Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society最新文献

*Define the various concepts of transplantation tolerance: Immunologically: unresponsiveness to donor antigens Clinically: ability to discontinue nonspecific immunosuppression Outcome-based: ability to prevent long-term immunologically mediated graft loss (i.e., chronic rejection). *Understand the various possible mechanism(s) involved in developing transplantation tolerance: Central tolerance: clonal deletion Peripheral tolerance: Blocking antibodies Cytokine imbalance Clonal T-cell anergy Active regulation of T- and B-cell proliferation. *Methods to achieve transplantation tolerance: Macrochimerism: recipient cytoablation and donor reconstitution Microchimerism: bone marrow augmentation, growth factors Intrathymic inoculation: central tolerance? T-cell costimulatory blockade: induction of T-cell anergy. *Limitations of achieving transplantation tolerance: No markers to define tolerance Poor understanding of acute and chronic rejection mechanisms (e.g., direct v indirect antigen presentation, high- v low-affinity T cells for alloantigen) What cells are involved in the development of tolerance? How stable is clinical tolerance: are the dynamics influenced by nontransplant factors (e.g., antigenic stimulation by viral factors)? Need for a two-pronged approach: nonspecific phase followed by specific phase?

Rejection of the liver allograft may be classified as massive hemorrhagic necrosis or acute and chronic rejection. Massive hemorrhagic necrosis is now rarely seen; it occurs within the first few days after transplantation and is associated with transplantation across the blood-type groups. Early acute rejection (within 28 days of transplantation) is usually of little clinical significance and responds well to additional immunosuppression, whereas later rejection is associated with a greater risk for progression to graft loss. The incidence of early, acute rejection is dependent on the immunosuppressive regimen used and will vary between 20% and 70%. Patients who undergo transplantation for hepatitis B viral infection and alcohol-related liver disease have a lower incidence of rejection compared with those who undergo transplantation for cholestatic diseases, such as primary sclerosing cholangitis and primary biliary cirrhosis. Other factors that influence the incidence of acute rejection include age, race of recipient, and preservation injury. The incidence of chronic rejection is declining; most centers report current rates of 4% to 8%, whereas in earlier series, rates of 15% to 20% were observed. The reasons for this decline are unknown, but may relate to better immunosuppression. Chronic rejection usually presents within the first year posttransplantation. The greatest risk factor for chronic rejection is transplantation for chronic rejection; other factors include indication (especially primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis); cytomegalovirus infection, and low levels of immune suppression.

Polyclonal and monoclonal antilymphocyte agents (antilymphocyte globulin, antithymocyte globulin, OKT3, anti-interleukin-2 receptor antibody) are potent immunosuppressive agents that differ fundamentally in their mechanisms of action from cyclosporine- and tacrolimus-based induction therapy. Clinical trials and retrospective studies show low rates of acute rejection can be obtained when biological antilymphocyte agents are used for induction immunosuppression in liver transplant recipients. Infectious complications are similar to those of conventional induction regimens, and the incidence of posttransplant lymphoproliferative disease is acceptably low when excessive doses are not used. Published series of liver transplant recipients have so far not shown the clear superiority of antilymphocyte induction therapy, in terms of patient and graft survival, compared with standard therapy (cyclosporine or tacrolimus plus steroids and azathioprine). At present, there is no ideal induction regimen recommended for all patients.

Whereas the impact of early (first 6 postoperative weeks) acute cellular rejection on patient survival among liver transplant recipients as a whole has been reported to be favorable, we hypothesized treatment for acute cellular rejection may have differing impacts on patient and graft survival in hepatitis C virus (HCV)-infected and HCV-negative transplant recipients. We studied the impact of immunosuppression and rejection on patient and graft survival among the 166 HCV-infected and 602 HCV-negative transplant recipients enrolled onto the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database. All data were collected prospectively. The association of early acute cellular rejection with mortality was determined using a Cox proportional hazards model with a time-dependent covariate. Median follow-up was 5.0 years for HCV-infected and 5.2 years for HCV-negative transplant recipients. HCV-infected transplant recipients experienced similar frequencies of acute cellular and steroid-resistant rejection as patients undergoing liver transplantation for most other indications. The mortality risk was significantly increased (relative risk = 2.4; P =.03) for HCV-infected transplant recipients who developed early acute cellular rejection compared with HCV-negative transplant recipients. None of the HCV-infected transplant recipients developed allograft failure secondary to chronic rejection. The choice of calcineurin inhibitor did not affect posttransplantation outcomes. Early acute cellular rejection occurs at similar frequencies in HCV-infected and HCV-negative transplant recipients. Although an episode of early acute cellular rejection is associated with a lower cumulative mortality among HCV-negative transplant recipients, the opposite is true for HCV-infected transplant recipients, who experience an increased risk for mortality after an episode of early acute cellular rejection. The adverse impact of early acute cellular rejection on patient survival should be considered in developing primary immunosuppression and acute cellular rejection treatment protocols for HCV-infected transplant recipients.

The introduction of cyclosporine (CsA) has been a major advance. Its use paved the way for successful programs in heart, lung, liver, kidney, and kidney-pancreas transplantation. The recent introduction of Neoral has overcome many of the problems associated with the use of Sandimmune (Novartis, Basel, Switzerland), including poor bioavailability, dependence on bile for absorption, and need for intravenous CsA early in the postoperative period. The use of Neoral has resulted in (1) a marked reduction in the incidence of acute cellular rejection, (2) ability to discontinue steroid therapy in the early posttransplantation period, and (3) low toxicity profiles. In direct comparison with tacrolimus, Neoral was equally efficacious and less toxic. This is even more impressive when one now realizes the monitoring of Neoral has been inadequate, and with more sensitive monitoring tools, including peak CsA level; a surrogate marker for C(max), CsA blood concentrations 2 hours after drug intake; or area under the CsA time-concentration curve, rejection rates may be improved, with improvement in toxicity profiles.

This report reviews the literature and discusses steroid withdrawal after hepatic transplantation. Our experience with steroid withdrawal is highlighted. The hypothesis is that steroid withdrawal from liver transplant recipients is safe and beneficial. A review of the English literature yielded 16 reports with a total of 901 patients (749 adults and 152 children). Most reports were nonrandomized and uncontrolled. Only two reports were randomized, controlled trials; three reports featured early steroid withdrawal (