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Dx Organ Transplant: Treatments:

Overview of Transplantation

"More than 1,000,000 have Listened to the i-Doctor Podcasts"
James A. was a 36 year old white male with heart failure secondary to mitochondrial dysfunction: mitochondrial cardiomyopathy. The University of Michigan refused his request for heart transplant and he was given a 6-month life-expectancy. The Editor treated with him a strong mixture of testosterone, nandrolone, SHBG complex, human growth hormone, carnitor, co-enzyme Q10 and nutritional intravenous infusions. James was able to improve his ejection fraction from NY IV of 15% to a normal of 45% (normal ejection fration in Michigan is 45-60%). He lived a normal life for 15 years,until unable to pay for his $10,000 per year medications. In fact, he lived as long as he would have been expected to, should he have received the transplant.

The Merck Manual Home Edition states:
"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), or, rarely, grafts from a different species (xenografts, or heterografts). Transplanted tissue may be cells (as for hematopoietic stem cell [HSC], lymphocyte, and pancreatic islet cell transplants), parts or segments of an organ (as for hepatic or pulmonary lobar transplants and skin grafts), or entire organs (as for heart or kidney transplants).

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 improve 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. These procedures are in an early experimental phase.

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 and increasingly for segmental liver, 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.

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.

Organ distribution: Allocation depends on disease severity for some organs (liver, heart) and on disease severity, time on the waiting list, or both for others (kidney, lung, bowel). In the US and Puerto Rico, organs are allocated first among 12 geographic regions, then among local Organ Procurement Organizations. If no recipient in the first region is suitable, organs are reallocated to recipients in other regions.

Pretransplantation Screening
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.

Tissue compatibility: In pretransplantation screening, recipients and donors are tested for human leukocyte antigens (HLAs; also called the major histocompatibility complex [MHC]) and for 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 HSC transplantation. Heart, liver, pancreas, and lung transplantation 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 mo) 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 and because end-stage renal disease is more common among blacks. Also, 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.

Infection: 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 (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), hepatitis B and C viruses, HIV, West Nile virus (if exposure is suspected), and Mycobacterium tuberculosisTB. Positive findings may require posttransplantation antiviral treatment (eg, for CMV infection or hepatitis B) 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 age > 65, poor functional or nutritional status (including severe obesity), HIV infection, and multiorgan insufficiency.

Psychologic and social factors also play a 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. However, they suppress all immune responses and contribute to many posttransplantation complications, including 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.

Calcineurin inhibitors (CNIs): 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 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 diabetes, hepatotoxicity, tophaceous gout, refractory hypertension, neurotoxicity, 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.

Rapamycins: 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 typically used to prevent heart transplant rejection; adverse effects are similar to those of sirolimus.

Immunosuppressive Igs: Examples are antilymphocyte globulin (ALG) and 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 CNIs 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. OKT3 (a mouse antibody) 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 can include severe CMV infection and development of neutralizing antibodies. With first 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, diarrhea, and possibly hypotension. Pretreatment with corticosteroids, antipyretics, and antihistamines can ameliorate these symptoms. The first-dose reaction less commonly includes chest pain, dyspnea, and wheezing, possibly due to complement activation. With subsequent doses, cytokine-release mediated adverse effects are usually much less severe; however, 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, which are humanized anti–IL-2 receptor antibodies, are increasingly being used to treat acute rejection of kidney, liver, and small-bowel transplants; they are 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.

Irradiation: 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.

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 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)
*Belatacept, another antibody that inhibits T-cell costimulatory pathways, can be used in kidney transplant recipients. However, incidence of progressive multifocal leukoencephalopathy, a deadly CNS disorder, appears to be increased, and incidence of viral infections is increased. Posttransplant lymphoproliferative disorder is another concern.

Posttransplantation Complications:
Complications include the following:
*Renal insufficiency

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.

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. Plasma exchange, which may clear circulating antibodies more rapidly, has been used with some success.

Acute rejection is graft destruction after transplantation and is caused by a T cell–mediated delayed hypersensitivity reaction to allograft histocompatibility antigens. Acute rejection is different from hyperacute and accelerated rejection because it is mediated by a de novo anti-graft T-cell response, not by preexisting antibodies. Therefore, it occurs later, about 5 days after transplantation. It accounts for about half 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, 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, 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 half 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. Tacrolimus has been reported to control chronic liver rejection in a few patients.

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 Fever of Unknown Origin (FUO)); 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 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 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 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 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 po once/day for 4 to 12 mo to prevent P. jirovecii infection or to prevent UTIs in kidney transplant patients. Neutropenic patients are sometimes given quinolone antibiotics (eg, levofloxacin 500 mg po or IV once/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.

Renal disorders:
GFR decreases 30 to 50% during the first 6 mo 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 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) 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.

Other complications:
Immunosuppressants (especially corticosteroids and CNIs) 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 CNIs, rapamycins (sirolimus, everolimus), or 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 Early complications). It can include inflammatory damage to tissues, especially the liver, intestine, and skin, as well as blood dyscrasia (see Early complications).

Medications Used in Treatment:
1. Antimetabolites: Imuran®/zathioprine, Cellcept®/myophenolate, Myfortic®/mycophenolate sodium, Azasan®/azathioprine
2. CNI Immunosuppressants: Prograf®/hecoria-tacrolimus, Sandimmune® Neoral®/cyclosporine, Astagraf®XL/tacrolimus
3. mTOR Inhibitors: Rapamune®/sirolimus
4. CTLA-4 Agonists: Nulojix®/belatacept

Suggested Links:
N.H.S. Choices/ Kidney Transplant (with Video)
N.H.S. Choices/ Heart Transplant (with Video)

[Editor] As noted in Anemia of Chronic Inflammation, nandrolone and IV iron may be of assistance in cases of anemia resistant to erythropoietin.

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