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Organ Transplantation ►Autograft - describes tissue transfer within the same individual (e.g., skin graft). ► Isograft - describes tissue transfer between genetically identical individuals (e.g., identical twins). ► Allograft - describes tissue transfer between genetically nonidentical members of the same species (includes living related donor and cadaver donor human transplants). Immunosuppression is required ► Xenograft - describes tissue transfer between different species. Immunosuppression is required. 5/7/2017 Dr.yekehfallah-PHd of nursing 2 Surgical Position ► Orthotopic: The old organ is removed, and the new one is placed in the same position. ►Heterotopic: The new organ is placed in a different position 5/7/2017 Dr.yekehfallah-PHd of nursing 3 Donors ► Cadaver donors are individuals with severe brain injury resulting in brain death, which is defined as complete irreversible cessation of all brain function, including the brain stem ► Diagnosis: The mainstay of diagnosis is the neurologic examination, which must demonstrate unresponsiveness, absence of spontaneous movement, and absence of reflexes from the brain stem and higher 5/7/2017 Dr.yekehfallah-PHd of nursing 4 ►The patient must be normothermic. ►Depressant drugs (especially barbiturates) must not be present. ►An apnea test result must be negative (i.e., no respiratory effort despite a high arterial carbon dioxide level). ►Electroencephalogram (EEG) and cerebral blood flow studies are optional. 5/7/2017 Dr.yekehfallah-PHd of nursing 5 Causes Cerebrovascular disease is most common followed by trauma 5/7/2017 Dr.yekehfallah-PHd of nursing 6 Mechanism of Cerebral Death 5/7/2017 Dr.yekehfallah-PHd of nursing 7 Causes of Brain Death Trauma Cerebral Hemorrhage Normal Subarachnoid Hemorrhage 5/7/2017 Dr.yekehfallah-PHd of nursing Cerebral Anoxia 8 exclusions ► Disseminated or uncured Extracranial cancers, sepsis, or poor organ function ►not contraindicated to donation 5/7/2017 Dr.yekehfallah-PHd of nursing 9 Living donors are individuals motivated by altruism ► Living unrelated donors on average share no more genes with a recipient than a cadaver donor. An example is the patient's spouse. ►Living related donors share a substantial portion of their genomes with the recipient 5/7/2017 Dr.yekehfallah-PHd of nursing 10 Requirements Living donors must be in almost perfect health, have normal function of the organ under consideration, and be good candidates for anesthesia and the operative procedure. The workup includes: ► ABO typing, tissue typing, and cross matching ► Complete history and physical examination; chest radiography; ECG; complete blood count ► 24-hour creatinine clearance and protein; serology for hepatitis B and C, CMV, and HIV; urinalysis; PPD ► For renal donors, arteriography and intravenous pyelogram (now combined as a helical computed tomography [CT] scan). 5/7/2017 Dr.yekehfallah-PHd of nursing 11 Risks ► Perioperative mortality for living kidney donors is 0.03% (3 per 10,000). ► A living donor provides one kidney, and the remaining kidney hypertrophies and achieves 80% of creatinine clearance before donation. ► Newer procedures include donation of the left lateral segment or a lobe of the liver and segment(s) or lobe(s) of the lung. ► 5/7/2017 Dr.yekehfallah-PHd of nursing 12 Risks ► ► In these procedures, the safety of the donor is not assured. ► Although, traditionally, most living kidney donations are performed as an open surgical procedure, there is increasing experience with laparoscopically performed nephrectomy. ► This method potentially offers the advantage of minimally invasive surgery while still producing an excellent kidney. 5/7/2017 Dr.yekehfallah-PHd of nursing 13 5/7/2017 Dr.yekehfallah-PHd of nursing 14 Removal of the donor organ ►The donor organ is removed in a formal surgical procedure, wherein the blood supply of the organ is controlled and then the organ is rapidly flushed with a cold (4 0C) solution to render it cold and ischemic. All organs are more tolerant of cold ischemia than warm (normothermic) ischemia 5/7/2017 Dr.yekehfallah-PHd of nursing 15 VIASPAN ► pentafraction 50 g, ► lactobionic acid 35.83 g, ► potassium phosphate monobasic 3.4 g, ► magnesium sulfate heptahydrate 1.23 g, ► raffinose pentahydrate 17.83 g, ► adenosine 1.34 g, ► allopurinol 0.136 g, ► total glutathione 0.922 g, ► potassium hydroxide 5.61 g, ► sodium hydroxide ► hydrochloric acid adjust to pH 7.4, ► water for injection q.s. ► The solution has an approximate calculated osmolarity of 320 mOsM, a sodium concentration of 29 mEq/L, and a potassium concentration of 125 mEq/L, and a pH of approximately 7.4 at room temperature. Litre bags of 1 000 mL. 5/7/2017 Dr.yekehfallah-PHd of nursing 16 ►The limit of cold ischemia with current preservation methods is 4 hours for the heart, 6 hours for a lung, 12 hours for the liver, 36 hours for the pancreas, and 40– 48 hours for a kidney. As the limit is approached or passed, the risk increases for delayed function, damage, or nonfunction of the organ 5/7/2017 Dr.yekehfallah-PHd of nursing 17 The immunologic compatibility of the donor and recipient influences the outcome for any type of organ transplant 5/7/2017 Dr.yekehfallah-PHd of nursing 18 5/7/2017 Dr.yekehfallah-PHd of nursing 19 ► ABO blood group compatibility. The same rules apply as for red blood cell transfusions ► The recipient's serum is tested for the presence of cytotoxic antibodies directed against surface antigens (usually antihuman leukocyte antigen [HLA]) on the T lymphocytes of the donor. If antidonor cytotoxic antibodies are present, the donor is unacceptable because the recipient's antibodies will immediately attack the new kidney and rapidly destroy it (hyperacute rejection; The recipient's serum is tested for the presence of cytotoxic antibodies directed against surface antigens (usually antihuman leukocyte antigen [HLA]) on the T lymphocytes of the donor. 5/7/2017 Dr.yekehfallah-PHd of nursing 20 5/7/2017 Dr.yekehfallah-PHd of nursing 21 ► A positive crossmatch is positive for the presence of preformed antidonor antibodies in the serum of the prospective recipient and precludes transplantation between that donor and the recipient. ► A negative crossmatch (i.e., absence of antidonor antibodies) is mandatory before the transplant. ► A few patients have antibodies against most other humans (so-called high panel-reactive antibody [PRA] patients).High-PRA patients have formed antibodies against a high proportion of a panel of human cells , which is used to screen for reactivity; therefore, acceptable donors are difficult to find. Also, high-PRA patients are at higher risk for early graft failure. 5/7/2017 Dr.yekehfallah-PHd of nursing 22 Human Leukocyte antigen (HLA) ►Six human HLA genes (HLA-A, -B, -C, -R, DP, and -DQ) are located on chromosome 6. ►HLA-C, -DP, and -DQ are not believed to be important in clinical transplantation 5/7/2017 Dr.yekehfallah-PHd of nursing 23 ► The contents of each chromosome 6 is a haplotype, and all humans have two of these chromosomes—one from the mother and one from the father. Therefore, six HLA antigens are defined by tissue typing (i.e., two each for HLA-A, -B, and -DR). ► HLA-A and -B have more than 40 defined types, which are designated numerically. HLA-DR has more than 10 defined types. An example of an HLA type is HLA-A2, 27; B1, 44; DR 3, 7. An example of a haplotype is HLA-A2; B1; DR7 5/7/2017 Dr.yekehfallah-PHd of nursing 24 Rejection The three types of rejection are: ►hyperacute ►acute ►chronic 5/7/2017 Dr.yekehfallah-PHd of nursing 25 Acute rejection • is a cell-mediated immune response initiated by helper T cells. The pace of proliferation of alloreactive T cell clones dictates that acute rejection usually occurs after the sixth post-transplant day. In some cases, a memory immune response can trigger cellular rejection sooner 5/7/2017 Dr.yekehfallah-PHd of nursing 26 ► 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 27 5/7/2017 Dr.yekehfallah-PHd of nursing 28 Chronic rejection usually occurs late. It has an insidious onset and is multifactorial, with both the cellmediated and humoral arms of the immune system involved. Chronic rejection is poorly understood and therefore not treatable or reversible. 5/7/2017 Dr.yekehfallah-PHd of nursing 29 5/7/2017 Dr.yekehfallah-PHd of nursing 30 Immunosuppression ►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”). 5/7/2017 Dr.yekehfallah-PHd of nursing 31 ► Immunosuppression attempts to disable or destroy, components of the immune response (typically lymphocytes). CONVENTİONAL is created by drug therapy; administration of biologic reagents (sera); and, rarely, radiation therapy. MULTIPLE DRUG THERAPY is standard and ims for synergistic immunosuppression while minimizing the side effects. 5/7/2017 Dr.yekehfallah-PHd of nursing 32 ►Immunosuppression can be loosely classified into THREE TYPES: ►induction regimens ►antirejection regimens ►maintenance therapy 5/7/2017 Dr.yekehfallah-PHd of nursing 33 ► Induction regimens aim to avoid rejection and establish good graft function within the first two post-transplant weeks. Induction regimens use an antilymphocyte serum plus part of the maintenance regimen, 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 5/7/2017 Dr.yekehfallah-PHd of nursing 34 ► Antirejection regimens are highdose, 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 35 ► 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 5/7/2017 Dr.yekehfallah-PHd of nursing 36 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 37 ► Methylprednisolon is used intravenously for induction or antirejection therapy. ► Prednison or prednisolon is given orally as maintenance therapy With good bioavailability. ► Side effects are common and include obesity, cushingoid facies, poor wound healing, atrophic skin, striae, and acne. 5/7/2017 Dr.yekehfallah-PHd of nursing 38 ►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 5/7/2017 Dr.yekehfallah-PHd of nursing 39 Calcineurin inhibitors ►have become the mainstays of most immunosuppressive regimens owing to their superior effectiveness. ►These drugs block the calcineurindependent pathway of helper T-cell activation, thus blocking transcription of cytokine genes that initiate and amplify the immune response 5/7/2017 Dr.yekehfallah-PHd of nursing 40 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 41 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 42 5/7/2017 Dr.yekehfallah-PHd of nursing 43 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 5/7/2017 Dr.yekehfallah-PHd of nursing 44 Azathioprine ►is a purine metabolism inhibitor. Toxicity causes leukopenia 5/7/2017 Dr.yekehfallah-PHd of nursing 45 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 5/7/2017 Dr.yekehfallah-PHd of nursing 46 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 47 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 5/7/2017 Dr.yekehfallah-PHd of nursing 48 • One agent is a humanized monoclonal antibody, dacliximab (Zenapax) and the other a mousehuman 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 longterm effects of these agents are not yet known. 5/7/2017 Dr.yekehfallah-PHd of nursing 49 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. 5/7/2017 Dr.yekehfallah-PHd of nursing 50 ? 5/7/2017 Dr.yekehfallah-PHd of nursing 51