Induction therapy with either anti-CD25 monoclonal antibodies or rabbit antithymocyte globulins in liver transplantation for hepatitis C

BACKGROUND: Hepatitis C virus (HCV)-related end-stage liver disease (ESLD) is the leading cause for orthotopic liver transplantation (OLT). The aim of our sequential study was to assess the safety and efficacy of induction therapy using either rabbit antithymocyte globulins (RATG) or anti-CD25 monoclonal antibodies. METHODS: From January 2000 to January 2003, 31 patients underwent OLT for HCV-related ESLD, and survived more than 1 month post-transplantation. Up to July 2001, induction relied on RATG (Thymoglobulins; Sangstat, Lyon, France) which was given for a median of 5 d, i.e. a total dose of 406 +/- 45 mg (n = 16; group I). Thereafter, induction was based on either basiliximab or dacluzimab (n = 15; group II). Steroids and tacrolimus (from day 1 onwards) were given as maintenance therapy. The primary end-points were at 6 months post-transplantation. RESULTS: Patient and graft survivals were excellent and similar in both groups. The acute rejection rate was 37.5% in group I and 20% in group II (p = ns). The rates of serious bacterial and fungal infections as well as cytomegalovirus infections were similar in both groups. Even if the overall pattern of post-transplant liver enzymes did not differ between the two groups, the rate of HCV recurrence tended to be higher in group II (80%) compared with group I (56.25%; p = ns) patients. Both induction therapies were clinically and biologically well tolerated. CONCLUSION: RATG induction therapy is as efficient and as safe as induction with anti-CD25 monoclonal antibodies.     

Rabbit antithymocyte globulin versus OKT3 induction therapy after heart-lung and lung transplantation: effect on survival, rejection, infection, and obliterative bronchiolitis

The superiority of different induction therapies after heart-lung and lung transplantation is not clearly established; specifically, whether monoclonal (OKT3) or polyclonal antibody induction therapy provides any advantage. Between 1989 and 1991 we used induction therapy with either rabbit antithymocyte globulin (RATG) or OKT3, given at random based on the availability of RATG. RATG was used in 25 patients (RATG group 1) and OKT3 in 38 patients (OKT3 group 1). Early results suggested a survival advantage with RATG. From 1992 until 1997 we used RATG induction therapy in 108 patients (RATG group 2). This study analyzed longer-term survival, infection, rejection, and obliterative bronchiolitis (OB) rates for RATG group 1 and OKT3 group 1 and assessed outcomes for RATG group 2. The 1-, 3-, and 5-year survival for RATG group 1 was 72 %, 72 %, and 52 % and for OKT3 group 1 was 63 %, 49 %, and 34 % (P < 0.05). The 1- and 3-year survival for RATG group 2 was 84 % and 74 %. The 1-, 3-, and 5-year actuarial freedom rates from lung rejection for RATG group 1 were 38 %, 38 %, and 31 % and for OKT3 group 1 were 21 %, 0 %, and 0 % (P < 0.01). The linearized rate (events/100 patient days) of all infections at 3 months was 1.55 ± 0.28 for RATG group 1 and 2.19 ± 0.27 for OKT3 group 1 (P = NS). The infection rate for RATG group 2 was 1.60 ± 0.13. The actuarial rates of freedom from OB at 1, 3, and 5 years for RATG group 1 were 84 %, 51 %, and 45 % and for OKT3 group 1 were 77 %, 61 %, and 36 % (P = NS), while for RATG group 2 the rates were 97 % and 92 % at 1 and 3 years (P < 0.01 vs RATG group 1 and OKT3 group 1). The use of RATG induction therapy from 1989 through 1991 resulted in improved actuarial survival and less rejection, without increased infection rates. The use of RATG since 1992 has continued to result in similar outcomes for survival, infection, and rejection. The time to onset of OB has improved further in recent years. This may be a result of recent improvements in cytomegalovirus (CMV) prophylaxis. Received: 10 February 2000 Accepted: 30 March 2001     

The Influence of Viral Genotypes and Rejection Episodes on the Recurrence of Hepatitis C After Liver Transplantation

Purpose. The aim of this study was to report the influence of hepatitis C virus (HCV) genotype and rejection episodes on the outcome of orthotopic liver transplantation (OLT), hepatitis recurrence, and progression to graft cirrhosis after OLT. Methods. Fifty-three patients who all had undergone OLT for end-stage liver cirrhosis were selected for this study. Hepatitis C genotype was determined. Recurrent hepatitis and rejection were diagnosed based on elevated liver function tests and a liver biopsy. Results. The patients were followed up for a mean of 51.9 ± 34.3 months. The cumulative survival rate was no different in OLT for hepatitis C and OLT for all other liver diseases. After OLT, serum HCV RNA was detected in 93%. Histological recurrence occurred in 85% of all patients. The 1-, 3-, and 5-year recurrence rates were 48%, 77%, and 85%, respectively. Of the 41 patients with recurrent hepatitis C, 4 (10%) had cirrhosis, 18 (44%) had hepatitis with fibrosis, and 91 (46%) had hepatitis without fibrosis at the end of follow-up. A total of 32% of the patients were infected by HCV genotype 1b and 68% by other HCV genotypes. The recurrence rates were significantly higher in patients infected with genotype 1b than in those with other genotypes (p = 0.04). Twenty of 48 patients (42%) experienced acute rejection. There was a strong association between the number of rejection episodes and the incidence of HCV-related cirrhosis (p < 0.01). Conclusion. Our findings showed the genotype 1b to result in a higher recurrence rate after OLT. On the other hand, rejection episodes were associated with a more rapid progression to graft cirrhosis. Received: May 7, 2002 / Accepted: November 19, 2002 RID="*" ID="*" Reprint requests to: H. Sugo     

Induction therapy by anti-thymocyte globulin (rabbit) versus basiliximab in deceased donor renal transplants and the effect on delayed graft function and outcomes

The use of induction therapy significantly reduces the incidence of acute rejection (AR) episodes posttransplantation and prevents delayed graft function (DGF). In our program, all adult deceased donor kidney transplant (DDKT) recipients receive immunosuppression induction therapy with either Basiliximab (anti-CD25 Ab) or rabbit anti-thymocyte globulin (RATG). Our protocol is risk adjusted such that patients who are at a higher risk for DGF or AR received RATG and all other patients receive anti-CD25 Ab. We hypothesized that treating our higher-risk patients with RATG induction at the time of transplantation would lead to a lower rate of DGF and better outcomes. From August 1, 2005 through August 31, 2010, 116 consecutive adult patients received a DDKT in a single academic transplantation center. All DDKT patients received induction with RATG or anti-CD25 Ab. The induction decision was made prior to transplantation based on donor and recipient risk factors for AR and DGF. Transplants that were deemed at higher risk for DGF or AR based on donor factors or recipient factors received RATG. Medical records and patient databases were reviewed retrospectively. The use of RATG in higher-risk recipients for DGF and AR did not significantly reduce the DGF rate. At 6 months the function of the allograft function measured as creatinine clearance or serum creatinine was lower in the RATG group than the patients who received anti-CD25 Ab induction. The choice of induction therapy did not improve outcomes in high-risk patients in this short-term study.     

Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease

Patients with human immunodeficiency virus (HIV) most often have hepatitis C virus (HCV) or hepatitis B (HBV) virus coinfection, or both, as a cause of their liver disease. Recent survival statistics show that patients infected with HIV treated with highly active antiretroviral therapy (HAART) can expect a significant prolongation of life by interfering with the natural progression of HIV to aquired immune deficiency syndrome (AIDS). Therefore, HIV-positive patients experiencing complications of liver failure are at greater immediate risk of dying from their end-stage liver disease (ESLD) rather than their HIV. Many transplant centers still consider HIV infection as a contraindication for orthotopic liver transplantation (OLT). At our two institutions, we believe that patients with HIV suffering from ESLD should be considered for OLT. This study evaluates the survival of patients undergoing OLT with HIV under HAART therapy. OLT was performed in 16 patients with HIV suffering from ESLD as a result of chronic HCV, chronic HBV, or fulminant hepatic failure (FHF). Collected data include patient demographics, patient and graft survival, pre-OLT assessments, and postoperative complications (including opportunistic infections). Ten patients at Pittsburgh and 6 patients at Miami received OLT. Of the 16 patients who received OLT, 14 remain alive to date. Thirteen of 16 patients are more than 12 months post-OLT, whereas the last patient is currently 6 months post-OLT. Five patients at Miami and 9 of 10 patients at Pittsburgh received HAART therapy before OLT, although 2 of the Pittsburgh patients had their HAART therapy discontinued before OLT because of significant liver dysfunction. The pre-OLT viral loads were undetectable in 13 of 16 patients. The cluster determinant (CD)4 count was less than 200 in 6 patients and greater than 100 in 2 patients before OLT. In all patients, CD4 counts increased above 200 in the post-OLT period. Tacrolimus toxicity associated with the pharmacologic inhibition of cytochrome p450 metabolism caused by protease inhibitors occurred in 6 patients after OLT. Six patients (38%) experienced acute cellular rejection immediately after OLT. Our experience suggests that OLT is effective in selected HIV-positive patients suffering from ESLD. Patient and graft survival was similar to non–HIV-positive patients suffering from the same indications for OLT. Acute cellular rejection was no less frequent that seen in non–HIV-positive patients. Given the complex pharmacologic interactions between the protease inhibitors and tacrolimus, careful monitoring, and attention is required to prevent toxicity or underdosing. (Liver Transpl 2003;9:239-247.)     

Induction with rabbit antithymocyte globulin versus induction with corticosteroids in liver transplantation: impact on recurrent hepatitis C virus infection

This study compares the clinical course of recurrent hepatitis C virus (HCV) infection between 64 patients, who were randomized to receive either rabbit antithymocyte globulin (RATG) or steroids as induction therapy with tacrolimus for maintenance. The HCV recurrence was assessed by HCV RNA levels, peak ALT at 3-6 months, the grade of inflammation at biopsy at 3-6 months posttransplant, progression of fibrosis, and survival. All patients had also received antiviral therapy with interferon alpha 2b and ribavirin, if there were no contraindications. There was no statistically significant difference between the two groups in terms of inflammation at 3 months, peak ALT, or HCV RNA. The survival between the two groups of patients was similar. It appears that steroid-free liver transplantation with RATG induction does not have any negative influence on HCV recurrence in hepatitis C patients after liver transplantation.     

The natural history of hepatitis C virus in pediatric liver transplant recipients.

Although rare in the pediatric population, the natural history of hepatitis C virus (HCV) recurrence in pediatric patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease secondary to HCV has not been well described. We performed an analysis of all 67 pediatric patients (< 17 years old) who have undergone OLT for HCV in the United States between 1/1988 and 6/2005. The 67 pediatric patients received a total of 83 OLTs for HCV. Following initial OLTs performed for HCV, the patient and allograft survival rates were 71.6% and 55.0%, respectively, at 5 years. Following retransplantation these rates decreased to 55.0% and 33.8%, respectively, following retransplantation. Recipients were listed for retransplantation after 31.3% of all OLTs, and overall recipients were retransplanted after 19.3% of OLTs. The overwhelming majority of retransplants were performed for HCV recurrence. A mean of 1.2 OLTs were performed per patient for HCV. The median time between OLTs for HCV was 290 days. In conclusion, the risk of HCV recurrence in pediatric OLT recipients is high and is associated with a high rate of retransplantation. Still, OLT represents the only treatment option that may achieve long-term survival in pediatric patients with end-stage liver disease secondary to HCV that is recalcitrant to medical management.     

Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy

BACKGROUND: In 2001, we published early results of a prospective randomized trial of 71 patients who received either steroids or rabbit antithymocyte globulin (RATG) for orthotopic liver transplantation (OLT). We now report follow-up on these patients and additional patients undergoing steroid-free OLT. METHODS: A total of 119 adult OLT recipients were prospectively randomized to receive either methylprednisolone 1,000 mg followed by a 3-month steroid taper or a steroid-free regimen of RATG 1.5 mg/kg during the anhepatic phase followed by a 1.5 mg/kg dose on posttransplant day 1. Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil in both groups. Mycophenolate mofetil was weaned over 3 months in the first 71 patients and over 2 weeks in the last 48 patients, achieving tacrolimus monotherapy by 2 weeks posttransplant. Subsequently, a group of 24 sequential OLT recipients received the steroid-free (RATG) protocol. Endpoints of the study were survival, rejection, infectious complications, posttransplant diabetes, and recurrent hepatitis C virus. RESULTS: One-year patient survival was 85% in each group of the prospective randomized trial with a mean follow-up of 18.5 months. One-year graft survival was 82% in the RATG group and 80% in the steroid group (P=not significant). Patient and graft survival of the 24 nonrandomized RATG patients was 96% with a mean follow-up of 3 months. The incidence of rejection was not significantly different; however, 50% of the patients in the steroid group required pulse steroids to reverse the rejection compared with only one patient (1.6%) in the RATG group (P=.03). The incidence of cytomegalovirus infection (P<.05) and posttransplant diabetes was higher in the steroid group (P=.03). There was a trend toward decreased severity of hepatitis C virus in the RATG group. CONCLUSIONS: Steroid-free liver transplantation using RATG and early tacrolimus monotherapy effectively reduces immunosuppression-related complications with excellent survival.     

Effect of early recurrence of hepatitis C on late biliary anastomotic stricture after liver transplantation

The aim of the current study was to clarify whether recurrence of hepatitis C (HCV) infection affects biliary complications after liver transplantation (OLT), with special reference to late biliary anastomotic strictures (LBAS). We reviewed 665 consecutive adult OLT recipients with a choledochocholedochostomy without T-tube placement between 1990 and 2005. Biliary anastomotic stricture was confirmed by ERCP. The LBAS was defined as stricture that occurred 30 days or more after OLT. Recurrence of HCV was diagnosed by histological examination using liver biopsy specimen and confirmed by the presence of HCV-RNA. Early HCV recurrence was defined as recurrence that occurred within 6 months after OLT; LBAS occurred in 54 patients (8% of total). Mean duration from OLT to occurrence of LBAS was 6.9 months (1-44 months). Patients with HCV infection had higher occurrence of LBAS than did non-HCV patients (11% vs 5%, P = .0093). Among HCV patients, those with early HCV recurrence had exclusively high rate of LBAS (16%). In multivariate analyses, early recurrence of HCV (P < .001, relative risk [RR] 6.4), as well as occurrence of HAT (P = .0018, RR 8.0), and prolonged CIT (P = .034, RR 3.3) were independent risk factors affecting LBAS. In conclusion, patients with HCV infection have increased occurrence of LBAS after OLT. Additionally, early recurrence of HCV contributes to a higher rate of LBAS.     

Infection with chronic hepatitis C virus and liver transplantation: A role for interferon therapy before transplantation

An analysis of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplant Registry data shows that the greater the viral load at the time of transplantation, the more rapidly clinically evident posttransplantation hepatitis C virus (HCV) disease recurs. These data suggest that aggressive pretransplantation treatment of HCV might delay recurrent posttransplantation HCV disease and enhance posttransplantation survival. We have taken an aggressive approach to treating HCV infection pretransplantation with the use of high-dose (5 MU) daily interferon α_2b in an effort to clear the virus before transplantation. A total of 27 patients with HCV-induced cirrhosis were seen and underwent transplantation at Loyola University Medical Center (Maywood, IL) between February 1997 and December 2001. There were 22 men and five women, with a mean age of 56 ± 2 years. The majority had genotype 1 disease (67%). Of the 27 patients, 7 had a baseline platelet count <50,000/mm³ and were excluded from interferon therapy. The remaining 20 were treated for a mean of 14 ± 2.5 (range, 0.5 to 33.5) months before orthotopic liver transplantation (OLT). Twelve (60%) responded to the therapy with serologic clearance of HCV before OLT. The mean time from initiation of therapy to the first negative qualitative polymerase chain reaction was 4.5 ± 1.5 (range, 0.5 to 12) months. Four of the 12 patients in whom the virus cleared did not have evidence of HCV recurrence after OLT, representing 20% of those treated and 33% of those who had HCV clearance before OLT. The duration of post-OLT freedom from HCV infection in these individuals has been 33.6 ± 11.3 (range, 0 to 47.4) months. These data suggest that with careful supervision, cirrhotic patients can tolerate high-dose interferon. In addition, a viral clearance can be achieved in a significant number of cirrhotic patients with high-dose interferon. One third of patients, in whom the HCV cleared before OLT, did not have evidence of disease recurrence after OLT. It is thus anticipated that with early and aggressive pre-OLT HCV therapy, possibly with the use of pegylated interferon, even better results may be obtained. (Liver Transpl 2003;9:905-915.)     

Peginterferon and ribavirin in patients with HCV cirrhosis after liver transplantation

The objective of the study was to assess the efficacy of antiviral therapy in patients with hepatitis C virus (HCV) recurrence after liver transplantation (OLT). We included 30 patients of mean age 56 years, who experienced HCV recurrence after OLT. Mean time from OLT to the beginning of therapy was 57 months (median: 43 months). All of them were on monotherapy: tacrolimus (n = 21), cyclosporine (n = 6), and mycophenolate mofetil (n = 3). Fourteen had previously been diagnosed with allograft HCV cirrhosis. Patients were treated with peginterferon alpha 2b (1.5 mug/kg/weekly SC) and ribavirin (10.6 mg/kg/d) for 48 (genotypes 1, 4) or 24 weeks (genotypes 2, 3). After a mean follow-up of 20 months, two patients had died due to biliary sepsis (while on therapy) and acute myocardial infarction (7 months after the end of therapy). End of treatment virological response was achieved in 19 patients (63.3%) and sustained virological response (SUR) in 14 (46.7%). Comparing cirrhotic and noncirrhotic patients, SVR was achieved in seven patients in both groups (50% vs 43.8%; P = .732). Every patient had some adverse event; in 11 patients (36.7%) it was withdrawn (seven cirrhotic and four noncirrhotic; P < .05), and in 12 the starting dose was decreased (40%). There were neither rejection episodes nor cirrhotic complications during therapy, but infections were more common in cirrhotic patients (57% vs 25%; P < .05). In HCV cirrhotic transplanted patients the sustained virological response to combined antiviral therapy was similar to that in noncirrhotic patients, but severe adverse events including infections were much more common.     

Cost-effectiveness of cadaveric and living-donor liver transplantation

BACKGROUND: Cadaveric liver transplantation (5-year survival >80%) represents the standard of care for end-stage liver disease (ESLD). Because the demand for cadaveric organs exceeds their availability, living-donor liver transplantation has gained increasing acceptance. Our aim was to assess the marginal cost-effectiveness of cadaveric and living-donor orthotopic liver transplantation (OLT) in adults with ESLD. METHODS: Using a Markov model, outcomes and costs of ESLD treated (1) conservatively, (2) with cadaveric OLT alone, and (3) with cadaveric OLT or living-donor OLT were computed. The model was validated with published data. The case-based scenario consisted of data on all 15 ESLD patients currently on our waiting list (3 women, 12 men; median age, 48 years [range, 33-59 years]) and on the outcome of all OLT performed for ESLD at our institution since 1995 (n=51; actuarial 5-year survival 93%). Living-donor OLT was allowed in 15% during the first year of listing; fulminant hepatic failure and hepatocellular carcinoma were excluded. RESULTS: Cadaveric OLT gained on average 6.2 quality-adjusted life-years (QALYs) per patient compared with conservative treatment, living-donor OLT, an additional 1.3 QALYs compared with cadaveric OLT alone. Marginal cost-effectiveness of a program with cadaveric OLT alone and a program with cadaveric and living-donor OLT combined were similar (E 22,451 and E 23,530 per QALY gained). Results were sensitive to recipient age and postoperative survival rate. CONCLUSIONS: Offering living-donor OLT in addition to cadaveric OLT improves survival at costs comparable to accepted therapies in medicine. Cadaveric OLT and living-donor OLT are cost-effective.     

The influence of cytomegalovirus viraemia on the outcome of recurrent hepatitis C after liver transplantation

BACKGROUND: Several interrelated host and hepatitis C virus (HCV) associated factors have been proposed to explain the variable outcomes in HCV recurrence. Recent evidence suggests that cytomegalovirus (CMV) infection not only is co-factor in progression of HCV recurrence but may precipitate allograft rejection. We investigated whether short-term CMV viremia influences HCV recurrence, the number and grade of acute rejection episodes, and the histological course of HCV recurrence during the first year after orthotopic liver transplantation (OLT) for HCV-related cirrhosis. METHODS: A cohort of 39 patients transplanted for cirrhosis HCV-related was analyzed. Patients were evaluated twice weekly for CMV infection by a blood polymerase chain reaction (PCR) assay. Triple therapy with cyclosporine or tacrolimus, azathioprine and prednisolone was the initial immunosuppressive regimen. Preemptive treatment with ganciclovir was started when two consecutive PCRs for CMV were positive. Liver biopsies were performed on day 7 after OLT or when indicated. A 3-day IV 1 g methilprednisolone was given to patients with moderate or severe rejection. Ishak's score was used to grade inflammation and to stage fibrosis. RESULTS: Neither CMV viremia nor CMV disease after OLT for HCV-related cirrhosis adversely influenced the incidence and grade of acute rejection episodes nor the histological outcome of post transplant HCV recurrence, during the first year after liver transplantation. CONCLUSION: CMV viremia as detected by PCR does not affect the progression of HCV recurrence in liver grafts.     

Liver transplantation using donors older than 80 years: a single-center experience

AIM: The shortage of organs for orthotopic liver transplantation (OLT) has forced transplantation centers to expand the donor pool by using donors traditionally labeled as "extended criteria donors." One such example is OLT using a donor with advanced age. MATERIALS AND METHODS: We retrospectively evaluated 10 patients who received a liver graft from cadaveric donors older than 80 years. We analyzed pretransplantation donor and recipient characteristics, as well as the evolution of the recipients. RESULTS: All 10 donors were older than 80 years (median age, 83.5; range, 80-93). No steatosis (>30%) was accepted in the older donor group. Medium follow-up was 19.5 months. The most frequent cause for OLT was hepatitis C virus (HCV) cirrhosis (8/10 patients). We had 1 case of primary nonfunction, 1 patient died immediately after surgery because of extrahepatic complications (cardiac arrest), and 2 other patients had a severe HCV recurrence and died after 1 and 2 years from OLT, respectively. Five patients had HCV recurrence and biliary complications were present in 60% of the patients. No cases of acute or chronic rejection were described. Overall survival rates after 1 and 3 years were 80% and 40%, respectively. CONCLUSIONS: Old donor age is not an absolute contraindication to OLT. Liver grafts from donors older than 80 years can be used knowing that there is a high risk of postoperative complications. Furthermore, the increased risk of developing severe HCV recurrence, related to older donor age, suggests that such livers should be used in HCV-negative recipients.     

Liver transplantation in HIV-positive patients

AIMS: The aim of this study was to evaluate the feasibility of liver transplantation (OLT) in human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfected patients in Italy. METHODS: Between September 2002 and April 2006, 12 HIV(+) coinfected patients (11 men, mean age 42 years) underwent OLT at our Institute. Eleven (91%) patients were HCV-positive and one was hepatitis B virus-positive. Pre-OLT plasma HIV 1-RNA level was undetectable and CD4(+) T-cell count >200 cells/microL for 3 months in all patients. Six patients had to stop highly active antiretroviral therapy (HAART) before OLT because of liver disease severity (n = 2) and for hepato cellular carcinoma (n = 4). RESULTS: The actuarial 1-, 2-, and 3-year survival rates were 83.3%, 58.3%, and 58.3%, respectively, which were significantly lower than those observed among HIV-negative patients transplanted in our center. Six patients are alive with a mean follow-up of 26 months (range: 5 to 46 months). We recorded a low rate of opportunistic infections and rejection. All alive patients have low levels of HIV RNA, and the CD4(+) T-cell counts increased after OLT. Nine patients developed early recurrence of hepatitis C requiring combination therapy with peg-interferon plus ribavirin. Significant improvement in the quality of life was observed in 7/11 patients. CONCLUSIONS: OLT in HIV-positive patients was feasible with good results in the short and medium term. Early severe HCV recurrence may be observed. Key challenges for the management of HIV(+) patients after transplantation included treatment of severe HCV recurrence and attention to the pharmacological interactions of HAART with immunosuppressive drugs.     

Orthotopic liver transplantation for autoimmune hepatitis and cryptogenic chronic hepatitis in children

BACKGROUND: Autoimmune hepatitis (AIH) and cryptogenic chronic hepatitis (CCH) are important causes of liver failure in children, frequently necessitating orthotopic liver transplantation (OLT). The aim of this study is to review disease progression and potential differences between subgroups of children with AIH and CCH. METHODS: The medical records of 65 children diagnosed with AIH or CCH between 1980 and 1998 were evaluated. RESULTS: The median age at presentation was 9 years, 8 months (range 4 months-19 years), and the median follow-up period was 8 years (range 3 months-18 years, 10 months). Forty-one patients (63%) were female. Twenty-eight patients were Hispanic, 28 were Caucasian, 8 were African-American, and 1 was Asian. Forty-three patients (66%) were diagnosed with type 1 AIH, 8 (12%) with type 2 AIH, and 14 (22%) with CCH. Forty patients (62%) underwent OLT (51% of those with type 1 AIH, 75% of those with type 2 AIH, and 86% of those with CCH). Thirteen (33%) of the transplanted patients experienced disease recurrence. African-American patients experienced a significantly higher rate of disease recurrence post-OLT than did Hispanic patients. Seven patients (11%) died, two without OLT, and five posttransplantation. CONCLUSIONS: AIH and CCH frequently necessitate OLT in children. CCH is a more aggressive disease than Type 1 AIH among children with these disorders. Ethnicity influences the rate of disease recurrence after liver transplantation.     

Hepatitis B and hepatitis C viruses in liver transplantation

Liver transplantation (LT) for end-stage liver disease (ESLD) secondary to hepatitis viruses has evolved rapidly during the last two decades. ESLD secondary to hepatitis C virus (HCV) accounts for approximately 50% of LT in the United States and Europe. Despite the decrease in the number of new HCV infections, the prevalence of advanced HCV-related liver disease is steadily increasing. In light of the near universal recurrence of posttransplantation HCV infection and our limited ability to treat recurrent disease, transplantation is in danger of being overrun by viral hepatitis, unless effective strategies can be used to treat disease, expand the donor pool of available organs, and prevent disease recurrence.In the early 1980s, results of LT for chronic hepatitis B virus infection were hampered by recurrent infection and subsequent allograft failure. However, with the introduction of passive immunoprophylaxis with hepatitis B immunoglobulin and treatment with potent nucleoside analogs, there has been a resurgence of LT for hepatitis B virus-related ESLD.Despite the wide acceptance of LT as a therapy for ESLD, there is little consensus on the appropriate immunosuppressive regimens, and prophylactic and therapeutic treatments vary widely from one center to another. This review summarizes available data and highlights appropriate strategies to improve outcomes.     

Anti-IL2 induction in liver transplantation with 93% rejection-free patient and graft survival at 18 months

BACKGROUND: Induction with the use of monoclonal antibodies targeting the alpha-chain (CD25) of the high-affinity IL2 receptor may avoid many of the adverse events associated with polyclonal antibodies and significantly impact on rejection-free long-term survival in orthotopic liver transplantation (OLT). METHODS: Forty-two consecutive deceased donor primary OLT were retrospectively analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after OLT) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels), and steroids (methylprednisolone 1 g intraoperatively followed by tapering doses). Mycophenolate mofetil (MMF) 1 g every 12 h was added to the drug combination as needed. The mean follow-up period was 19.3 months (range: 4.8-35.9 months). RESULTS: The average Model for End-Stage Liver Disease score was 26 (range: 15-40). A total of 39 patients (93%) remained rejection-free during follow-up with an actuarial rejection-free probability of 95% within 3 months. The actuarial patient and graft survival rate (Kaplan-Meier estimated) at 2 years was 93%. Twenty-five patients (60%) were completely off steroids within 3 months post-OLT (mean: 51.1 days, range: 10-90 days). By the 10th month post-OLT, 30/39 (77%) of the patients were completely off steroids. At last follow-up, 30/39 (77%) are on tacrolimus monotherapy with an average dose of 4 mg per day. Six patients (15%) are on double therapy, receiving a combination of tacrolimus and prednisone (two patients) or tacrolimus and MMF (two patients) or tacrolimus and mycophenolic acid (two patients). Only three patients (8%) are receiving triple therapy at last follow-up. Nine patients (21%) experienced at least one episode of infection. Only six (26%) of a total of 23 hepatitis C virus (HCV) recipients developed histology-proven HCV recurrence, with a mean onset of recurrence post-OLT of 3.2 months (range: 1.3-6.3 months). Of these six patients, two are presently undergoing treatment with interferon and ribavirin, one was treated and became HCV RNA negative, one was not treated, one declined treatment, and two died of HCV recurrence. None of the 42 study patients developed cytomegalovirus infection or posttransplant lymphoproliferative disease. CONCLUSIONS: These preliminary data suggest that basiliximab, given in combination with a tacrolimus-based immunosuppressive regimen, is safe and associated with a low incidence of acute rejection and excellent short-term rejection-free graft and patient survival rate after OLT.     

Induction immunosuppression with rabbit antithymocyte globulin in pediatric liver transplantation.

Routine use of rabbit antithymocyte globulin (RATG) induction therapy remains controversial in pediatric liver transplantation. We reviewed our experience of 18 cadaveric liver transplants in 18 children over a span of 2 years. All patients received the same immunosuppression: perioperative steroid therapy with taper, 3 doses of RATG, and maintenance therapy of steroids and tacrolimus started on postoperative day 3. Mean follow-up was 2.2 +/- 0.2 years. End-stage liver disease was secondary to biliary atresia in 10 patients (56%) and metabolic disorders in 4 patients (22%). Graft and patient survival were 89%. Serum bilirubin was 1.2 mg/dL, 1.1 mg/dL, 0.5 mg/dL, and 0.5 mg/dL at 1, 3, 6, and 12 months, respectively. The 2 mortalities were secondary to multiple organ system failure. Overall rejection rate was 17% (3/18). Rejection episodes occurred at 4, 6, and 7 months. Two patients were treated with steroids; the third was treated with OKT3. No patient has developed posttransplant lymphoproliferative disease. Serum creatinine was 0.7 mg/dL, 0.6 mg/dL, 0.6 mg/dL, and 0.6 mg/dL at 1, 3, 6, and 12 months, respectively, among surviving patients. In conclusion, our data suggest that RATG induction with steroid and tacrolimus maintenance therapy is safe, easy to use, and effective in the prevention of rejection.     

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.