Post-transplant complications

Contraindications to transplantation

Absolute contraindications to transplantation include active infection, neoplasms (except hepatocellular carcinoma limited to the liver), and pregnancy. Relative contraindications include age over 65 years, severe functional and nutritional impairment (including severe obesity), HIV infection, multiple organ failure, metabolic disorders, and high risk of graft failure. The decision to transplant patients with relative contraindications varies among centers; in HIV-infected patients who have undergone transplantation, immunosuppressants are safe and effective.

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Rejection after transplantation

Rejection of solid organs can be fulminant, accelerated, acute or chronic (late). These types of rejection overlap to some extent in time, but differ in the histological picture. Symptoms of rejection vary depending on the organ.

Fulminant rejection begins within 48 hours of transplantation and is caused by preexisting complement-fixing antibodies to graft antigens (presensitization). Once pretransplant screening has been established, such rejection is quite rare (1%). Hyperacute rejection is characterized by thrombosis of small vessels and graft infarction. No treatment is effective except graft removal.

Accelerated rejection begins 3-5 days after transplantation and is caused by the presence of pre-existing non-complement-fixing antibodies to graft antigens. Accelerated rejection is also quite rare. Histopathologically, it is characterized by cellular infiltrates with or without vascular changes. Treatment consists of high-dose pulse glucocorticoid therapy or, if vascular changes are present, antilymphocyte drugs. Plasmapheresis is used to help remove circulating antibodies more quickly.

Acute rejection is the destruction of the graft from the 6th day to the 3rd month after transplantation and is a consequence of T-mediated delayed hypersensitivity reaction to allograft histocompatibility antigens. This complication accounts for half of all cases of rejection that occur within 10 years. Acute rejection is characterized by mononuclear cell infiltration with varying degrees of hemorrhage, edema, and necrosis. Vascular integrity is usually preserved, despite the fact that the primary target is the vascular endothelium. Acute rejection is often reversed by intensive immunosuppressive therapy (eg, pulse glucocorticoid therapy and ALG). After suppression of the rejection reaction, significantly damaged parts of the graft are replaced by areas of fibrosis, the remnants of the graft function normally, the doses of immunosuppressants can be reduced to low levels, and the allograft can survive for a long time.

Chronic rejection is a dysfunction of the allograft, often without fever, usually beginning months or years after transplantation, but sometimes within a few weeks. Causes are varied and include early antibody-mediated rejection, ischemia around the transplant site, reperfusion injury, drug toxicity, infections, and vascular disorders (hypertension, hyperlipidemia). Chronic rejection accounts for the other half of all rejection cases. Proliferating neointima, consisting of smooth muscle cells and extracellular matrix (transplant atherosclerosis), gradually occludes the vessel lumen over time, leading to patchy ischemia and fibrosis of the graft. Chronic rejection progresses gradually despite immunosuppressive therapy; no treatment with proven efficacy exists.

Infections

Immunosuppressants, secondary immunodeficiency states that accompany organ damage, and surgical intervention make patients more susceptible to infections. Less commonly, transplanted organs are a source of infection (eg, cytomegalovirus).

General signs include fever, often without localization. Fever may be a symptom of acute rejection, but is usually accompanied by signs of graft dysfunction. If these signs are absent, the approach is the same as for other fevers of unknown origin; the time of onset of symptoms and objective signs after transplantation will help in the differential diagnosis.

In the first month after transplantation, most infections are caused by hospital flora and fungi that infect other surgical patients (e.g., Pseudomonas sp, which causes pneumonia, gram-positive flora, which causes wound infections). Of greatest concern in terms of early infection are those microorganisms that can infect the graft or its vascular system at the suture site, leading to the development of a mycotic aneurysm or suture dehiscence.

Opportunistic infections occur 1-6 months after transplantation (see the reference book for treatment). Infections can be bacterial (eg, listeriosis, nocardiosis), viral (due to infection with cytomegalovirus, Epstein-Barr virus, varicella zoster virus, hepatitis B and C viruses), fungal (aspergillosis, cryptococcosis, Pneumocystis jiroveci infection) or parasitic (strongyloidiasis, toxoplasmosis, trypanosomiasis, leishmaniasis).

The risk of infection decreases to the general population level after 6 months in approximately 80% of patients. About 10% of patients have complications of early infections, such as viral infection of the graft, metastatic infections (cytomegalovirus retinitis, colitis) or virus-induced tumors (hepatitis and hepatocellular carcinoma, human papillomavirus, basal cell carcinoma). The remaining patients develop chronic rejection requiring high doses of immunosuppressants (5 to 10%), and the risk of opportunistic infections remains constantly high.

After transplantation, most patients receive antibiotics to reduce the risk of infection. The choice of drug depends on the individual risk and the type of transplant; the regimen includes trimethoprim-sulfamethoxazole 80/400 mg orally once a day for 4-12 months to prevent Pneumocystis jiroveci infection or urinary tract infections in renal transplant patients. In patients with neutropenia, quinolone antibiotics (levofloxacin 500 mg orally or intravenously once a day) are given to prevent gram-negative infections. Administration of inactivated vaccines in the posttransplant period is safe; the risks of administration of live attenuated vaccines must be weighed against the potential benefits, especially in patients receiving low doses of immunosuppressants.

Renal disorders

The glomerular filtration rate decreases from 30% to 50% during the first 6 months after solid organ transplantation in 15% to 20% of patients. They usually also develop hypertension. These abnormalities are most common in recipients of intestinal transplants (21%) and least common in heart and lung transplants (7%). The nephrotoxic and diabetogenic effects of calcineurin inhibitors, as well as renal insult around the graft site, pretransplant renal failure or hepatitis C, and use of nephrotoxic drugs undoubtedly contribute. After the initial decrease, the glomerular filtration rate usually stabilizes or decreases more slowly; however, the risk of death increases fourfold unless a subsequent kidney transplant is performed. Renal failure after transplantation can be prevented by early discontinuation of calcineurin inhibitors, but the safe minimum dose is unknown.

Oncological diseases

Long-term immunosuppressive therapy increases the incidence of virus-induced neoplasms, especially squamous and basal cell carcinoma, lymphoproliferative disease (mainly B-cell non-Hodgkin lymphoma), anogenital (including cervical) cancer, and Kaposi's sarcoma. Treatment is the same as in patients who have not undergone transplantation; reduction or interruption of immunosuppressive therapy is usually not required for low-grade tumors, but is recommended for aggressive tumors or lymphomas. Transfusion of partially HLA-matched cytotoxic T lymphocytes is currently under investigation as a possible treatment for some forms of lymphoproliferative disease. Bone marrow biopsy is recommended in such patients.

Other complications of transplantation

Immunosuppressants (especially glucocorticoids and calcineurin inhibitors) increase bone resorption and the risk of osteoporosis in patients at risk before transplantation (eg, due to decreased physical activity, tobacco and alcohol consumption, or preexisting renal impairment). Although not routinely prescribed, vitamin D, bisphosphonates, and other antiresorptive agents may play a role in preventing these complications.

The problem in children is growth failure, mainly as a consequence of prolonged glucocorticoid therapy. This complication can be controlled by gradually reducing the dose of glucocorticoids to the minimum level that will prevent transplant rejection.

Systemic atherosclerosis may result from hyperlipidemia due to the use of calcineurin inhibitors and glucocorticoids; it usually appears more than 15 years after kidney transplantation.

Graft versus host disease (GVHD) occurs when donor T cells are activated against the recipient's own antigens. GVHD primarily affects the recipient's hematopoietic stem cells, but can also affect the recipient's liver and small bowel graft.