Organ Transplantation

Defintion

Organ transplantation is an integral component of modern medicine that has transformed the management of a wide variety of pediatric and adult medical conditions, in many cases providing long-term survival outcomes in what were otherwise fatal diseases. Organ transplantation can effectively restore vital organ function in patients with a variety of medical conditions, including inherited and genetic disorders (e.g., bone marrow failure syndromes, sickle cell disease, congenital cardiac disease), end-organ damage caused by chronic disease (e.g., diabetes-associated chronic renal disease, cardiomyopathy, Crohn disease), and cancer (e.g., leukemia, multiple myeloma, hepatocellular carcinoma). In some situations, organ transplantation is the only available option and is essential for survival; in other situations, it offers the potential for improved disease control and better quality of life. Kidney, heart, liver, pancreas, lung, small bowel, bone marrow, and composite tissues (composed of skin, muscle, tendon, nerves, bone, and blood vessels) may be considered for transplantation for the appropriate recipient.

Essential principles of organ transplantation involve (1) the immunology underlying proper donor and recipient matching and (2) the need for immunosuppressive therapy for prevention and management of graft rejection. Bone marrow, or hematopoietic cell transplantation (HCT), is unique in that there is no sophisticated surgical procedure but rather a cellular infusion of hematopoietic stem cells (which naturally home to the bone marrow where hematopoiesis is established), and rather than risk of long-term chronic graft rejection as with solid organ transplantation, the major immune-mediated complication is graft-versus-host disease (GVHD), in which the engrafted donor immune system attacks the recipient host tissues in an autoimmune-like manner. Solid organ transplantation is limited primarily by the availability of organ donors and limitations in organ procurement from cadavers. In some cases, organs are obtained from living donors, primarily with renal transplantation and HCT but also with newer approaches to partial pancreas and liver transplantation.

Organ transplant recipients require comprehensive dental screening and clearance before transplantation to reduce infection risk. After transplantation, these patients have unique oral health considerations that are largely related to the administration of immunosuppressive medications and corresponding long-term immunosuppression. In the context of HCT, in addition to immunosuppression, GVHD can have a significant and quite direct impact on oral health and function. The dentist must understand the basic principles of risk assessment and dental treatment planning before organ transplantation, as well as be able to provide safe and appropriate long-term comprehensive oral health care management in the posttransplantation setting.

CRITICAL COMPLICATIONS: Organ transplant recipients are at high risk for developing oral infections as well as noninfectious long-term complications, including oral cancer. These events could prove fatal. Before transplantation, dentists must work closely with the medical team to develop a dental management plan that will be effective and safe for the patient. The dentist must understand how to assess risk based on history and clinical findings and be able to recognize oral complications and provide appropriate management or referral.

Epidemiology

The first attempts at organ transplantation in the 1950s and 1960s were followed by increased activity that unfortunately resulted in very poor survival outcomes. Major advances in organ transplantation have been facilitated by improved understanding of, and mechanisms for, donor–recipient matching, development of effective immunosuppressive agents, improved surgical techniques (including percutaneous biopsy of solid transplanted organs to monitor rejection), and the acceptance of the concept of “brain death” as a definition for determining death of potential donors. Transplantation of the kidney, liver, heart, lungs, intestines, pancreas, and bone marrow may be considered as a treatment option, in many cases lifesaving, for selected patients with end-organ disease ( Tables 21.1 and 21.2 ).

TABLE 21.1
Adult Survival Rates After Organ Transplantation *
Organ Organs Transplanted in U.S.—Adults (2015) * ( n ) 1-Year Patient Survival Rate (Deceased Donor) (%) 3-Year Patient Survival Rate (Deceased Donor) (%) 1-Year Patient Survival Rate (Living Donor Recipients) (%) 3-Year Patient Survival Rate (Living Donor Recipients) (%)
Kidney 17,161 96.7 91.4 98.8 95.8
Pancreas (all) 186
Pancreas alone 97.6 94.9
Pancreas after kidney 94.1 95.9
Pancreas–kidney (SPK) 719 97.4 95.1
Liver 6547 91.3 82.7 90.3 86.4
Heart 2347 90.4 84.3
Lung 2016 87.2 69.3
Heart–lung 12 83.3 54.2
Intestine 83 76.3 65.3

* Data from Organ Procurement and Transplantation Network. Data optn.transplant.hrsa.gov/data .

Data from SRTR transplant program reports, June 2016 www.srtr.org/ .

TABLE 21.2
Pediatric Survival Rates After Organ Transplantation *
Organ Organs Transplanted in U.S.—Pediatric (2015) * ( n ) 1-Year Patient Survival Rate (Deceased Donor) (%) 3-Year Patient Survival Rate (Deceased Donor) (%) 1-Year Patient Survival Rate (Living Donor Recipients) (%) 3-Year Patient Survival Rate (Living Donor Recipients) (%)
Kidney 718 99.7 99.0 98.8 99.1
Pancreas (all) 42
Pancreas alone
Pancreas after kidney
Pancreas–kidney (SPK) 0
Liver 580 95.5 93.0 97.6 95.7
Heart 456 92.4 88.1
Lung 41 86.7 72.2
Heart–lung 3
Intestine 58 86.5 77.5

* Data from Organ Procurement and Transplantation Network. Data. optn.transplant.hrsa.gov/data .

Data from SRTR transplant program reports, June 2016. www.srtr.org/ .

No pediatric survival is calculated for this organ.

Kidney Transplantation.

A team led by Dr. Joseph E. Murray, a Nobel laureate, performed the first successful human organ transplant procedure in Boston in 1954 using a kidney donated by the patient’s identical twin brother. Today more than 10,000 renal transplantations are performed annually in the United States and more than 75,000 worldwide. The most common indications for kidney transplantation is end-stage renal disease secondary to glomerulonephritis, pyelonephritis, diabetic nephropathy, and congenital kidney disorders. The 1-year survival rate among renal transplant recipients is greater than 97%, and the 5-year survival rate is more than 90%, providing longer survival and better quality of life than dialysis.

Heart Transplantation.

The first human heart transplantation was performed in 1967 in Cape Town, South Africa. The primary indications for heart transplantation include severe cardiomyopathy, severe coronary artery disease, and congenital heart disease. Nearly 2500 heart transplant procedures are performed annually in the United States, with a 1-year survival rate of greater than 90% and a 5-year survival rate of 75%.

Liver Transplantation.

Since liver transplantation was first successfully performed in 1967, this procedure has offered the only option for long-term survival in patients with acute liver failure and end-stage liver disease. More than 6000 liver transplant procedures are performed annually worldwide, with clinical indications including extrahepatic biliary atresia, primary biliary cirrhosis, chronic hepatitis (HCV infection), advanced cirrhosis, sclerosing cholangitis, nonalcoholic steatohepatitis, alcoholic liver disease, fulminant hepatic failure, and hepatobiliary cancers. Survival rates at 1 and 5 years are over 85% and 70%, respectively.

Pancreas and Islet Cell Transplantation.

The first pancreas transplant procedure, which also included a duodenum and a kidney, was performed in 1966 by a team led by Kelly and Lillehei at the University of Minnesota in a patient with diabetic nephropathy. The objective of pancreas transplantation is to restore normal blood glucose levels, effectively curing diabetes and limiting the progression of diabetes-related complications. Pancreas transplantation can be performed in several ways: pancreas transplant alone, simultaneous pancreas and kidney transplant (either both from deceased donor, or pancreas from deceased donor and kidney from live donor), and pancreas after kidney transplant. The primary indication for pancreas transplantation is in persons with diabetes mellitus (overwhelmingly type 1) who have or are at high risk of secondary complications (e.g., nephropathy), have life-threatening hypoglycemic awareness, or are likely to develop either of these conditions and are sufficiently fit to survive the procedure. Pancreas transplantation is performed far less frequently for pancreatitis or cancer. The number of pancreas transplants performed annually has been decreasing, now at approximately 1000 per year in the United States, possible because of improved insulin delivery systems as well as increasing use of islet cell transplantation. When taking into account all types of pancreas transplantation, the survival rates are greater than 96% at 1 year and more than 80% at 5 years.

Pancreatic islet cell transplantation is an effective alternative to whole-pancreas transplantation in which islet cells are isolated from the donor pancreas (after being surgically removed) and infused into the recipient. The primary indication for islet cell transplantation is brittle diabetics with hypoglycemic unawareness (patients who are unaware of deep drops in blood glucose levels) that is not compatible with daily life and without advanced cardiac disease or nephropathy.

Lung Transplantation.

Lung transplantation was first performed in 1963 and today is the standard of care therapy for select patients with advanced and disabling pulmonary diseases that are not amenable to other medical or surgical therapies. Lung transplantation remains a fairly high risk procedure with a median recipient survival time of just more than 5 years. Indications for lung transplantation include chronic obstructive pulmonary disease, α 1 -antitrypsin deficiency, idiopathic pulmonary fibrosis, cystic fibrosis, and idiopathic pulmonary arterial hypertension (IPAH). Patients may be considered for single lung or bilateral lung transplantation and less frequently (≈3% of all lung transplants) combined heart–lung transplantation in patients with Eisenmenger syndrome with surgically uncorrectable cardiac defects as well as select patients with IPAH.

Intestinal Transplantation.

Intestinal transplantation is a lifesaving procedure indicated for management of intestinal failure (IF) secondary to a range of pathologic conditions. In 2000, the U.S. Centers for Medicare & Medicaid Services approved isolated small bowel intestinal, combined liver–intestinal, and multivisceral transplantation as standard of care for patients with irreversible intestinal and parenteral nutrition failure. With advances in medical management of IF, the number of intestinal transplants performed annually in the United States has steadily decreased from 198 in 2007 to 106 in 2012. Given the abundance of lymphoid tissue within the graft, recipients are at high risk for acute and chronic rejection but also to a lesser extent GVHD, although this tends to be a much more limited condition compared with GVHD post-HCT.

Survival outcomes are lowest in adult intestine–liver recipients, with 1- and 5-year survival rates of 69.1% and 46.1%, respectively, and highest in pediatric intestine recipients, with 1- and 5-year survival rates of 89.2% and 81.4%, respectively. Risk of early graft loss is considerable, with the primary causes being sepsis, rejection, and cardiovascular events.

Hematopoietic Cell Transplantation.

Since Thomas et al first reported successful bone marrow transplantation between identical twins in 1956, it has become a standard therapy for certain hematologic deficiencies and malignancies. Because the hematopoietic progenitor stem cells actually serve as the “graft” that homes to and repopulates the recipient marrow, and with the majority of donor grafts obtained from peripheral blood stem cells rather than from harvested bone marrow, this procedure is more commonly referred to as hematopoietic cell transplantation . With malignant disease, much of the benefit of HCT is in the potent graft-versus-tumor effect, in which engrafted donor cells mount an alloimmune response against residual malignant cells, effectively providing long-term immunotherapy. Autologous HCT, in which a patient’s stem cells are collected, isolated, and preserved before receiving high-dose myeloablative chemotherapy and then reinfused as a “stem cell rescue” procedure, is not truly “transplantation” because there is no allograft, and it is only discussed briefly in this chapter.

Even when donor–recipient human leukocyte antigen (HLA) matching is optimized and despite administration of GVHD prophylaxis regimens with immunosuppressive medications, GVHD is a major complication of allogeneic HCT and the leading cause of nonrelapse mortality. The most common indications for HCT include acute and chronic leukemia, myelodysplastic syndrome, lymphoma, aplastic anemia, severe immunodeficiency syndromes, and hemoglobinopathies. The Center for International Blood and Marrow Transplantation (CIBMTR) reports nearly 8000 allogeneic HCT procedures performed annually in the United States. Survival outcomes vary widely based on a number of factors, including underlying diagnosis and status at time of transplantation, donor type, and graft characteristics.

Vascularized Composite Tissue Allotransplantation.

Composite tissues that may be transplanted include skin, mucosa, muscle, and bone, among other structures, and may be used to replace lost or dysfunctional anatomic structures. Composite tissue allotransplantation, although never lifesaving, has the potential to greatly improve the recipient’s quality of life. Because the procedure requires long-term immunosuppression, this carries risks of opportunistic infection, organ failure, and cancer. The first successful hand transplantation was reported by Dubenard et al in 1998 and the first partial face transplantation in 2005. In addition, there have been less frequent reports of transplantation of other tissues, including the abdominal wall, larynx, and penis. This is a rapidly developing yet still largely experimental procedure within the field with highly variable graft survival outcomes.

Etiology

The remarkable successes in transplant medicine have been largely related to advances in the understanding of key clinical immunologic principles of donor–recipient matching, establishment and coordination of organ donor networks, incorporation of standardized immunosuppression regimens, and improvements in supportive care. HLA matching of donor and recipient reduces the risk of graft rejection (and in the case of HCT, also GVHD), a major complication of organ transplantation characterized by a host immune response to tissues expressing nonself histocompatibility antigens.

Donor–Recipient Matching.

Donors and recipients are matched using two different laboratory tests. First, HLA antigen expression is determined on donor and recipient leukocytes through serologic or more frequently DNA-typing assays. The second test is serologic cross-matching, which functionally measures recipient immune cell response to exposure to donor cell antigens, and, in the case of HCT, donor immune cell response to recipient cell antigens. Serologic cross-matching is particularly important in the primarily vascularized grafts of the kidney and heart. This test exposes donor cells to recipient serum and evaluates for the detection of antibodies to red blood cell or HLA antigens, both of which correlate with acute graft rejection. The National Marrow Donor Program (NMDP), which coordinates unrelated donor matching for HCT, requires high-resolution DNA-based matching of HLA-A, HLA-B, HLA-C, and DRB1, optimally with a four of four match, or if not possible, then a single mismatch at one of the four loci. The Organ Procurement and Transplant Network (OPTN) requires HLA-A, HLA-B, and DR antigen typing of the donor and recipient.

Organ Donation Networks.

The United Network for Organ Sharing (UNOS; www.unos.org ) is a nonprofit organization that operates the OPTN under a long-term contract from the U.S. Department of Health and Human Services. The Organ Center of the OPTN/UNOS supports the U.S. transplant community 24 hours a day, 365 days a year, through providing resource support about organ-sharing policies and processes, managing the computerized donor–recipient match results, coordinating donation of deceased donor organs, and arranging transportation for shared organs. Approximately 70% of patients requiring HCT do not have a matched related donor, necessitating coordination of matched unrelated graft donations through a robust and highly organized network of volunteer donors. The NMDP coordinates all aspects of donation and matching throughout all US HCT centers. The CIBMTR ( www.cibmtr.org ) is a research collaboration between the NMDP and the Medical College of Wisconsin that facilitates critical observational and interventional research through a large network of transplant centers, a clinical outcomes database, and scientific and statistical expertise. The vast majority of organ donations within the United States are coordinated through the NMDP (for HCT) and OPTN (for solid organs).

Immunosuppressive Medications.

Despite optimal HLA matching, even in matched related donor kidney and hematopoietic cell transplants, nonspecific immunosuppressive agents are necessary to prevent acute and chronic graft rejection. Although effective at preventing and managing rejection, long-term administration of immunosuppressive therapies increases the recipient’s susceptibility to infection and malignancy. The main immunosuppressive medications used in transplant medicine include corticosteroids (prednisone; methylprednisolone for intravenous therapy), antimetabolites (azathioprine and now typically mycophenolate mofetil), calcineurin inhibitors (CNIs; cyclosporine and tacrolimus), and mTOR (mammalian target of rapamycin) inhibitors (sirolimus, everolimus; Table 21.3 ). Immunosuppressive medications may be used in the following clinical situations: induction therapy (profound immuosuppression at the time of transplant surgery), GVHD prophylaxis, management of acute rejection and acute GVHD episodes, and maintenance immunosuppression for management of chronic rejection and chronic GVHD. Other immunosuppressive therapies used include antithymocyte globulin (ATG); monoclonal antibody therapies such as alemtuzumab, rituximab, and basiliximab; and extracorporeal photopheresis. With solid organ transplantation, induction typically consists of prednisone and a CNI (with or without mycophenolate and other agents), with varying tapering regimens based on a variety of factors. Acute rejection episodes are managed with high-dose corticosteroids and antilymphocyte (e.g., ATG) therapies.

TABLE 21.3
Immunosuppressive Medications Commonly Used in Transplant Medicine
Agent Class Mechanism of Action Important Side Effects or Monitoring Important Drug Interactions Oral Complications
Prednisone Corticosteroid Blocks cytokine gene transcription Cushing syndrome, diabetes, hypertension, myopathy, avascular necrosis, osteoporosis, glaucoma, cataracts Potentiates effects of concomitant therapy with other immunosuppressive medications Increases risk of oral candidiasis, recrudescent HSV infection, poor healing
Broadly acting immunosuppressant
Cyclosporine Calcineurin inhibitor Inhibits IL-2 gene transcription Hypertension, nephrotoxicity, tremors Fluconazole may increase cyclosporine levels Gingival overgrowth
Reduces activation of T cells BUN/Cr, LFTs, potassium, magnesium, lipid panel, serum drug levels
Tacrolimus Calcineurin inhibitor Inhibits IL-2 gene transcription Hypertension, nephrotoxicity, tremors Fluconazole may increase tacrolimus levels Pyogenic granuloma–like lesions
Reduces activation of T cells Cr, potassium, fasting blood glucose, serum drug levels
Azathioprine Nucleoside inhibitor Impairs DNA synthesis Leukopenia, myelosuppression, hepatotoxicity
Inhibits T and B cell proliferation Cr, CBC, LFTs
Mycophenolate mofetil Nucleoside inhibitor Impairs DNA synthesis Hypertension, anemia, leukopenia, diarrhea
Inhibits T- and B-cell proliferation CBC, Cr
Sirolimus mTOR inhibitor Inhibits mTOR complex Hyperlipidemia, diabetes Fluconazole may increase sirolimus levels Aphthous-like ulcers
Reduces T cell proliferation Lipid panel, serum drug levels
Everolimus mTOR inhibitor Inhibits mTOR complex Hyperlipidemia, diabetes Fluconazole may increase everolimus levels Aphthous-like ulcers
Reduces T cell proliferation Lipid panel, fasting blood glucose, serum drug levels

BUN, Blood urea nitrogen; CBC, complete blood count; Cr, creatinine, HSV, herpes simplex virus; IL-2, interleukin-2; LFT, liver function test; mTOR, mammalian target of rapamycin.

With HCT, in addition to the conditioning regimen (which prevents rejection and allows for engraftment), a GVHD prophylaxis regimen is administered that typically consists of a short course of methotrexate and long-term CNI therapy that is gradually tapered over 3 to 6 months in the absence of GVHD. Chronic rejection and chronic GVHD are managed similarly with various combinations of immunosuppressive agents.

Pathophysiology and Complications

Complications associated with organ transplantation generally consist of graft rejection, problems related to chronic immunosuppressive therapy, and special problems specific to the transplanted organ.

Graft Rejection.

Graft rejection is a potentially very serious complication of organ transplantation that can occur despite donor–recipient matching and the administration of immunosuppressive medications. Hyperacute rejection of solid organs occurs within 48 hours of surgical anastomosis and is mediated by preformed antibodies and complement activation, and it requires immediate graft removal; this complication is generally avoidable through cross-matching. Acute rejection , mediated by T cells and antibodies, occurs within the first 90 days after transplantation and generally responds to high-dose steroids and antilymphocyte therapies. Chronic rejection of solid organs is primarily antibody mediated and, despite treatment with immunosuppressive medications, is generally irreversible.

Immunosuppression and Infection Risk.

Immunosuppressive medications nonspecifically block T- and B-cell activity as well as innate immunity effector cells and pathways, significantly increasing the risk for infection. Screening of donor and recipient for major infections before transplant is essential to reduce the risk of infectious complications. In addition, transplant recipients receive extensive education and guidance on other preventive strategies, including hygiene, environmental exposures, and food safety handling. Signs and symptoms of infection may be subtle or even nonexistent because of the effects of immunosuppressive therapies, and, in some cases, a more aggressive workup may be necessary to confirm or rule out a diagnosis. Although most HCT recipients eventually have all immunosuppressive therapy discontinued, those who develop GVHD may require years of immunosuppressive therapy, and solid organ transplant recipients generally require lifelong immunosuppression. Patients with chronic rejection or chronic GVHD require more intense immunosuppression and are therefore at even higher risk for infection.

In the early posttransplant period, patients are primarily at risk for nosocomial infections (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), opportunistic infections (e.g., oropharyngeal candidiasis, aspergillus), and donor-derived infections. Viridans streptococci are bacterial microorganisms frequently isolated from blood cultures of patients undergoing HCT, and poor dental health has been associated with an increased risk of streptococcal bacteremia in this setting. From 1 to 6 months posttransplantation, when patients tend to be most highly immunosuppressed, there is high risk of both opportunistic infections (e.g., BK virus, adenovirus) and reactivation of latent infections (e.g., cytomegalovirus [CMV]). Invasive fungal infections tend to occur within the first 3 months of transplantation. Infections occurring more than 6 months after transplantation tend to be typical community-acquired infections (e.g., pneumonia; urinary tract infections, especially in kidney transplant recipients) but may have more severe manifestations than in the general population. HCT recipients are at highest risk for infection because the entire immune system in effect is reconstituted over a period of months to years.

Other Side Effects of Immunosuppressive Medications.

In addition to increasing the risk of infection, immunosuppressive medications are associated with various short- and long-term side effects that can have significant medical implications for these patients ( Table 21.3 ). CNI therapy (cyclosporine and tacrolimus) is associated with development of chronic kidney disease and renal insufficiency that can progress to end-stage renal disease; therefore, routine renal function monitoring is indicated, and medication levels in the blood are carefully monitored. Other potential complications of CNI therapy include tremors, magnesium wasting, hypertension, hyperkalemia, hyperuricemia, and hyperglycemia. Mycophenolate is associated with myelosuppression and gastrointestinal (GI) side effects (diarrhea and inflammatory bowel disease–like condition). Azathioprine has a similar mechanism of action as mycophenolate but is used less frequently because of less favorable side effect profile. Side effects of prednisone therapy increase with dose and duration and include hyperglycemia (which can progress to diabetes requiring insulin), hypertension, hyperlipidemia, osteoporosis and avascular necrosis. The mTOR inhibitors (sirolimus and everolimus) are associated with cytopenia and hyperlipidemia, requiring routine laboratory and blood level monitoring.

Cancer Risk.

Organ transplant patients are at increased risk for posttransplant lymphoproliferative disease (PTLD) and nonmelanoma skin cancers related to the intensity and duration of immunosuppressive therapy and sun exposure, including dysplastic and malignant lip lesions. In addition to nonmelanoma skin cancers, HCT patients are at significantly increased risk for melanoma, liver, oral cavity, brain, thyroid, and bone cancers. PTLD is a lymphoma-like condition, often but not always EBV positive and of B-cell origin, that typically develops in the early posttransplant period when patients are highly immunosuppressed. The incidence of PTLD ranges from approximately 1% in renal transplant recipients and matched related and unrelated HCT, to 4.5% in liver transplantation. Management of PTLD includes reduction of immunosuppression (if feasible) and chemotherapy (e.g., anti-CD20 monoclonal antibody therapy), with an overall 5-year survival rate of 40% to 60%.

Organ-Specific Complications

Kidney Transplantation.

Although BK virus infection can affect any transplant patient, renal transplant recipients are at particular risk for BK virus nephropathy. This can be distinguished from rejection by biopsy and is managed primarily with reduction of immunosuppression. Renal graft rejection is monitored primarily by serum creatinine measurement rather than biopsy, and if graft failure occurs, hemodialysis can be initiated.

Heart Transplantation.

Cardiovascular disease affecting the transplanted heart can arise from the donor heart because of preexisting pathology; de novo related to traditional or existing risk factors; or from allograft vasculopathy, a form of coronary artery disease and a major source of morbidity. Because of denervation as part of the surgical transplant procedure, heart transplant recipients do not typically experience symptoms of angina and therefore require intensive monitoring for allograft vasculopathy by annual angiography. All heart transplant recipients receive lifelong statin therapy regardless of lipid levels. In addition to surveillance by endomyocardial biopsy, rejection may present with typical symptoms of heart failure.

Liver Transplantation.

In addition to graft rejection, recurrent underlying disease for which transplant was indicated is a potentially serious complication in liver transplantation and can lead to transplant failure. Both HCV infection and alcohol abuse have high likelihoods of recurrence and require routine screening and active treatment if detected.

Lung Transplantation.

Rejection in lung transplant recipients may present with dyspnea, cough, and hypoxia. Lung function is monitored by spirometry with transbronchial lung biopsy performed as needed to rule out or confirm acute rejection. Bronchiolitis obliterans, the characteristic feature of chronic rejection, is less readily determined by transbronchial biopsy and is therefore diagnosed and monitored based primarily on spirometric measures and changes over time.

Hematopoietic Cell Transplantation.

Although graft rejection is relatively rare in HCT because of the effective immunosuppression of the conditioning regimen, GVHD is a very serious and potentially life-threatening complication in which engrafted donor lymphocytes mount a multifaceted alloimmune-mediated attack against the recipient–host tissue, resulting in a wide range of autoimmune disease–like features. Acute GVHD typically occurs within the first 100 days after HCT and is characterized by skin rash, elevated liver transaminases, and diarrhea. Chronic GVHD typically occurs after day +100, affecting most frequently the skin, mouth, eyes, liver, and lungs, contributing to significant disability, reduced quality of life, and mortality. Of note, end-organ pathology of chronic graft rejection in solid organ transplantation and chronic GVHD can be very similar, for example, with bronchiolitis obliterans with lung transplantation and GVHD.

Solid organ transplantation can very rarely be associated with GVHD. The risk is greatest with intestinal transplantation, but GVHD has been reported after transplantation of other solid organs. With facial transplantation, graft rejection of transplanted skin and oral mucosa presents clinically and histopathologically identical to GVHD.

Clinical Presentation

Signs and Symptoms

In the absence of treatment-related comorbidities (e.g. chronic rejection, GVHD, infections), transplant recipients with good organ function generally have normal function and performance status, similar to the general population. With chronic rejection of solid organs, depending on the degree and extent of organ function compromise, the clinical presentation may resemble that of the pretransplant disease status. Signs and symptoms of GVHD vary widely, with skin rash and diarrhea most common in the acute setting and skin rash and fibrosis, oral lichenoid inflammation and sensitivity, and eye dryness and discomfort most common in the chronic setting.

Laboratory and Diagnostic Findings

Laboratory testing in the transplant patient is critical for monitoring organ function, metabolism of medications, and infectious diseases. Protocols depend on the transplanted organ and institutional preferences. Blood pressure is monitored at every visit. A lipid panel and diabetes screening test should be ordered every 6 to 12 months, especially in patients on long-term CNI and corticosteroid therapies. Monitoring of serum creatinine is important in renal transplant recipients to screen for rejection, as well as in all patients on CNIs and other immunosuppressive agents because of potential renal toxicity. Similarly, liver function testing is routinely performed in liver transplant recipients because rejection causes elevated transaminases, bilirubin, and alkaline phosphatase. The liver is also a frequent target of GVHD. Pulmonary function is monitored by spirometry (referred to generally as pulmonary function tests) and indicated in lung transplant patients as well as HCT patients with GVHD or shortness of breath. Pancreas transplant rejection may manifest with compromised endocrine function or an increase in amylase levels.

Surveillance needle biopsy is routinely performed for most solid organs to screen for rejection. In some cases, biopsies may be obtained weekly or monthly early after transplantation and then less frequently (e.g., annually) thereafter; however, protocols vary among centers. GVHD can generally be determined from clinical features alone, but involved tissue histopathology (e.g., skin, oral mucosa, GI) may be helpful in supporting or ruling out the diagnosis. Cyclosporine, tacrolimus, and sirolimus are monitored by routine measurement of serum trough levels, with doses adjusted accordingly if needed. CMV reactivation is monitored at predefined intervals by quantitative polymerase chain reaction, with a positive assay triggering initiation of preemptive therapy with ganciclovir, a reduction in the intensity of immunosuppression (if feasible), and intensified monitoring. Transplant patients with a history of invasive fungal infection may be monitored for evidence of recurrent infection by serum glucan and galactomannan antigen testing.

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Sep 3, 2018 | Posted by in General Dentistry | Comments Off on Organ Transplantation
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