Ferdinand Mühlbacher

3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome

BACKGROUND Mortality after liver transplantation depends on heterogeneous recipient and donor factors. Our aim was to assess risk of death and to develop models to help predict mortality after liver transplantation. METHODS We analysed data from 34,664 first adult liver transplants from the European Liver Transplant Registry to identify factors associated with mortality at 3-months (n=21,605 in training dataset) and 12-months (n=18,852 in training dataset) after transplantation. We used multivariable logistic regression models to generate mortality scores for each individual, and assessed model discrimination and calibration on an independent validation dataset (n=9489 for 3-month model and n=8313 for 12-month model). FINDINGS 2540 of 21,605 (12%) individuals in the 3-month training sample had died by 3 months. Compared with those transplanted in 2000-03, those transplanted earlier had a higher risk of death. Increased mortality at 3-months post-transplantation was associated with acute liver failure (adjusted odds ratio 1.61), donor age older than 60 years (1.16), compatible (1.22) or incompatible (2.07) donor-recipient blood group, older recipient age (1.12 per 5 years), split or reduced graft (1.96), total ischaemia time of longer than 13 h (1.38), and low United Network for Organ Sharing score (score 1: 2.43; score 2: 1.67). However, cirrhosis with hepatocellular carcinoma, alcohol cirrhosis, hepatitis C or primary biliary cirrhosis, donor age 40 years or younger, or less, hepatitis B, and larger size of transplant centre (> or = 70 transplants per year) were associated with improved early outcomes. The 3-month mortality score discriminated well between those who did and did not die in the validation sample (C statistic=0.688). We noted similar findings for 12-month mortality, although deaths were generally underestimated at this timepoint. INTERPRETATION The 3-month and 12-month mortality models can be effectively used to assess outcomes both within and between centres. Furthermore, the models provide a means of assessing the risk of post-transplantation mortality, giving clinicians important data on which to base strategic decisions about transplant policy in particular individuals or groups.

Preservation solutions for transplantation

Eurocollins has almost been abandoned because of the glucose disadvantage. UW is certainly the most used preservation solution for livers, kidneys, and pancreases with excellent clinical and experimental preservation data. UW can certainly be considered the current golden standard solution. However, the disadvantage of high viscosity, high price, uneasy handling of many 1-L bags, and the fact that the radical scavenger glutathion cannot be detected in the bags by chemical analysis (presumably due to diffusion) encourage competitors to produce new compounds with better cost to effect ratios. HTK has a firm place in cardiac preservation; by demonstration of equal safety and efficacy in preserving livers and kidneys, at least in the middle and lower range of cold ischemia time, HTK will be sued more frequently, particularly with the consideration of lower price and more easy handling aspects. The suggested high volume perfusion is not really necessary, calculation based on a total volume of 10 L for a multiorgan donor show significant cost reductions. Celsior is current only used for cardiac preservation. Beyond all aspects of conservation and preservation potencies of all these fluids, it must not be forgotten that cold ischemia itself is a risk factor for organ function. Therefore, cold ischemia time should be kept as short as possible. People are willing to accept 24 hours or more cold ischemia time in kidney transplantation because organ failure can be treated by dialysis. In other organs, where immediate organ function is essential, like in clinical heart transplantation, cold ischemia is hardly ever extended beyond 6 hours. Why are hearts and kidneys so different? Very likely, there is no difference, and the outstanding results in living unrelated kidney transplants is mostly due to short cold ischemia time.

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.

Current value of intraoperative sonography during surgery for hepatic neoplasms

Noninvasive liver imaging has developed rapidly resulting in increased accuracy for detecting primary and secondary hepatic tumors. Intraoperative ultrasonography (IOUS) was commonly considered to be the gold standard for liver staging, but the current value of IOUS is unknown in view of more sophisticated radiologic tools. The purpose of this prospective study was to evaluate the impact of IOUS on the treatment of 149 patients undergoing liver surgery for malignant disease (colorectal metastasis, 61 patients; hepatoma, 52 patients; other hepatic malignant tumors, 36 patients). The sensitivities of computed tomography (CT), helical CT, magnetic resonance imaging, and IOUS in patients with colorectal metastases were 69.2%, 82.5%, 84.9%, and 95.2% in a segment-by-segment analysis; in patients with hepatoma their sensitivities were 76.9%, 90.9%, 93.0%, and 99.3%; and in patients with other hepatic malignancies they were 66.7%, 89.6%, 93.3%, and 98.9%, respectively. Additional malignant lesions (AMLs) were first detected by inspection and palpation in 20 patients (13.4%). In another 18 patients (12.1%) IOUS revealed at least one AML. Overall, the findings obtained only by IOUS changed the surgical strategy in 34 cases (22.8%). It was concluded that IOUS, having undergone some refinement as well, still has immense diagnostic value in hepatectomy candidates. Frequently avoiding palliative liver resection and occasionally disproving unresectability as assessed by preoperative imaging, IOUS still has a significant impact on surgical decision making and should still be considered the gold standard.RésuméOn a récemment assisté à une amélioration importante dans la précision de la détection des tumeurs primitives et secondaires du foie par l’imagerie non-invasive. L’échographie peropératoire (EPO) a été considérée comme l’examen de référence («gold standard») dans le Staging du foie, mais la valeur de l’EPO est discutée à présent en raison de l’apparition d’investigations radiologiques plus sophistiquées. Le but de cette étude prospective a été d’évaluer l’impacte de l’EPO au cours d’une résection hépatique pour maladie maligne chez 149 patients (métastases d’origine colorectale: 61 patients; carcinome hépatocellulaire: 52 patients; autres tumeurs hépatiques malignes: 36 patients). Chez les patients ayant des métastases d’origine colorectale, la sensibilité de la tomodensitométrie simple (TDM), de la tomodensitométrie hélicoïdale (TDMh), de la résonance magnétique (RM) et l’EPO a été de 69.2%, 82.5%, 84.9% et 95.2% dans une analyse du foie segment par segment. Chez les patients porteurs de carcinome hépatocellulaire, la sensibilité de ces différentes méthodes était, respectivement, de 76.9%, 90.9%, 93% et 99.3%; chez les patients ayant d’autres tumeurs malignes du foie, la sensibilité était, respectivement, de 66.7%, 89.6%, 93.3% et 98.9%. D’autres lésions malignes ont été détectées à l’inspection et à la palpation chez 20 patients (13.4%). De plus, chez 18 autres patients (12.1%), l’EPO a décelé au moins une lésion maligne supplémentaire. Globalement, les données obtenues par l’EPO ont changé la stratégie chirurgicale dans 34 cas (22.8%). On conclue que l’EPO, grâce à quelques raffinements, a toujours une immense valeur diagnostique pour les candidats à l’hépatectomie. En évitant à certains patients une résection palliative, et en permettant, de temps à autre, une résection jugée impossible par les investigations préopératoires, l’EPO garde un impacte significatif sur la décision chirurgicale et devrait continuer à être le «gold standard».ResumenEl rápido desarrollo de los métodos no invasivos ha conferido una mayor precisión diagnóstica de los tumores hepáticos tanto primarios como secundarios. La ecografÍa intraoperatoria (IOUS) se consideró como el mejor método diagnóstico para la estadificación hepática, pero en la actualidad, su valor está en entredicho ante los nuevos y sofisticados estudios radiológicos. El objetivo de este estudio prospectivo fue evaluar el valor de la IOUS en el tratamiento quirúrgico de 149 pacientes con neoplasias malignas de hÍgado (metástasis colorrectales n=61; hepatomas n=52; otros tumores hepáticos malignos n=36). El análisis secuencial segmentario demostró en pacientes con metástasis colorrectales una sensibilidad para la tomografÍa axial o helicoidal computarizada (CT y hCT) del 69.2% y 82.5%, para la resonancia magnética nuclear (MR) del 84.9% y para la IOUS del 95.2%. En pacientes con hepatomas la sensibilidad de estos métodos fue del 76.9%, 90.9%, 93% y 98.9%. En 20 pacientes (13.4%) lesiones malignas adicionales (AML) se diagnosticaron por inspección y palpación. En otros 18 pacientes (12.1%) la IOUS fue capaz de detectar al menos una AML. En 34 casos (22.8%) el conjunto de hallazgos obtenidos exclusivamente con la IOUS propició un cambio de estrategia quirúrgica. En conclusión, la IOUS, con sus recientes mejoras, sigue teniendo un inmenso valor diagnóstico para aquellos que son candidatos a una hepatectomÍa. Previene, con frecuencia, las resecciones hepáticas paliativas y, ocasionalmente, contradice el diagnóstico de irresecabilidad obtenido con otros medios diagnósticos. La IOUS sigue teniendo un importante valor a la hora de establecer una decisión quirúrgica y continúa siendo el mejor método diagnóstico.

Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver

BACKGROUND/AIMS Thrombocytopenia secondary to cirrhosis of the liver and portal hypertension is a well-known complication of advanced stage liver disease, but theories about the underlying pathogenetic mechanisms, mostly centering on splenic sequestration and destruction of platelets, have failed to solve the problem so far. METHODS Peripheral platelet count and thrombopoietin levels in human plasma were measured in 28 patients with cirrhosis of the liver. Seven of those patients underwent orthotopic liver transplantation and five patients portal decompression by transjugular intrahepatic portosystemic shunt. Thrombopoietin plasma levels were followed for 14 days after the interventions. RESULTS No measurable thrombopoietin was detectable in the plasma of 28 thrombocytopenic patients with cirrhosis of the liver, in contrast to thrombocytopenic patients without liver disease. Seven of these patients with cirrhosis underwent orthotopic liver transplantation, resulting in a rise of thrombopoietin levels within 2 days after transplantation. The rise in platelet number followed with a mean lag of 6 days, and shortly thereafter, thrombopoietin levels returned to levels below the limit of detection. Five patients with thrombocytopenia, who underwent only decompression of portal hypertension, showed no rise in either thrombopoietin levels or platelet count. CONCLUSIONS Thrombocytopenia associated with liver disease may at least in part be attributable to inadequate thrombopoietin production in the failing liver.

Efficacy of liver transplantation for alcoholic cirrhosis with respect to recidivism and compliance.

Many transplant centers are reluctant to accept alcoholic patients for OLT because of their supposed potential for alcoholic recidivism and poor compliance with the required immunosuppressive regimen, both of which result in graft failure. Only inconclusive data related to these arguments are available. From May 1982 to January 1993, 58 patients received OLT at our institution for end-stage cirrhosis, where alcohol was the only toxic component. The indication for OLT in these patients was considered with particular attention to recidivism and compliance. Overall survival in this group was 71% and 63% at 1 and 5 years, respectively, with an average survival time of 78 months. Actuarial survival of patients transplanted since January 1989 (n = 37) was 86% and 83% at 1 and 2 years (average survival 42 months). Nonfatal clinical endpoints were analyzed in those patients surviving at least 3 months (n = 44). Return to alcohol abuse has been documented in 14 persons at routine short-term outpatient checkups. The estimated risk for alcoholic recidivism amounts to 31%, with a median follow-up of 33 months. Compliance with immunosuppressive regimen was expressed as a dependent value of acute rejection episodes (0.3 per patient, median follow-up 33 months), chronic rejection (occurred in none of the patients), and measurements of CsA HPLC blood trough level (92.2% within the target range). The preversus postoperative improvement of employment, marital, and social status after OLT showed a statistically significant difference. Unwillingness to offer OLT to individuals with alcoholic liver disease because of failure to demonstrate 100% long-term abstinence appears difficult to defend in the face of good results in survival, compliance, and social rehabilitation.

Genome-wide gene-expression patterns of donor kidney biopsies distinguish primary allograft function.

Roughly 25% of cadaveric, but rarely living donor renal transplant recipients, develop postischemic acute renal failure, which is a main risk factor for reduced long-term allograft survival. An accurate prediction of recipients at risk for ARF is not possible on the basis of donor kidney morphology or donor/recipient demographics. We determined the genome-wide gene-expression pattern using cDNA microarrays in three groups of 36 donor kidney wedge biopsies: living donor kidneys with primary function, cadaveric donor kidneys with primary function and cadaveric donor kidneys with biopsy proven acute renal failure. The descriptive genes were characterized in gene ontology terms to determine their functional role. The validation of microarray experiments was performed by real-time PCR. We retrieved 132 genes after maxT adjustment for multiple testing that significantly separated living from cadaveric kidneys, and 48 genes that classified the donor kidneys according to their post-transplant course. The main functional roles of these genes are cell communication, apoptosis and inflammation. In particular, members of the complement cascade were activated in cadaveric, but not in living donor kidneys. Thus, suppression of inflammation in the cadaveric donor might be a cheap and promising intervention for postischemic acute renal failure.

12‐month follow‐up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

The LIS2T study was an open‐label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA‐ME) (Neoral) (n = 250) (monitoring of blood concentration at 2 hours postdose) C2 or tacrolimus (n = 245) (monitoring of trough drug blood level [predose]) C0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA‐ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased‐ and living‐donor recipients. Significantly fewer hepatitis C–positive patients died or lost their graft by 12 months with CsA‐ME (5/88, 6%) than with tacrolimus (14/85, 16%) (P < 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA‐ME (100 ± 50 days) than with tacrolimus (70 ± 40 days) (P < 0.05). Median serum creatinine at 12 months was 106 μmol/L with CsA‐ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months (13% vs. 5%, P < 0.01). Of patients who were diabetic at baseline, more tacrolimus‐treated individuals required anti‐diabetic treatment at 12 months (70% vs. 49%, P = 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA‐ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline. Liver Transpl 12:1464–1472, 2006.

Early Basal Insulin Therapy Decreases New-Onset Diabetes after Renal Transplantation

No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better β-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of β cells.

Arginase release following liver reperfusion : evidence of hemodynamic action of arginase infusions

Immediately after hepatic reperfusion in human or-thotopic liver transplantation, high amounts of arginase are released from the graft, thereby influencing nitric oxide metabolism. This metabolic alteration may be one component of the ischemia-reperfusion syndrome in OLT with its hemodynamic disturbances (e.g., systemic hypotension, pulmonary hypertension). The aim of this study was to compare hemodynamic and metabolic changes following OLT in the pigs with those obtained under arginase infusions in catheterized, anesthetized pigs. Following liver revascularization in the pigs, plasma arginase concentrations increased from 48±19 IU/L to 2613 ±944 IU/L, resulting in a drop in plasma levels of L-arginine (-87%) and in a drop in nitrite (-82%) and nitrate (-53%) concentrations. Of the measured organspecific hemodynamic alterations, the mean pulmonary arterial pressure increased from 17±2 mmHg to 30±5 mmHg, whereas the flow/pressure index of the portal vein decreased about 60%. A primed continuous infusion of arginase (25,000 IU) increased plasma arginase levels to a maximum of 3,690±962 IU and evoked a decrease of L-arginine, but did not alter plasma nitrite or nitrate levels. The administration of arginase in healthy pigs did not influence cardiac output, mean arterial pressure, heart rate, or total peripheral resistance, but led to an increase of mean pulmonary arterial pressure from 19±3 to 48±5 mmHg and to a reduction of arterial hepatic blood flow from 229±65 ml/min to 154±41 ml/min. From this we conclude that high levels of liver arginase cause hemodynamic alterations in the lung and the liver. We hypothesize that the pulmonary hypertension and the reduced hepatic blood flow found during the immediate reperfusion period after OLT are possibly related to the increased arginase release due to the hepatic damage of the graft.