Transplants may be
The patient’s own tissue (autografts; eg, bone, bone marrow, and skin grafts)
Genetically identical (syngeneic [between monozygotic twins]) donor tissue (isografts)
Genetically dissimilar donor tissue (allografts, or homografts)
Rarely, grafts from a different species (xenografts, or heterografts)
Transplanted tissue may be
Cells (as for hematopoietic stem cell Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more [HSC] transplants, lymphocyte transplants, and pancreatic islet cell Pancreatic Islet Cell Transplantation Islet cell transplantation (into the recipient's liver) has theoretical advantages over pancreas transplantation; the most important is that the procedure is less invasive. A secondary advantage... read more transplants)
Parts or segments of an organ (as for liver Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more or pulmonary lobar transplants and skin grafts Skin grafts Many different types of tissues can be transplanted, including skin, bone, cartilage, adrenal tissue, fetal thymus, corneas, and composite transplantation of tissues to restore the face or extremities... read more )
Entire organs (as for heart transplants Heart Transplantation Heart transplantation is an option for patients who have any of the following and who remain at risk of death and have intolerable symptoms despite optimal use of drugs and medical devices:... read more , kidney transplants Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more , hand/facial transplants, and uterine transplants)
Tissues Tissue Transplantation Many different types of tissues can be transplanted, including skin, bone, cartilage, adrenal tissue, fetal thymus, corneas, and composite transplantation of tissues to restore the face or extremities... read more (eg, composite tissue grafts, corneas Corneal Transplantation Corneal transplantations are done for several reasons: To reconstruct the cornea (eg, replacing a perforated cornea) To relieve intractable pain (eg, severe foreign body sensation due to recurrent... read more )
Tissues may be grafted to an anatomically normal site (orthotopic; eg, heart transplants) or abnormal site (heterotopic; eg, a kidney transplanted into the iliac fossa).
Almost always, transplantation is done to replace an end-stage diseased organ, thereby restoring an essential function and improving patient survival. However, some procedures (eg, hand, larynx, tongue, and facial transplantation) enhance the quality of life but do not improve survival and have significant risks related to surgery and immunosuppression. Some of these procedures are highly specialized and done infrequently but are no longer considered experimental.
With rare exceptions, clinical transplantation uses allografts from living related, living unrelated, or deceased donors. Living donors are often used for kidney and HSC transplants, less frequently for segmental liver transplants, and rarely for pancreas and lung transplants. Use of deceased-donor organs (from heart-beating or non–heart-beating donors) has helped reduce the disparity between organ demand and supply; however, demand still far exceeds supply, and the number of patients waiting for organ transplants continues to grow.
Graft rejection and graft-vs-host disease
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 (particularly bone marrow, intestine, and liver) are at risk of graft-vs-host disease. Risk of these complications is minimized by pretransplantation screening and immunosuppressive therapy during and after transplantation.
A new organ allocation system has been implemented for livers and other organs. Under the new system, transplant candidates receive an organ based on medical urgency and the distance between the donor hospital and transplant hospitals. It replaces the previous system that was based primarily on the geographic boundaries of donation service areas and transplant regions. Now, livers and other organs from all adult deceased donors are offered first to compatible transplant candidates who have the most urgent need (Status 1A and 1B) and are listed at transplant hospitals within 500 nautical miles of the donor hospital. After offers are made to the most urgent candidates, organs are offered to candidates at hospitals within distances of 150, 250, and 500 nautical miles of the donor hospital. In kidney allocation, wait time remains a strong factor, and, for all organs, pediatric organs are primarily allocated to pediatric candidates first.
Before the risk and expense of transplantation are undertaken and scarce donor organs are committed, medical teams screen potential recipients for medical and nonmedical factors that may affect the likelihood of success.
In pretransplantation screening, recipients and donors are tested for
Human leukocyte antigens Human Leukocyte Antigen (HLA) System The human leukocyte antigen (HLA) system (the major histocompatibility complex [MHC] in humans) is an important part of the immune system and is controlled by genes located on chromosome 6.... read more (HLAs; also called the major histocompatibility complex [MHC])
Recipients are tested for
Presensitization to donor antigens
HLA tissue typing is most important for the following:
The most common types of hematopoietic stem cell (HSC) transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more
Transplantation of the following typically occurs urgently, 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 because immunosuppressive therapy has become more effective.
ABO compatibility and HLA compatibility are important for graft survival. ABO mismatches can precipitate hyperacute rejection of vascularized grafts (eg, kidney, heart), which have ABO antigens on the endothelial surfaces. Presensitization to HLA and ABO antigens results from prior blood transfusions, transplantations, or pregnancies and can be detected with serologic 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 months) who have not yet produced isohemagglutinins.
High-dose IV immune globulin and plasma exchange have been used to suppress HLA antibodies and facilitate transplantation when a more compatible graft is not available. Costs are high, but midterm outcomes are encouraging and appear similar to those in unsensitized patients.
Even 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.
Although matching for HLA and ABO antigens generally improves graft survival, nonwhite patients are disadvantaged because
Organ donation is less common among nonwhites, and, thus, the number of potential nonwhite donors is limited.
End-stage renal disease is more common among blacks, and, thus, the need for organs is greater.
Nonwhite patients may have different HLA polymorphisms from white donors, a higher rate of presensitization to HLA antigens, and a higher incidence of blood types O and B.
Donor and recipient exposure to common infectious pathogens and active as well as latent infections must be detected before transplantation to minimize risk of transmitting infection from the donor and risk of worsening or reactivating existing infection in the recipient (due to use of immunosuppressants).
This screening usually includes the history and tests for cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex virus (HSV), varicella-zoster virus, hepatitis B and C viruses, HIV, West Nile virus (if exposure is suspected), and Mycobacterium tuberculosis (for tuberculosis). Positive findings may require posttransplantation antiviral treatment (eg, for CMV infection Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more or hepatitis B Hepatitis B, Chronic Hepatitis B is a common cause of chronic hepatitis. Patients may be asymptomatic or have nonspecific manifestations such as fatigue and malaise. Diagnosis is by serologic testing. Without treatment... read more ) or contraindicate transplantation until the infection is controlled (eg, if HIV with AIDS is detected).
Contraindications to transplantation
Absolute contraindications to transplantation include the following:
Active infection, except possibly infection in the recipient if it is confined to the organ being replaced (eg, liver abscesses)
Cancer (except hepatocellular carcinoma confined to the liver and certain neuroendocrine tumors in the recipient)
A positive cross-match identified by lymphocytotoxic testing
Relative contraindications include the following:
Age > 65
Poor functional or nutritional status (including severe obesity)
Psychologic and social factors also play an important role in success of transplantation. For example, people who abuse drugs or who are psychologically unstable are less likely to firmly adhere to the necessary lifelong regimen of treatments and follow-up visits.
Eligibility decisions for patients with relative contraindications differ by medical center. Immunosuppressants are well-tolerated by and effective in HIV-positive transplant recipients.
Immunosuppressants control graft rejection and are primarily responsible for the success of transplantation (see table Immunosuppressants Used to Treat Transplant Rejection Immunosuppressants Used to Treat Transplant Rejection ). However, they suppress all immune responses and contribute to many posttransplantation complications, including development of cancer, acceleration of cardiovascular disease, and even death due to overwhelming infection.
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. Further reduction of immunosuppressant doses long after transplantation and protocols for inducing tolerance of donor organs are under study.
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.
Regimens that reduce the need for corticosteroids (steroid-sparing regimens) are being developed.
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 dose-dependent adverse effect of cyclosporine 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 Epstein-Barr virus. Other adverse effects include diabetes, hepatotoxicity, tophaceous gout, refractory hypertension, neurotoxicity (including tremor), increased incidence of other tumors, and less serious effects (eg, gum hypertrophy, hirsutism, hypertrichosis). Serum cyclosporine levels do not correlate with effectiveness or toxicity.
Tacrolimus is the most commonly used drug in kidney, liver, pancreas, and small-bowel 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 has 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. In patients taking tacrolimus, lymphoproliferative disorders seem to occur more often, even just weeks after transplantation, and may resolve partly or completely when the drug is stopped. If lymphoproliferative disorders occur, tacrolimus should be stopped, and cyclosporine or another immunosuppressive drug should be 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. Systemic hypersensitivity reactions occur in > 5% of patients. Azathioprine is often used with low doses of calcineurin inhibitors.
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 (or tacrolimus) and corticosteroids to patients with a kidney, heart, or liver transplant. The most common adverse effects are leukopenia, nausea, vomiting, and diarrhea. It has all but replaced azathioprine in most transplant applications.
These drugs (sirolimus, everolimus) block a key regulatory kinase (mammalian target of rapamycin [mTOR]) 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 useful for patients with renal insufficiency. Adverse effects include hyperlipidemia, interstitial pneumonitis, leg edema, impaired wound healing, and bone marrow depression with leukopenia, thrombocytopenia, and anemia.
Everolimus is used to prevent kidney and liver transplant rejection. Adverse effects are similar to those of sirolimus.
Antilymphocyte globulin (ALG)
Antithymocyte globulin (ATG)
Both are fractions of animal antisera directed against human cells: lymphocytes (ALG) and thymus cells (ATG). 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 calcineurin inhibitors to be started later, thereby reducing 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.
Anti–IL-2 receptor monoclonal antibodies inhibit T-cell proliferation by blocking the effect of IL-2, secreted by activated T cells. Basiliximab, which is a humanized anti–IL-2 receptor antibody and the only IL-2 receptor antibody still available, is used to treat acute rejection of kidney, liver, and small-bowel transplants; it is also used as adjunct immunosuppressive therapy at the time of transplantation. The only adverse effect reported is anaphylaxis, but an increased risk of lymphoproliferative disorders cannot be excluded.
Belatacept, another antibody that inhibits T-cell costimulatory pathways, can be used in kidney transplant recipients. However, incidence of progressive multifocal leukoencephalopathy, a deadly central nervous system viral disorder, appears to be increased, and incidence of other viral infections is also increased. Posttransplant lymphoproliferative disorder is another concern. Belatacept is used rarely in kidney transplant recipients who are at increased risk of nephrotoxicity resulting from calcineurin inhibitor use.
Irradiation of a graft, local recipient tissues, or both can be used to treat kidney transplant rejection when other treatment (eg, corticosteroids and ATG) has been 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. However, because immunosuppressants are now so effective, the need for irradiation is extremely rare.
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
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 (under study)
Complications include the following:
Rejection of solid organs may be hyperacute, accelerated, acute, or chronic (late). These categories can be distinguished histopathologically and approximately by the time of onset. Symptoms vary by organ (see table Signs of Transplant Rejection by Category Manifestations of Transplant Rejection by Category ).
Hyperacute rejection has the following characteristics:
Occurs within 48 hours of transplantation
Is caused by preexisting complement-fixing antibodies to graft antigens (presensitization)
Is characterized by small-vessel thrombosis and graft infarction
It has become rare (1%) as pretransplantation screening has improved. No treatment is effective except graft removal.
Accelerated rejection has the following characteristics:
Occurs 3 to 5 days after transplantation
Is caused by preexisting noncomplement-fixing antibodies to graft antigens
Is characterized histopathologically by cellular infiltrate with or without vascular changes
Accelerated rejection is also rare. Treatment is with high-dose pulse corticosteroids or, if vascular changes occur, antilymphocyte preparations. Plasma exchange, which may clear circulating antibodies more rapidly, has been used with some success.
Acute rejection is graft destruction after transplantation and has the following characteristics:
Occurs later, about 5 days after transplantation (because unlike hyperacute and accelerated rejection, acute rejection is mediated by a de novo anti-graft T-cell response, not by preexisting antibodies)
Is caused by a T cell–mediated delayed hypersensitivity reaction to allograft histocompatibility antigens
Is characterized by mononuclear cellular infiltration, with varying degrees of hemorrhage, edema, and necrosis but with vascular integrity usually maintained (although vascular endothelium appears to be a primary target)
Acute rejection accounts for about half of all rejection episodes that occur within 10 years. Acute rejection is often reversed by intensifying immunosuppressive therapy (eg, with pulse corticosteroids, ALG, or both). 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. It has the following characteristics:
Typically occurs months to years after transplantation but sometimes within weeks
Has multiple causes, including early or late antibody-mediated rejection, periprocedural ischemia and reperfusion injury, drug toxicity, infection, and vascular factors (eg, hypertension, hyperlipidemia)
Is characterized pathologically by proliferation of neointima consisting of smooth muscle cells and extracellular matrix (transplantation atherosclerosis), which gradually and eventually occludes vessel lumina, resulting in patchy ischemia and fibrosis of the graft (in liver transplant recipients, paucity of bile ducts can be the leading pathologic feature)
Chronic rejection accounts for most of the other half of all rejection episodes. Chronic rejection progresses insidiously despite immunosuppressive therapy; no established treatments exist. Tacrolimus has been reported to control chronic liver rejection in a few patients.
Transplant patients become vulnerable to infections because of
Use of immunosuppressants
Secondary immunodeficiencies that accompany organ failure
Rarely, a transplanted organ is the source of infection (eg, cytomegalovirus [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 fever of unknown origin Fever of Unknown Origin (FUO) Fever of unknown origin (FUO) is body temperature ≥ 38.3° C (101° F) rectally that does not result from transient and self-limited illness, rapidly fatal illness, or disorders with clear-cut... read more ; timing of symptoms and signs after transplantation helps narrow the differential diagnosis.
In the first month after transplantation, most infections are caused by the same hospital-acquired bacteria and fungi that infect other surgical patients (eg, Pseudomonas species 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 months after transplantation (for treatment, see elsewhere in THE MANUAL). Infections may be bacterial (eg, listeriosis, nocardiosis), viral (eg, due to BK virus, CMV, Epstein-Barr virus, varicella-zoster virus, or hepatitis B or C virus), fungal (eg, aspergillosis, cryptococcosis, Pneumocystis jirovecii infection), or parasitic (eg, strongyloidiasis, toxoplasmosis, trypanosomiasis, leishmaniasis). Historically, many of these infections were associated with the use of high-dose corticosteroids.
Risk of infection returns to baseline in about 80% of patients after 6 months. 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 subsequent hepatocellular carcinoma, human papillomavirus and subsequent basal cell carcinoma). Others develop chronic rejection, require high doses of immunosuppressants (5 to 10%), and remain at high risk of opportunistic infections indefinitely. Risk of infection varies depending on the graft received and is lowest for recipients of kidney allografts and highest for recipients of liver and lung transplants.
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 orally once a day for 4 to 12 months to prevent P. jirovecii infection or to prevent urinary tract infections in kidney transplant patients. Neutropenic patients are sometimes given quinolone antibiotics (eg, levofloxacin 500 mg orally or IV once a day) to prevent infection with gram-negative organisms. Often, patients are treated prophylactically with ganciclovir or acyclovir because CMV and other viral infections occur more frequently in the first months after transplantation, when doses of immunosuppressants are highest. The doses given depend on patients' renal function.
Inactivated vaccines can be safely given posttransplantation. Risks due to live-attenuated vaccines must be balanced against their potential benefits because clinically evident infection and exacerbation of rejection are possible in immunosuppressed patients, even if blood levels of immunosuppressants are low.
GFR decreases 30 to 50% during the first 6 months after solid organ transplantation in 15 to 20% of patients. These patients usually also develop hypertension. Incidence is highest for recipients of small-bowel transplants (21%) because high blood levels of immunosuppressants (usually calcineurin inhibitors [CNIs]) are needed to maintain the graft. Incidence is lowest for recipients of heart-lung transplants (7%). Nephrotoxic and diabetogenic effects of CNIs are the most important contributor, but periprocedural renal damage, pretransplantation renal insufficiency, and use of other nephrotoxic drugs also contribute.
After the initial decrease, GFR typically stabilizes or decreases more slowly; nonetheless, mortality risk quadruples in patients progressing to end-stage renal disease requiring dialysis unless subsequent kidney transplantation is done. Renal insufficiency after transplantation may be prevented by early weaning from CNIs, but a safe minimum dose has not been determined.
Long-term immunosuppression increases incidence of virus-induced cancer, especially squamous and basal cell carcinoma, lymphoproliferative disorders (mainly B-cell non-Hodgkin lymphoma), anogenital (including cervical) and oropharyngeal cancer, and Kaposi 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. In particular, purine metabolism antagonists (azathioprine, mycophenolate mofetil) are stopped, and tacrolimus is stopped if a lymphoproliferative disorder develops.
Osteoporosis can develop in patients who are at risk of osteoporosis before transplantation (eg, because of reduced physical activity, use of tobacco and/or alcohol, or a preexisting renal disorder) because immunosuppressants (especially corticosteroids and calcineurin inhibitors) increase bone resorption. 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.
Atherosclerosis can result from hyperlipidemia due to use of calcineurin inhibitors, rapamycins (sirolimus, everolimus), or corticosteroids; it typically occurs in kidney transplant recipients > 15 years posttransplantation.
Graft-vs-host disease (GVHD) occurs when donor T cells react against recipient self-antigens. GVHD primarily affects hematopoietic stem cell recipients Early complications Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more but may also affect liver and small-bowel transplant recipients. It can include inflammatory damage to tissues, especially the liver, intestine, and skin, as well as blood dyscrasia.
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