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FOUNDATION OVERVIEW

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Rejection is a primary barrier to success of solid organ transplantation. There are three types of graft rejection that can occur after solid organ transplantation: antibody mediated, acute cellular, and chronic rejection. Antibody-mediated rejection is mediated by antibodies against donor antigens present on the vascular endothelium and typically occurs intraoperatively or within days after receiving ABO blood type mismatched or positive crossmatch organ transplant. Avoiding mismatched transplant or desensitizing recipients with donor-specific antibodies may prevent this mode of rejection, but treating antibody-mediated rejection remains challenging. Acute cellular rejection is the most common type of rejection and is generally reversible with appropriate diagnosis and timely treatment. It results from an orchestrated immune response that involves alloantigen presentation by antigen-presenting cells that leads to alloreactive T cells. The cytotoxic T cells infiltrate the graft and cause direct tissue damage, whereas the helper T cells produce cytokines to cause subsequent immunological and inflammatory events. Although acute cellular rejection can occur anytime following transplant, the risk is highest in the first several months after transplant. Prevention and treatment of acute cellular rejection is of utmost importance, as it is a significant predictor of chronic rejection. The exact etiology of chronic rejection is unknown. It is a slow process of graft fibrosis and arteriopathy, which results in graft dysfunction, usually manifested years after transplantation. While acute cellular rejection can be treated pharmacologically, the only therapy for chronic rejection is retransplantation.

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Signs and symptoms of rejection are nonspecific pain and tenderness over graft site, fever, and lethargy. If left untreated, rejection leads to clinically significant organ dysfunction. The diagnosis of rejection is made based on histological findings from a biopsy specimen of the transplant organ.

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PREVENTION OF REJECTION

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Immunosuppression Regimen

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Over the last 30 years, advances in immunosuppression have contributed to the improvement in patient and graft survival rates following solid organ transplantation largely by preventing acute cellular rejection. The goal of immunosuppression after solid organ transplantation is to prevent graft rejection and to minimize the undue side effects such as infection, malignancy, and drug toxicity. In order to achieve this goal, a combination of immunosuppressant drugs with different mechanisms of action is employed at relatively low doses. The mainstay of current maintenance immunosuppressive regimens (the “triple drug regimen”) includes a calcineurin inhibitor (tacrolimus or cyclosporine), an antiproliferative agent (mycophenolate or azathioprine), and corticosteroids (Table 19-1). The most common initial regimen consists of tacrolimus, mycophenolate mofetil, and prednisone. Typically these agents are used in high doses in the early weeks post-transplant, with dosages tapering down as the risk of acute cellular rejection decreases. In addition to the maintenance immunosuppression, antibody induction (antithymocyte globulins or basiliximab) can be used at the time of transplant in select patients. Antibody induction therapy has shown to reduce acute cellular rejection rates compared to no induction at all. In an effort to further minimize the negative ...

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