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Einleitung und Fragestellung / Introduction and Background

Liver transplantation (LT) is a successful treatment option for end-stage liver. After LT, liver-related, infectious and cardiovascular complications contribute to reduced graft and patient survival. These conditions are associated with an increase in von Willebrand factor antigen (VWF-Ag), which was previously also correlated with survival in cirrhotic patients. We evaluated VWF-Ag as predictive marker after LT.

Methodik / Methods

We conducted a prospective study in patients after first LT treated at the University Hospital Heidelberg. Patients that were seen for follow-up after LT in the outpatient clinic of our department between November 2012 and August 2013 were screened. To be included, patients had to be at least 18 years of age at time of inclusion, and only patients after first LT were eligible. We measured VWF-Ag in these patients and followed them prospectively with regard to the primary endpoint, namely retransplantation-free survival.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Six of the 80 patients died or received re-LT during follow-up. Median VWF-Ag was 510.6% in these patients and significantly higher (P=0.001) than in the patients alive at the end of follow-up (median: 186.8%). ROC analysis (AUC: 0.914) revealed an optimal cut-off of 286.8% for prediction of the primary end-point (sensitivity: 100%, specificity: 81.1%). Survival was longer in patients with a VWF-Ag below this cut-off compared to those with a higher VWF-Ag (P<0.001 according to log-rank test). VWF-Ag was associated with retransplantation-free survival in multivariate analysis as was alkaline phosphatase (ALP), but not MELD score, donor age, or cold ischemia time. A score combining VWF-Ag and ALP showed impressive capability in ROC analysis (AUC: 0.958) to distinguish between patients with regard to the primary endpoint.

VWF-Ag is a non-invasive marker to predict outcome in patients after LT. Its diagnostic performance increased when combined with ALP in a newly developed score.

Einleitung und Fragestellung / Introduction and Background

Cardiovascular disease (CVD) is one of the leading causes of death in liver transplant recipients (LTxRs). Impaired glomerular filtration rate (GFR) is a risk factor for CVD. In the 24 month (M) post-hoc analysis of the H2304 study, everolimus (EVR) with reduced tacrolimus (rTAC) or  tacrolimus withdrawal (TAC-WD) provided adequate immunosuppression, improved renal function and reduced the incidence of major adverse cardiac events (MACE) compared with standard TAC (TAC-C). Here we present the post-hoc analysis of the CVD risk at 36M post LTx, from the randomized H2304 extension study.

Methodik / Methods

H2304 is a 24M, randomized, open-label, multicenter study in which LTxRs on day 30 post-Tx were randomized to receive either EVR+rTAC (n = 245), EVR+TAC-WD (n = 229) or TAC-C (n = 242). After the core study, LTxRs were followed up for additional 12M. Renal function was measured by estimated glomerular filtration rate (eGFR) using the four-variable Modification of Diet in Renal Disease (MDRD4) formula. Adverse events (AEs) associated with MACE (ischaemic heart disease, cardiac failure, sudden death and ischaemic stroke) were used to determine the CV risk of this extension study population.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Of the 716 randomized LTxRs, 282 were followed up till M36. At M36, eGFR values for TAC-WD, EVR+rTAC and TAC-C arms were 86 ± 27.4, 85.2 ± 30.5 and 70.8 ± 22.9 mL/min/1.73 m²_. The cumulative incidence of MACE was lower in the TAC-WD arm (n = 3; 15.6/1000 patient-years [PY]) compared with EVR+rTAC (n = 8; 22.5/1000 PY) and TAC-C (n = 13; 59.8/1000 PY) arms. The risk of MACE was also significantly lower (P = 0.0105) in the TAC-WD arm compared with the TAC-C arm. This M36 follow-up post-hoc analysis suggests that compared with TAC-C, EVR facilitated reduction or withdrawal of TAC, provides better renal function and is associated with lower incidence of MACE.

Einleitung und Fragestellung / Introduction and Background

Tumor recurrence is the most frequent cause of death after liver transplantation (LTX) for hepatocellular carcinoma (HCC). To identify factors influencing intra- and extra-hepatic recurrence, we reviewed patients treated at our department from 1995 to 2014.

Methodik / Methods

Methods:

Our tumor register provided data of 146 consecutive patients on age, sex, Child stage, AFP, tumor diameter, number of tumors, venous invasion on histological definitve examination (VI), Milan-, BCLC and Duvoux-score, and time and location of recurrence. We differentiated between intra-hepatic (within the liver ± distant metastases) and extrahepatic (distant metastases only) recurrence (IHR and EHR, respectively). For multivariate analyses a COX-model was used.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Results:

After a median follow-up time of 45 (3-148) months after LTX, 15 patients had IHR, 28 had EHR. The respective cumulative 10 year recurrence rates (10-Y RR) were 11 ± 3%, and 23 ± 4%. 10-Y RR for TR were statistically significantly influenced by Milan-, BCLC- and Duvoux-Score (p= 0.013, 0.045, and <0.001, respectively), number of tumors (p=0.002), AFP-level > 100 ng/ml (p=0.018), and VI (p<0.001). 10-Y RR for EHR followed the same pattern. For IR, we did not see a statistically significant difference in 10-Y RR for Milan, AFP and BCLC-score.

Venous invasion, Milan-, BCLC and Duvoux-score were included in a COX model. Only Duvoux-score and VI proved to be of independent influence on 10-Y RR for TR (p=0.013, HR 2.920; p<0.001, HR 3.896; respectively). The same factors influenced 10-Y RR for EHR (p=0.022, HR 3.602; p=0.002, HR 4.128; respectively). For IHR only VI independently influenced 10-Y RR (p=0.031, HR 3.744).

Conclusions:

In our series venous invasion was the most important factor influencing recurrence.

 

Einleitung und Fragestellung / Introduction and Background

As many other chronic diseases, type 1 diabetes has a direct impact on the quality of life. The present study investigates the influence of simultaneous pancreas-kidney transplantation (SPK) on the quality of life of patients with type 1 diabetes.

Methodik / Methods

The health related quality of life was measured retrospectively with the Short Form Health Survey (SF 36) in 146 patients (65f:81m, mean age: 51,9±8,5) after successful pancreas-kidney transplantation and 51 patients (23f:28m, mean age: 45,7±8,1) on the waiting list. Quality of life was compared between the two groups and the influence of other variables (duration of diabetes, duration on dialysis, gender, age, comorbidities) on quality of life was included. The patients that underwent transplantation had a mean duration of diabetes of 31,3±7,7 years and a mean time on dialysis of 26±24 months, the patients on the waiting list had a mean duration of diabetes of 30,9±8,7 years and a mean time on dialysis of 33,9±36,5 months.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Comparing the two groups, the physical and mental health summary scales of the quality of life showed significantly better results in the group of patients with a successful transplantation than in the group of patients on the waiting list (p<0,01). After transplantation, there was a highly significant improvement in physical functioning, general health perceptions, social functioning, vitality and mental health (p<0,001). Male patients of both groups showed significantly less physical pain, more vitality and a better mental health. Compared to German norm data, the transplant patients had a similar quality of life to the group of patients aged 61 to 70. A tendency towards better results in those patients within a shorter postoperative timespan after transplantation could be seen.

Overall there is a significant increase in health-related quality of life in patients after successful combined pancreas-kidney transplantation.

Einleitung und Fragestellung / Introduction and Background

We retrospectively analyzed long-term pancreatic and renal graft function, patient and graft survival and major complications after combined pancreatic-kidney transplantation (SPK) and Tacrolimus (Tac) or Cyclosporine A (CyA) monotherapy.

Methodik / Methods

Between 1979 – 2015 performed at our center, 7 out of 489 SPKs patients were converted to Tac (n=6) or CyA (n=1) monotherapy in response to hematologic side effects  (n=6) or biopsy-proven BK-nephropathy (n=1). Prior to monotherapy, patients were treated with Tac plus MMF (n=5) or Tac plus Rapamycine (n = 1, study) or Tac-monotherapy (study, converted to CyA due to idiopathic thrombopenia), respectively, for a period of 62.1 (30-144) months (mean).

Ergebnisse und Schlussfolgerungen / Results and Conclusions

At 133 (48-205) months all patients are alive with a stable pancreatic and renal function (mean creatinine 1.7 mg/dL +/-0.7 SD, blood glucose 97.1 mg/dL+/-12.2 SD, HbA1c 5.3%+/-0.3 SD, C-peptide 4.2 ng/L+/-2.1 SD, Tac-/CyA -level 5.6 +/- 1.8 SD / 107 ng/mL).All major complications (urosepsis, incisional hernia, portal vein thrombosis, bleeding telangiectasia of graft duodenum, idiopathic portal hypertension, mild acute rejection, idiopathic thrombopenia, n=1 each) were controllable. In one patient a biopsy proven acute vascular rejection (at month 33 within Tac-monotherapy, 155 month post transplant, C4d negative) was treated by adding MMF (discontinued after 6 weeks due to leucopenia and diarrhea) plus prednisolone (discontinued after 5 weeks for severe skin dystrophy). No antibody mediated rejection was observed. The most recent DSA screening was negative in 2 patients and is missing for logistic reasons in 5.

Conclusion: Late after SPK, Tac-/CyA monotherapy seems to be feasible in patients suffering from side effects of non-CNI immunosuppressants. Cautious dose adjustments, careful trough level monitoring and particular attention to strict adherence to the drug treatment may be particularly relevant in this context.

Einleitung und Fragestellung / Introduction and Background

Donor specific antibodies (DSA) developed as a risk factor after livertransplantation (LT) for complicated processes. Monitoring of DSAs is not yet standardized neither is the therapeutic procedure in case of humoral graft damage. This analysis wants to define factors that predispose patients for the development of DSAs after LT.

Methodik / Methods

We established a database collecting clinical and demographic data of 400 liver transplant recipients receiving aftercare in the liver transplant unit of the university hospital Essen. Antibody-detection was performed by using Luminex single antigen beads and a mean fluorescence intensity (MFI) value of more than 500 was considered positive. For statistical analysis we employed SPSS software. A p-value less than 0.05 was considered statistically significant.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

The indication for livertransplantation is associated with DSAs. Patients who received LT due to an autoimmune liver disease developed DSAs significantly more often than patients with any other indication (29,3 %; p ≤ 0,022). Patients who receive LT due to a hepatocellular carcinoma (HCC) have a significantly lower risk to develop DSAs: of 79 patients with HCC only 6 (7,6 %) developed detectable DSAs (p ≤ 0,002). The risk to develop DSAs increases significantly 8 years after LT (p ≤ 0,005). Interestingly, significantly less patients (10,6 %; p ≤ 0,025) who receive an mTor-Inhibitor-based immunosuppressive regimen do develop DSAs after LT compared to patients receiving a calcineurin-inhibitor (CNI) –based immunosuppressive therapy (43,1 %).

Potentially due to a certain immunologic predisposition, patients with autoimmune liver diseases have a higher risk for the development of humoral graft damage and need a closer monitoring for DSAs. Immunosuppression with an mTor -inhibitor does obviously have a protective effect on DSA development and may be preferred for immunosuppression in those patients with a higher risk.

Einleitung und Fragestellung / Introduction and Background

The allograft rejection (AR) has generally been considered a T-cell-dependent immune process. It is known that lymphocyte regress after transplantation depends on sphingosine 1-phosphate (S1P) receptor-1. Treatment with 2-Acetyl-4-tetra-hydroxybutyl imidazole (THI), a potentially immunosuppresant drug, inhibits the S1P-degrading enzyme and plays a fundamental role in the immune response. The aim of this experimental study is to evaluate the protective effects with mono-therapy after LTx in a rat model, or Certican®-combined THI treatment of the recipients. An understanding of this preconditioning of the allograft is essential for the design of therapeutic strategies as well as an improvement of survival after LTx for recipients with relevant immunosuppressant toxicity.

Methodik / Methods

Orthotopic arterialised LTx in a rat model. The recipients are divided into 4 groups:

group I (controls without THI or Certican® pre-/treatment/immunosuppression of the

recipients, n=6); group II (immunsuppression of the recipients with  high-dose Certican®, n=10); group III (pre-/treatment of the recipients with THI, n=10); group IV (pre-/treatment and immunosuppression of the recipients with low-dose Certican® and day 0-14 after LTx with THI, n=10).

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Our preliminary data (histopathological findings and FACS) with application of a single THI-injection 60 minutes before LTx show a significant decrease of CD4+/CD8+ populations of the T-lymphocytes in the recipients` peripheral blood and liver allograft. These results indicate that lymphopenia in the peripherial blood compartment is caused by a rapid sequestration after THI treatment, and gives credence to the theory that the reduction of T-lymphocytes with THI alone or in combination with low-dose Certican® before reperfusion will prevent or reduce acute rejection episodes in liver allografts.

The study is of considerable interest as it draws attention to the modulation of immune function after solid organ transplantation.

Einleitung und Fragestellung / Introduction and Background

Das postoperative Schmerzmanagement bei Nierenlebendspendern ist ein wesentlicher Faktor für die empfundene Belastung der Operation. Dies spielt besonders für die zukünftige Akzeptanz der Nierenlebendspende in Zeiten des Organmangels eine wichtige Rolle. Die auf Opiaten basierende Standardschmerztherapie (SPT) gemäß WHO-Guidelines ist aufgrund ihrer Nebenwirkungen (Übelkeit, Erbrechen, Darmparalyse) limitiert. Die postoperative kontinuierliche Infusion von Lokalanästhetikum (CILA) mittels intraoperativ eingelegter Katheter bietet eine Alternative, die besonders bei der hand-assistierten retroperitoneoskopischen Spendernephrektomie (HARP) aufgrund des umschriebenen Operationsgebietes vielversprechend zu sein scheint. Ziel dieser Studie war es zu evaluieren, ob durch CILA die Opiatdosis nach HARP im Vergleich zur SPT  verringert werden kann.

Methodik / Methods

Es wurde ein prospektive Beobachtungstudie bei 30 Lebendspender nach HARP für 72 h postoperativ durchgeführt. Primärer Outcome-Parameter war der Unterschied in der Morphinäquivalenzdosis zwischen Patienten, die mit CILA und SPT behandelt wurden im Vergleich zu Patienten, die nur die SPT erhielten.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

An Tag 0 benötigten die Lebendspender mit CILA signifikant weniger MEQ im Vergleich zur Gruppe mit alleiniger SPT (6.3mg, IR 4.2-11.2 vs. 16.8mg, IR 10.5-22.1; p=0.009). An Tag 1 war die MEQ ebenfalls geringer, der Unterschied aber nicht mehr signifikant (5.25mg, IR 2.1-13.3 vs. 13.3mg, IR 6.7-23.8; p=0.15). An Tag 2 und 3 lag kein Unterschied mehr vor (Tag 2: 13.3mg, IR 0.0-20.0 vs. 13.3mg, IR 6.7-13.3; p=0.708; Tag 3: 13.3mg, IR 0.0-26.7 vs. 13.3mg, IR 6.7-20; p=0.825). Im gesamten Zeitraum (Tag 0-3) war der Opiatverbrauch mit CILA ebenfalls geringer (39.6mg, IR 10.9-70.5 vs. 59.6mg IR 42.4-72.9; p=0.187).

Die postoperative kontinuierliche Infusion von Lokalanästhetikum in das Operationsgebiet ist ein effektives Instrument, den Opiatverbrauch in den ersten 24 Stunden bei Spendern, die mittels HARP operiert worden, sind zu senken.

Einleitung und Fragestellung / Introduction and Background

Acute liver failure (ALF) is a condition with loss of nearly complete liver function after severe damage which may result in the need for liver transplantation. One reason for ALF is the overdose of drugs like acetaminophen (APAP). Reliable test systems to identify hepatotoxicity are essential to study the mechanism of liver damage of known drugs and to predict unexpected drug-related liver injury of new drug candidates.

Methodik / Methods

We established a human-based ex-vivo liver model able to keep hepatic functionality for up to 30 hours and investigated drug-induced liver injury using APAP as model substance. Hourly samples from the perfusate were taken for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. APAP was applied after 8 hours of perfusion with 6.5 mg per gram of deployed liver tissue.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers after 20 h of perfusion (p < 0.005). Four liver sections revealed weak damage with significantly higher ICG half-lives after 28 h of perfusion (p < 0.05). Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in humans and reflects well the inter-individual differences upon drug response observed in patients.

Einleitung und Fragestellung / Introduction and Background

Hepatocyte transplantation is of large potential as an additional treatment modality for certain liver diseases. However, insufficient engraftment and long-term acceptance of cellular allografts  remain major challenges and still hamper broad clinical application. Aim of this study thus was to investigate whether i) immunosuppressive drugs known from solid organ transplantation show similar effectiveness for suppression of the immune response induced by primary human hepatocytes (PHH) and ii) isolated PHH are vulnerable to toxicity induced by these immunosuppressive agents potentially hampering cell engraftment in vivo.

Methodik / Methods

PHH were isolated from resected liver specimens using a 2-step-collagenase perfusion technique. Adherent PHH were then co-culture with allogenic lymphocytes in terms of a mixed lymphocyte hepatocyte culture (MLHC) to characterize the immune response induced. Lymphocytes were labeled with PKH-26 to determine proliferation via flow-cytometry. MLHC was performed in the absence and presence of Cyclosporin, Everolimus, Belatacept and methylprednisolone (incubation time of 10 days). In addition, metabolic activity of PHH was assessed using the MTT-assay.

Ergebnisse und Schlussfolgerungen / Results and Conclusions

Allogenic PHH induce a predominantly CD4⁺ T-cell response in vitro. The immune response is well susceptible to suppression by Cyclosporin, Everolimus as well as Belatacept, whereas addition of methylprednisolone resulted only in minor reduction of T-cell proliferation. Cyclosporin, Belatacept and methylprednisolone had no significant inhibitory effects on metabolic activity of PHH in vitro as compared to controls . However, application of Everolimus significantly reduced the metabolic activity of PHH. In conclusion, Cyclosporin, Everolimus and Belatacept seem effective immunosuppressive drugs concerning alloreactivity inMLHC, nonetheless, Everolimus might turn out disadvantageous concerning cell engraftment and proliferation in vivo.