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Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)‐assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta‐analysis on the impact of CT‐assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11–3.05, p = 0.02) and 1.72 (95% confidence interval 0.99–3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End‐stage Liver Disease score. Less‐consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment. This systematic review and meta‐analysis describes the association between low skeletal muscle mass and impaired outcome in patients listed for or undergoing liver transplantation.

Viral infections, including cytomegalovirus (CMV), abrogate transplantation tolerance in animal models. Whether this also occurs in humans remains elusive. We investigated how CMV affects T cells and rejection episodes after liver transplantation (LT). Phenotype and alloreactivity of peripheral and allograft‐infiltrating T cells from LT patients with different CMV status were analyzed by flow cytometry. The association of CMV status with early and late acute rejection was retrospectively analyzed in a cohort of 639 LT patients. CMV‐positivity was associated with expansion of peripheral effector memory T cell subsets after LT. Patients with CMV primary infection showed donor‐specific CD8+T cell hyporesponsiveness. While terminally differentiated effector memory cells comprised the majority of peripheral donor‐specific CD8+T cells in CMV primary infection patients, they were rarely present in liver allografts. Retrospective analysis showed that R−D+serostatus was an independent protective factor for late acute rejection by multivariate Cox regression analysis (hazard ratio [HR] = 0.18, 95% CI = 0.04–0.86, p = 0.015). Additionally, CMV primary infection patients showed the highest Vδ1/Vδ2 γδ T cell ratio, which has been shown to be associated with operational tolerance after LT. In conclusion, our data suggest that CMV primary infection may promote tolerance to liver allografts, and CMV status should be considered when tapering or withdrawing immunosuppression. By analyzing the phenotype and alloreactivity of peripheral T cells in humans after liver transplantation, the authors show that primary cytomegalovirus infection is associated with the development of donor‐specific CD8+ hyporesponsiveness, and is accompanied by a diminished incidence of late acute rejection and signs of operational tolerance.

This study reviews the clinical impact of rotavirus infection in the setting of organ transplantation and disseminates the interactions among the virus, host, and immunosuppressive medications.

Results of the REFINE study, a multicenter prospective trial designed to examine whether choice of calcineurin inhibitor affects the rate of liver fibrosis due to posttransplant hepatitis C virus recurrence, show that overall fibrosis progression is similar in patients receiving either cyclosporine or tacrolimus, whereas in patients receiving steroid‐free regimens, the use of cyclosporine leads to reduced severity of fibrosis progression at one year after liver transplantation.

Early conversion from tacrolimus to a regimen combining everolimus with low‐exposure tacrolimus improves renal function at two years post‐liver transplantation. See editorial by Bhat and Charlton on page 1633.

In a prospective, multicenter, open‐label study, de novoliver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced‐exposure tacrolimus (EVR+Reduced TAC) or (iii) standard‐exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy‐proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (−3.0%; 95% CI −8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m2, 97.5% CI 3.74, 13.27 mL/min/1.73 m2, p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

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.

Ischemic‐type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia‐reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.

Organ transplant recipients are highly susceptible to viral infections early after transplantation. Plasmacytoid dendritic cells (PDC) play a major role in antiviral immunity. Therefore, we determined the numbers of circulating PDC after liver transplantation (LTX) and established the effects of immunosuppressive drugs on PDC survival and function. PDC were determined longitudinally in 13 LTX recipients treated with prednisone and cyclosporin or tacrolimus. Purified PDC were cultured with or without clinically relevant concentrations of cyclosporin, tacrolimus or prednisolone. Apoptosis induction was monitored by determination of active caspase-3, nuclear condensation and annexin-V/7AAD staining. After LTX, a 4-fold reduction in the number of circulating PDC was observed (p < 0.01), which recovered partially after discontinuation of prednisone treatment. In vitro, prednisolone induced apoptosis in PDC, while cyclosporin and tacrolimus did not. Higher doses of prednisolone were needed to induce apoptosis in Toll-like receptor (TLR)-stimulated PDC. However, non-apoptosis inducing concentrations of prednisolone suppressed interferon-alpha production, upregulation of co-stimulatory molecules and allo-stimulatory capacity of TLR-stimulated PDC. In conclusion, prednisolone induces apoptosis in PDC, which explains the decline in circulating PDC numbers after transplantation. Moreover, prednisolone suppresses the functions of TLR-stimulated PDC. Therefore, corticosteroid-free immunosuppressive therapy may reduce the number and severity of viral infections after transplantation.

Background: Drug pharmacokinetics may be altered during liver transplantation. Cefotaxime (CTX), used as perioperative prophylaxis, demonstrates time-dependent killing and therefore continuous infusion might have pharmacodynamic advantages. Objectives: To determine the pharmacokinetics of CTX and desacetylcefotaxime (DCTX) in serum, bile and urine during continuous and intermittent infusion when performing liver transplantation. Methods: Fifteen patients undergoing liver transplantation were studied after continuous infusion (CI) (4000 mg iv per 24 h following a loading dose of 1000 mg) and intermittent bolus infusion (BI) (1000 mg iv four times daily). Samples were collected during the first 48 h after liver transplantation. Concentrations of CTX and DCTX were determined by HPLC. Results: During surgery, the mean concentration in serum after CI was 18 mg/L. The lowest serum concentration was 5 mg/L in the CI group and levels were undetectable in the BI group. Target serum concentrations of ≥4 mg/L were reached for 100% of the dosing interval during CI and ∼60% during BI. Post-operatively, the mean concentration in serum after CI was 26 mg/L. The lowest serum concentration was 8 mg/L in the CI group and levels were undetectable after BI. The peroperative pharmacokinetics of CTX in this patient group were deranged and variable, mainly caused by an increased volume of distribution and decreased hepatic clearance. Metabolism was hampered, but DCTX area under the curve (AUC)/CTX AUC ratios varying between 0.7–0.9 were reached peroperatively. Post-operatively, DCTX AUC/CTX AUC ratios were higher (1.1–1.4). Unchanged CTX in bile was ∼0.1% of the administered dose, leading to concentrations >4 mg/L throughout the dosing interval for both regimens. Conclusion: Although an intermittent bolus infusion of CTX 1000 mg produces t > target concentration for 60% of the dosing interval during liver transplantation, serum concentrations may be insufficient during the reperfusion phase. Continuous infusion overcomes this. Post-operatively, CTX clearance is impaired by decreased metabolic clearance and there is substantial accumulation of DCTX. In bile, sufficient concentrations of CTX and its active metabolite are reached with both regimens.

End-stage liver disease caused by chronic hepatitis C viral infection is one of the major indications for liver transplantation. However, evidence for ongoing viral replication can already be found days after surgery and may lead sequentially to lobular hepatitis, chronic active hepatitis, fibrosis and liver cirrhosis. In some patients, this evolution is remarkably fast, most probably enhanced by the immunosuppressive therapy. A minority of patients develop a clinical picture of progressive cholestatic liver disease with histological signs of chronic rejection, which may necessitate retransplantation. While the 1- and 5-year survival rates for all patients transplanted because of hepatitis C virus (HCV)-induced liver cirrhosis are satisfactory, severe complications of disease recurrence are nonetheless expected during the first and second decade after liver transplantation. Larger and preferably randomized studies are needed to investigate whether combination therapy with interferon and ribavirin, preferably initiated as soon as possible after liver transplantation, prevents the fast evolution to cirrhosis without the appearance of chronic rejection and the expected complications of recurrent end-stage HCV-induced liver disease. The final goal should be the inhibition of viral replication even before liver transplantation, but other antiviral strategies should probably be used to attain this goal in patients with decompensated cirrhosis. Although the recurrence of a hepatitis C infection and concomitant disease in the liver graft may cause substantial morbidity, end-stage liver disease and liver failure caused by a chronic hepatitis C infection remain good indications for liver transplantation.

We analyzed the results of passive immunization against CMV in 146 heart transplant recipients. The 65 seronegative recipients were prophylactically treated with anti-CMV immunoglobulins during and after the operation. Twenty-nine of these 65 patients received a seropositive donor heart. CMV infection occurred in 21/65 seronegative and in 40/81 seropositive recipients (difference not significant). The incidence of CMV infection in seronegative recipients of a CMV-matched donor heart (3/34) was significantly lower than in seronegative recipients of a positive donor heart and lower than in seropositive recipients, but no significant difference in infection rate was found between the two latter groups (18/29 vs. 40/81). Although primary infection more frequently resulted in CMV disease than secondary infection (11/21 vs. 10/40) no difference in incidence of disease was noted between seronegative and seropositive patients (11/65 vs. 10/81), nor was there a difference in the severity of symptoms following primary or secondary infection. There was a higher incidence of CMV disease in all patients who received a heart from a seropositive donor versus a seronegative donor. However, after transplantation of a heart from a seropositive donor the incidence (27%) of CMV disease observed in our passively immunized seronegative patients was the same as in the patients with naturally acquired seropositivity. There was no difference in the prevalence of coronary artery disease between patients with and without CMV infection or disease. We conclude that using the current passive immunization scheme the occurrence of CMV infection and disease is largely dependent on the serostatus of the donor.

Summary In ten auxiliary partial liver transplant recipients selective bowel decontamination (SBD) was used to reduce infections due to gram-negative microorganisms and fungi. During SBD no gram-negative infections occurred. Candida peritonitis was observed in one patient. After discontinuation of SBD serious infections of gram-negative origin did occur and three fungal infections were seen. SBD seems to have a favourable effect in reducing infections by gram-negative microorganisms and fungi. Most striking was the number of enterococcal infections that occurred. Five out of ten patients developed enterococcal infections which in two cases contributed to a fatal outcome. These infections occurred after increase of the number of enterococci in faeces and concomitant positive cultures of bile, ascites or wound drains. This increase could be due to the use of SBD. Also, the kind of biliary anastomosis may play an important role in the relatively high incidence of enterococcal infections. In the postoperative period, recurrence of hepatitis B infection in the liver graft was observed in all patients with cirrhosis due to this virus. Problems caused by other viral infections or protozoal infections remained limited in these ten patients.

Summary An assay is described for handling clinical specimens for the detection of cytomegalovirus. It consists of low-speed centrifugation of the specimen on human embryonic lung cells, using a technique adapted from chlamydial culture, followed by detection using a monoclonal antibody against the cytomegalovirus early antigen in an immunofluorescence technique. This assay was compared with the conventional cell culture system. 161 specimens obtained from 52 patients were studied; from 14 patients CMV was isolated in at least one specimen (in total 28 specimens). The centrifugation technique led to positive results generally within 24 to 48 h, whereas the cell culture took an average of 16.5 days to develop the typical cytopathic changes. No cross-reactions between the cytomegalovirus monoclonal antibody and other viruses present (herpes simplex virus and adenovirus) were observed. The centrifugation technique is a reproducible and rapid method in the diagnosis of cytomegalovirus infection.

Administration of di-n-propylacetate (DPA), an inhibitor of SSA-dehydrogenase, produces in naive rats abstinence behaviour which can be blocked by morphine and bicuculline and may be useful as a behavioural correlate of increased GABA-ergic activity. The usefulness of this model has been demonstrated by studying the effec of bicuculline, picrotoxin, strychnine, morphine, aminooxyacetic acid, 3-mercaptopropionate and thiosemicarbazide on DPA-induced abstinence behaviour. Behaviour was suppressed both by bicuculline or picrotoxin, while the selective glycine antagonist strychnine was ineffective. A comparable syndrome could not be evoked by treatment with aminooxyacetic acid, a GABA-transaminase inhibitor, indicating that the effect of DPA was not caused by inhibition of this enzyme. Instead, aminooxyacetic acid suppressed the DPA-induced abstinence behaviour, suggesting that two GABA-ergic systems with opposite effects on behaviour can be distinguished. The syndrome was also suppressed by convulsant doses of 3-mercaptopropionate, while thiosemicarbazide was ineffective. Abstinence behaviour was further suppressed by morphine with an ED50 of 0.5 mg/kg and this action could be clearly separated from its depressant effect on locomotor activity in non-treated animals. These results suggest that morphine receptors may be involved in DPA-induced abstinence behaviour. Based on these experiments a model has been proposed for GABA-ergic terminals being under the inhibitory influence of GABA-ergic autoreceptors. It is proposed that DPA-induced abstinence behaviour may be useful as a model of increased GABA-ergic activity to aid study of the regulation and properties of the GABA-ergic system in vivo.

The release of heparin has been mentioned as one of the causes of hypocoagulability after reperfusion of the liver graft. It has been ascribed to endogenous heparin released from the donor liver or to exogenous heparin in the preservation fluid that is released into the recipient after sequestration into the graft during preservation. The aim of this study was to investigate whether systemic administration of heparin to the donor before the hepatectomy contributes to the appearance of heparin in the recipient after reperfusion. We studied 20 patients undergoing an auxiliary heterotopic liver transplantation; 15 donors had received heparin immediately before circulation arrest (median 300 IU/kg body weight), but 5 had not. The thrombin time (TT),activated partial thromboplastin time (aPTT), and heparin neutralization test were determined at several intervals during the transplantation.

In this paper, deposition of Multi-Walled Carbon Nanotube (MWCNT) on Poly-Tetra-Fluoro-Ethylene (PTFE) layer is studied for the purpose of gas sensing. Previously, Platinized Carbon (Pt/C) for sensor application was successfully deposited on thin PTFE layer, but it was difficult to deposit MWCNT on PTFE based on the same method. Three methods including changing anode (copper instead of steel), changing solvent (mixture of ethanol and acetone instead of isopropanol) and using a conductive PTFE layer were used to perform successful deposition. Stability of CNT in solvents and the possible mechanism for deposition were investigated. Finally, the function of PTFE/CNT coated layers in the working electrode of an oxygen gas sensor produced by three different Electrophoretic Deposition (EPD) routes were studied.

The major cause of increased tissue‐type plasminogen activator (t‐PA) activity during orthotopic liver transplantation (OLT) is still unclear. Both lack of hepatic clearance of t‐PA in the anhepatic period and/or increased endothelial release from the graft upon reperfusion have been suggested. Heterotopic liver transplantation (HLT) avoids resection of the host liver and is therefore a useful model to differentiate these two possibilities. The fibrinolytic system was evaluated in ten patients with OLT and in 18 patients with HLT. A marked increment in t‐PA activity was observed during the anhepatic period of OLT, which rapidly normalized after reperfusion. In contrast t‐PA activity levels remained normal in HLT. As a reflection of the increased t‐PA activity fibrin degradation products were markedly elevated during OLT and plasminogen and α2‐antiplasmin decreased simultaneously during the anhepatic period. In conclusion, the lack of hepatic clearance during the anhepatic period is the most important factor in the evolution of increased t‐PA activity during OLT.

In a double-blind placebo-controlled study, the value of prophylactic anti-CMV immunoglobulin administration was evaluated in 39 kidney transplant recipients treated for rejection with rabbit antithymocyte globulin. Passive immunization completely prevented CMV-related death, although it did not reduce the incidence of CMV isolation, viremia, or disease.

Cytomegalovirus (CMV) infections remain a major clinical problem after renal transplantation. Reported incidences of CMV disease range from 17 to 25% in patients with azathioprine treatment and from 2 to 23% in patients on cydosporin A. CMV-related death occurs in 1–3% of the total kidney transplant population. CMV seronegative kidney recipients of a transplant from a seropositive donor are especially at risk for primary infection as CMV can be transmitted by the transplant. In patients treated with antilymphocyte globulin (ALG) preparations for rejection, CMV disease is diagnosed three to four times more frequent than in patients without ALG therapy. Prevention of CMV infection is possible by selecting CMV seronegative donors for seronegative recipients. Active and passive immunization does not prevent CMV infection after renal transplantation, but immunoprophylaxis may result in less severe CMV disease. Effective treatment of clinical overt CMV disease is possible with the new guanine analogue ganciclovir. However, the use of this drug is associated with neutropenia, especially in patients with compromised kidney function. More pharmacokinetic data are needed to determine optimal dosing schemes.