Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation.

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Sorafenib treatment for recurrent hepatocellular carcinoma after liver transplantation.

BACKGROUND: With an increasing number of patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (OLT), HCC recurrence remains the main limiting factor for long-term survival. We herein report our experience with sorafenib treatment for HCC recurrence post-OLT. PATIENTS AND METHODS: We reviewed data on transplanted HCC patients receiving sorafenib for HCC recurrence. RESULTS: Fourteen patients were included for the period November 2006 to February 2011. There were 9 men and 5 women of median age of 57 years. Twelve patients (86%) received rescue grafts through Eurotransplant allocation. Median values for alpha fetoprotein levels, Model for End-Stage Liver Disease score, sorafenib daily dose, and length of treatment were 97 ng/mL, 10, 400 mg, and 6.5 months, respectively. Sorafenib side effects led to discontinuation (n = 4) or reduction (n = 2) of the daily dose. Four patients experienced tumor progression during treatment. Seven patients are currently alive, 3 patients died of tumor progression, and 4 patients of non-tumor-related causes of death. Median survival was 25 months. CONCLUSION: Sorafenib treatment for HCC recurrence in transplant recipients represents a challenging oncologic approach that requires further validation in prospective, multicenter studies.

Combined mycophenolate mofetil and minimal dose calcineurin inhibitor therapy in liver transplant patients: clinical results of a prospective randomized study.

BACKGROUND: Long-term complications of calcineurin inhibitor (CNI)-based immunosuppression after liver transplantation (LT) have a marked impact on patient morbidity and mortality. METHODS: In this prospective study, LT patients with renal dysfunction were randomized (2:1) to either receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI trough levels (MMF group) or to continue their maintenance CNI dose (control group). RESULTS: In the MMF group (n = 60), renal function assessed by serum creatinine improved >10% in 67% of patients, was stable in 32%, and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (+/-SD) significantly decreased from 1.86 +/- 0.43 to 1.55 +/- 0.38 mg/dL and the corresponding calculated glomerular filtration rate (cGFR) significantly increased from 39.9 +/- 10.1 to 49.2 +/- 11.9 mL/min over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased, and no allograft rejection occurred. In the control group (n = 30), there were no significant changes in mean serum creatinine and cGFR (1.78 +/- 0.59 mg/dL at baseline vs 1.93 +/- 0.86 mg/dL at month 12, and 41.3 +/- 13.2 mL/min vs 38.7 +/- 11.2 mL/min, respectively), liver enzymes and blood pressure throughout the study. CONCLUSIONS: Combined MMF and minimal dose CNI therapy after LT is safe, and improves kidney function and the cardiovascular risk profile.

Recurrent giant biloma following deceased donor split liver transplantation.

Biliary complications remain a substantial cause of morbidity following liver transplantation (LT), with a reported incidence of 10-15% after full-size LT, and even higher after living donor, split, and reduced size LT. We report herein the case of a patient with a recurrent giant biloma following deceased donor split LT, which despite its volume was treated conservatively.

Clinical trial: switch to combined mycophenolate mofetil and minimal dose calcineurin inhibitor in stable liver transplant patients--assessment of renal and allograft function, cardiovascular risk factors and immune monitoring.

BACKGROUND: Calcineurin inhibitor (CNI)-related nephrotoxicity significantly contributes to chronic renal failure after liver transplantation. METHODS: In this prospective study, liver transplantation patients with renal dysfunction were randomized either to receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI-trough levels (MMF group), or to continue their maintenance CNI dose (control group). Immune monitoring was performed in a subgroup of the patients. RESULTS: In the MMF group (n = 50), renal function assessed by serum creatinine improved >10% in 62% of patients, was stable in 36% and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (+/- s.d.) significantly decreased from 1.90 +/- 0.44 mg/dL to 1.61 +/- 0.39 mg/dL and the corresponding calculated glomerular filtration rate significantly increased from 38.8 +/- 9.6 mL/min/1.73 m(2) to 47.0 +/- 11.8 mL/min/1.73 m(2) over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased. In the control group (n = 25), there were no significant changes with respect to the investigated parameters. The MMF group had significantly lower numbers of circulating cytotoxic T cells compared with the controls; whereas regulatory T cells significantly increased. CONCLUSION: Combined MMF and minimal dose CNI therapy after liver transplantation is nephroprotective and may promote allograft tolerance.

Ribavirin with either standard or pegylated interferon to treat recurrent hepatitis C after liver transplantation.

AIM: To investigate the efficacy of two anti-viral protocols in hepatitis C virus-reinfected liver transplant recipients. METHODS: In this prospective study, 26 liver transplant patients were treated with standard interferon-alpha2b for 12 months or standard interferon-alpha2b for 3 months followed by pegylated interferon-alpha2b for 9 months. Interferon was combined with ribavirin in all patients. The histological course of the study population was compared with an untreated historic control group (n = 38) with similar baseline characteristics. RESULTS: The sustained virological response rates in the standard interferon group and in the pegylated interferon group were 27.3% and 26.7%, respectively. Only 29% of patients with sustained virological response had end of treatment histological response, whereas 47% of viral non-responders showed end of treatment histological response. The percentage of patients with histological improvement was significantly higher in the study population when compared to the controls. Univariate analysis indicated that hepatitis C virus genotype non-1, high baseline alanine aminotransferase, the time interval between liver transplant and interferon therapy and the body mass index predicted sustained virological response. In the multivariate model, baseline alanine aminotransferase and the body mass index remained a significant predictor of sustained virological response. CONCLUSIONS: Both treatment regimens offer similar efficacy profiles. Failure to eradicate hepatitis C virus should not lead to treatment discontinuation if serial liver biopsies demonstrate histological response.

Long-term response of primary biliary cirrhosis (stage I) to therapy with ursodeoxycholic acid.

We report about a 56-year-old asymptomatic female patient, who was examined in April 1991 for an increase of biochemical parameters of the liver. Based on the biochemical and serological results (abnormal cholestatic liver function tests, positive antimitochondrial antibodies) as well as liver biopsy primary biliary cirrhosis stage I was diagnosed. Therapy with ursodeoxycholic acid (12mg/kg body-weight/die) was started. Follow-up examinations indicated that cholestatic parameters had normalized and antimitochondrial antibodies became negative. In a further biopsy of the liver nearly regular liver parenchyma was demonstrated. Thus, therapy with ursodeoxycholic acid was stopped. However, in November 1992 cholestatic parameters increased again and, antimitochondrial antibodies recurred (subtype anti-M9: positive) without any clinical symptoms. Ursodeoxycholic acid therapy was reintroduced again. Within 3 months cholestatic parameters returned to normal and antimitochondrial antibodies were eliminated again. Since then ursodeoxycholic acid has been given continuously and a long-term remission as defined by clinical, serological and histological criteria could be maintained until today. This case report indicates a serological remission and a marked histological improvement in a female patient with an early stage of primary biliary cirrhosis (stage I) during therapy under ursodeoxycholic acid. It has to be discussed whether certain early stages of primary biliary cirrhosis with benign antimitochondrial antibody-profile (anti-M9: positive) respond well to long-term treatment with ursodeoxycholic acid.

Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: preliminary results of an open prospective study.

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI (n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose (n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 +/- 0.36 versus 1.58 +/- 0.33 mg/dL, P < .001) and BUN (39.2 +/- 11.8 versus 29.9 +/- 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 +/- 10.8 versus 61.6 +/- 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 +/- 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 +/- 19 versus 130 +/- 14 mm Hg, P < .01) and diastolic (82 +/- 9 to 74 +/- 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 +/- 25.9 versus 25.2 +/- 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.

[The effect of alcohol on portal vein hemodynamics in nutritional-toxic liver cirrhosis]. / Einfluss von Alkohol auf die Hämodynamik der Pfortader bei nutritiv-toxischer Leberzirrhose.

The influence of alcohol on portal vein haemodynamics was assessed prospectively in 30 patients (20 men, 10 women; mean age 54.3 [34-70] years) with nutritional-toxic cirrhosis of the liver (Child-Pugh stages A-C) and portal vein hypertension. During the period of observation hepatic vein occlusion pressure as an indirect measure of portal vein pressure was repeatedly determined. In addition, the size of oesophageal varices and the Child-Pugh stage were monitored. After complete alcohol abstinence of one year, portal vein pressure fell from 23.11 to 12.43 mm Hg (-46%, P < 0.001), the Child-Pugh score from 8.08 to 7.2 (-10.9%, not significant), and the size of oesophageal varices was reduced from grade 1.33 to grade 0.79 (-40%, P < 0.02). On resuming alcohol abuse, portal vein pressure increased by an average of 10 mm Hg (+60%, P < 0.001) to its previous level of 25 mm Hg. The portal vein pressure has thus proved to be a sensitive gauge of alcohol abstinence or abuse. Lasting, absolute alcohol abstinence is essential in nutritional-toxic liver cirrhosis.