immunology allergic disorders
Overview of Transplantation
Posttransplantation Complications
Complications include the following: Rejection Infection Renal insufficiency Cancer Atherosclerosis 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 Manifestations of Transplant Rejection by Category ). Hyperacute rejectionhas 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 rejectionhas 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 rejectionis graft destruction after transplantation and has the following characteristics: Occurs later, about 5 days after transplantation, and 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 rejectionis 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.Tacrolimushas 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 Surgery 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 (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,Pseudomonasspecies 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 [a common opportunistic polyomavirus in kidney transplant recipients], CMV, Epstein-Barr virus, varicella-zoster virus, or hepatitis B or hepatitis C virus), fungal (eg, aspergillosis, cryptococcosis,Pneumocystis jiroveciiinfection), 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 includetrimethoprim/sulfamethoxazole 80/400 mg orally once a day for 4 to 12 months to preventP. jiroveciiinfection or to prevent urinary tract infections in kidney transplant patients. Neutropenic patients are sometimes given quinolone antibiotics (eg,levofloxacin500 mg orally or IV once a day) to prevent infection with gram-negative organisms. Often, patients are treated prophylactically withgancicloviroracyclovirbecause 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 Restrictions, Precautions, and High-Risk Groups 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. Glomerular filtration rate (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) are needed to maintain the graft. Incidence is lowest for recipients of heart-lung transplants (7%). Nephrotoxic and diabetogenic effects of calcineurin inhibitors 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 calcineurin inhibitors, 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) are stopped, andtacrolimusis stopped if a lymphoproliferative disorder develops. Osteoporosiscan 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 ofvitamin 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. Atherosclerosiscan result from hyperlipidemia due to use of calcineurin inhibitors, rapamycins (sirolimus,everolimus), or corticosteroids; it typically occurs in kidney transplant recipients>15 years posttransplantation. (GVHD) occurs when donor T cells react against recipient self-antigens. GVHD primarily affects Early complications 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. Goutcan be exacerbated in patients with pre-existing hyperuricemia and/or a history of gout, especially those undergoing kidney or heart transplantation, and may be exacerbated posttransplantation because of drug interactions. Aggressive preoperative treatment of patients with increased risk with uric acid lowering drugs may be helpful in prevention. 