Preemptive antiviral treatment for hepatitis C virus after living donor liver transplantation

Background

Recurrence following liver transplantation for hepatitis C virus (HCV), which is universal, affects long-term outcomes. Treatment with interferon (IFN) and ribavirin (RBV), the only widely available options at this time, have been faced with low tolerability and overall unsatisfactory results in deceased donor liver transplantation (DDLT). However, its place after living donor liver transplantation (LDLT) remains a matter of debate. Since most LDLT cases are performed in a planned manner at a lower Model for End-stage Liver Disease (MELD) score compared to DDLT, we have aggressively applied preemptive INF/RBV in our series.

Patients and methods

We studied 122 adult recipients who underwent LDLT for HCV-related end-stage liver disease. The preemptive IFN/RBV protocol initiated treatment promptly after improvement in the patient's general condition with a low-dose IFN alpha2b and RBV (400 mg/d) followed by a gradual increase in the INFalpha2b dosage. Finally, we applied pegylated IFN (1.5 ug/kg/wk) and RBV (800 mg/d). The treatment was continued for 12 months after serum HCV-RNA became negative, which was defined as the end-of-treatment response (ETR). The response was considered to be a sustained viral response (SVR) if there were negative serologic results without antiviral treatment for another 6 months. Splenectomy was performed at the time of LDLT to improve tolerability to INF/RBV. The median age of the patients was 55 yrs (range = 23-66), with male dominance (87 males and 35 females). Median MELD score was 14 (range = 6-48). The series included 72 patients with hepatocellular carcinomas, and six with HIV coinfections. In 98 cases, HCV genotype was 1b.

Results

Overall survival at 5 years was 79%. Cumulative response rates under the protocol were ETR 56% and SVR 44% at 5 years.

Conclusions

Preemptive IFN/RBV therapy after LDLT for HCV is feasible with acceptable outcomes.     

Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C

Background

Antiviral therapy has achieved sustained virological response (SVR) in less than one third of orthotopic liver transplantation (OLT) patients with recurrent hepatitis C.

Aim

The aim of this study was to identify predictors of SVR in OLT patients treated with pegylated interferon and ribavirin (PEG+RBV) for recurrent hepatitis C virus (HCV).

Methods

We analyzed data from our transplantation database for 62 subjects treated with PEG+RBV between August 2001 and September 2008. After univariate examination for factors known to be associated with SVR, significant associations (P < .05) were probed using multivariate logistic regression. Kaplan-Meier patient and graft survival analyses were compared between patients with (n = 19; 30.6%) versus without SVR.

Results

On univariate analysis, longer duration of therapy, low pretreatment HCV RNA (<1 million IU/mL), and early virological response (EVR) were associated with SVR. On multivariate analysis, only low pretreatment HCV RNA predicted SVR. Patient survival was significantly higher in the SVR group.

Conclusions

Covariates associated with SVR among OLT patients with recurrent HCV were similar to the pretransplantation group. Potentially modifiable risk factors, such as obesity, diabetes mellitus, and metabolic syndrome, were not significant predictors of treatment response. Patient survival was associated with SVR, highlighting the impact of successful HCV therapy on long-term post-OLT outcomes.     

Mycophenolate Mofetil Monotherapy in Patients Who Underwent Liver Transplantation for Hepatitis C Cirrhosis

Introduction

Mycophenolate mofetil (MMF) monotherapy has recently been proposed for liver transplant recipients with adverse events (nephrotoxicity, hypertension) related to calcineurin inhibitors. We analyzed the influence of MMF on the clinical course of recurrent hepatitis C.

Methods

Among 1038 patients who underwent liver transplantation (OLT) from April 1986 to October 2006, we analyzed 48 adult recipients (4.6%) whose diagnosis was hepatitis C virus (HCV) cirrhosis and who were converted from calcineurin inhibitors to MMF monotherapy.

Results

The 36 men and 12 women, had a mean age at OLT of 52.9 ± 7.2 years; the time elapsed from OLT to the onset of MMF monotherapy was 72.5 ± 47.6 months (range = 11-210). The mean follow-up after monotherapy was 19 ± 16.1 months (range = 2-67). Indications for conversion were: chronic renal dysfunction with HCV in 45 patients; HCV recurrence in two; and hypertension plus HCV recurrence in one subject. When the indication was renal dysfunction (excluding three patients who underwent hemodialysis), the mean creatinine values decreased significantly from baseline to 6 months of monotherapy from 1.63 ± 0.61 mg/dL to 1.51 ± 0.78 mg/dL (P < .03). The creatinine clearance only improved significantly from the baseline value of 56.6 ± 16.8 mL/min to the value at 3 months of monotherapy—63.6 ± 18.4 mL/min (P < .001). At the last outpatient visit, creatinine and creatinine clearances had not changed significantly. The mean diastolic blood pressure did improve significantly at the end of the study. The mean glucose levels decreased but not significantly at the last outpatient visit. Liver function tests did not change significantly after conversion to MMF monotherapy. The acute rejection rate was 8.3%, and adverse events related to MMF monotherapy were present in 9 patients (18.7%).

Conclusions

Conversion from calcineurin inhibitors to MMF monotherapy in patients who underwent OLT for HCV transiently improved renal function and hypertension. The acute rejection rate was low, and adverse events were usually well tolerated.     

Indications for and Survival After Liver Retransplantation

Introduction

Orthotopic liver retransplantation (re-OLT) is the therapeutic option for hepatic graft failures. Survival after re-OLT is poorer than after primary OLT. Given that there is an organ shortage, it is essential that we optimize our use of this scarce resource. We evaluated the results of re-OLT among 58 consecutive Re-OLT.

Materials and Methods

Using registry data from our Liver Transplantation Unit, we performed a retrospective cohort study of adult urgent versus elective re-OLT between 1991 and 2008. We recorded the indications for the initial OLT, and the intervals from OLT to re-OLT as well as age and gender. Using the Rosen model to stratify patients into low-intermediate-, and high-risk groups we calculated survivals.

Results

Among 661 adult liver transplantations, 56 patients (8.4%) underwent late re-OLT at a median of 654.4 days post-OLT. There were 17 (29%) urgent re-OLT and 41 elective cases (71%). Vascular complications were the most common cause of urgent re-OLT (64%); elective re-OLT was primarily due to chronic rejection (56.1%). Overall survival for retransplanted patients was significantly lower among urgent procedures (82.4% vs 48.8%), as well as for overall survival after re-OLT for patients with hepatitis C virus (HCV) versus other etiologies.

Conclusion

These data confirmed the utility of retransplantation in elective and emergency situations. Liver re-transplantation has a high morbidity and mortality. It requires multidisciplinary experience to decide inclusion and prioritization criteria for re-OLT, especially among patients with HCV.     

Immunosuppression With Low-Dose Daclizumab in Liver Transplant Recipients With Impaired Kidney Function: A Single-Center Experience

Background

Nephrotoxicity of calcineurin inhibitors (CNI) may exert detrimental effects, particularly in orthotopic liver transplantation (OLT) patients with impaired kidney function. Immunosuppression with daclizumab permits delayed introduction of CNI, and may be preferred for patients with kidney dysfunction. This retrospective analysis of our experience using daclizumab was performed among patients who underwent transplantation with impaired kidney function.

Methods

We analyzed 168 patients. A serum creatinine (Cr) level >1.5 mg/dL was the indication for a protocol with low-dose daclizumab (50 mg intravenous [IV], day 0 and day 4), mycophenolate mofetil (MMF; 500 mg twice daily IV/orally), and tapering doses of prednisolone from day 0 after OLT. CNI were introduced at day 4-15 after OLT. Patients with a Cr level <1.5 mg/dL received immunosuppression with CNI+MMF+steroids or CNI+steroids.

Results

Fourteen patients fulfilled the criterion for daclizumab immunosupression. Their Cr and creatinine clearance (CrCl) values at OLT were 2.85 ± 1.22 mg/dL and 19 ± 11 mL/min, respectively. In the remaining 154 patients, Cr and CrCl results were 0.88 ± 0.3 mg/dL and 107 ± 82 mL/min, respectively. At discharge, the daclizumab group showed Cr and CrCl estimates of 0.97 ± 0.45 mg/dL and 86 ± 34 mL/min (P < .0001 for both, when compared with prior to OLT). Both Cr and CrCl levels at discharge were not different from those values of patients who underwent transplantation with normal kidney function. The incidence of acuterejection was 14% in the daclizumab group and 18% in the other recipients (P = not significant [NS]).

Conclusions

Immunosuppression with low-dose daclizumab and delayed introduction of CNI was safe and did not increase the risk of an acute rejection episode, thus offerring an excellent therapeutic option for patients who undergo transplantation with impaired kidney function.     

Outcome of Combined Liver and Kidney Transplantation in Hepatitis C: A Single-Center Long-Term Follow-up Experience

Introduction

Hepatitis C (HCV) cirrhosis is the prevalent liver disease requiring liver transplantation in the United States. Candidates who also have end-stage renal disease, chronic renal disease stage 4, or prolonged hepatorenal syndrome are considered for combined liver and kidney transplantation (CLKT).

Materials and methods

We performed a retrospective study of HCV(+) and HCV(−) CLKT patients with more than 12 months of follow-up and HCV(+) patients with isolated liver transplant (OLT) to compare the outcomes of various groups.

Results

Since 1988, 2983 OLTs were performed at our institution including 58 CLKTs. Of these, 23 were HCV(+) subjects who were significantly older than HCV(−) CLKT patients. Race, pretransplant dialysis time, renal indication for CLKT, Model for End-stage Liver Disease score, donor age, liver and kidney rejection as well as occurrence of posttransplant hypertension were similar among HCV(+) and HCV(−) CLKT patients. Posttransplant diabetes was observed in 80% of the HCV(+) group and 30% of the HCV(−) group (P = .01). Renal function seemed to be better in HCV(−) when compared with HCV(+) subjects at 5 years (P = .09). Overall patient survival for HCV(+) CLKT, HCV(−) CLKT, and HCV(+) OLT groups at 1, 2, and 5 years were not significantly different (P = .6).

Conclusion

HCV positivity should not exclude appropriate candidates for CLKT.     

Liver transplantation in patients with cryptogenic cirrhosis: long-term follow-up

Objective

The objective of this study was to evaluate long-term survival, histological diagnoses, and mobility of patients with cryptogenic cirrhosis (CC) treated with orthotopic liver transplantation (OLT).

Patients and Methods

We performed a retrospective analysis of 35 patients who underwent transplantation with CC among 800 OLT patients. There were no differences in gender, mean age of 47 years, average MELD (Model for End-stage Liver Disease) of 16, and hepatocellular carcinoma incidence (8%).

Results

In 28.6% of patients, the diagnosis of CC was wrong. There was no incidence of an acute rejection episode and a low incidence of complications, although the postoperative mortality rate was 20%, of chronic rejection was 25%, and recurrence of disease was 4%. Cumulative at 3-, 5-, and 10-year survivals were lower than the other OLT. Survival was lower in patients receiving suboptimal grafts.

Conclusions

One of 3 patients who underwent transplantation for CC had a specific etiologic diagnosis. The chronic rejection rate and postoperative mortality rate were higher than other etiologies, and survivals at 5, 10, and 15 years were lower than other OLT.     

Outcome of treatment with pegylated interferon and ribavirin in heart transplant recipients with chronic hepatitis C

Background/aim

The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current treatment for chronic hepatitis C (CHC). The treatment is thought to suppress viral replication and induce viral clearance via immunomodulatory effects. For this reason, concern exists for the use of this treatment in recipients of a solid organ transplantation. We sought to evaluate the safety and efficacy of PEG-IFN/RBV in heart transplant recipients with CHC.

Methods

From June 2005 to September 2009, we treated three CHC patients with heart transplantation. PEG-IFN alpha2b and RBV doses and treatment duration were set according to the hepatitis C virus (HCV) genotype and body weight as per current recommendations. Dose reductions were dictated by individual patient tolerability. Cardiac safety was monitored by clinical examinations, echocardiography, and measurement of troponin I and B-type natriuretic peptide, as well as endomyocardial biopsies.

Results

All three patients, displayed HCV genotype 1b infection, viral loads of >5 logs, and a Scheuer fibrosis score ≥ 2. Two of them completed the prescribed treatment course becoming sustained virological responders. The other patient had an initial complete virological response, but subsequently experienced a viral breakthrough after reduction of PEG-IFN and withdrawal of RBV due to severe anemia. We observed no cardiovascular adverse events nor rejection episodes. Posttreatment clinical history and examination, electrocardiography, and echocardiography did not show any sign of graft dysfunction.

Conclusions

Treatment with PEG-IFN/RBV may be safely offered to stable heart transplant recipients with CHC and signs of liver disease progression. Close monitoring of treatment safety is mandatory.     

Have we changed the liver retransplantation survival?

Introduction

Orthotropic liver retransplantation (RT) is the therapeutic option for the failure of an allograft. Patient and graft survival rates after RT are inferior to primary liver transplantation (OLT). Because of the limited number of donors, it is essential that we optimize their use. We reviewed 68 consecutive retransplantations to evaluate their results.

Materials and Methods

Using registry data from our Liver Transplantation Unit, we performed a retrospective cohort study of adult RT between 1991 and 2010. Patients were divided into 2 groups (urgent vs elective RT) to compare the utility of RT. We also analyzed data collected at the time of RT, including age, gender, indications for primary OLT and RT (hepatitis C virus [HCV]+ and HCV−). At various stages (1991-2000, 2001-2006, and 2007-2010), we calculated probability survival curves according to the Kaplan-Meier method with comparisons using the log-rank test.

Results

Among 771 adult liver transplantations, 68 (8.8%) underwent late secondary OLT. 21 (31%) cases were urgent and 47 elective RT (69%). Vascular complications was the most common cause for urgent RT, and chronic rejection, for elective RT. Differences were also detected in the overall survival of RT patients; mortality was significantly lower among the urgent procedures (15% vs 47.8%). Significantly differences were also detected in overall survival for RT patients between 2007 and 2010 (81.7% with urgent RT and 76.5% with elective situations).

Conclusion

These data confirmed the utility of RT in elective and emergency situations. Overall survival of elective RT patients has improved in recent years. Liver RT requires a multidisciplinary team to decide the inclusion and prioritization of elective RT cases on the OLT waiting list.     

Results of Treatment of Acute Liver Failure Patients With Use of the Prometheus FPSA System

Objective

Herein we have presented the results of treatment of acute liver failure (ALF) patients with the use of the Prometheus FPSA dialysis system.

Materials and Methods

To January 2009, we performed 278 FPSA procedures in 114 patients, including 52 experience and ALF. The patients who underwent the FPSA procedure consisted of 32 women and 20 men of overall mean age of 33 ± 12 years. The causes of ALF were: Wilson's disease (n = 15), unknown origin ALF (n = 11), amanita phalloides intoxication (n = 7), paracetamol intoxication (n = 8), acute hepatitis B virus (HBV)/hepatitis C virus (HCV) infection (n = 7), liver insufficiency after parenchymal resection (n = 2) drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (n = 1), rabdomyolysis (n = 1), or primary nonfunction (PNF) after orthotopic liver transplantation (OLT) (n = 1). All procedures were performed using the Prometheus 4008H Fresenius Medical Care liver support system. The average number of treatments per patient was 2.41 and the average time for each FPSA treatment was 6.3 hours. The average heparin dose used during the procedure was 750 IU/h.

Results

After the whole treatment regimen, we observed significant improvements in the biochemical results. The average concentrations improved: serum ammonia (before 249.2 μg/dL versus after 109.7 μg/dL); serum bilirubin (before 21.53 mg/dL versus after 8.81 mg/dL), serum aspartate aminotransferase (AST; before 2456.4 U/L versus after 1068.8 U/L); serum alanine aminotransferase (ALT; before 2958.2 U/L versus after 1595.8 U/L); serum urea (before 58.5 mg/dL versus after 21.1 mg/dL); serum creatinine (before 2.9 mg/dL versus after 1.7 mg/dL); and pH value (before 7.11 versus after 7.32). After Prometheus treatment OLT was performed in 33 patients. Among the 28 who survived (53.8%), 22 underwent OLT and 6 did not have OLT. Among the 24 patients who died (46.2%), 13 were before OLT and 11 after OLT.

Conclusion

The Prometheus 4008H Fresenius Medical Care Liver support system was useful method of detoxification for patients with ALF, serving as an element of pretransplantation care.     

Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C

BACKGROUND: Histological recurrence of the hepatitis C virus (HCV) occurs in the majority of persons transplanted for cirrhosis as a result of HCV. Herein we analyze our experience with the use of both conventional and pegylated (PEG) interferon (IFN) in combination with ribavirin (RBV) in liver transplant recipients with recurrent HCV. Methods: Patients transplanted between 1992 and 2001 with post-orthotopic liver transplantation (OLT) histological recurrence of HCV, and who were treated with at least 6 months of IFN or PEG-IFN in combination with RBV were included in this analysis. A retrospective chart review was performed. Results: A total of 31 patients were included. Fifteen were treated with IFN/RBV and 16 with PEG-IFN/RBV. Of these 16, 11 had been begun on IFN/RBV and were changed to PEG-IFN/RBV because of persistent viremia. Three patients (20%) in the IFN/RBV group and six patients (37.5%) in the PEG-IFN/RBV group experienced a virologic response (VR) on therapy. Of the six patients experiencing VR in the PEG-IFN/RBV group, three (50%) were IFN/RBV non-responders. There were two sustained VRs (SVR). The 65.6% of all patients experienced a biochemical response (BR) on therapy. Seven deaths were observed. Dose modifications of IFN or PEG-IFN (87.1%) and RBV (80.6%) and the requirement for hematopoietic growth factors were frequent. Conclusions: Treatment of recurrent HCV infection with combination of IFN or PEG-IFN and RBV produced an on-therapy VR in 29% and BR in 65% of patients. Hematologic toxicity and dose modifications were frequent. Our experience with antiviral therapy for HCV post-OLT remains disappointing but PEG-IFN + RBV appears to produce VR in a sizable portion of IFN + RBV non-responders.     

Risk factors for bleeding and transfusion during orthotopic liver transplantation

Objective

While orthotopic liver transplantation (OLT) can be associated with haemorrhage, the risk factors for bleeding and transfusion remain difficult to predict. Perioperative transfusion has potentially deleterious side effects and impairs graft and patient survival. Preoperative identification of patients at high risk of bleeding is of clinical interest to manage perioperative transfusion and blood product storage.

Study design

Retrospective study.

Patients and methods

All OLT conducted between 2004 and 2008 in the University Hospital of Bordeaux were studied. Risk factors for bleeding greater than one blood volume and for massive red blood cell (RBC) transfusion were determined using univariate and multivariate analysis. Thresholds were determined with ROC curve analysis.

Results

One hundred and forty-eight transplantations were studied. Preoperative haemoglobin and Child class A were independent protective risk factors for bleeding greater than one blood volume (OR 0.81 [0.67-0.98] and 0.27 [0.10-0.72], respectively). Preoperative Hb was a protective risk factor (OR 0.71 [0.58-0.88]) whereas history of oesophageal varicose bleeding was a risk factor (OR 4.67 [1.45-15.05]) for transfusion of more than eight RBC.

Conclusion

Risk factors for bleeding and transfusion during OLT identified in this study were of little clinical usefulness so blood products should always be available during the procedure.     

Plasma exchange therapy for thrombotic thrombocytopenic purpura in pediatric patients with liver transplantation

Purpose

Sporadic cases of thrombotic thrombocytopenic purpura (TTP) have been reported in bone marrow and solid organ transplant patients receiving cyclosporine (CsA). We reported our experience with TTP using plasma exchange (PE) therapy in patients with liver transplantation (OLT).

Methods

Between March, 1993, and May, 2007, 400 patients underwent OLT, including 146 pediatric living-donor liver transplantation (LDLT). Four pediatric patients developed TTP after OLT: three were males and one female of mean age at the time of transplantation of 7.8 ± 3.6 years. The four recipients had the following indications for OLT: two glycogen storage disease, one biliary atresia, and one fulminant hepatic failure. Four patients initially received triple drug immunosuppression consisting of CsA, azathioprine, and steroids.

Results

Four (1%) patients developed TTP after OLT. All four patients were pediatric in the age group. The mean age at the time of TTP diagnosis was 8.0 ± 3.2 years, with a mean postoperative interval to TTP of 78.8 ± 114.2 days. The mean baseline platelet count was 7.0 ± 7.1 × 10,000. The eventual platelet count was 21.1 ± 20.8 × 10,000 after PE. These patients received PE 6.0 ± 4.2. The mean baseline serum creatinine was 0.8 ± 0.8 mg/dL. The mean peak serum creatinine was 2.3 ± 2.3 mg/dL. The mean serum CsA level was 717.5 ± 106.0 ng/mL before TTP diagnosis. Four patients were diagnosed by blood peripheral smears. The causes of TTP were CsA-associated in three patients and venoocclusive disease (VOD) in one patient. Three patients improved their platelet counts after PE therapy. Two patient changed from CsA to FK 506, one underwent reduced CsA dosage, and one stopped CsA. Three patients died of recurrent VOD, infection, and intrapulmonary hemorrhage. Only one patient survived.

Conclusions

The incidence of TTP in our series was lower. It only developed in pediatric patients. The causes of TTP were associated with CsA and/or VOD. The mortality was high after the TTP diagnosis. We concluded that TTP was a potentially fatal condition, but an early diagnosis with prompt institution of therapy with invasive PE therapy may reduce its mortal consequences.     

The Relationship Between Inhalational Anesthetic Requirements and the Severity of Liver Disease in Liver Transplant Recipients According to Three Phases of Liver Transplantation

Purpose

Orthotopic liver transplantation (OLT) patients are known to show decreased intraoperative anesthetic requirements compared with patients undergoing other liver surgeries. The aim of this study was to determine the relationship between inhalational anesthetic requirements and the severity of liver disease among OLT patients.

Methods

Fifty patients undergoing first living donor OLT were divided into 2 groups: model for end-stage liver disease (MELD) score <20 (low-MELD group; n = 25) versus, MELD score ≥20 (high-MELD group; n = 25). Anesthesia was maintained with desflurane and inspired concentration was titrated to maintain the bispectral index between 40 and 50. Neither intraoperativel opioid nor epidural or intrathecal analgesia was used. End-tidal desflurane concentration (ETdes) was measured every 5 minutes and averaged in 30-minute intervals. These values were divided into 3 phases: preanhepatic (P 0.5 hour, P 1 hour, and P 1.5 hours), anhepatic (A 0.5 hour, A 1 hour, A 1.5 hours, and A 2 hours), and postreperfusion (R 0.5 hour, R 1 hour, R 1.5 hours, R 2 hours, R 2.5 hours, and R 3 hours). Results were compared between the 2 groups.

Results

The demographic and intraoperative data were similar between the 2 groups. ETdes to maintain comparable anesthetic depth was significantly lower during the preanhepatic and anhepatic phases in the high-MELD than the low-MELD group, but there was no significant difference during the postreperfusion period.

Conclusions

OLT patients with high MELD scores showed less inhalational anesthetic requirements during the preanhepatic and the anhepatic periods than those with low MELD scores.     

Cytomegalovirus Infection After Liver Transplantation: Prophylaxis and Preemptive Treatment—A Single-Center Experience

Background

Cytomegalovirus (CMV) infection represents one of the most frequent opportunistic infections following solid-organ transplantation. The incidence and severity of CMV infection depend on the immunosuppressive regimen, the CMV serostatus of donor and recipient, and the type of transplant.

Methods

We evaluated CMV infection rates during the last 2 years in our center: March 2007 to March 2009. We enrolled 55 patients—13 females and 42 males—who underwent liver transplantation (OLT) due to hepatitis C virus (HCV) cirrhosis (n = 9), hepatitis B virus (HBV) cirrhosis (n = 5) HCC both on HCV and HBV cirrhosis (n = 37), or autoimmune disease (n = 4). Fifty percent of the patients received tacrolimus (TRL) and the others cyclosporine (CsA), both dosed according to weight. All patients received oral acyclovir (400 mg/td or less, adapted to renal function) as herpes simplex prophylaxis for 6 months. CMV prophylaxis prescribed CMV- hyperimmunoglobulin on postoperative days 1 and 7. CMV infection was monitored using polymerase chain reaction (PCR <1000 IU/mL) according to the following schedule: every week for the first month, every 2 weeks from month 2 to 3 and monthly from month 4 to 6. Patients were treated when three positive PCR results not affected by immunosuppressive dose reduction or when the PCR showed DNA greater than three times the limit of detection. CMV treatment stipulated valgancyclovir (900 mg twice daily) until three consecutive PCRs were negative or for 3 months dosed according to renal function. PCR was measured every 2 weeks during treatment.

Results

Among the patients who were all D⁺/R⁺ (CMV-Immunoglobulin G [IgG]⁺/IgG⁺). 10 required treatment (18%) within 3 months from OLT. There subjects were prescribed TRL (n = 4) or CsA (n = 6). No renal impairment was observed among treated patients. Of those having the infection, one died due to other causes—sepsis from candida at 5 months after OLT.

Conclusion

CMV-hyperimmunoglobulin on postoperative days 1 and 7 did not confer protection for CMV among OLT patients. Preemptive treatment with intravenous gancyclovir plus valgancyclovir per os seemed to be useful and safe in infected patients requiring treatment.     

Combined liver kidney transplantation: critical analysis of a single-center experience

Combined liver kidney transplantation (LKT) can be successfully performed on patients with liver and renal failure; however, outcomes are inferior to liver transplantation alone (OLT). Our aim was to determine the indications for and outcome of LKT and whether patients with longer wait times required more frequent LKT versus OLT alone.We included 18/93 adults who underwent LKT from August 2007 to August 2010 for hepatitis C virus (HCV, n = 7), alcohol (n = 5), nonalcoholic steatohepatitis (n = 2), primary biliary sclerosis, polycystic kidney disease with liver involvement, hepatic adenomatosis, and ischemic hepatitis. Eleven were originally listed for LKT and 7 required listing for-kidney transplantation while awaiting OLT. Eight were on dialysis when first listed and 10 had a low glomerular filtration rate or known kidney disease.The mean calculated Model for End-Stage Liver Disease (MELD) score for LKT was 31.2 ± 3.54. Seven had hepatocellular carcinoma in explants. Two patients had acute cellular kidney rejection that responded to treatment. Recurrence of HCV was documented in 5 patients within 6 months of LKT; 2/5 received HCV therapy (interferon and ribavirin) without renal allograft rejection. One-year liver graft/patient survival was 94% after LKT. One patient died at 6 months post LKT due to severe HCV recurrence. Last mean serum creatinine level was 1.35 ± 0.28 mg/dL for LKT patients.LKT is a safe procedure with favorable outcomes even in patients with a high MELD score. Transplantation of patients with a high MELD score due to regional variations in organ allocation results in additional use of kidneys by OLT patients. Improved organ allocation algorithms in OLT would help to reduce combined transplants, sparing more kidneys.     

Impact of Tumor Characteristic on the Outcome of Liver Transplantation in Patients With Hepatocellular Carcinoma

Introduction

Orthotopic liver transplantation (OLT) is a well-established treatment for cirrhotic patients with hepatocellular carcinoma (HCC) who meet the Milan criteria. The aim of this study was to identify predictors of survival among 65 patients with HCC in cirrhotic livers who underwent liver transplantation (OLT).

Methods

From January 2001 to December 2008, we performed 655 OLT in 615 patients. HCC was diagnosed in 58 patients before OLT and in 65 by histological examination of the explanted livers; 74% of the patients met Milan criteria by histological examination.

Results

The median follow-up was 27 months (range = 1-96). We analyzed patient age and gender, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number/size, vascular invasion, and differentiation grade. There was no significant difference in survival among patients grouped according to the Model for End-stage Liver Disease staging system for HCC. The 5-year survival of patients with low differentiated (G3) HCC was significantly worse than that of those with moderately differentiated (G2) or well-differentiated (G1) HCC: 50%, 81%, and 86% respectively, (P < .01). Patients with microvascular invasion displayed a worse 5-year survival than those without vascular invasion (42% vs 80%; P < .01).

Conclusions

The analysis indicated that the histological grade of the tumors and evidences of microscopic vascular invasion were the most useful predictive factors for overall survival among patients with cirrhosis after liver transplantation for HCC.     

Elevated CD4/CD25 T-cell Frequency and Function During Hepatitis C Virus Recurrence After Liver Transplantation

Background/Aim

Factors involved in hepatitis C virus (HCV) recurrence versus acute cellular rejection are not fully understood. The aim of the present study was to investigate whether patients with recurrence after liver transplantation (OLT) showed similar CD4⁺/CD25⁺ cell frequency and function as those who became chronically infected.

Patients and Methods

After written informed consent, we enrolled 20 patients (group A) who underwent OLT with HCV recurrence within 6 months. HCV-RNA and hypertransaminasemia were used to assess the reactivation of viral hepatitis. CD4⁺/CD25⁺ T cells were enumerated using a flow cytometry assay, gated on CD3 cells, stained for FoxP3. After immunomagnetic sorting (Dynal, Oslo, NW), Treg suppressor activity was measured, as the ability to inhibit proliferation of autologous CD4⁺/CD25⁻ T cells (anti-CD3/CD28 stimulation—1:2, 1:20 ratio). Eight patients with acute hepatitis C who evolved to a chronic infection after 6 months (group B) were used as positive controls, while 10 healthy individuals were negative controls (group C).

Results

We did not observe any difference in CD4⁺/CD25⁺ frequency or function among group A compared with group B (CD4⁺/CD25⁺ = 14% ± 2% versus CD4⁺/CD25⁺ = 16% ± 3%), although both groups were significantly increased with respect to group A (CD4⁺/CD25⁺ = 6% ± 3%; Mann-Whitney U test, P < .01).

Conclusion

Patients developing HCV recurrence after OLT have the same immunoregulatory network as patients with acute hepatitis C evolving to persistent infection, likely suggesting that CD4⁺/CD25⁺ numbers may be a marker to predict recurrence of HCV after OLT.     

Sirolimus in Pediatric Liver Transplantation: A Single-Center Experience

Background and Aims

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.

Methods

Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.

Results

PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.

Conclusions

Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.     

Administration of a Recombinant Factor Vlla in Patients Undergoing Liver Transplantation for Fulminant Hepatic Failure

Background

Fulminant hepatic failure (FHF) is associated with profound clotting disturbances leading to the risk of a major blood loss during orthotopic liver transplantation (OLT). Application of a recombinant factor VIIa (rVIIa) that promptly corrects clotting abnormalities remains controversial in the OLT setting. We conducted a retrospective analysis of the effect of rVIIa on the prothrombin time (PT) and other perioperative parameters in patients transplanted for FHF in our center.

Materials and Methods

Nineteen consecutive patients (9 males/10 females) of overall mean age of 33 ± 13 years underwent the procedure due to: Wilson's (n = 8), non-A-non-B hepatitis (n = 6) or Amanita phalloides toxicity (n = 5). All subjects received rVIIa at a mean dose of 54 ± 16 μg/kg body weight at 10 minutes before the skin incision. The PT was measured at 15 minutes and 12 hours after injection. Data were analyzed with StatView program with P < .05 considered significant.

Results

Rapid correction of PT was observed in all patients: the mean PT before injection was 37 ± 14 versus 14 ± 3 after 15 minutes (P < .0001). Twelve hours after the injection the PT was 19 ± 5 (P < .0001 vs before injection and P < .0007 vs 15 minutes after injection). Two patients died at 1 and 4 days after OLT. Mean red blood cell requirement was 5 ± 4 U and fresh frozen plasma was 11 ± 5 U. The mean operative time was 527 ± 126 minutes and intensive care unit stay 8 ± 9 days. None of the patients developed thromboembolic complications.

Conclusion

Administration of rVIIa caused a rapid improvement in the PT shortly after injection. It was safe and not associated with any thromboembolic events in our series.