 61 children (median age 3.3years, range 0.01-15.5years, 31 boys and 30 girls) in 2009-2014 were retrospectively reviewed. The incidence of complications and revisions during the first 6months after implantation was analyzed depending on children's weight and diagnosis. RESULTS: 17 out of 70 catheters needed a surgical revision within 6months after implantation (24.3%). Peritonitis was the most common complication affecting 18.6% of peritoneal dialysis catheters followed by obstruction and dislocation, which it occurred in 9 (12.9%) and 7 (10%) catheters, respectively. Leakage (n=5) only occurred in children with a weight of less than 10kg. The total proportion of complications was higher in children with less than 10kg of weight (P<0.001). CONCLUSION: PD is safe in children with acute renal failure and older children with chronic renal failure; however children with a weight of less than 10kg are more likely to develop complications.

Effects of FTY720 on peripheral blood lymphocytes and graft infiltrating cells in a rat model of chronic renal allograft rejection.

AIMS: Chronic renal allograft loss is still an unsolved problem in kidney transplantation. We evaluated the impact of FTY720, a S1P receptor agonist, known to deplete lymphocytes from the peripheral blood by sequestering them into lymph nodes and Peyer's patches, on blood lymphocytes and graft infiltrating cells in a rat model of chronic real allograft rejection. METHODS: LEW rats served as recipients for LEW.1U7B kidney grafts. All animals were treated with CsA (5mg/kg) for 10 days after renal transplantation and monitored for kidney function, peripheral blood lymphocytes and graft infiltrating cells. In the intervention group (n=7) FTY720 therapy was started 7 weeks post-KTx in a dose of 0.5 mg/kg p. o. three times a week. RESULTS: In the control group the survival of the rats was 9, 11, 18 and 4 × 24 weeks, in the intervention group 2 × 8, 9, 2 × 11, 18 and 20 weeks. While in the intervention group the number of T- and B-lymphocytes in the peripheral blood was successfully reduced during FTY720 treatment, both groups showed significant amounts of T- and B-lymphocytes in the kidney grafts. Animals in both groups developed donor specific antibodies, extensive albuminuria and severe chronic changes in the grafts. CONCLUSIONS: FTY720 was highly effective to reduce T- and B-lymphocytes in the peripheral blood, but not effective in clearing their infiltration in the graft. Graft survival was not prolonged by FTY720 treatment starting late after kidney transplantation.

De novo mTOR inhibitor-based immunosuppression in ABO-incompatible kidney transplantation.

ABO-incompatible (ABOi) kidney transplantation (KTx) has become an accepted therapeutic option in renal replacement therapy for patients without a blood group-compatible living donor. Using different desensitization strategies, most centers apply B-cell depletion with rituximab and maintenance immunosuppression (IS) with tacrolimus and mycophenolic acid. This high load of total IS leads to an increased rate of surgical complications and virus infections in ABOi patients. Our aim was to establish ABOi KTx using an immunosuppressive regimen, which is effective in preventing acute rejection without increasing the risk for viral infections. Therefore, we selected a de novo immunosuppressive protocol with low-dose calcineurin inhibitor and the mTOR inhibitor everolimus for our ABOi program. Here, we report the first 25 patients with a complete three-yr follow-up treated with this regimen. Three-yr patient survival and graft survival were 96% and 83%. The rate of acute T-cell-mediated rejections was low (12%). Cytomegalovirus (CMV) infection was evident in one patient only (4%). Surgical complications were common (40%), but mild in 80% of cases. We demonstrate that ABOi KTx with a de novo mTOR inhibitor-based regimen is feasible without severe surgical or immunological complications and a low rate of viral infections.

Determination of Ethyl Glucuronide in Hair for Detection of Alcohol Consumption in Patients After Liver Transplantation.

BACKGROUND: Early detection of alcohol misuse in orthotopic liver transplantation recipients is essential to offer patients support and prevent organ damage. Here, ethyl glucuronide, a metabolite of ethanol found in hair (hEtG), was evaluated for detection of alcohol consumption. METHODS: In 104 transplant recipients, 31 with underlying alcoholic liver disease (ALD) and 73 with non-ALD, hEtG was determined in addition to the alcohol markers urine EtG, blood ethanol, methanol, and carbohydrate-deficient transferrin. Results were compared with patients' self-reports in a questionnaire and with physicians' assessments. RESULTS: By physicians' assessments, 22% of the patients were suspected of consuming alcohol regularly, although only 6% of the patients acknowledged consumption of a moderate or high amount of alcohol. By testing all markers except for hEtG, alcohol consumption was detected in 7% of the patients. When hEtG testing was added to the assessment, consumption was detected in 17% of the patients. Hair-EtG determination alone revealed chronic alcohol consumption of >10 g/d in 15% of the patients. ALD patients had a positive hEtG result significantly more often than non-ALD patients did (32% versus 8%; P = 0.003). Also, the concentration of hEtG was higher in ALD patients (P = 0.049) and revealed alcohol abuse with consumption of >60 g ethanol per day in 23% of ALD and 3% of non-ALD patients. Patients' self-reports and physicians' assessments had a low sensitivity of 27% and 67%, respectively, for detecting regular alcohol intake as indicated by hEtG. CONCLUSIONS: Hair-EtG determination improved the detection of liver transplant patients who used alcohol, and revealed regular alcohol consumption in 32% of ALD and 8% of non-ALD patients.

Outcome of liver re-transplantation in children--impact and special analysis of early re-transplantation.

In case of graft failure, re-LTX is the only life-saving option but it has been associated with inferior results. This study analyzes the outcome following pediatric re-LTX with a main focus on the timely relation between initial transplant and re-LTX. All pediatric LTX at our institution between 2000 and 2010 divided into patients with primary LTX and patients undergoing re-LTX early (≤30 days) or late (>30 days) after previous LTX were analyzed. Two hundred and ninety-eight primary LTX(79%), 33 early (9%), and 46 late (12%) re-LTX were performed. Patient/graft survival was significantly worse for children undergoing early re-LTX compared to primary LTX and late re-LTX (p = 0.024/0.001 and p = 0.015/0.03). One-/five-yr graft survival rates were 66%/49% for early re-LTX compared to 86%/76% for late re-LTX and 90%/74% for primary LTX. The inferior results in children undergoing early re-LTX were due to events occurring in the first six months with similar survival thereafter. No difference in outcome was evident after adjustment of the groups for high-urgency status. Outcome was excellent for primary LTX and late re-LTX, supporting late re-LTX in children. Early re-LTX takes an elevated risk of early graft loss and patient death; however, beyond the early postoperative period, the outcome was comparable.

Determination of ethyl glucuronide in hair improves evaluation of long-term alcohol abstention in liver transplant candidates.

BACKGROUND & AIMS: Prior to listing patients for Orthotopic liver transplantation (OLT) an abstention period of 6 months is required. Ethyl glucuronide in the hair is a new reliable marker for the assessment of alcohol consumption. Here, the diagnostic value of determining the ethyl glucuronide concentration in the hair of liver transplant candidates was evaluated. METHODS: In 63 transplant candidates with alcoholic liver cirrhosis and 25 control patients with cirrhosis of other aetiologies alcohol markers, i.e. hEtG, urine EtG, blood ethanol, methanol and carbohydrate deficient transferrin were determined in parallel to an interview with a psychologist. RESULTS: A total of 19 (30%) transplant candidates admitted alcohol consumption within the last 6 months, while 39/63 (62%) were positive for at least one alcohol marker. In 52% of the 44 candidates denying alcohol consumption, abstention was disproved by detecting at least one positive alcohol marker, in 83% of cases by a positive hEtG result. In the control patients stating abstention from alcohol all hEtG tests were negative. No impact of renal or liver function on hEtG results was detected. A specificity of 98% and a positive predictive value of 92% were calculated for testing hEtG in proximal hair segment and applying a cut-off of 30 pg/mg. CONCLUSIONS: In 52% of patients denying alcohol consumption within the last 6 months, alcohol abstention was disproved, in 83% of cases by hEtG testing. Therefore, hEtG is a promising new marker for the evaluation of long-term alcohol abstention in liver transplant candidates.

A formula to calculate the standard liver volume in children and its application in pediatric liver transplantation.

Due to a lack of available size-matched liver grafts from children, most pediatric recipients are transplanted with technical variant grafts from adult donors. Size requirements for these grafts are not well defined, and consequences of mismatched graft sizes in pediatric liver transplantation are not known. Existing formulas for calculation of a standard liver volume are mostly derived from adults disregarding the age-related percentual liver weight changes in children. In this study, we aimed to establish a formula for general use in children to calculate the standard liver volume. In a second step, the formula was applied in pediatric patients undergoing liver transplantation at our institution between 2000 and 2010 (n = 377). Analysis of a large number (n = 388) of autopsy data from children by regression analysis revealed a best fit for two formulas: "Formula 1," children 0 to ≤1 year (n = 246): standard liver volume [ml] = -143.062973 +4.274603051 * body length [cm] + 14.78817631 * body weight [kg]; "Formula 2," children >1 to <16 years (n = 142): standard liver volume [ml] = -20.2472281 + 3.339056437 * body length [cm] + 13.11312561 * body weight [kg]. In comparison with children receiving size-matched organs, we found an elevated risk of liver graft failure in children transplanted with a small-for-size graft, whereas large-for-size organs seem to have no negative impact.