Jan Schmidt

A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus After Liver Transplantation—PROTECT

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal‐sparing alternative. In this randomized 1‐year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post‐LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft‐Gault formula (−2.9 mL/min in favor of EVR, 95%‐CI: [−10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (−7.8 mL/min, 95%‐CI: [−14.366; −1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy‐proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI‐based to EVR‐based immunosuppression proved to be a safe alternative post‐LTx that deserves further investigation in terms of nephroprotection.

Monitoring of intraportal liver cell application in children.

Despite recent advances and promising results in children, liver cell transplantation (LCT) should still be regarded as an experimental therapy. Several substantial complications are known from animal studies and individual patients. However, safety data on liver cell infusion in children are scarce. We used LCT in four children of different ages (3 weeks to 11 years, 3–40 kg) and underlying diseases [acute liver failure (n = 1), urea cycle disorders (n = 2), and Crigler-Najjar syndrome (n = 1)]. Vital parameters, portal vein flow (PVF), portal vein pressure (PVP), and liver enzymes were measured every 5 min during cell application and hourly thereafter between applications. An application protocol with discontinuation rules depending on changes in PVF and PVP was developed and successfully applied. Application was feasible in all children despite the catastrophic overall condition of the patient with acute liver failure. No application-related changes in vital parameters were found, and none of the children experienced clinical signs of portal vein thrombosis, pulmonary embolism, or anaphylactic reactions. Time courses for changes in PVF, PVP, and liver enzymes were obtained. Thorough monitoring of portal vein pressure and duplex sonography according to a defined protocol is likely to increase safety of cell application in pediatric LCT.

Budd-Chiari Syndrome: Long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt

BackgroundBudd-Chiari syndrome (BCS) generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Treatment depends on the underlying cause, the anatomic location, the extent of the thrombotic process and the functional capacity of the liver. It can be divided into medical treatment including anticoagulation and thrombolysis, radiological procedures such as angioplasty and transjugular intrahepatic porto-systemic shunt (TIPS) and surgical interventions including orthotopic liver transplantation (OLT). Controlled trials or reports on larger cohorts are limited due to rare disease frequency. The aim of this study was to report our single centre long term results of patients with BCS receiving one of three treatment options i.e. medication only, TIPS or OLT on an individually based decision of our local expert group.Methods20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome.Results16 women and 4 men with a mean age of 34 ± 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 ± 2.4 revisions (range: 0-8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively.ConclusionOur results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS.

Immunomonitoring of nuclear factor of activated T cells–regulated gene expression: The first clinical trial in liver allograft recipients

Long‐term calcineurin inhibitor (CNI) treatment can cause serious side effects in liver allograft recipients. An optimal risk‐to‐benefit ratio for CNI blood levels has not been established. Pharmacodynamic drug monitoring through the measurement of the CNI biological activity, that is, the expression of nuclear factor of activated T cells (NFAT)–regulated genes, seems to be a promising approach. The residual gene expression (RGE) of NFAT‐regulated genes 2 and 1.5 hours after cyclosporine A (CsA) and tacrolimus (FK‐506) intake was measured in 100 liver allograft recipients with 1 or more years of follow‐up post‐transplantation. The mean RGE in all patients was 62% ± 33%. A significant negative correlation between the CsA (P < 0.0001, r = −0.8026) and FK‐506 peak levels (P < 0.0001, r = −0.6982) and the RGE of all NFAT‐regulated genes was observed. Clinical reliability was proven too. In conclusion, the data presented in this pilot study reveal the applicability of the pharmacodynamic monitoring of CNI efficacy in liver allograft recipients. To confirm the advantage of individualized pharmacodynamic drug monitoring over pharmacokinetic drug monitoring with respect to clinical outcomes, controlled, prospective studies are needed. Liver Transpl, 2011.

Iodine removal in intravenous dual-energy CT-cholangiography: Is virtual non-enhanced imaging effective to replace true non-enhanced imaging?

PURPOSEnTo evaluate whether virtual non-enhanced imaging (VNI) is effective to replace true non-enhanced imaging (TNI) applying iodine removal in intravenous dual-energy CT-cholangiography.nnnMATERIALS AND METHODSnFrom April 2009 until February 2010, fifteen potential donors for living-related liver transplantation (mean age 37.6±10.8 years) were included. Potential donors underwent a two-phase CT-examination of the liver. The first phase consisted of a single-energy non-enhanced CT-acquisition that provided TNI. After administration of hepatobiliary contrast agent, the second phase was performed as a dual-energy cholangiographic CT-acquisition. This provided VNI. Objective image quality (attenuation values [bile ducts and liver parenchyma] and contrast-to-noise ratio) and subjective overall image quality (1 - excellent; 5 - non diagnostic) were evaluated. Effective radiation dose was compared.nnnRESULTSnFor TNI and VNI, attenuation values for bile ducts were 16.8±11.2HU and 5.5±17.0HU (p<0.05) and for liver parenchyma 55.3±8.4HU and 58.1±10.6HU (n.s.). For TNI and VNI, contrast-to-noise ratio was 2.6±0.6HU and 6.9±2.1HU (p<0.001). For VNI, subjective overall image quality was 1 in ten datasets, 2 in four datasets and 3 in one dataset. Effective radiation dose for the dual-energy cholangiographic CT-acquisition was 3.6±0.9mSv and for two-phase single-energy CT-cholangiography 5.1±1.3mSv (p<0.001).nnnCONCLUSIONnIn this study on iodine removal in intravenous dual-energy CT-cholangiography, subjective image quality is equivalent, contrast-to-noise ratio is improved and effective radiation dose is reduced when VNI is performed. The differences between TNI and VNI with respect to attenuation values seem to have limited clinical relevance and therefore we consider VNI as effective to replace TNI.

Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells

BACKGROUND & AIMSnDifferential expression of tumor-relevant proteins based on aberrant proteasomal degradation may contribute to human (hepato)carcinogenesis. Recently, we identified the E3 ubiquitin ligase seven in absentia homolog (SIAH)-1 as frequently dysregulated in human hepatocellular carcinoma (HCC). We therefore systematically analyzed the expression, functional relevance, as well as possible downstream effectors of SIAH-1 in human liver carcinogenesis.nnnMETHODSnSIAH-1 expression was analyzed at the transcript and protein levels in human hepatocarcinogenesis and in HCC cells. Proliferation, apoptosis, and migration of different HCC cell lines were examined after siRNA-mediated inhibition of SIAH-1. In order to identify downstream effectors that mediate SIAH-1 effects, correlative analyses of protein expression profiles were performed.nnnRESULTSnIn HCC tissues both reduction of cytoplasmic SIAH-1 and especially its nuclear accumulation positively correlated with HCC progression. RNA interference revealed that nuclear expression of SIAH-1 predominantly supported HCC cell proliferation and migration while only moderately affecting anti-apoptosis. In de-differentiated human HCCs, nuclear SIAH-1 accumulation significantly correlated with the expression of the transcription factor far-upstream element (FUSE)-binding protein (FBP)-3. In vitro, SIAH-1 positively and indirectly regulated FBP-3 which itself primarily supported HCC cell proliferation. Indeed, high level expression of FBP-3 in human HCCs significantly correlated with reduced overall survival of patients.nnnCONCLUSIONSnNuclear accumulation of the E3 ubiquitin ligase SIAH-1 supports different pro-tumorigenic cellular processes associated with tumor growth and tumor cell dissemination in human hepatocarcinogenesis. It promotes HCC cell proliferation by at least partly employing the transcription factor FBP-3. Therefore, interference with SIAH-1 activity represents a promising approach to suppress HCC growth.

Living donor liver transplantation in adults in the MELD era in Germany – a multi‐center retrospective analysis

The aim of this analysis was to provide an update on the current trend in living donor liver transplantation (LDLT) for adult recipients in the model of end stage liver disease (MELD) era in Germany and to encourage a wider implementation of LDLT. We descriptively analysed the data of LDLTs in Germany from 15 December 2006 to 31 December 2009 using a multi‐center retrospective analysis via a questionnaire and data provided by Eurotransplant. Ten German centers performed LDLTs in adults. Eighty four transplantations in 50 male recipients and 34 female recipients were performed during the review period, ranging from 1 to 16 LDLTs per center. Hepatocellular carcinoma in cirrhosis (15/84) was the most common transplantation indication. The recipient mean lab‐MELD score was 15 (±8). Six re‐transplantations were necessary after initial LDLTs. The 1‐year patient survival was 81%. We obtained data of 79/84 donors. The incidence of complications was 30.4% (nu2003=u200324). There were no grade 5 complications according to the Clavien classification. LDLT is an established treatment option that may reduce the waiting time, provides high quality split liver grafts and should be advocated in the MELD era to reduce organ shortage and ‘death on the waiting list’.

Aberrant demethylation of the recoverin gene is involved in the aberrant expression of recoverin in cancer cells

Please cite this paper as: Aberrant demethylation of the recoverin gene is involved in the aberrant expression of recoverin in cancer cells. Experimental Dermatology 2010; 19: 1023–1025.

Cytomegalovirus Infection After Liver Transplantation Incidence, Risks, and Benefits of Prophylaxis

BACKGROUNDnCytomegalovirus (CMV) infection and related disease is a feared complication after liver transplantation. Antiviral prophylaxis is recommended in clinical practice guidelines depending on the CMV status of both donor and recipient as well as the individual risk profile.nnnMETHODSnWe retrospectively analyzed 211 liver transplant recipients with respect to the incidence of CMV infection after transplantation, the influence of donor and recipient CMV status, and the effect of antiviral prophylaxis. In addition, the underlying liver disease and immunosuppressive regimen were compared with the incidence of CMV infection. Patients were divided into 4 groups according to CMV donor/recipient (D/R) profile: group A (D-/R-) 28 patients (13.3%), group B (D-/R+) 64 patients (30.3%), group C (D+/R+) 79 patients (37.4%), and group D (D+/R-) 40 patients (19.0%).nnnRESULTSnCMV infection was observed in 17.9%, 29.7%, 24.1%, and 22.5% of the patients, respectively, with no significant difference in infection rates between the groups. CMV infection occurred in 5 patients (17.9%) in the presumed low-risk profile (group A), despite an antiviral prophylaxis in 4 out of these 5 patients. In contrast, CMV infection occurred in only 9/40 patients (22.5%) in the presumed high-risk profile (group D). The most frequent infection rates were found in groups B and C (R+ groups). After successful treatment of CMV infection, no recurrence was detected. Underlying liver disease or immunosuppressive protocol had no influence on CMV infection.nnnCONCLUSIONnApproximately one fourth of patients will acquire CMV infection after liver transplantation independent of donor/recipient status. Surprisingly, antiviral prophylaxis does not seem to be sufficient to reduce this proportion of patients, either in presumed high-risk or in presumed low-risk situations.

Interventional radiologic procedures in the treatment of complications after liver transplantation.

The aim of this study is to report our interventional radiologic procedures (IRP) in liver transplant (LTX) patients. These include procedures for biliary, arterial, venous, and portal complications, as well as the treatment of infected and non‐infected fluid collections.