Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

YKL-40-gene polymorphism affects acute cellular rejection and fibrosis progression after transplantation for hepatitis C virus-induced liver disease.

BACKGROUND AND AIM: The development of end-stage graft disease is suspected to be partially determined by an individual genetic background. The aim of our study was to determine the prevalence of YKL-40-gene polymorphism in hepatitis C virus (HCV)-positive patients and its impact on the incidence of acute cellular rejection (ACR), graft fibrosis and antiviral treatment response. METHODS: A total of 149 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for YKL-40 (rs4950928; G/C) by TaqMan Genotyping Assay. The results were correlated with 616 post-transplant graft biopsies regarding inflammation, fibrosis and evidence for ACR. RESULTS: No association of YKL-40-genotypes was observed regarding mean inflammation grade (P = 0.216) and antiviral treatment outcome (P = 0.733). However, the development of advanced fibrosis (F3-4) was significantly faster in patients with YKL-40-G-allele: t(CC) = 4.6 versus t(CG/GG) = 2.4 years; P = 0.006. Patients with lower fibrosis (F0-2) compared to advanced fibrosis (F3-4) received significantly more frequent dual immunosuppression (calcineurin inhibitors [CNIs]/mofetile mycophenolate [MMF] vs CNIs; P = 0.003). ACR-occurrence was associated with YKL-40-genotypes (ACR: CC = 60.4%, CG = 25.0% and GG = 14.6% vs non-ACR: CC = 74.2%, CG = 23.8% and GG = 2.0%; P = 0.009) and with gender compatibility between donor and recipient (P = 0.012). CONCLUSION: Fibrosis progression and ACR-incidence after transplantation for HCV-induced liver disease seem to be under genetic control. The negative impact of G-allele on post-transplant events observed in our study, deserves attention and should be verified in larger liver transplantation-cohorts.

Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial.

BACKGROUND: Calcineurin inhibitors (CNIs) play the key role in immunosuppressive protocols yet are often associated with numerous side effects. Renal insufficiency, hypertension, hyperglycemia, and increased risk of secondary malignancy are major problems in short- and long-term follow-up of liver transplant patients. Mycophenolate mofetil (MMF) has proved to be a potent immunosuppressive agent free of the CNI-associated side effects. PATIENTS AND METHODS: One hundred fifty patients who received liver transplantation at our institution (1998-2003) were prospectively randomized: 75 patients continued CNI standard therapy, 75 patients were switched to MMF monotherapy, and follow-up was 5 years. Incidence of rejection, renal complication, cardiovascular, neurological and gastrointestinal adverse effects, and diabetes and malignancy development was recorded. Graft biopsies were performed every 2 to 3 years. RESULTS: No significant difference regarding the incidence of acute rejection was detected. A trend to higher rejection frequency was apparent in the MMF monotherapy group. Chronic rejection was absent; organ and patient survival were identical in the two groups. No significant difference occurred concerning the incidence of cardiovascular, gastrointestinal or neurological adverse effects, or the development of malignancies. Renal function improved significantly in patients with renal insufficiency when patients treated with CNI were switched to MMF monotherapy. CONCLUSION: MMF monotherapy may serve as safe long-term immunosuppression after liver transplantation for a subgroup of patients. Especially for patients with renal insufficiency MMF offers immunosuppression without the risk of nephrotoxicity.

Influence of basiliximab induction therapy on long term outcome after liver transplantation, a prospectively randomised trial.

BACKGROUND: In OLT induction therapy with interleukin-2-receptor antibodies is often applied as part of the standard immunosuppression protocol. It was the aim of this study to determine if Basilixirnab mduction therapy serves to reduce the incidence of acute rejection episodes and improves graft function and survival in the long term after OLT. MATERIAL/METHODS: We prospectively analysed 99 patients transplanted at our institution (1997-2000). Patients were randomised to two study groups: 51 patients received Basiliximab induction combined with Calcineurin inhibitors and steroids, 48 patients received CNIs and steroids only. Incidence and severity of rejection, graft and patient survival and intensity of long-term immunosuppression were analysed. Frequency of CNI and steroid induced adverse effects were recorded. RESULTS: In our patient collective we could not detect a significant impact of Basiliximab induction therapy on the fre queny of acute or chronic rejection. CNI levels were almost identical in both groups; graft and patient survival rates were not influenced by the application of induction therapy. CONCLUSIONS: In our patient collective induction therapy does not have a general positive influence on the post transplant course. A slight improvement in long term renal function could be detected for Basiliximab treated patients.

Peginterferon alfa-2b plus ribavirin for the treatment of hepatitis C recurrence following combined liver and kidney transplantation.

BACKGROUND: Several studies have demonstrated safety and efficacy of treatment protocols using pegylated interferon alfa-2b (PegIntron) and ribavirin in hepatitis C (HCV) recurrence and liver transplantation but no data exists about antiviral treatment following combined liver and kidney transplantation. PATIENTS: Six patients with recurrent HCV (genotype 1 [n = 5] and 4 [n = 1]) received peginter-feron alfa-2b (1 ug/kg/weekly) and ribavirin (600 mg) for 48 weeks. Sustained virologic response was defined as undetectable HCV-RNA 24 weeks after termination of therapy. All patients underwent liver biopsies prior to treatment and after 72 weeks and liver enzymes (ASAT) and serum creatinine levels were obtained regularly. RESULTS: In 4/6 patients, viral load prior to treatment was below 1,000,000 (IU/mL). SVR was achieved in 3/6 (50%) patients. None of the patients developed signs of deteriorating kidney function or rejection. One patient without SVR had HCV related liver graft failure and died 13 months later. Side effects like neutropenia (50%) and anemia (50%) were treated with G-CSF, erythropoietin, and dose reduction of peginterferon and ribavirin. CONCLUSIONS: In a small group of patients with combined kidney and liver transplantation, peginterferon-alfa2b is safe and effective to achieve SVR in HCV recurrence. Larger scale studies are warranted to further validate our results.