Steatotic Livers Are More Susceptible to Ischemia Reperfusion Damage after Transplantation and Show Increased γδ T Cell Infiltration.

Liver transplantation (LTx) is often the only possible therapy for many end-stage liver diseases, but successful long-term transplant outcomes are limited by multiple factors, including ischemia reperfusion injury (IRI). This situation is aggravated by a shortage of transplantable organs, thus encouraging the use of inferior quality organs. Here, we have investigated early hepatic IRI in a retrospective, exploratory, monocentric case-control study considering organ marginality. We analyzed standard LTx biopsies from 46 patients taken at the end of cold organ preparation and two hours after reperfusion, and we showed that early IRI was present after two hours in 63% of cases. Looking at our data in general, in accordance with Eurotransplant criteria, a marginal transplant was allocated at our institution in about 54% of cases. We found that patients with a marginal-organ LTx showing evidence of IRI had a significantly worse one-year survival rate (51% vs. 75%). As we saw in our study cohort, the marginality of these livers was almost entirely due to steatosis. In contrast, survival rates in patients receiving a non-marginal transplant were not influenced by the presence or absence of IRI. Poorer outcomes in marginal organs prompted us to examine pre- and post-reperfusion biopsies, and it was revealed that transplants with IRI demonstrated significantly greater T cell infiltration. Molecular analyses showed that higher mRNA expression levels of CXCL-1, CD3 and TCRγ locus genes were found in IRI livers. We therefore conclude that the marginality of an organ, namely steatosis, exacerbates early IRI by enhancing effector immune cell infiltration. Preemptive strategies targeting immune pathways could increase the safety of using marginal organs for LTx.

Definition, reasons, and risk factors for mortality of patients listed for liver transplantation - a single-center study.

BACKGROUND: In Germany, following the principle "sickest first", patients awaiting liver transplantation (LTPL) are often transplanted with high MELD score and run the risk that they can no longer be transplanted, getting "too sick for transplant". METHODS: In a retrospective single-center study, we analyzed the mortality of adult patients on the waiting list for LTPL during the years 2014 to 2017. To stratify risk factors, we compared characteristics of deceased and transplanted patients. RESULTS: The main reasons for mortality were sepsis (42.9 %), malignancy (24.3 %) and bleeding (10.0 %). Risk factors for mortality (OR, univariate logistic regression, p < 0.05) were acute on chronic liver failure (ACLF), loss of E-MELD, sepsis, pneumonia, proof of pathogens, candidemia, stay at ICU, multiple organ failure and mechanical ventilation. Multivariate analysis revealed pneumonia (p < 0.001) and high MELD (p = 0.031) as risk factors. Transplantation was more likely in patients with E-MELD. We suggest a Waiting List Mortality Index for Transplantation (WMIT), by dividing deceased patients to transplanted patients to assess mortality. Average WMIT in our cohort was 0.65. CONCLUSIONS: Mortality on the waiting list is mainly determined by pneumonia and infections in high-MELD patients. Therefore, patients with ACLF after infections should be prioritized for LTPL. A WMIT might suitably represent waiting list mortality.

First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases.

OBJECTIVES: To analyze long-term oncological outcome along with prognostic risk factors in a large cohort of patients with colorectal liver metastases (CRLM) undergoing ALPPS. BACKGROUND: ALPPS is a two-stage hepatectomy variant that increases resection rates and R0 resection rates in patients with primarily unresectable CRLM as evidenced in a recent randomized controlled trial. Long-term oncologic results, however, are lacking. METHODS: Cases in- and outside the International ALPPS Registry were collected and completed by direct contacts to ALPPS centers to secure a comprehensive cohort. Overall, cancer-specific (CSS), and recurrence-free (RFS) survivals were analyzed along with independent risk factors using Cox-regression analysis. RESULTS: The cohort included 510 patients from 22 ALPPS centers over a 10-year period. Ninety-day mortality was 4.9% and median overall survival, CSS, and RFS were 39, 42, and 15 months, respectively. The median follow-up time was 38 months (95% confidence interval 32-43 months). Multivariate analysis identified tumor-characteristics (primary T4, right colon), biological features (K/N-RAS status), and response to chemotherapy (Response Evaluation Criteria in Solid Tumors) as independent predictors of CSS. Traditional factors such as size of metastases, uni versus bilobar involvement, and liver-first approach were not predictive. When hepatic recurrences after ALPPS was amenable to surgical/ablative treatment, median CSS was significantly superior compared to chemotherapy alone (56 vs 30 months, P < 0.001). CONCLUSIONS: This large cohort provides the first evidence that patients with primarily unresectable CRLM treated by ALPPS have not only low perioperative mortality, but achieve appealing long-term oncologic outcome especially those with favorable tumor biology and good response to chemotherapy.

Acute Kidney Injury and Renal Regional Oxygen Saturation During Pediatric Liver Transplantation.

BACKGROUND Kidney injury is a complication among children undergoing liver transplantation (pLTx). Cystatin C serum concentration seems to be superior to creatinine-based determination of kidney injury in adults and children. Near-infrared spectroscopy (NIRS) technology provides non-invasive and real-time measurement of renal tissue oxygenation. Here, we compared renal tissue oximetry (rSrO2) with conventional diagnostic criteria cystatin C and creatinine concentration in children undergoing pLTx. MATERIAL AND METHODS rSrO2 was measured intraoperatively in children undergoing pLTx over the left kidney, and was statistically compared with pre- and postoperative serum creatinine and cystatin C concentrations. RESULTS rSrO2 was affected by hemoglobin concentration, bilirubin concentration, and FiO2. Statistical analysis demonstrated that rSrO2 was significantly reduced in children with preoperative pathologic increased cystatin C concentrations compared to children without (63.7±4.3 vs. 53.4±4.9, p<0.05). We did not detect a significant difference in rSrO2 between children who developed postoperative renal impairment, either determined by increased postoperative cystatin C concentration, creatinine concentration, or the pRIFLE criteria. Intraoperative increase or decrease in rSrO2 did not predict the development of postoperative kidney injury. CONCLUSIONS In children with liver failure undergoing pLTx, a preoperative decrease in rSrO2 indicates compromised renal function. However, intraoperative rSrO2 is not predictive of postoperative kidney injury.

Surgical Aspects of Liver Transplantation and Domino Liver Transplantation in Maple Syrup Urine Disease: Analysis of 15 Donor-Recipient Pairs.

Liver transplantation (LT) has been shown to be a feasible treatment in patients with severe forms of maple syrup urine disease (MSUD). Because of a sufficient extrahepatic enzyme activity in non-MSUD individuals, the organ of MSUD patients can be used as a domino graft. We performed a retrospective data collection of all LTs for MSUD carried out at the University Medical Center Hamburg-Eppendorf (2016-2018). Moreover, data from all consecutive domino LTs of the MSUD grafts either transplanted at our institution or allocated to other transplant centers were analyzed. During the study period, 15 LTs in MSUD patients were performed (12 children, 3 adults; median age, 10.9 years; range, 0.3-26.1 years). Biliary complications occurred in 20%, and 13.3% suffered from bleeding complications. No further surgical problems occurred. At present, all MSUD patients are alive with a well-functioning liver graft and on an unrestricted diet. In total, 14 consecutive domino LTs were performed. No surgical complications requiring intervention occurred. One patient died because of HCC relapse, and all other patients are alive with good liver graft function. In conclusion, the use of MSUD livers as domino grafts is safe and allows application of LT in MSUD patients without net extraction of a liver graft from the limited donor pool.

Technical Aspects of Orthotopic Liver Transplantation-a Survey-Based Study Within the Eurotransplant, Swisstransplant, Scandiatransplant, and British Transplantation Society Networks.

BACKGROUND: Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. However, technical aspects of OLT are still subject of ongoing debate and are widely based on personal experience and local institutional protocols. METHODS: An international online survey was sent out to all liver transplant centers (n = 52) within the Eurotransplant, Swisstransplant, Scandiatransplant, and British Transplant Society networks. The survey sought information on center-specific OLT caseload, vascular and biliary reconstruction, graft reperfusion, intraoperative control of hemodynamics, and drain policies. RESULTS: Forty-two centers gave a valid response (81%). Out of these, 50% reported piggy-back and 40.5% total caval replacement as their standard technique. While 48% of all centers generally do not apply veno-venous bypass (vvBP) or temporary portocaval shunt (PCS) during OLT, vvBP/PCS are routinely used in six centers (14%). Portal vein first reperfusion is used in 64%, followed by simultaneous (17%), and retrograde reperfusion (12%). End-to-end duct-to-duct anastomosis without biliary drain (67%) is the most frequently performed method of biliary reconstruction. No significant associations were found between the center caseload and the surgical approach used. The predominant part of the centers (88%) stated that techniques of OLT are not evidence-based and 98% would participate in multicenter clinical trials on these topics. CONCLUSION: Technical aspects of OLT vary widely among European centers. The extent to which center-specific variation of techniques affect transplant outcomes in Europe should be elucidated further in prospective multicenter trials.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Analysis of Liver Tumors Using Preoperative and Intraoperative Contrast-Enhanced Ultrasound (CEUS/IOCEUS) by Radiologists in Comparison to Magnetic Resonance Imaging and Histopathology.

Purpose To evaluate the diagnostic significance of preoperatively and intraoperatively performed contrast-enhanced ultrasound (CEUS/IOCEUS) in the diagnosis of liver tumors in comparison to magnetic resonance imaging (MRI) and histopathology. Materials and Methods Retrospective analysis of 70/317 patients who underwent surgery for liver tumors between January 2012 and October 2015. Findings of CEUS and IOCEUS were compared to MRI. CEUS and IOCEUS were performed using multifrequency linear probes (1 - 5, 6 - 15 MHz) after bolus injection of 1 - 5 ml sulfur hexafluoride microbubbles. The histopathology after surgical resection, MRI morphology (T1, T2, VIBE, diffusion sequences) and wash-in/wash-out kinetics of CEUS were evaluated. Results In 70 analyzed patient cases, 64 malignant liver lesions could be detected. 6 patients had benign liver lesions. Among the 64 malignant lesions, there were 28 metastases, 24 hepatocellular carcinomas (HCC), 9 cholangiocellular carcinomas (CCC) and 3 gallbladder carcinomas. 2 of the 6 benign liver lesions were hemangiomas, 2 were adenomas, 1 was an FNH and 1 was a complicated cyst. There was no significant difference when determining the lesion's malignancy/ benignity (p = 1.000). Furthermore, there was no statistical significance between preoperative CEUS and MRI regarding the general differential diagnosis of a tumor (p = 0.210) and the differential diagnosis classification between HCCs (p = 0.453) and metastases (p = 0.250). There was no statistical significance in tumor size (10 mm - 151 mm; mean 49 mm SD +/- 31 mm) and location (tumor size p = 0.579; allocation to liver lobes p = 0.132; segment diagnosis p = 0.121) between preoperatively performed CEUS and MRI. The combination of preoperative MRI and CEUS for lesion detection showed significant differences compared to CEUS or MRI only (p < 0.001 for CEUS; p = 0.004 for MRI). IOCEUS offered the substantial advantage of locating additional liver lesions (p = 0.004 compared to preoperative MRI, p = 0.002 compared to preoperative CEUS). In 10/37 cases (27 %) IOCEUS could locate further liver lesions which had not been identified during CEUS and/or MRI preoperatively, so that operative therapy was adapted accordingly and resection was extended if necessary. Conclusion CEUS proves to be a dynamic imaging method for preoperative diagnosis of liver tumors showing high diagnostic significance in the characterization of a tumor's microvascularization, its entity and its size. During liver operations CEUS plays an important role in surgical therapy decisions. Citation Format · Huf S, Platz Batista da Silva N, Wiesinger I et al. Analyse von Lebertumorentitäten mittels präoperativer und intraoperativer Kontrastmittelsonografie (CEUS/IOCEUS) durch Radiologen im Vergleich zur Magnetresonanztomografie und zur Histopathologie. Fortschr Röntgenstr 2017; 189: 431 - 440.

Results of the TOP Study: Prospectively Randomized Multicenter Trial of an Ex Vivo Tacrolimus Rinse Before Transplantation in EDC Livers.

BACKGROUND: Organ shortage results in the transplantation of extended donor criteria (EDC) livers which is associated with increased ischemia-reperfusion injury (IRI). Experimental studies indicate that an organ rinse with the calcineurin inhibitor tacrolimus before implantation protects against IRI. The tacrolimus organ perfusion study was initiated to examine the effects of ex vivo tacrolimus perfusion on IRI in transplantation of EDC livers. METHODS: A prospective randomized multicenter trial comparing ex vivo perfusion of marginal liver grafts (≥2 EDC according to Eurotransplant manual) with tacrolimus (20 ng/mL) or histidine-tryptophane-ketoglutarate solution (control) was carried out at 5 German liver transplant centers (Munich Ludwig-Maximilians University, Berlin, Heidelberg, Mainz, Regensburg) between October 2011 and July 2013. Primary endpoint was the maximum alanine transaminase (ALT) level within 48 hours after transplantation. Secondary endpoints were aspartate transaminase (AST), prothrombine ratio, and graft-patient survival within an observation period of 1 week. After an interim analysis, the study was terminated by the scientific committee after the treatment of 24 patients (tacrolimus n = 11, Control n = 13). RESULTS: Tacrolimus rinse did not reduce postoperative ALT peaks compared with control (P = 0.207; tacrolimus: median, 812; range, 362-3403 vs control: median, 652; range, 147-2034). Moreover, ALT (P = 0.100), prothrombine ratio (P = 0.553), and bilirubin (P = 0.815) did not differ between the groups. AST was higher in patients treated with tacrolimus (P = 0.011). Survival was comparable in both groups (P > 0.05). CONCLUSIONS: Contrary to experimental findings, tacrolimus rinse failed to improve the primary endpoint of the study (ALT). Because 1 secondary endpoint (AST) was even higher in the intervention group, the study was terminated prematurely. Thus, tacrolimus rinse cannot be recommended in transplantation of EDC livers.

Selection and use of immunosuppressive therapies after liver transplantation: current German practice.

In recent years, immunosuppression (IS) after liver transplantation (LT) has become increasingly diversified as the choice of agents has expanded and clinicians seek to optimize the balance of immunosuppressive potency with the risk of adverse events in individual patients. Calcineurin inhibitors (CNIs) are the primary agents used for patients undergoing liver transplantation. Other therapeutic agents like interleukin-2 receptor antagonists are not universally administered, but can be considered for the delay or reduction in CNI exposure. An early addition of mycophenolate mofetil (MMF) or the mTOR inhibitor everolimus also allows for the reduction in the CNI dose. To reduce the risk of malignancy, in particular of skin tumors, as well as to prevent the deterioration of renal function, everolimus-based therapy may be advantageous. Apart from patients with autoimmune hepatitis, steroids are withdrawn within 3-6 months after transplantation. Overall, immunosuppression can only be standardized in a limited proportion of patients due to specific clinical requirements and risk factors. Future studies should attempt to refine accurate individualization of the immunosuppressive regimen in specific difficult-to-treat patient subpopulations.

Calcineurin Inhibitor Free De Novo Immunosuppression in Liver Transplant Recipients With Pretransplant Renal Impairment: Results of a Pilot Study (PATRON07).

BACKGROUND: Renal impairment and high model of end-stage liver disease scores before liver transplantation (LT) are increasingly common. PATIENTS AND METHODS: This was a single-arm, 2-step prospective trial of bottom-up calcineurin inhibitor (CNI)-free de novo immunosuppressive treatment (mycofenolate mofetil, steroids, basiliximab) with delayed introduction of sirolimus in patients with renal impairment. Primary endpoint was immunologic safety assessed by the incidence of steroid-resistant rejection within the first 30 days after liver transplantation. RESULTS: Twenty-seven patients were included with a median age of 56 years and labMELD of 28. Baseline glomerular filtration rate was 38 (Cockroft-Gault) and 24 mL/min (modification of diet in renal disease). No steroid-resistant rejections occurred within 30 days. Incidence of biopsy proven acute rejection was 18.5%. Sirolimus was started on day 10 (range, day 1 to day 48). The rate switched to CNI treatment by 1 year was 44%; 1-year overall survival was 93%. Renal function improved significantly, reflected by a Δglomerular filtration rate of 31 mL/min from baseline to 1 year (P = 0.006). Per protocol analysis revealed freedom from CNI, but not presence of sirolimus within the first 30 days, as critical for renal recovery. CONCLUSIONS: Initial de novo CNI-free immunosuppressive bottom-up treatment is safe in selected patient groups. The critical period for relevant recovery of renal function seems to be the early period (first 30 days), independent from presence of sirolimus.

Clinical management of patients receiving cell-based immunoregulatory therapy.

Administering immunoregulatory cells as medicinal agents is a revolutionary approach to the treatment of immunologically mediated diseases. Isolating, propagating, and modifying cells before applying them to patients allows complementation of specific cellular functions, which opens astonishing new possibilities for gain-of-function antigen-specific treatments in autoimmunity, chronic inflammatory disorders, and transplantation. This critical review presents a systematic assessment of the potential clinical risks posed by cell-based immunotherapy, focusing on treatment of renal transplant recipients with regulatory macrophages as a concrete example.

Compliance and tolerability of subcutaneous hepatitis B immunoglobulin self-administration in liver transplant patients: a prospective, observational, multicenter study.

BACKGROUND: Subcutaneous self-administration of hepatitis B immunoglobulin (HBIg) prophylaxis is preferred by patients, but compliance with the assigned regimen in routine practice is undocumented. MATERIAL AND METHODS: A prospective, observational, 18-week, open-label, single-arm, multicenter study assessed compliance and tolerability in maintenance liver transplant patients self-administering subcutaneous HBIg at home according to local practice. RESULTS: Sixty-one patients were analyzed (median follow-up 18 weeks, range 14.0-27.9 weeks), with 961/1006 injections (95.5%) administered at home during the study. Other than in 4 patients, HBIg was prescribed for weekly administration (500 IU/L, n=39; 1000 IU/L, n=18) at study entry. Eighteen patients (29.5%) were assigned a dose lower than recommended in the Summary of Product Characteristics. The primary variable of compliance failure, defined as ≥ 1 hepatitis B surface antibody (anti-HBs) serum trough level <100 IU/L, occurred in 4 patients (6.6%; 95% CI 1.8%, 15.9%), 3 of whom were receiving a dose below that recommended for their body weight. Anti-HBs levels exceeded 100 IU/L in all patients at the final visit. Mean (SD) anti-HBs level at the first and final study visits was 248 (97) IU/L and 255 (104) IU/L, respectively. Patient compliance was graded good or very good by physicians in 91.8% of cases. No patients tested positive for HBsAg or HBV-DNA. Four patients experienced ≥ 1 adverse drug reactions, none of which was serious. No patient discontinued HBIg due to adverse events. CONCLUSIONS: Subcutaneous HBIg home-based self-administration under routine, real-life conditions is well-tolerated and associated with high compliance and maintaining protective anti-HBs serum concentration.

Portal vein omentin is increased in patients with liver cirrhosis but is not associated with complications of portal hypertension.

BACKGROUND: Omentin is a visceral fat-derived adipokine associated with endothelium-dependent vasodilation. Impaired endothelial function is a major cause of portal hypertension in liver cirrhosis. The aim was to assess associations of omentin with systemic markers of endothelial function, namely arginine and asymmetric dimethylarginine (ADMA) and complications of portal hypertension in liver cirrhosis. MATERIALS AND METHODS: Systemic omentin was measured by ELISA in portal venous serum (PVS), systemic venous serum (SVS) and hepatic venous serum (HVS) of 40 patients with liver cirrhosis and 10 liver-healthy controls. ADMA and arginine were determined in SVS of the patients by ELISA. RESULTS: Omentin is elevated in PVS and tends to be increased in SVS and HVS of patients with liver cirrhosis compared with controls. Omentin is principally expressed in visceral fat, and PVS omentin tends to be higher than SVS levels. Lower HVS than PVS omentin suggests that omentin may be partly removed from the circulation by the liver. Omentin in serum is not associated with stages of liver cirrhosis defined by CHILD-POUGH or MELD score and is not affected in patients with ascites. HVS omentin tends to be reduced in patients with large varices compared with patients without/with small varices. Arginine/ADMA ratio is reduced in patients with massive ascites but is not associated with variceal size. Further, Arginine/ADMA ratio does not correlate with omentin. CONCLUSION: Current data show that PVS omentin is increased in liver cirrhosis but is not associated with complications of portal hypertension.

Unconventional RORγt+ T cells drive hepatic ischemia reperfusion injury.

An emerging body of evidence suggests a pivotal role of CD3(+) T cells in mediating early ischemia reperfusion injury (IRI). However, the precise phenotype of T cells involved and the mechanisms underlying such T cell-mediated immune responses in IRI, as well as their clinical relevance, are poorly understood. In this study, we investigated early immunological events in a model of partial warm hepatic IRI in genetically targeted mice to study the precise pathomechanistic role of RORγt(+) T cells. We found that unconventional CD27(-)γδTCR(+) and CD4(-)CD8(-) double-negative T cells are the major RORγt-expressing effector cells in hepatic IRI that play a mechanistic role by being the main source of IRI-mediating IL-17A. We further show that unconventional IRI-mediating T cells are contingent on RORγt, as highlighted by the fact that a genetic deficiency for RORγt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27(-)γδTCR(+) and CD4(-)CD8(-) double-negative T cells as the major source of IL-17A via RORγt in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.

Protocol TOP-Study (tacrolimus organ perfusion): a prospective randomized multicenter trial to reduce ischemia reperfusion injury in transplantation of marginal liver grafts with an ex vivo tacrolimus perfusion.

BACKGROUND: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. METHODS/DESIGN: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation's definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. DISCUSSION: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. TRIAL REGISTER: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095.

Bile duct damage after cold storage of deceased donor livers predicts biliary complications after liver transplantation.

BACKGROUND & AIMS: The aim of this study was to examine the development of biliary epithelial damage between organ retrieval and transplantation and its clinical relevance for patients. METHODS: Common bile duct samples during donor hepatectomy, after cold storage, and after reperfusion were compared to healthy controls by hematoxylin and eosin (H&E) staining and immunofluorescence for tight junction protein 1 and Claudin-1. A bile duct damage score to quantify biliary epithelial injury was developed and correlated with recipient and donor data and patient outcome. RESULTS: Control (N=16) and donor hepatectomy bile ducts (N=10) showed regular epithelial morphology and tight junction architecture. After cold storage (N=37; p=0.0119), and even more after reperfusion (N=62; p=0.0002), epithelial damage, as quantified by the bile duct damage score, was markedly increased, and both tight junction proteins were detected with inappropriate morphology. Patients with major bile duct damage after cold storage had a significantly increased risk of biliary complications (relative risk 18.75; p<0.0001) and graft loss (p=0.0004). CONCLUSIONS: In many cases, the common bile duct epithelium shows considerable damage after cold ischemia with further damage occurring after reperfusion. The extent of epithelial damage can be quantified by our newly developed bile duct damage score and is a prognostic parameter for biliary complications and graft loss. Possibly, in an intraoperative histological examination, this bile duct damage score may influence decision-making in transplantation surgery.

Treatment-emergent adverse events after infusion of adherent stem cells: the MiSOT-I score for solid organ transplantation.

BACKGROUND: Cellular therapy after organ transplantation is emerging as an intriguing strategy to achieve dose reduction of classical immunosuppressive pharmacotherapy. Here, we introduce a new scoring system to assess treatment-emergent adverse events (TEAEs) of adherent stem cell therapies in the clinical setting of allogeneic liver transplantation (for example, the MiSOT-I trial Eudract CT: 2009-017795-25). METHODS: The score consists of three independent modalities (set of parameters) that focus on clinically relevant events early after intravenous or intraportal stem cell infusion: pulmonary toxicity, intraportal-infusional toxicity and systemic toxicity. For each modality, values between 0 (no TEAE) and 3 (severe TEAE) were defined. The score was validated retrospectively on a cohort of n=187 recipients of liver allografts not receiving investigational cell therapy between July 2004 and December 2010. These patients represent a control population for further trials. Score values were calculated for days 1, 4, and 10 after liver transplantation. RESULTS: Grade 3 events were most commonly related to the pulmonary system (3.5% of study cohort on day 4). Almost no systemic-related TEAEs were observed during the study period. The relative frequency of grade 3 events never exceeded 5% over all modalities and time points. A subgroup analysis for grade 3 patients provided no descriptors associated with severe TEAEs. CONCLUSION: The MiSOT-I score provides an assessment tool to score specific adverse events that may occur after adherent stem cell therapy in the clinical setting of organ transplantation and is thus a helpful tool to conduct a safety study.