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post-transplant day. In some cases, a memory immune response can trigger cellular rejection sooner.

The diagnosis is usually made via the detection and workup of graft dysfunction, culminating in a biopsy.

Acute rejection is treatable and reversible by a short course of high-dose immunosuppressive drugs.

When acute rejection is refractory to treatment or recurs, graft failure can result.

Acute rejection usually takes place within 3 months of transplant and rarely occurs after 1 year, unless triggered by an event such as infection or lack of adequate immunosuppression.

Chronic rejection usually occurs late. It has an insidious onset and is multifactorial, with both the cell - mediated and humoral arms of the immune system involved. Chronic rejection is poorly understood and therefore not treatable or reversible.

H Immunosuppression (Table 24-2)

Almost all allografts require indefinite suppression of the recipient's immune system to prevent rejection. This is in contrast to tolerance, in which the recipient's immune system responds normally to all antigens except those of the donor (i.e., the donor antigens are “tolerated”).

Immunosuppression attempts to disable or destroy components of the immune response (typically lymphocytes).

Conventional immunosuppression is created by drug therapy; administration of biologic reagents (sera); and, rarely, radiation therapy.

Multiple drug therapy is standard and aims for synergistic immunosuppression while minimizing the side effects.

Immunosuppression can be loosely classified into three types: induction regimens, antirejection regimens, and maintenance therapy.

Induction regimens aim to avoid rejection and establish good graft function within the first two posttransplant weeks. Induction regimens use an antilymphocyte serum plus part of the maintenance regimen (see I H 2 c), withholding one drug to avoid unwanted side effects.

The nephrotoxicity of cyclosporine and tacrolimus is of particular concern after any transplant.

Impaired healing of the bronchial anastomosis from high-dose steroids is disadvantageous after lung transplantation.

Antirejection regimens are high-dose, short-term (<3 weeks) treatments aimed at reversing acute rejection episodes. These regimens include high-dose (pulse) corticosteroids, typically methylprednisolone, antilymphocyte sera, or monoclonal antibodies.

Maintenance therapy provides long-term immunosuppression to prevent rejection. These regimens usually include two or three drugs. The principal drugs are cyclosporine or tacrolimus. One of these is combined with a corticosteroid (e.g., prednisone), and a third drug may be added. More recently, coritcosteroids have been eliminated from maintenance regimens.

Corticosteroids have broad anti -inflammatory and immunosuppressive effects. Generally, they inhibit all types of leukocytes, in contrast to the other immunosuppressive drugs, which are more lymphocyte selective.

Methylprednisolone is used intravenously for induction or antirejection therapy.

Prednisone or prednisolone is given orally as maintenance therapy. With good bioavailability, drug levels are not needed.

Side effects are common and include obesity, cushingoid facies, poor wound healing, atrophic skin, striae, and acne.

In contrast to the prevalent side effects, complications include diabetes, hypertension, osteoporosis, aseptic necrosis (usually of the hips), cataracts, peptic ulcer disease, and psychiatric disturbances. These broad complications have led many centers to successfully eliminate steroids from maintenance protocols.

Calcineurin inhibitors have become the mainstays of most immunosuppressive regimens owing to their superior effectiveness. These drugs block the calcineurin -dependent pathway

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of helper T -cell activation, thus blocking transcription of cytokine genes that initiate and amplify the immune response. This mechanism is more specific for the alloimmune response to an organ allograft than the older drugs (e.g., corticosteroids, azathioprine). Therefore, lower doses of other immunosuppressive drugs can be used, the incidence and severity of rejection are decreased, and outcomes are improved. They are typically used for maintenance therapy.

TABLE 24-2 Immunosuppressive Drugs

Cyclosporine dosing is adjusted to achieve a desired trough blood level because bioavailability is low and varies greatly.

Toxicity includes nephrotoxicity, hypertension, neurotoxicity, hirsutism, gingival hyperplasia, and hyperlipidemia.

At appropriate levels, cyclosporine does not cause progressive deterioration in renal function.

Tacrolimus (FK-506) is more potent than cyclosporine. Dosing is done by trough levels. Toxicity is similar to cyclosporine without hirsutism, hyperlipidemia, and gingival hyperplasia but with headache, diarrhea, and an increased risk of diabetes.

Antimetabolites are drugs that inhibit purine or pyrimidine metabolism, thereby inhibiting rapidly dividing cells, including clonally proliferating alloreactive T cells. They are usually used as third maintenance immunosuppressants with corticosteroids and a calcineurin inhibitor.

Azathioprine is a purine metabolism inhibitor. Toxicity causes leukopenia.

Mycophenolate mofetil is a purine metabolism inhibitor that appears to be more lymphocyte specific than azathioprine. When used as a third drug, the incidence of acute rejection is significantly decreased. Toxicity includes reversible bone marrow suppression and gastrointestinal side effects.

Antilymphocyte sera are biologic agents derived from animals immunized against human determinants. Two agents that are used for either induction or antirejection therapy are muromonab CD3 (OKT3) and antithymocyte globulin (ATG). Muromonab CD3 is a murine monoclonal immunoglobulin (IgG) to an antibody that binds to the CD3 antigen on human T cells. Antithymocyte globulin is a polyclonal antilymphocyte serum harvested from horses or rabbits, which depletes T cells.

Interleukin-2 (IL-2) receptor blockers. Two IL -2 receptor blockers have been developed. Studies have suggested that when used as part of an immunosuppressive regimen including steroids and cyclosporine, these agents can reduce the frequency of acute rejection in kidney transplant recipients. IL -2 receptor blockers bind to the IL -2 receptor alpha chain on the surface of activated T lymphocytes. One agent is a humanized monoclonal antibody, dacliximab (Zenapax) and the other a mouse -human chimeric monoclonal antibody, basiliximab (Simulect). Simulect is given at transplant and is repeated 4 days later, whereas Zenapax is given within 24 hours of transplant and then at 14 -day intervals for four doses. No significant adverse reactions or drug interactions have been reported with these agents. The long-term effects of these agents are not yet known.

Sirolimus (Rapamycin) is the newest drug. It binds to the same intracellular carrier site as does tacrolimus and may partially antagonize its effects. It is synergistic with cyclosporine. It acts at a separate, later site of T -cell activation than the calcineurin inhibitors. Side effects include hypercholesterolemia, hypertriglyceridemia, and mild bone marrow suppression.

I General complications of immunosuppression

Infections. The nonspecificity of current immunosuppression also impairs host defenses against a diverse group of pathogens (e.g., opportunistic infections).

A broad range of bacterial, fungal, and protozoal organisms are an uncommon cause of infections, but they require prompt diagnosis and treatment, as they can be lethal.

CMV is a frequent infectious problem in the early months after a transplant. The risk is related to prior exposure (serostatus), and seronegative recipients of organs from seropositive donors are at highest risk. The agent for prophylaxis and treatment of CMV infection is ganciclovir.

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Neoplasia. The three major areas of increased risk are skin cancer, post-transplant lymphoproliferative disorders (PTLDs), and oral squamous cell cancers or female genital tract cancers.

Skin cancer. Squamous cell cancers of sun -exposed skin are very common in post-transplant patients.

PTLD is a form of lymphoma, commonly arising from B cells and usually associated with EBV. Early stages may respond to acyclovir and profound reduction in immunosuppression. Later stages are treatable with chemotherapy, but the prognosis is poor.

Oral squamous cell cancers and female genital tract cancers (e.g., cervical, vaginal, labial) occur with greater frequency in post-transplant patients.

Parenthood after transplantation

Acute rejection is common. Severity is determined histologically.

Chronic rejection is manifest as graft coronary artery disease. This process has a different distribution from atherosclerotic coronary disease because it favors smaller arteries. Accordingly, it is difficult to treat with angioplasty or bypass surgery and may require retransplantation.

Hypertension and renal insufficiency from cyclosporine or tacrolimus can be difficult to manage.

Mortality. Almost 10% of recipients die in the first month after transplantation. These deaths are often related to multiple organ failure or initial graft failure. Another 5% die during the next 11 months. Patient survival at 1 year is 85%.

Long -term patient survival is 70% at 5 years. Patient survival for heart and liver recipients is very similar.

III Lung Transplantation

Lung transplantation can involve one or two lungs.

A

Candidates have end -stage pulmonary parenchymal or vascular disease. They are New York Heart Association class III or IV, and they have an anticipated survival of less than 2 years without transplantation. Abstinence from tobacco for a minimum of 6 months is mandatory. Three common indications account for 70% of candidates: emphysema or chronic obstructive pulmonary disease, including α 1 -antitrypsin deficiency (45%), primary

pulmonary hypertension (12%), and cystic fibrosis (10%).

B

Specific assessment of the following is critical.

Cardiac function. If left ventricular function is too poor, or if surgically uncorrectable congenital heart defects are present (usually Eisenmenger's syndrome), the patient is not a candidate for lung transplantation but may be considered for a heart -lung transplant.

If patients have bilateral pulmonary infections (e.g., from cystic fibrosis), they require double -lung transplants, because retention of an infected lung allows spread to the transplanted lung. Otherwise, single - lung transplants are used.

Renal and hepatic function must be adequate. Contraindications include current or recent tobacco or alcohol use and advanced pulmonary disease (e.g., ventilator-dependent conditions, intractable pulmonary infections, or excessive steroid requirements [for bronchospasm]).

C Operative strategy

Lung transplants are orthotopic, with excision of the diseased lung(s).

Lung transplantation has gained acceptance only recently. Many obstacles have appeared en route to success.

The question of whether a single transplanted lung is adequate to treat patients has been resolved affirmatively, at least for restrictive lung diseases.

Substantial difficulties with healing of the bronchial anastomosis have been improved.

The lung represents a large immunologic target, requiring more immunosuppression than most other transplants.

Single -lung transplants are performed via lateral thoracotomy. Cardiopulmonary bypass is not usually required, unless pulmonary artery pressures rise excessively or blood gases deteriorate excessively when the pulmonary artery is clamped.