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All allograft recipients are at risk of graft rejection; the recipient's immune system recognizes the graft as foreign and seeks to destroy it. Recipients of grafts containing immune cells are at risk of graft-vs-host disease. Risk of these complications is minimized by pretransplantation screening and immunosuppressive therapy during and after transplantation.
Pretransplantation
Screening
In pretransplantation screening, recipients and donors are tested for human leukocyte antigen (HLA) and ABO antigens, and recipients are tested for presensitization to donor antigens. HLA tissue typing is most important for kidney and the most common types of hematopoietic stem cell (HSC) transplantation. Heart, liver, pancreas, and lung transplantation typically occurs quickly, often before HLA tissue typing can be completed, so the role of matching for these organs is less well established.
HLA tissue typing of peripheral blood or lymph node lymphocytes is used to match the most important known determinants of histocompatibility in the donor and recipient. More than 1250 alleles determine 6 HLA antigens (HLA-A, -B, -C, -DP, -DQ, -DR), so matching is a challenge; eg, in the US, only 2 of 6 antigens on average are matched in kidney donors and recipients. Matching of as many HLA antigens as possible significantly improves functional survival of grafts from living related kidney and HSC donors; HLA matching of grafts from unrelated donors also improves survival, although much less so because of multiple undetected histocompatibility differences. Better immunosuppressive therapy has expanded eligibility for transplantation; HLA mismatches no longer automatically disqualify patients for transplantation.
ABO compatibility and HLA compatibility are important for graft survival. ABO mismatches can underlie hyperacute rejection of highly vascular grafts (eg, kidney, heart), which have ABO antigens on the surfaces. Presensitization to HLA and ABO antigens results from prior blood transfusions, transplantations, or pregnancies and can be detected with serology tests or, more commonly, with a lymphocytotoxic test using the recipient's serum and donor's lymphocytes in the presence of complement. A positive cross-match indicates that the recipient's serum contains antibodies directed against ABO or class I HLA antigens in the donor; it is an absolute contraindication to transplantation, except possibly in infants (up to age 14 mo) who have not yet produced isohemagglutinins. High-dose IV immune globulin has been used to suppress HLA antibodies and facilitate transplantation, but long-term outcomes are unknown. A negative cross-match does not guarantee safety; when ABO antigens are compatible but not identical (eg, donor O and recipient A, B, or AB), hemolysis is a potential complication due to antibody production by transplanted (passenger) donor lymphocytes.
Matching for HLA and ABO antigens improves graft survival, but nonwhite patients are at a disadvantage because they may have different HLA polymorphisms from white donors, a higher rate of presensitization to HLA antigens, and blood types (O and B).
Exposure to common infectious pathogens and active infections must be detected before transplantation to minimize risk of infection. This screening usually includes the history; serologic tests for cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), hepatitis B and C viruses, and HIV; and tuberculin skin testing. Positive findings may require posttransplantation antiviral treatment (eg, for CMV infection or hepatitis B) or contraindicate transplantation (eg, if HIV is detected).
Immunosuppression
Immunosuppressants control graft rejection and are primarily responsible for the success of transplantation. However, they suppress all immune responses and contribute to many posttransplantation complications, including death due to overwhelming infection. Except when HLA-identical transplants are used, immunosuppressants must usually be continued long after transplantation, but initially high doses can be reduced a few weeks after the procedure, and low doses can be continued indefinitely unless rejection occurs.
Corticosteroids:
A high dose is usually given at the time of transplantation, then is reduced gradually to a maintenance dose, which is given indefinitely. Several months after transplantation, corticosteroids can be given on alternate days; this regimen helps prevent growth restriction in children. If rejection occurs, high doses are reinstituted.
Calcineurin
inhibitors:
These drugs ( cyclosporine , tacrolimus ) block T-cell transcription processes required for production of cytokines, thereby selectively inhibiting T-cell proliferation and activation.
Cyclosporine is the most commonly used drug in heart and lung transplantation. It can be given alone but is usually given with other drugs (eg, azathioprine , prednisone ), so that lower, less toxic doses can be used. The initial dose is reduced to a maintenance dose soon after transplantation. The drug is metabolized by the cytochrome P-450 3A enzyme, and blood levels are affected by many other drugs. The most serious adverse effect is nephrotoxicity; cyclosporine causes vasoconstriction of afferent (preglomerular) arterioles, leading to glomerular apparatus damage, refractory glomerular hypoperfusion, and, eventually, chronic renal failure. Also, B-cell lymphomas and polyclonal B-cell lymphoproliferation occur more often in patients receiving high doses of cyclosporine or combinations of cyclosporine and other immunosuppressants directed at T cells, possibly because of an association with EBV. Other adverse effects include hepatotoxicity, refractory hypertension, increased incidence of other tumors, and less serious effects (eg, gum hypertrophy, hirsutism). Serum cyclosporine levels do not correlate with effectiveness or toxicity.
Tacrolimus is the most commonly used drug in kidney, liver, pancreas, and intestinal transplantation. Tacrolimus may be started at the time of transplantation or days after the procedure. Dosing should be guided by blood levels, which are influenced by the same drug interactions as for cyclosporine . Tacrolimus may be useful when cyclosporine is ineffective or causes intolerable adverse effects. Adverse effects of tacrolimus are similar to those of cyclosporine except tacrolimus is more prone to induce diabetes; gum hypertrophy and hirsutism are less common. Lymphoproliferative disorders seem to occur more often in patients taking tacrolimus , even weeks after transplantation. If they occur and a calcineurin inhibitor is required, tacrolimus should be stopped, and cyclosporine substituted.
Purine
metabolism inhibitors:
Examples are azathioprine and mycophenolate mofetil . Azathioprine , an antimetabolite, is usually started at the time of transplantation. Most patients tolerate it indefinitely. The most serious adverse effects are bone marrow depression and, rarely, hepatitis. Azathioprine is often used with low doses of cyclosporine .
Mycophenolate mofetil (MMF), a prodrug metabolized to mycophenolic acid, reversibly inhibits inosine monophosphate dehydrogenase, an enzyme in the guanine nucleotide pathway that is rate-limiting in lymphocyte proliferation. MMF is given with cyclosporine and corticosteroids to patients with a kidney, heart, or liver transplant. The most common adverse effects are leukopenia, nausea, vomiting, and diarrhea.
Rapamycins:
These drugs ( sirolimus , everolimus) block a key regulatory kinase in lymphocytes, resulting in arrest of the cell cycle and in inhibition of lymphocyte response to cytokine stimulation.
Sirolimus is typically given with cyclosporine and corticosteroids and may be most useful for patients with renal insufficiency. Adverse effects include hyperlipidemia, impaired wound healing, and bone marrow depression with leukopenia, thrombocytopenia, and anemia.
Everolimus is typically used to prevent heart transplant rejection; adverse effects are similar to sirolimus .
Immunosuppressive
Igs:
Examples are antilymphocyte globulin (ALG) and antithymocyte globulin (ATG), which are fractions of animal antisera directed against human lymphocytes or thymus cells, respectively. ALG and ATG suppress cellular immunity while preserving humoral immunity. They are used with other immunosuppressants to allow those drugs to be used in lower, less toxic doses. Use of ALG or ATG to control acute episodes of rejection improves graft survival rates; use at the time of transplantation may decrease rejection incidence and allow cyclosporine to be started later, thereby reducing its toxicity. Use of highly purified serum fractions has greatly reduced incidence of adverse effects (eg, anaphylaxis, serum sickness, antigen-antibody–induced glomerulonephritis).
Monoclonal antibodies (mAbs):
mAbs directed against T cells provide a higher concentration of anti-T-cell antibodies and fewer irrelevant serum proteins than do ALG and ATG. The murine mAb OKT3 is the only mAb currently available for clinical use. OKT3 inhibits T-cell receptor (TCR)–antigen binding, resulting in immunosuppression. OKT3 is used primarily to control episodes of acute rejection; it may also be used at the time of transplantation to reduce incidence or delay onset of rejection episodes. However, benefits of prophylactic use must be weighed against adverse effects, which include severe CMV infection and development of neutralizing antibodies; these effects preclude using OKT3 for an actual rejection episode. With 1st use, OKT3 binds to the TCR-CD3 complex, activating the cell and triggering release of cytokines, which cause a syndrome of fevers, rigors, myalgias, arthralgias, nausea, vomiting, and diarrhea. Pretreatment with corticosteroids, antipyretics, and antihistamines can ameliorate these symptoms. The 1st-dose reaction less commonly includes chest pain, dyspnea, and wheezing, possibly due to complement activation. Repeated use is associated with increased incidence of EBV-induced B-cell lymphoproliferative disorders. Rarely, aseptic meningitis and hemolytic uremic syndrome occur.
Anti-IL-2 receptor monoclonal antibodies inhibit T-cell proliferation by blocking the effect of IL-2, secreted by activated T cells. Basiliximab and daclizumab , two humanized anti-TaT (HAT) antibodies, are increasingly being used to treat acute rejection of kidney, liver, and intestinal transplants; they are also used as adjunct immunosuppressive therapy at the time of transplantation. The only adverse effect reported is anaphylaxis, but a single trial suggests that daclizumab , when used with cyclosporine , MMF, and corticosteroids, may increase mortality rates. Also, experience with IL-2 receptor antibodies is limited, and an increased risk of lymphoproliferative disorders cannot be excluded.
Irradiation:
Irradiation of a graft, local recipient tissues, or both can be used to treat kidney transplant rejection episodes when other treatment (eg, corticosteroids and ATG) is ineffective. Total lymphatic irradiation is experimental but appears to safely suppress cellular immunity, at first by stimulation of suppressor T cells and later possibly by clonal deletion of specific antigen-reactive cells.
Future therapies:
Protocols and agents to induce graft antigen-specific tolerance without suppressing other immune responses are being sought. Two strategies are promising: blockade of T-cell costimulatory pathways using a cytotoxic T lymphocyte–associated antigen 4 (CTLA-4)-IgG1 fusion protein; and induction of chimerism (coexistence of donor and recipient immune cells in which graft tissue is recognized as self) using nonmyeloablative pretransplantation treatment (eg, with cyclophosphamide , thymic irradiation, ATG, and cyclosporine ) to induce transient T-cell depletion, engraftment of donor HSCs, and subsequent tolerance of solid organ transplants from the same donor.
Posttransplantation Complications
Rejection:
Rejection of solid organs may be hyperacute, accelerated, acute, or chronic (late). These categories overlap somewhat in timing but can be distinguished histopathologically. Symptoms vary by organ (see
Table 1: Transplantation: Signs of Transplant Rejection ).
Hyperacute rejection occurs within 48 h of transplantation and is caused by preexisting complement-fixing antibodies to graft antigens (presensitization). It has become rare (1%) as pretransplantation screening has improved. Hyperacute rejection is characterized by small-vessel thrombosis and graft infarction. No treatment is effective except graft removal.
Accelerated rejection occurs 3 to 5 days after transplantation and is caused by preexisting noncomplement-fixing antibodies to graft antigens. Accelerated rejection is also rare. It is characterized histopathologically by cellular infiltrate with or without vascular changes. Treatment is with high-dose pulse corticosteroids or, if vascular changes occur, antilymphocyte preparations. Plasmapheresis, which may clear circulatory antibodies more rapidly, has been used.
Acute rejection is graft destruction 6 days to 3 mo after transplantation and is caused by a T cell–mediated delayed hypersensitivity reaction to allograft histocompatibility antigens. It accounts for about 1⁄2 of all rejection episodes that occur within 10 yr. Acute rejection is characterized by mononuclear cellular infiltration, with varying degrees of hemorrhage, edema, and necrosis. Vascular integrity is usually maintained, although vascular endothelium appears to be a primary target. Acute rejection is often reversed by intensifying immunosuppressive therapy (eg, with pulse corticosteroids and ALG). After rejection reversal, severely damaged parts of the graft heal by fibrosis, the remainder of the graft functions normally, immunosuppressant doses can be reduced to very low levels, and the allograft can survive for long periods.
Chronic rejection is graft dysfunction, often without fever, typically occurring months to years after transplantation but sometimes within weeks. Causes are multiple and include early antibody-mediated rejection, periprocedural ischemia and reperfusion injury, drug toxicity, infection, and vascular factors (eg, hypertension, hyperlipidemia). Chronic rejection accounts for most of the other 1⁄2
of all rejection episodes. Proliferation of neointima consisting of smooth muscle cells and extracellular matrix (transplantation atherosclerosis) gradually and eventually occludes vessel lumina, resulting in patchy ischemia and fibrosis of the graft. Chronic rejection progresses insidiously despite immunosuppressive therapy; no established treatments exist.
Infection:
Immunosuppressants, secondary immunodeficiencies that accompany organ failure, and surgery make transplant patients more vulnerable to infections. Rarely, a transplanted organ is the source of infection (eg, CMV).
The most common sign is fever, often without localizing signs. Fever can also be a symptom of acute rejection but is usually accompanied by signs of graft dysfunction. If these signs are absent, the approach is similar to that for other FUO (see Biology of Infectious Disease: Fever of Unknown Origin (FUO)); timing of symptoms and signs after transplantation helps narrow the differential diagnosis.
In the 1st month after transplantation, most infections are caused by the same hospital-acquired bacteria and fungi that infect other surgical patients (eg, Pseudomonas sp causing pneumonia, gram-positive bacteria causing wound infections). The greatest concern with early infection is that organisms can infect a graft or its vascular supply at suture sites, causing mycotic aneurysms or dehiscence.
Opportunistic infections occur 1 to 6 mo after transplantation (for treatment, see elsewhere in The Manual). Infections may be bacterial (eg, listeriosis, nocardiosis), viral (eg, due to CMV, EBV, VZV, or hepatitis B or C virus), fungal (eg, aspergillosis, cryptococcosis, Pneumocystis
jiroveci infection), or parasitic (eg, strongyloidiasis, toxoplasmosis, trypanosomiasis, leishmaniasis).
Risk of infection returns to baseline for about 80% of patients after 6 mo. About 10% develop complications of early infections, such as viral infection of the graft, metastatic infection (eg, CMV retinitis, colitis), or virus-induced cancers (eg, hepatitis and hepatocellular carcinoma, human papillomavirus and basal cell carcinoma). Others develop chronic rejection, require high doses of immunosuppressants (5 to 10%), and remain at high risk of opportunistic infections indefinitely.
After transplantation, most patients are given antimicrobials to reduce risk of infection. Choice of drug depends on individual risk and type of transplantation; regimens include trimethoprim/sulfamethoxazole 80/400 mg po once/day for 4 to 12 mo to prevent P. jiroveci infection or to prevent UTIs in kid-ney transplant patients. Neutropenic patients are sometimes given quinolone antibiotics (eg, levofloxacin 500 mg po or IV once/day) to prevent gram-negative infection. Inactivated vaccines can be safely given posttransplantation; risks due to live-attenuated vaccines must be balanced against their potential benefits, especially for patients taking low doses of immunosuppressants.
Renal
disorders:
GFR decreases 30 to 50% during the 1st 6 mo after solid organ transplantation in 15 to 20% of patients. They usually also develop hypertension. Incidence is greatest for recipients of intestinal transplants (21%) and least for recipients of heart-lung transplants (7%). Nephrotoxic and diabetogenic effects of calcineurin inhibitors are the most important contributor, but periprocedural renal insults, pretransplantation renal insufficiency or hepatitis C infection, and use of other nephrotoxic drugs also contribute. After the initial decrease, GFR typically stabilizes or decreases more slowly; nonetheless, mortality risk quadruples unless subsequent kidney transplantation is done. Renal insufficiency after transplantation may be prevented by early weaning of calcineurin inhibitors, but a safe minimum dose has not been determined.
Cancer:
Long-term immunosuppression increases incidence of virus-induced cancer, especially squamous and basal cell carcinoma, lymphoproliferative disease (mainly B-cell non-Hodgkin lymphoma), anogenital (including cervical) cancer, and Kaposi's sarcoma. Treatment is similar to that of cancer in nonimmunosuppressed patients; reduction or interruption of immunosuppression is not usually required for low-grade tumors but is recommended for more aggressive tumors and lymphomas. Transfusion of partially HLA-matched cytotoxic T cells is under study as a possible treatment for some forms of lymphoproliferative disease. Surveillance with bone marrow biopsies in affected patients is recommended.
Other
complications:
Immunosuppressants (especially corticosteroids and calcineurin inhibitors) increase bone resorption and risk of osteoporosis for patients who are at risk before transplantation (eg, because of reduced physical activity, tobacco and alcohol use, or a preexisting renal disorder). Although not routine, use of vitamin D, bisphosphonates, or other antiresorptive drugs after transplantation may play a role in prevention.
Failure to grow, primarily as a consequence of chronic corticosteroid use, is a concern in children. Growth failure can be mitigated by tapering corticosteroids to the minimum dose that does not lead to graft rejection.
Systemic atherosclerosis can result from hyperlipidemia due to use of calcineurin inhibitors and corticosteroids; it typically occurs in kidney transplant recipients > 15 yr posttransplantation.
Graft vs host disease (GVHD) occurs when donor T cells react against recipient's self-antigens. GVHD primarily affects hematopoietic stem cell recipients but may also affect liver and small-bowel transplant recipients (see Transplantation: Procedure).
Contraindications
Absolute contraindications to transplantation include active infection, cancer (except hepatocellular carcinoma confined to the liver), and pregnancy. Relative contraindications include age > 65, poor functional or nutritional status (including severe obesity), HIV infection, multiorgan insufficiency, substance abuse disorders, and high likelihood of nonadherence. Eligibility decisions for patients with relative contraindications differ by medical center; immunosuppressants are safe and effective for HIV-positive transplant recipients.
Last full review/revision November 2005
Content last modified November 2005
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