General Surgery (Board Review Series) 1st Edition
6
Immunology and Transplantation
Shawn J. Pelletier
- Immunology
- Types of immunity
- Characteristics
- of innate (natural) and acquired immunity are outlined in Table 6-1.
- Cellular immunityis predominantly mediated by T lymphocytes. Major groups include
- helper T cells (CD4+).
- cytotoxic/suppressor T cells (CD8+).
- Cytokines
- that mediate lymphocyte function are described in Table 6-2.
- The major functionsof the cellular immune response include
- regulation of antibody response.
- host defense against intracellular bacteria (e.g., Mycobacterium tuberculosis).
- host defense against viruses, fungi, and parasites.
- acute and chronic graft rejection.
- tumor rejection.
- Humoral immunity
- is predominantly mediated by B lymphocytes and plasma cells.
- The major function
- is production of antibodies.
- The antibody response to infectionis important in
- opsonization of bacteria.
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- neutralization of toxins and viruses.
- allergy (i.e., hay fever).
- pathogenesis of autoimmune disorders and hyperacute rejection.
Table 6-1. Types of Immunity
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Immunity
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Characteristics
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Examples
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Natural
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Nonspecific, innate, not acquired through contact with an antigen
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Skin and mucous membranes, natural killer cells, phagocytosis, complement cascade
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Acquired
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Specific, occurs after exposure to an antigen, may be active or passive Active: Production of antibodies or specific lymphoid cell response after contact with foreign antigen, long-term slow onset Passive: Resistance based on antibodies preformed in another host, rapid availability, short half-life
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Tetanus toxoid, resistance to mumps after receiving vaccine Antitetanus immunoglobulin
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Table 6-2. Characteristics of Cytokines
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Cytokine
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Predominant Source
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Effect
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IL-1
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Macrophages
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Activates T cells, B cells, neutrophils, epithelial cells, fibroblasts
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IL-2
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Helper T cells
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Stimulates helper and cytotoxic T cells, synergistic with IL-4 to stimulate B cells
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IL-4
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Helper T cells
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Promotes growth and differentiation of B cells, enhances synthesis of IgE, increases MHC II induction on B cells
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IL-6
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Predominantly macrophages, monocytes, T cells
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Stimulates fibroblast and B cell proliferation, and acute phase protein synthesis by the liver*
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IL-10
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Helper T cells, macrophages
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Increases MHC II on B cells, inhibits T helper response, decreases cytokine release from macrophages
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IFN-γ
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Helper T cells, cytotoxic lymphocytes
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Differentiation of B cells to IgG, kills T cells, increases MHC I and II on macrophages and other cells, antiviral
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TNF-α
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Predominantly macrophages, monocytes
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Activates macrophages and induces NO production, mobilizes neutrophils, pyrogenic, activates B and T lymphocytes
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*Acute phase proteins include ceruloplasmin, C3 complement, α1-antitrypsin, fibrinogen, C-reactive protein, and amyloid-A-protein. IL = interleukin; Ig = immunoglobulin; MHC = major histocompatibility complex; IFN = interferon; NO = nitric oxide.
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- Major histocompatibility complex (MHC) and transplantation (Table 6-3)
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- The MHC
- is located on chromosome 6.
- encodes the genes for human leukocyte antigens (HLA).
Table 6-3. Major Histocompatability Complex (MHC)
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MHC Class
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Genomic loci
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Cells Expressing Specific MHC
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Immunologic Significance
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Class I
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HLA-A, HLA-B, HLA-C
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Nearly universal to all nucleated cells
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Associated with cytotoxic or T cell function (CD8) response to antigen
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Class II
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HLA-DP, HLA-DQ, HLA-DR
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Macrophage, B cells, dendritic cells of the spleen, and Langerhans' cells of skin
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Associated with T helper function (CD4)
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HLA = human leukocyte antigen.
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- HLA proteins
- are alloantigens(i.e., they differ among members of the same species).
- Each person has 2 haplotypes, or 2 sets of these genes, maternal and paternal.
- The proteins encoded by both the maternal and paternal chromosomes are expressed (codominance).
- Class I and II antigens
- are detected in the laboratory either by
- A serologic testthat reacts lymphocytes with known specific antibodies and complement to determine cell lysis.
- Polymerase chain reaction(PCR) analysis.
- The haplotypes of class I and II antigens
- are usually determined for both the donor and recipient before kidney transplantation.
- The main lociinclude
- HLA-A.
- HLA-B.
- HLA-DR.
- A heterozygousindividual will have 6 antigens (2 of each).
- A higher frequency of matching
- of these antigens between the recipient and the donor may be associated with a lower rate of graft rejectionfor some organs.
- Attempting to match antigens
- may offer significant advantage, particularly for kidney and pancreas transplantation.
- A small advantage is probably offered for heart transplantation by HLA matching.
- HLA matching is less important for liver transplantation.
- In addition to these major antigens
- there are minor antigenscoded for by genes other than the MHC.
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- Compatibility between blood type
- (i.e., A, B, and O) encoded for by genes other than the MHC is also required for successful transplantation.
- Liver transplantation can be performed across blood type barriers.
Table 6-4. Four Main Types of Hypersensitivity Reactions
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Type
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Description
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Mechanism
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Examples
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I
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Anaphylactic
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Antigen induces IgE production and release of mast and basophil granules containing histamine, serotonin, prostaglandins
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Hay fever, asthma, urticaria
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II
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Cytotoxic
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IgG or IgM binds to antigen on cell membrane and activates complement
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ABO transfusion reaction, Goodpasture's syndrome, rheumatic fever
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III
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Immune-Complex
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Antigen and antibody form complexes that deposit in organs and may activate complement
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Arthus reaction, serum sickness, poststreptococcal glomerulonephritis
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IV
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Delayed
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CD4 T lymphocytes form mononuclear infiltrate within hours to days after exposure to antigen
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Tuberculin skin test (PPD), contact hypersensitivity
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Ig = immunoglobulin.
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- Clinical syndromes of the immune response
- Hypersensitivity reactions
- Hyperacute rejection
- is the response to preformed antibodiesthat bind to the allograft at the time of implantation.
- results in the destruction of the graft in minutes to hours.
- This typically occurs in the presence of
- ABO incompatibility.
- high titer of anti-donor class I HLA antibodies.
- Liver allografts
- are relatively resistant to hyperacute rejection.
- A panel reactive antibody (PRA) test
- can be performed by adding recipient serum to a panel of cells with known HLA to determine the percent of cells that react with the recipient serum.
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- A normal individual
- will not have anti-HLA antibodies (i.e., PRA = 0%–5%).
- An elevated PRA
- may be due to previous blood transfusions, transplantation, pregnancy, or autoimmune disorder.
- suggests an increased likelihood of a positive crossmatch.
- Crossmatching
- is used to prevent hyperacute rejection by determining if a recipient has preformed antibodies to donor lymphocyte surface antigens.
- Hyperacute rejection
- is a major barrier to transplantation from other species (i.e., xenotransplantation).
- Acute rejection
- usually occurs days to weeks after transplantation but may occur at any time after transplantation.
- Acute rejection is initiated
- by T cell dependent immunity.
- Most current immunosuppressive regimens
- are directed toward preventing acute rejection with inhibition of T cell immunity.
- Chronic rejection
- occurs months to years after transplantation.
. Chronic rejection is characterized by
- the loss of normal histologic structure.
- fibrosis.
- atherosclerosis.
- Factors contributingto chronic rejection include
- repeated bouts of acute rejection.
- drug toxicity.
- recurrent infections.
- ischemic damage at the time of harvest or transplant.
- use of older or suboptimal organs.
- noncompliance with immunosuppression.
- Prevention of chronic rejection
- requires specific attention to these causes.
- Immunosuppression
- The current clinical use of immunosuppressive agents
- depends on the organ transplanted.
- frequently varies by institution.
- General principles of immunosuppression
- Induction therapy
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- involves administering high doses of immunosuppression (usually antibody therapy) at the time of transplantation to prevent rejection.
- Maintenance therapy
- involves administering lower, less toxic doses of immunosuppressive agents following high-dose induction therapy.
- Characteristics of the various agents
- used are outlined in Table 6-5.
- Complications of immunosuppressive therapy
- are also outlined in Table 6-5.
- Immunosuppressed individuals
- are more susceptible to infectionby typical bacterial pathogens and also by unusual organisms.
- The common pathogens
- and timing of infection are demonstrated in Figure 6-1.
- Chronic suppression
- of the immune system can also lead to malignancy.
- Squamous cell carcinoma
- is the most common.
- is generally not aggressive.
- can be treated by local excision.
- Post-transplant lymphoproliferative disease (PTLD)
- is the next most common.
- may be related to malignant transformation by Epstein-Barr virus.
- Treatment includes the reduction or withdrawal of immunosuppression.
- Conventional chemotherapy and radiation therapy are used for aggressive tumors.
- Other malignancies include
- Kaposi's sarcomaand cervical carcinoma related to papilloma virus.
- The incidence of more common neoplasms
- (i.e., breast, lung, and colon) may be slightly increasedin the transplant population.
III. Classification of Organ Transplants
- An autograft
- is the transfer of an individual's own tissue from one site to another.
- is not associated with a specific immune response against the tissue.
- An isograft (syngeneic graft)
- is transplantation between identical twins.
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- is accepted without immunosuppression (e.g., the first successful kidney transplant).
Table 6-5. Clinical Immunosuppressive Agents
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Drug
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Mechanism of Action
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Clinical Use
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Side Effects
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Glucocorticoids
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Hormone receptor-steroid complex binds to DNA, alters transcription and translation, affects T cells and macrophages
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Key component of maintenance therapy, treatment for rejection
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Cushingoid features, hypertension, weight gain, hyperglycemia/glucose intolerance, osteoporosis poor wound healing, pancreatitis, peptic ulcer, psychosis
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Azathioprine
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Inhibits purine synthesis, blocks RNA/DNA synthesis; affects T cells > B cells
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Maintenance therapy: allows lower doses of glucocorticoids and cyclosporine
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Leukopenia, thrombocytopenia, hepatitis, pancreatitis, dermatitis, alopecia, infections
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Mycophenolate mofetil
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Inhibits inosine monophosphate dehydrogenase, blocks DNA synthesis; more specific for lymphocytes
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Decreases incidence of rejection versus azathioprine in renal transplantation
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GI symptoms (e.g., nausea, diarrhea, cramping), leukopenia, anemia, infections
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Cyclosporine
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Binds to cyclophilin (an isomerase enzyme); decreases IL-2 and other cytokine release from T cells
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Induction therapy and maintenance
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Nephrotoxicity, hypertension, hyperkalemia, hyperuricemia, gout, gingival hypertrophy, hirsutism, tremors, seizures, hyperglycemia, hemolytic uremic syndrome
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Tacrolimus FK506)
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Binds to FK binding proteins, effects similar to cyclosporine
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Induction and maintenance therapy, “rescue” of grafts failing on cyclosporine
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Nephrotoxicity, neurotoxicity, diabetes
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Antithymocyte globulin (ATG)
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Polyclonal antibodies directed against T cell receptors (CD2, CD3, CD4, CD8) as well as B cells, monocytes, and granulocytes
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Induction therapy, treatment of steroid resistance, recurrent, or severe rejection
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Fever, chills, nausea, vomiting, leukopenia, thrombocytopenia, myalgia/arthralgia, diarrhea, headache, rash, pruritis, urticaria, phlebitis
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OKT3
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Murine monoclonal antibody directed against the CD3 complex on T cells
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Induction therapy, treatment of steroid resistant, recurrent, or severe rejection
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Cytokine release syndrome, fever, chills, dyspnea, wheezing, pulmonary edema, tachycardia, hypotension, anaphylaxis
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GI = gastrointestinal; IL = interleukin.
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Figure 6-1. Major pathogens and usual timing for infections after organ transplantation. (Adapted with permission from Rubin RH, Wolfson JS, Cosimi AB, Tolkoff-Rubin NE: Infection in renal transplant recipients. Am J Med 1981;70:406.) CMV = cytomegalovirus; GI = gastrointestinal; HSV = herpes simplex virus; VZV = varicella-zoster virus.
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- An allograft (homograft)
- is a graft between genetically different members of the same species (i.e., from one human to another).
- A xenograft (heterograft)
- is a graft transplanted between 2 species (e.g., a baboon heart to a human recipient).
- These result in hyperacute rejectionin an immunocompetent host.
- Xenograft transplantation is currently undergoing experimental evaluation for clinical application.
- Kidney Transplantation
- Donors for kidney transplants
- come from 3 sources:cadaver, living related, and living unrelated donors.
- All donors, both living and cadaveric, should
- have good renal function.
- be free of systemic infection or cancer (except for a primary brain tumor).
- be screened for human immunodeficiency virus (HIV) and hepatitis.
- Renal recipients
- About 30% have a living relative suitable for donation.
- The relative must be
- ABO compatible.
- in good medical and psychological condition.
- of legal age.
- willing to donate.
- Living donors
- have a low risk of complications.
- The remaining kidney hypertrophies
- and provides up to 80% of the original renal function after several months.
- The most common complication
- is wound infection(~ 1%).
- The most common cause of death
- (~ 1 in 5000) is pulmonary embolus.
- Laparoscopic donor nephrectomy can now be safely performed.
- Donor evaluation
. Before donation, donors should be evaluated with
- history and physical.
- chest radiograph.
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- electrocardiogram (ECG).
- urinalysis.
- complete blood count.
- blood urea nitrogen (BUN).
- creatinine (Cr).
- Suitable donorsshould then be evaluated with
- an arteriogram.
- spiral computed tomography (CT) scan, or magnetic resonance imaging (MRI).
- Organs with multiple renal arteries will require anastomosis of the small accessory arteries.
- Small accessory renal veins may be ligated.
- The need for cadaver donors
- far outweighs the supply.
. Brain death must be established
- before removal of organs.
- Clinical criteria for brain death
- are the absence of spontaneous respiration, cranial reflexes, and response to stimuli.
- A known cause for the condition must exist over a period of time, and must be irreversible.
- Confirmatory findings include
- absence of cerebral blood flow.
- an isoelectric electroencephalogram.
- sustained apnea in the presence of an elevated CO2.
- Organs are removed
- before or shortly after cardiac arrest.
- Solutions used to preserve the organs
- after harvest and before transplantation include Euro-Collinsor University of Wisconsin (UW) solution.
- These contain large sugars not absorbed by cells creating an osmotic gradient that prevents swelling of cells.
- Antioxidants, electrolytes, and nutrients are also present.
- The kidney
- should then be transplanted within 30 hoursto prevent a high rate of acute tubular necrosis.
- may also be preserved for 3 days with continuous pulsatile perfusion.
- Disease states
- leading to the need for renal transplantationare listed in Table 6-6.
- Most patients
- will require hemodialysisor peritoneal dialysis while awaiting the availability of a suitable organ.
- Recipients receiving an organ from a living donor
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- may be transplanted before the need for dialysis.
Table 6-6. Causes of End-Stage Organ Disease Leading to Transplantation*
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Kidney
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Liver
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Pancreas
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Heart
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Heart-Lung
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Lung
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Diabetes mellitus (30%) Glomerulonephritis (25%) Hypertension Polycystic kidney disease Reflux pyelonephritis Goodpasture's syndrome Congenital renal hypoplasia Renal cortical necrosis Alport's syndrome Systemic lupus erythematosus
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Hepatitis C (30%) Alcoholic cirrhosis (25%) Hepatitis B Autoimmune hepatitis Cryptogenic hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Fulminant hepatic failure Malignant neoplasms Biliary atresia Budd-Chiari syndrome Wilson's disease Hemochromatosis α1-antitrypsin deficiency
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Insulin-dependent diabetes mellitus
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Ischemic cardiomyopathy (40%) Idiopathic cardiomyopathy (35%) Congenital cardiomyopathy Familial cardiomyopathy
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Primary pulmonary hypertension Fibrotic lung disease Cor pulmonale Cystic fibrosis Congenital heart disease with Eisenmenger's syndrome α1-Antitrypsin deficiency
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Chronic obstructive pulmonary disease (30%) Idiopathic pulmonary fibrosis (17%) α1-Antitrypsin deficiency Cystic fibrosis Primary pulmonary hypertension Sarcoidosis Idiopathic bronchiectasis Lymphangiomyomatosis Pulmonary fibrosis from previous chemotherapy or radiation therapy
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*Percent given in parentheses for more common indications.
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- Few absolute contraindications exist
- for kidney transplantation recipients.
- Children younger than 1 year old and adults older than 70 have received transplants.
- Absolute contraindications include
- active malignancy.
- septicemia.
- severe cardiopulmonary debilitation.
- Five-year survivaland quality of life are improved in renal transplant recipients compared to those on hemodialysis.
- Five-year survival of a diabetic patient on dialysis is ~ 40%.
- Surgical procedure
- The renal graft
- is commonly placed in the iliac fossavia an oblique, lower abdominal incision (heterotopic).
- The donor renal artery
- and vein are anastomosed to the recipient's iliac artery and vein, respectively.
- Continuity of the urinary tract
- is often reestablished by ureteroneocytostomy (donor ureter to recipient bladder).
- A Foley catheteris used for several days postoperatively to decompress the bladder and protect the anastomosis.
- Bilateral nephrectomies
- Indications for bilateral nephrectomiesinclude
- polycystic kidney disease with recurrent infections.
- recurrent hematuria requiring multiple transfusions.
- refractory, severe hypertension.
- Complications
- Vascular complications
- occur in less than 1% of recipients.
- Renal artery stenosis
- may result in severe hypertensionand be secondary to rejection.
- Renal vein thrombosis
- or iliofemoral thrombosis may be treated with anticoagulation or urokinase.
- Urine extravasationmay occur because of
- ureteroneocystostomy leakage.
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- ureteral necrosis.
- ureteral obstruction.
- Surgical intervention is often required.
- A lymphocele
- may occur from leakage of nearby lymphatics in the iliac fossa.
- Lymphoceles may become infected or large enough to obstruct the ureter or renal vasculature.
- These frequently need to be drained surgically.
- Recipients may experience complications
- of immunosuppression (see II D) including cyclosporine-induced or tacrolimus-induced nephrotoxicity.
- Acute cellular rejection
- usually occurs within the first 3 months but may occur sooner or years later.
. Diagnosis
- is made by multiple findings.
- Signs and symptomsmay include
- fever.
- malaise.
- oliguria.
- hypertension.
- tenderness over the graft.
- Laboratory evaluation
- of blood and urine usually reveal a rising BUN and serum Cr.
- A renal ultrasound
- may be useful in ruling out obstruction of the ureter and for assessing blood flow to the kidney.
- A radioisotope perfusion scanmay be useful to evaluate
- renal blood flow.
- tubular function.
- the patency of the ureter.
- Percutaneous kidney biopsy
- is frequently used to evaluate patients with suspected rejection.
- The differential diagnosisincludes
- infection
- acute tubular necrosis from preservation injury or ischemia.
- cyclosporine nephrotoxicity.
- urinary obstruction or extravasation.
- return of original disease.
- chronic rejection.
- Treatment to prevent loss of allograft
- includes the prompt administration of antirejection therapy [e.g., high-dose steroids, OKT3, or antithymocyte globulin (ATG)].
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- Liver Transplantation
- A suitable liver donor
- is usually a brain-dead, heart-beating donor.
- Preferably, donors
- are hemodynamically stable.
- have acceptable liver function tests.
- have serum Na+less than 170.
- Features that predict poor graft functioninclude
- steatosis in over 30% of hepatocytes.
- cold preservation time over 18 hours.
- increasing donor age.
- Reduced-size grafting
- (i.e., transplantation of the left lobe or left lateral segment only) can be used to transplant an adult liver to an adult or pediatric recipient.
- Success of reduced-size grafting has led to living-related liver transplantationat some centers.
- Causes of end-stage liver disease
- leading to liver transplantation are listed in Table 6-6.
- Transplantation is indicated
- when the chance of a life-threatening complication occurring over a 1–2 year period is estimated to be greater than 50%.
- Contraindications to transplantationin a recipient include
- extrahepatic malignancy.
- septicemia.
- severe cardiopulmonary disease.
- active substance abuse (e.g., alcohol).
- Surgical implantation of the liver
- includes the associated factors below.
- Hemodynamic instability
- may occur during clamping of the inferior vena cava (IVC).
- may be avoided by using venovenous bypass.
- Revascularization of the allograft
- is commonly performed by anastomosis of the donor suprahepatic-IVC, infrahepatic-IVC, portal vein, and hepatic artery to corresponding structures in the recipient.
- Biliary tract continuity
- is commonly performed by choledochocholedochostomy(anastomosis of donor to recipient bile duct) or choledochoenterostomy.
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- Post-transplant complications
- Technical complications include
- bleeding.
- hepatic artery thrombosis.
- portal vein thrombosis.
- biliary stenosis and leaks.
- intra-abdominal infection.
- Primary nonfunctionimmediately after implantation requires retransplantation within 5–7 days.
- Complications
- of infection and immunosuppression may also occur (see II D and Table 6-5).
- Acute allograft rejection
- occurs in ~50% of liver recipients.
- is most common within the first 4 weeks after transplantation.
- Symptoms
- are nonspecific and include fever and general malaise.
- Liver function tests
- Evaluation includes
- Doppler ultrasoundto assess hepatic blood flow.
- Percutaneous liver biopsy
- The differential diagnosis includes
- the technical complications listed in Section V D 1 and drug toxicity.
- Survival
- Overall 1-year survival is ~ 80% – 85%.
- Pancreas Transplantation
A.
A pancreas is typically procured from someone who
- is a heart-beating donor.
- is 3–55 years old.
- does not have acute pancreatitis or pancreatic injury.
- does not have a history of diabetes.
- Organs are preserved safely
- for 20–30 hoursusing UW solution and hypothermia.
- Living related segmental grafts
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B.
The indication for pancreatic transplantation
- although controversial, includes Type I insulin-dependent diabetes mellitus.
- If possible, transplantation should be performed before the development of end-stage complications.
- These complications include
- blindness caused by retinopathy.
- disabling neuropathy.
- extensive vascular disease.
- end-stage nephropathy.
- These are not, however, contraindicationsto transplantation.
- In patients with renal failure, transplantation
- can occur prior to, at the same time as, or after kidney transplantation.
- Contraindications to transplantation are
- similar to those for kidney transplantation (see IV C).
- Multiple techniques exist
- for the recipient transplant operation.
- The arterial blood supply is reconstructed
- using the donor celiac axis or donor iliac artery.
- Pancreatic exocrine drainage
- via donor duodenum can be established enterically or into the bladder (Figure 6-2).
- Measuring urinary amylase
- after a bladder anastomosis allows for early detection of rejection.
- A bladder anastomosisis associated with metabolic acidosis from
- HCO3- loss in the urine.
- hematuria.
- urethral strictures.
- frequent urinary tract infections.
- reflux pancreatitis.
- Complications may include
- pancreatic thrombosis.
- peripancreatic fluid collections.
- adult respiratory distress syndrome.
- bleeding.
- pancreatic fistula formation.
- Monitoring for rejection
- Hypoglycemia
- may occur after irreversiblerejection occurs.
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- Rejection of a renal allograft
- usually occurs before pancreatic rejection.
- can be useful if both were transplanted simultaneously.
- Urinary amylase monitoring
- is useful if a bladder anastomosis was performed.
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Figure 6-2. Vascular and bladder anastomoses in a kidney and pancreas transplantation. (Adapted with permission from Sollinger SW, Knechtle SJ: Pancreas Transplantation. In:Textbook of Surgery: The Biological Basis of Modern Surgical Practice, 15th ed. Edited by David C. Sabiston, Jr. Philadelphia, WB Saunders, 1996, p 474.)
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- Survival
- Overall 1-year survival is ~ 90%.
VII. Heart Transplantation
A.
Characteristics of suitable brain-dead cardiac donors generally include
- being younger than 60 years old.
- no history of cardiac disease.
- normal ECG and echocardiogram.
- ABO compatibility.
- donor within 20%–50% of recipient size.
- minimal vasopressor support.
B.
Allografts can be preserved with
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- cardioplegia and hypothermia for 4 hours.
C.
Recipients usually have Class IV heart failure
- [New York Heart Association (NYHA) classification] with less than 1 year expected survival.
- Common causes of heart failure
- that require transplantation are listed in Table 6-6.
- Recipients must have cardiac disease
- not amenable to conventional medical or surgical therapy.
- Pulmonary hypertensionin the recipient is associated with
- increased perioperative morbidity and mortality.
- an increased risk of graft failure.
- Recipients should also be HIV-negative
- and free of malignancy or active infection.
- Donor and recipient operations
- are done in concert because of a relatively short cold preservation time.
- The recipient heart
- is excised, leaving portions of the right and left atria.
- The donor right and left atria
- are trimmed appropriately and then anastomosed to the corresponding donor atria.
- The aortic and pulmonary anastomoses
- The heart rate
- is initially supported by isoproterenol or atrial pacing because the graft is denervated.
- Post-transplant complications include
- immunosuppression toxicity.
- infection, including mediastinitis and sternal wound infection.
- accelerated allograft coronary artery disease.
- Diagnosis
- of cardiac rejection can be difficult.
- Clinical signsinclude the new onset of
- cardiac arrhythmia.
- fever.
- malaise.
- hypotension.
- shortness of breath.
- Echocardiography
- is frequently used to characterize a poor functioning heart secondary to rejection.
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- Routine endomyocardial biopsies
- remain the mainstay of diagnosis.
- Survival
- Overall 1-year survival is ~ 80%–90%.
VIII. Combined Heart–Lung Transplantation
- For combined heart–lung transplantation
- a close size matchis necessary, with the donor being either smaller or the same size as the recipient.
- The donor lungsshould
- demonstrate adequate gas exchangewith
- the PO2higher than 400 mm Hg on 100% O2.
- normal compliance demonstrated by peak airway pressures of less than 30 mm Hg with normal tidal volumes.
- They should also be
- absent of purulent secretions.
- clear on chest radiograph.
- The donor heart and lungs are removed
- en blocand can be preserved for 4 hours.
- Indications for heart–lung transplantation
- are listed in Table 6-6.
- General indications include end-stage disease in both organs or end-stage disease in one organ with poor function in the other, prohibiting single organ transplantation.
- The surgical procedure involves
- transplantation of the heart and lungs en bloc by anastomosis of the trachea, right atrium, and aorta.
- Post-transplant complications include
- those related to infections and immunosuppression.
- those seen with heart or lung transplant individually (see VII E).
- Most recipients experience
- an episode of rejection within the first 2 weeks.
- Rejection in the heart
- does not necessarily correspond to that seen in the lung, which is more common.
- Routine endomyocardial biopsies
- Rejection of a lung allograft is diagnosed on clinical parametersincluding
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- decreased oxygenation.
- infiltrate on chest film.
- fever and general malaise.
- characteristic histologic findings of rejection on transbronchial lung biopsy.
- Bronchiolitis obliterans
- may represent a form of chronic rejection in the lung.
- occurs in ~ 50% of recipients.
- begins to appear several months after transplantation.
- Patients developshortness of breath and have a decreased forced expiratory flow (FEF)25%–75%.
- Treatmentprimarily involves increased immunosuppression, but is generally not very effective.
- Strictures and breakdown of bronchial anastomoses
- may occur and usually represent the presence of ischemia.
- Lung Transplantation
- Criteria for potential donors
- are similar to those described for cardiopulmonary transplantation (see VIII A 1).
- Eligible lung transplant recipients
are those with
- end-stage lung disease.
- a life expectancy of 1–2 years.
- Common causes of lung disease
- requiring transplantation are listed in Table 6-6.
- Contraindications to transplantationinclude
- uncontrolled sepsis.
- active malignancy.
- continued smoking.
- The surgical procedure
- may involve a single or bilateral lung transplantation.
- Potential recipients with cystic fibrosis or other septic lung disease usually undergo bilateral lung transplantation.
- Post-transplant complications
- are similar to those described for the lung under heart–lung transplantation (see VIII D).
- Survival
- Overall 1-year survival for single lung transplantationis ~ 65%.
- Overall 1-year survival for bilateral lung transplantationis ~ 70%.
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Review Test
Directions: Each of the numbered items or incomplete statements in this section is followed by answers or by completions of the statement. Select the ONE lettered answer or completion that is BEST in each case.
- A 47-year-old man with a history of alcoholic liver disease (his last drink was over 3 years ago) is admitted to the intensive care unit because of variceal bleeding. During evaluation for blood transfusions, he is found to have blood type A1. During the first 7 days in the ICU, he develops ascites refractory to medical therapy, encephalopathy, and hepatorenal syndrome. Because he is not expected to survive more than another week, he is listed for liver transplantation. Which of the following is the most appropriate donor organ for this patient?
(A) The left hepatic lobe from his 17-year-old son
(B) A liver from a brain-dead 38-year-old man with human immunodeficiency virus (HIV)
(C) A liver from a brain-dead 38-year-old man with hepatitis C
(D) A pig liver
(E) A liver from a donor with blood type O+
1–E. The patient described has acute or chronic hepatic failure and is not expected to live beyond 7 days. He is, therefore, a United Network for Organ Sharing (UNOS) status IIA and requires urgent liver transplantation. Although not ideal, living related liver donation is acceptable, however, the donor should be 18 years or older. Transplantation from donors with hepatitis C has a high rate of occurrence of these viral infections in the recipient. Xenotransplantation is experimental at this time. Liver transplantation can be performed across blood type barriers (e.g., B donor, O recipient) but this is associated with a decreased survival. A donor with blood type O, however, is an appropriate donor for liver transplantation.
- A 27-year-old woman develops oliguria 10 days after an uncomplicated kidney transplant. Evaluation includes a kidney biopsy that demonstrates a lymphocytic infiltrate in the tubular interstitium. Because she does not respond to steroid boluses over several days, a repeat biopsy is performed. OKT3 therapy is started for steroid resistant rejection. That afternoon, the patient develops severe rigors, a temperature of 39.3°C, a blood pressure of 89/64 mm Hg, and shortness of breath. Which one of the following is the most likely explanation for these findings?
(A) Fluid overload due to renal insufficiency
(B) Treatment with OKT3
(C) Cytomegalovirus viremia
(D) Renal graft rejection
(E) Pneumocystis carinii pneumonia
2–B. Cytokine release syndrome from treatment with OKT3 is the most likely explanation for the findings described. The binding of OKT3 to CD3 antigens on T cells leads to the release of cytokines, resulting in symptoms similar to this patient's. Cytokine release syndrome is associated most commonly with the first dose. Pretreating with diphenhydramine, acetaminophen, steroids, and narcotics can reduce the symptoms. Fluid overload is not commonly associated with fevers and rigors. Cytomegalovirus and Pneumocystis cariniipneumonia do not commonly occur within the first month after transplantation. Allograft rejection itself is associated with fever but would be less likely to explain the other symptoms.
- During cardiac transplantation, a recipient requires multiple blood transfusions from blood loss during surgery. During the operation, the patient develops sudden hypotension, bleeding from intravenous sites and wound edges, along with severe tachycardia. Which of the following is the most likely cause of these findings?
(A) Type I immediate hypersensitivity
(B) Type II cytotoxic hypersensitivity
(C) Previous aspirin therapy
(D) Type IV delayed hypersensitivity
(E) Previous warfarin therapy
3–B. Blood transfusion reaction—a type II cytotoxic hypersensitivity—commonly is associated with hypotension, tachycardia, and diffuse bleeding in an anesthetized patient. This reaction occurs when preformed antibodies to transfused red blood cell antigens are present in the recipient, leading to complement mediated lysis. Type I reactions are mediated by immunoglobulin (Ig)E to allergen, leading to mast cell or basophil degranulation. Previous aspirin or warfarin therapy would likely be associated with persistent bleeding throughout the operation and would not lead to sudden hypotension. Type IV sensitivity occurs 48–72 hours after exposure to antigen and is associated with sensitized helper T cells.
- After an uncomplicated renal transplantation, a patient inadvertently removes his Foley catheter on the first postoperative day. Why should the Foley catheter be reinserted?
(A) Hourly urine output monitoring is necessary.
(B) Foley catheters decrease the risk of urinary tract infections (UTI).
(C) Foley catheters decompress the bladder.
(D) Urethral strictures occur more commonly after kidney transplantation.
(E) Use of Foley catheters prevents acute rejection.
4–C. After ureteroneocystostomy, decompression of the bladder for several days using a Foley catheter allows healing of the anastomosis. Urine output monitoring aids in detection of renal hypoperfusion and graft rejection but can be accurately measured in this setting without the use of a Foley catheter. Foley catheters are associated with an increased rate of urinary tract infections. Overdistension of the bladder can lead to breakdown of the anastomosis of the ureter to the bladder. Although ureter strictures are not uncommon after renal transplantation, urethral strictures are rare. Foley catheters do not prevent rejection.
- A 49-year-old woman develops markedly increased liver enzymes on the ninth postoperative day after liver transplantation for hepatitis C. Further evaluation includes a Doppler ultrasound demonstrating adequate hepatic blood flow, and liver biopsy demonstrating endothelialitis and bile duct damage. Which of the following therapies is most likely to be effective?
(A) Interferon therapy for recurrent hepatitis C
(B) Steroid bolus therapy for rejection
(C) Reoperation for portal vein thrombosis
(D) Reoperation for bile duct stricture
(E) Observation with repeat biopsy in 1 week
5–B. The pathologic findings and time course described are consistent with acute cellular rejection. More than half of liver transplant recipients will develop acute rejection, most within the first 4 weeks. Initial therapy often includes steroid boluses. Hepatitis C, like many other indications for transplantation, may recur 3–6 months after transplantation. Adequate hepatic blood flow on Doppler ultrasound decreases the likelihood of portal vein thrombosis. Bile duct strictures are often associated with jaundice and characteristic pathologic findings. Observation alone may lead to graft loss due to rejection.
- A 59-year-old man with chronic renal insufficiency presents for repeat kidney transplantation after loss of a previous graft. After the arterial and venous anastomosis are complete, the vascular clamps are removed and excellent perfusion of the kidney is observed. Thirty minutes later, the kidney is noted to have a bluish discoloration, loss of perfusion, and lack of urine production. Which of the following statements is true regarding this patient?
(A) This is due to class II HLA antibodies.
(B) A similar reaction is the major barrier to xenotransplantation.
(C) This reaction cannot be avoided.
(D) This reaction does not occur in cardiac recipients.
(E) Emergent treatment with OKT3 is indicated.
6–B. The development of a bluish discoloration, and loss of perfusion and function within minutes to hours after revascularization is rare, but often due to hyperacute rejection. Hyperacute rejection occurs when preformed recipient antibodies act against class I donor antigens. Humans have preformed antibodies to animal antigens, making hyperacute rejection the major barrier to xenotransplantation. This reaction can almost always be avoided by performing a crossmatch. This assay is performed by adding donor serum to recipient lymphocytes in the presence of complement. If preformed antibodies are in the donor serum, cell lysis will occur. Although liver allografts are relatively resistant to hyperacute rejection, heart, pancreas, lung, and kidney are susceptible. Hyperacute rejection is refractory to therapy and almost always results in loss of the graft. OKT3 is indicated in the setting of acute rejection but has less of a role in hyperacute rejection.
- An 18-year-old woman with cystic fibrosis underwent bilateral lung transplantation 15 months ago. She now presents with a dry cough, and dyspnea refractory to bronchodilators. She has been observed to have a serial decline in her forced expiratory volume (FEV) over the past 3 months. Transbronchial lung biopsy is consistent with obliterative bronchiolitis (OB). Which of the following statements is true?
(A) No satisfactory treatment for reversal of this condition currently exists.
(B) The fibrosis can be reversed with increased immunosuppression.
(C) Most patients stop progressing with adequate therapy.
(D) OB occurs in less than 5% of all lung transplants.
(E) OB is a manifestation of acute rejection.
7–A. Obliterative bronchiolitis (OB) has become recognized as the main impediment to long-term survival after lung transplantation. At present, no satisfactory therapy can reverse the fibrosis once it occurs. Although current treatment often involves increased immunosuppression, most patients continue to have progression of disease. OB occurs in ~ 50% of lung transplant recipients and is believed to be a manifestation of chronic rejection.
Directions: Each set of matching questions in this section consists of a list of four to twenty-six lettered options followed by several numbered items. For each numbered item, select the appropriate lettered option(s). Each lettered option may be selected once, more than once, or not at all.
Questions 8-10
- Cyclosporine
- Mycophenolate mofetil
- OKT3
- Cyclophosphamide
- Antithymocyte globulin (ATG)
- Azathioprine
- Tacrolimus
- Glucocorticoids
Match each immunologic drug with the most likely associated description.
- A 49-year-old man with steroid resistant rejection of a renal allograft develops high fever, tachycardia, and shortness of breath 30 minutes after administration of this medication. (SELECT 1 DRUG)
8-C. OKT3 is a monoclonal antibody directed against the CD3 complex commonly used for induction therapy and treatment of steroid resistant rejection. Binding of OKT3 to the CD3 complex induces the release of multiple cytokines, and is associated with fever, chills, wheezing, pulmonary edema, tachycardia, hypotension, and rarely, death. This occurs most commonly within 30 minutes to 4 hours after the first dose and usually subsides with subsequent doses.
- Patients receiving this agent specifically have significantly decreased production of interleukin (IL)-2. (SELECT 2 DRUGS)
9-A and G. Cyclosporine and tacrolimus both function by decreasing the release of interleukin (IL)-2. Cyclosporine is useful for induction and maintenance therapy but has no benefit in treating rejection. In contrast, tacrolimus can be used for resistant rejection and “rescue therapy” of grafts failing on cyclosporine.
- When used in transplant recipients, this agent specifically binds to multiple cell surface receptors on the T cell. (SELECT 1 DRUG)
10-E. Antithymocyte globulin (ATG) and antilymphocyte globulin are polyclonal antibodies directed against T cell antigens including CD2, CD3, CD4, and CD8, as well as B cell, platelet, monocyte, and granulocyte antigens. OKT3 is a monoclonal antibody directed against the CD3 antigen of T cells. These three agents are used for induction therapy as well as treatment of resistant or severe rejection.
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