INTRODUCTION

Transplantation is the treatment of choice for the restoration of function in end-stage organ disease. Innovative surgical techniques have played a major role in enhancing the success of organ transplants, leading to improved graft and patient survival. Advances in the biology of organ preservation have led to improved cold storage of the solid organs, improving the overall quality of the transplanted organs and diminishing the damage incurred by warm ischemia, allowing optimization of the medical conditions of the donor and the recipient. Furthermore, insights into the biology of immune responses to transplanted tissues have aided in the development of immunosuppressive techniques to prevent the rejection of the organ transplant while minimizing the morbidities associated with chronic immunosuppression. The main limitation to even greater use of transplantation as a treatment modality for end-stage organ damage remains the shortage of organ donors.

Attempts at organ and bone marrow transplantation date back to the 1800s. Dr. Joseph Murray performed the first successful human renal transplantation between identical twin brothers in 1954. This procedure was well tolerated, as there was no rejection by the genetically identical recipient. The first successful allogeneic (not genetically identical) transplantation was a kidney transplant between fraternal twins performed in 1959, in which the recipient was “conditioned” (immunosuppressed to prevent rejection) by total body irradiation. In 1962, a successful cadaveric donor renal transplantation was achieved, and in 1966, a pancreas transplantation was successfully performed. In the following year, the first human liver transplantation was performed, resulting in a 13-month survival. In the same year, a heart was transplanted. In 1968, a genetically related bone marrow transplantation (today referred to as a hematopoietic stem cell transplantation [HSCT]) was performed, and in 1973, a genetically unrelated HSCT was performed. Lung transplantation has also been performed both as a single procedure and in combination with a heart transplantation. The first heart–lung transplantation in the United States was done in 1981, and the first ever single-lung transplantation was performed in Canada in 1983. Other organs that have been successfully transplanted include the small bowel, skin, various limbs, face, and components of the human eye.

In past decades, significant advances—including tissue typing and the development of immunosuppressive medications and medication regimens—have increased the success of transplantation. Overall, long-term patient survival has also significantly increased over the past 30 years, in both solid organ and HSCT recipients. Most transplant clinicians consider the discovery of the immunosuppressive agent cyclosporine (CSA) to be the most significant advance in transplantation medicine. This medication was approved for use in 1983. Both solid organ and non–solid organ transplantations are becoming more routine throughout the world. In November 2013, over 120,000 patients in the United States alone were waiting for a solid organ transplant. In 2012, 28,052 solid organs were transplanted, approximately the same number as was seen in 2005, and in 2019, 39,719 transplants were performed (Table 20-1).¹

As the process of solid organ transplantation expands, there is a continued need to increase the supply of organs suitable for transplantation. The limitation of available donor organs will hopefully become less of an issue with increased awareness of organ donation and perhaps with collaborative sharing initiatives, alternative organ procurement methods, including xenografts or stem cell–derived tissue, or printed organs.

The likelihood of a dentist having to treat a transplanted patient is increasing, as many of these transplant recipients resume a normal life after transplantation and many achieve long-term survival beyond 10 years. This chapter reviews different aspects of transplant medicine pertinent for the oral health professional.

CLASSIFICATION

Most transplant clinical classification systems employ both the type of tissue transplanted and the genetic relationship of the tissue to the recipient. It is extremely important for the dental clinician to know exactly what type of transplantation was performed, as both the management and the prognosis are intimately related. This will become evident later in this chapter.

Some authorities broadly divide transplantations into solid organ/tissue transplant or HSCT. Virtually all solid organs/tissues have been transplanted, including heart, lung, kidney, liver, stomach, intestine, pancreas, skin, tendons, nerves, veins, and eye components, as well as composite tissue transplants, including the face and the limbs. HSCT is another type of transplantation frequently used to treat various hematologic and some nonhematologic malignancies, as well as other disorders. HSCT uses either an autologous “self” donor graft or a “nonself” donor (allogeneic graft).

Classification of transplants can also be based broadly on the genetic relationship of the recipient to the donor. For the purpose of this chapter, the transplanted cell, tissue, or organ is referred to as the graft. A transplant to and from one’s self (autograft) is known as an autologous transplant. A transplantation from an identical twin (identical genetic makeup) is known as an isograft, with the process of this type of transplantation known as isogeneic or syngeneic transplantation. Most transplants are from donors that are not genetically identical to the recipient (allografts). These types of transplants are known as allogeneic transplants. Finally, transplants from donors of one species to recipients of another species (xenografts) are known as xenogeneic transplants.

Due to the scarcity of isografts and the obvious limitations to autografts, allogeneic transplants are most commonly used today. The success of allogeneic transplantation relies on more or less sophisticated mechanisms for identifying and matching specific genetic markers between the donor and the recipient depending on the organ, as well as suppressing the recipient’s immune system to prevent transplant rejection. These are concepts that serve as the basic foundation in transplantation medicine. In the future, these concepts may be extended and improved to allow transplantation across species. Tissue xenografts, which have been treated to reduce their immunogenicity, have been used as a successful treatment modality in some applications (i.e., porcine heart valves), but whole-organ xenografts have been unsuccessful. Research regarding genetically altered xenografts is ongoing. When the important immunologic barriers to xenogeneic transplantation are eliminated, the use of animal donors may possibly alleviate the relative paucity of available organs. Of course, significant ethical questions, as well as transplant longevity and transmissible infectious diseases from animals, are issues that must be addressed before these types of transplants become commonplace. Bioengineered tissues that have been fabricated in vitro and transplanted back into the patient have also been successful, including a trachea and a bladder.

TRANSPLANTATION IMMUNOLOGY

Transplantation immunology encompasses most aspects of the human immune response to alloantigens expressed by the recipient as well as the donor organ/tissue. When donor and recipient genetic disparities exist, the recipient mounts a specific immune response to the alloantigens expressed by the donor grafted organ/tissue. In addition, donor T cells contained within the transplanted graft or organ can recognize foreign tissue in the host and mount a “graft-versus-host” reaction. Transplantation medicine would be grossly unsuccessful if this concept were not appropriately appreciated and manipulated.

T lymphocytes are the primary, though not the only, cells that mediate graft rejection as well as graft-versus-host disease (GVHD). T cells can become activated shortly after transplant by recognizing foreign major and minor human leukocyte antigen (HLA) molecules. The major histocompatibility complex (MHC), a genetic region found on the short arm of chromosome number 6 of all mammalian cells, codes for HLA molecules that allow immune cells to identify self from nonself. Although there are many other gene products, from more than 30 histocompatibility gene loci, which can stimulate graft rejection, it is the HLA system that produces the strongest immunologic response.

MHC genes are inherited from each parent; every child has components of both the mother’s and the father’s HLAs on their cell surfaces. The MHC/HLA system is broadly divided into regions. MHC class I and class II regions are those significantly involved in rejection and GVHD (see later in the chapter). MHC class I regions include HLA-A, -B, -C, -E, -F, and -G. (The present role of the -E, -F, and -G regions in transplantation is not well understood.) MHC class II regions include HLA-DR, -DQ, -DP, -DO, and -DN. MHC class II genes have two chains, allowing for four different gene products for each locus.

The MHC has extensive polymorphism, allowing remarkable diversity among genes of the HLA system. There are over 180 different class I alleles in the HLA-B region alone and over 220 class II alleles in just one loci of the HLA-DR region that have been recognized in humans. Deoxyribonucleic acid (DNA)-based typing (see below) has led to a more specific and detailed classification of the transplantation genes, such that the HLA alleles are related to their DNA sequences.

HLA class I antigens are expressed on most nucleated cells and on red blood cells, whereas class II antigens are expressed only on certain cells known as antigen-presenting cells (APCs). APCs include macrophages, B cells, dendritic cells, and some endothelial cells. The expression of these MHC gene products (antigens) on a cell’s surface is regulated by various cytokines such as interferon (IFN) and tumor necrosis factor (TNF).

In the setting of solid organ transplantation, the transplanted foreign MHC molecules activate the immune response by stimulating the recipient’s T cells to respond to foreign antigens. The interaction of the MHC of the donor cells with the recipient’s T-cell receptor initiates the immune reaction that can lead to rejection. T cells can be activated either by the donor’s or the recipient’s APCs, resulting in the expression and production of lymphokines and cytokines that promote activation of cytotoxic T cells, activation of B cells, and activation of natural killer cell activity, as well as promote enhanced expression of MHC and increased macrophage activity. This, in turn, causes further immune reactions that result in direct tissue damage and damage to the vascular endothelium of the graft, which may ultimately result in graft rejection.

Despite the treatment of recipients with immunosuppressive drugs, the potential for immunologic rejection is not entirely eliminated. Rejection may be characterized as acute, a process evolving rapidly over days to weeks. Acute rejection can occur at any time, from hours after transplant to years later. This acute process is related to the primary activation of T cells and usually can be reversed by modifying or intensifying the immunosuppressive regimen.

Chronic rejection of the allograft is also a significant problem leading to organ failure. This type of rejection is slow and insidious and in most cases cannot be reversed by conventional immunosuppressive drugs. It likely occurs by continued, albeit muted, cell-mediated toxicity that results in vascular endothelial damage of the transplanted organ (as well as other actions, which have not been fully elucidated), leading ultimately to graft failure.

Another type of rejection is known as hyperacute rejection; this occurs within minutes to hours after a transplantation procedure. This pattern of rejection occurs in patients who have undergone previous transplantations, patients who have had multiple pregnancies, and patients who have had multiple blood transfusions. It is caused by the presence of preformed antidonor antibodies in the recipient that activate complement cascade, resulting in severe damage to the parenchymal constituents of the graft, which often cannot be reversed.

Transplant immunology is even more complicated in the setting of allogeneic HSCT. Without proper immune suppression, residual host lymphocytes can mediate graft rejection, leaving a patient aplastic. However, unlike solid organ transplant, a hematopoietic stem cell graft has large numbers of mature lymphocytes capable of reacting against nonself antigens in the host in inducing GVHD. Donor leukocytes tend to react against the skin, liver, and gastrointestinal tract. Occasional involvement of the lungs can be seen as well. GVHD varies from nonexistent in approximately 50% of patients to severe and life-threatening. GVHD remains one of the major limitations to successful HSCT. Intensive therapies designed to minimize GVHD have resulted in higher rates of relapse from loss of the potential “graft-versus-tumor” (GVT) effect and from higher rates of infection. Ultimately, therapies that may limit GVHD and retain the important GVT activity of the donor graft will be needed to improve the outcomes of HSCT, and several strategies are in clinical testing.

It should also be noted that in unusual cases after solid organ transplant, mature donor lymphocytes transplanted with the organ can engraft and likewise cause GVHD. This is particularly complicated and similar to “transfusion-associated GVHD” (TA-GVHD), which can lead to marrow aplasia without the support of a donor stem cell graft. Similar to TA-GVHD, the prognosis is often poor, and treatment requires early recognition and intensive intervention with immune suppression.

CLINICAL INDICATIONS

The clinical indications for transplantation vary, but the disease outcome can be fatal without the transplant. The more common indications for transplantation are listed in Table 20-2.

Other indications can be added to this list when quality of life can be improved by transplantation. For example, autologous HSCT may ameliorate the effects of systemic lupus erythematosus or other autoimmune disorders. HSCT has been performed as a treatment for the management of various metabolic disorders and solid tumors, germ cell tumors, and neuroblastoma.²

In recent years there has been a steady increase in vascularized composite allograft transplantations. These include facial, craniofacial, hand, limb, and genitourinary transplantations. Such transplantations prompt new ethical questions.³

MEDICAL MANAGEMENT

Medical management of the transplant candidate focuses on successfully preventing rejection. In solid organ transplantation, when the donor and recipient tissue are genetically identical (autologous or syngeneic), the outcome of the transplantation relies upon the surgical success of the procedure. For autologous HSCT, success is largely dependent on the high-dose chemotherapy or radiation used to eradicate residual malignant cells prior to HSCT. When tissue from genetically different sources is transplanted, a sophisticated means of preventing rejection must be instituted to ensure graft survival, and in the setting of allogeneic stem cell transplant, methods must be used to prevent both graft rejection and severe GVHD. Transplantation surgeons and oncologists have improved the surgical procedures for various transplantations. Medical management to achieve longer-term successful grafts and longer-term overall patient survival has been quite successful, yet it still is fraught with longer-term complications. The success of an allogeneic transplantation relies on the ability to identify and match certain genetic markers between the donor and the recipient while suppressing the recipient’s immune system in order to prevent rejection.

BLOOD AND TISSUE TYPING

Standard ABO and Rh blood typing is performed to prevent hyperacute rejection of the transplant based on isoagglutinin incompatibility. ABO matching is mandatory for solid organ transplant and directly impacts short-term graft survival. ABO matching does not appear to impact graft survival after allogeneic HSCT; the impact on patient outcomes such as relapse is controversial, but is likely to be small and of unclear significance that may depend on graft source and disease.

Cross-matching (crossing recipient serum with donor lymphocytes) is usually done to prevent hyperacute rejection in allogeneic solid organ transplants. This is a basic serologic test that is regarded as necessary, particularly in those allogeneic transplant recipients who have previously experienced massive immune challenges such as a prior transplantation, multiple pregnancies, or multiple blood transfusions, and have developed preformed anti-HLA antibodies. The existence of preformed alloantibodies is detected by single HLA antigen bead technology. Since transplantation of solid organs (heart, lung, liver) often requires some expediency, time-consuming complex cross-matching or tissue typing cannot be performed. Instead, absence of antibodies to a panel of cells (defined in advance and known as panel-reactive antibodies) is usually adequate for heart and lung transplantation. Interestingly, MHC compatibility in liver transplantation seems negligible in achieving better outcomes. This is fortunate, because the timing of liver transplantation often precludes HLA typing.

The most critical matching criterion for allogeneic HSCT is tissue typing to determine and match HLA. HLA molecules are found on donor and recipient cells, and in the setting of HSCT are critical for determining engraftment and complications such as GVHD. HLA typing is much less critical in renal transplantations and for graft survival in liver or heart transplantations. Tissue typing can be performed by serologic assays, but more commonly, most typing is performed using rapid DNA-based testing methods. Polymorphisms in HLA antigens are common, and it is now practical and routine to test not just for HLA antigens but for HLA alleles. In the setting of allogeneic HSCT, it is clear that allele level matching improves outcomes. Matching at class I HLA-A, -B, -C, and class II (HLA-DR) is critical in all cases. The role of matching at the HLA class II molecule DQ is less clear and a single DQ mismatch does not seem to impact the outcome after HSCT.

IMMUNOSUPPRESSION

Immunosuppressive regimens vary among transplant centers and according to organ type (intestines, liver, etc.). Since tissues in allogeneic transplants are not genetically identical, medications used to control the immune response are essential for graft survival. All allogeneic transplantations initially require immunosuppression to prevent acute and hyperacute and/or acute cellular rejection. Furthermore, most allogeneic solid organ transplant recipients require lifelong maintenance immunosuppression and may require even more intensive immunosuppression should they develop rejection. Long-term immunosuppression is usually not required in allogeneic HSCT, and autologous HSCT generally requires no immunosuppression at all.

Most immunosuppressive medications are nonspecific and cannot prevent a specific component of the immune response. More sophisticated and directed agents are currently in development that will allow for graft tolerance while allowing the immune reaction to infection or other detrimental antigens to remain intact.

One of the most significant advances in transplantation has been made in pharmacotherapeutic immunosuppression. As mechanisms of graft rejection are better understood, agents become more specific in their mode of immune modulation.

Immunosuppression in solid organ transplant can be divided into induction (used at the time of implantation of the graft or soon after) and maintenance (to prevent rejection long term) (Figure 20-1). The most frequently used contemporary medication classes are discussed in this chapter (see Table 20-3), with a brief review of some key formulations.

Calcineurin Inhibitors

Calcineurin activates a nuclear component of T cells that is thought to initiate gene transcription for the formation of interleukin (IL)-2. The development of calcineurin inhibitors (known as CNI), specifically cyclosporine A (CSA) in 1981, was a watershed moment in solid organ transplantation and immediately lead to drastically lower rates of rejection.

Cyclosporine

CSA is a cyclic polypeptide macrolide medication derived from a metabolite of the fungus Tolypocladium inflatum. It specifically and reversibly inhibits immunocompetent lymphocytes in the G0 and G1 phase of the cell cycle by binding with the intracellular protein cyclophilin, and inhibiting calcineurin, which is presumed to inhibit IL-2 by preventing gene expression. CSA also reduces the expression of IL-2 receptors. This medication has some effect on humoral immunity but not on phagocytic function, neutrophil migration, macrophage migration, or direct bone marrow suppression. Absorption of this drug is variable, and blood levels must be drawn 2 hours after dosing to ensure that the drug is in the therapeutic range.

Drug	Type	Indications	Major Side Effects†	Implications in the Dental Office†
Cyclosporine	Calcineurin inhibitor	Maintenance IS	Nephrotoxicity Neurotoxicity Elevation of blood pressure Cosmetic side effects PTLD	Immunosuppression related‡ Drug–drug interaction (P-450 CYP3A)§ Vital signs monitoring Gingival overgrowth Risk of neoplasm
Tacrolimus	Calcineurin inhibitor	Maintenance IS	Nephrotoxicity Neurotoxicity Post-transplantation diabetes mellitus Elevation of blood pressure PTDM	Immunosuppression related‡ Drug–drug interaction (P-450 CYP3A)§ Vital signs monitoring Risk of neoplasm
Sirolimus	mTOR inhibitor Antiproliferative	Maintenance IS Potential treatment for chronic rejection Used in CNI-sparing IS	Delayed wound healing Hyperlipidemia Hypertriglyceremia Proteinuria Bone marrow suppression Interstitial pneumonitis	Immunosuppression related§ Drug–drug interaction (P-450 CYP3A)§ Vital signs monitoring Risk of neoplasm
Everolimus	mTOR Inhibitor Antiproliferative	Maintenance IS Potential treatment for chronic rejection Used in CNI-sparing IS	Delayed wound healing Hyperlipidemia Hypertriglyceremia Proteinuria Bone marrow suppression	Risk for osteonecrosis of the jaws Risk of neoplasm
Azathioprine	Antimetabolite	Adjuvant to maintenance IS	Bone marrow suppression Hepatotoxicity	Immunosuppression related‡ Risk of neoplasm
Mycophenolate mofetil	Antimetabolite	Adjuvant to maintenance IS	Immunosuppressant‡ Leukopenia	Immunosuppression related‡ Absorption is altered by antibiotics, antacids, and bile acid binders Risk of neoplasm
ATG/ALG	Polyclonal antibody	Induction IS Treatment of very severe rejection	Leukopenia PTLD Pulmonary edema Renal dysfunction	Immunosuppression related‡ Risk of neoplasm
Basiliximab	Monoclonal antibody	Induction IS	Pulmonary edema Renal dysfunction	Immunosuppression related‡ Risk of neoplasm
Corticosteroids	Nonspecific immunosuppressant	Induction IS Maintenance IS Treatment of acute rejection	(see Box 20-1)	Immunosuppression related‡ Peptic ulcer related (avoid NSAIDs) Vital signs monitoring Poor wound healing Risk of neoplasm Steroid supplement may be needed with stressful procedures As applicable for diabetes, if develops Possible history of bisphosphonates

ASA, acetylsalicylic acid; ATG/ALG, antithymocyte globulin/antilymphocyte globulin; CNI, calcineurin inhibitor; CV, cardiovascular; IS, immunosuppression; mTOR, mammalian target of rapamycin; NSAIDs, nonsteroidal anti-inflammatory drugs; PTDM, post-transplantation diabetes mellitus; PTLD, post-transplantation lymphoproliferative disorder.

^* Major mechanisms of action are outlined in the text.

^† Partial listing only.

^‡ Use of an immunosuppressant results in an increased risk of infection.

^§ Dental/oral pharmacotherapeutics that are metabolized by the liver’s cytochrome P-450 CYP3A system alter this drug’s serum levels. This group of medications includes, but is not limited to, erythromycin, clarithromycin, azole antifungals, benzodiazepines, carbamazepine, colchicine, prednisolone, and metronidazole.

Tacrolimus

Tacrolimus (FK-506; Prograf) is a macrolide immunosuppressant produced by Streptomyces. Similar to CSA, it suppresses cell-mediated reactions by suppressing T-cell activation. Tacrolimus inhibits calcineurin by interacting with an intracellular protein known as the FK-binding protein. Consequently, T cells are not activated, and cell-mediated cytotoxicity is impeded. There may be a lower incidence of rejection with the use of tacrolimus compared with the use of CSA in liver, kidney, and lung transplantations. Overall graft and patient survival rates in kidney transplantations do not seem to differ significantly with the use of this medication, although the safety profiles do differ and seem to favor tacrolimus.⁴

ANTIMICROBIAL MEDICATION

In addition to immunosuppressive medication regimens, antimicrobial medication regimens are important in preventing infection in the transplant recipient. These regimens vary from center to center and from program to program. Transplant patients are typically profoundly immunosuppressed for months. Many factors affect the pace of immune reconstitution, but it is common to use prophylactic antibiotics for bacterial, protozoan, fungal, and viral infections. Antimicrobial medication coverage has proven to be effective in the prevention of common transplant-associated infections (Table 20-4).

The Centers for Disease Control and Prevention (CDC) have published updated guidelines for preventing opportunistic infections among HSCT recipients based upon the quality of the evidence supporting the recommendation. Prophylaxis is, however, very different from the empiric treatment required in febrile neutropenia.

COMPLICATIONS

Complications with transplantation are still common and require close evaluation and management. General complications can be broadly characterized into those caused by rejection, side effects from medication, and those induced by immunosuppression. Additionally, there are some organ-specific complications observed in certain types of transplantation.

Rejection

As previously mentioned, rejection of the transplanted organ remains a significant obstacle to long-term transplant graft and patient survival. Rejection is characterized by time course and mechanism of injury. Rejection leads to end-organ damage and can lead to allograft failure, often associated with reappearance of complications of organ failure. Clinically, rejection may manifest in many ways, including abnormal liver function such as bilirubin, albumin, and International Normalized Ratio (INR; liver failure); a decreased metabolism of medications (rejection of liver/kidney); or even complete organ failure and death (rejection of liver/lung/heart). In cases of end-organ disease (except those of kidney failure), retransplantation may be the only way to prevent death.

Rejection is continually screened for throughout the post-transplantation period. Most chronic rejections are insidious and are detected by laboratory analysis and by organ biopsy. Graft biopsy provides a reliable means to assess rejection. An alternative approach to monitoring rejection in a transplanted heart is the use of pacemakers to record changes in ventricular evoked response (VER). Subtle changes in VER have been correlated with rejection of heart transplants.

Complications of Immunosuppression Medication

Medications used to produce immunosuppression and prevent graft rejection have significant systemic side effects, which pose serious complications to the transplant recipient. Some of the major side effects are listed here (Table 20-3); however, complete drug information can be obtained through an appropriate medication reference source.

CSA, a mainstay in immunosuppression, is nephrotoxic and may alter renal function. It is also associated with hypertension and lowering of seizure threshold, as well as rare cases of hepatotoxicity. It also has cosmetic side effects such as gingival hyperplasia and hirsutism that can be quite concerning to patients. CSA is metabolized via the P-450 CYP3A system of the liver; therefore, it has many drug interactions, including interactions with drugs frequently used in dentistry, such as lidocaine and oxycodone.

Tacrolimus has been associated with hypertension and nephrotoxicity. In addition, it is neurotoxic and rare hepatotoxicity has been described.⁴ There are many other side effects associated with the use of this medication, one of which is the development of insulin-dependent post-transplantation diabetes mellitus (PTDM). The incidence of PTDM appears to be higher with tacrolimus use than with CSA use in liver transplantation. Tacrolimus is metabolized by the P-450 CYP3A system in the liver. It is 99% protein bound and requires titration. Tacrolimus also has significant interactions with medications used in dentistry, such as ibuprofen and metronidazole.

Sirolimus causes or exacerbates proteinuria and may cause abnormal liver enzymes. It can cause stomatitis and oral ulceration and lead to interstitial pneumonitis in rare cases.⁴ Sirolimus is also associated with a high incidence of hyperlipidemia owing to elevated triglyceride and cholesterol levels. Being a substrate for P-450 CYP3A, sirolimus interferes too with the metabolism of other medications.

AZA may cause bone marrow suppression, resulting in pancytopenia, which leaves the patient not only susceptible to opportunistic infections, but also at significant risk for bleeding. It also causes skin rash and pancreatitis in some patients.⁴

MMF has significant drug interactions that are particularly important to the dentist. One interaction commonly cited occurs as a result of antibiotic regimens that can alter gastrointestinal flora, leading to dramatic changes in MMF drug levels. For example, if a patient is taking a broad-spectrum antibiotic for a dentoalveolar infection, the possibility and probability of an abnormal MMF level do exist. Other medications, such as antacids (containing magnesium or aluminum) and bile acid binders, may also interfere with the absorption of MMF. MMF is usually well tolerated, without significant hepatotoxicity (although higher doses are associated with gastrointestinal symptoms of nausea, vomiting, and diarrhea) or nephrotoxicity, but hematologic alterations (mostly leukopenia) can be a side effect. It is also teratogenic.

Monoclonal and polyclonal antibodies can be associated with a severe reaction known as cytokine release syndrome. Cytokines (including TNF-α) are rapidly released, resulting in significant medical issues, including fever, chills, nephrotoxicity, vomiting, pulmonary edema, and, in a few instances, arterial thrombosis.

Both monoclonal and polyclonal antibodies have been associated with significant side effects (in addition to significant cytokine release), including a high risk of viral/fungal infection and an increased incidence of post-transplantation lymphoproliferative disorder (PTLD).

Corticosteroids, another mainstay used in transplantation immunosuppression, can have multiple detrimental side effects (Box 20-1).

Cytotoxic agents such as cyclophosphamide, busulfan, and TBI cause bone marrow suppression, resulting in pancytopenia.

Complications of Immune Modulation

Immunosuppression used to prevent rejection of a transplanted organ also can pose serious complications to the recipient, including life-threatening infections and cancer.

Infections after HSCT are a significant problem. The type of transplant and the time that has transpired since the transplantation often predict the specific infection. For example, patients who have had an HSCT usually have broad immunologic defects, either due to their underlying disease or more likely from a combination of immunosuppressive drugs and delayed immune reconstitution. This impacts all components of the immune system. These patients are at a significantly higher risk of infection than are those patients transplanted with solid organs. Additionally, transplants of certain organs are associated with a greater likelihood of a particular infection.

Specific Complications of Transplantation

LONG-TERM PROGNOSIS POST TRANSPLANT

Transplantation outcomes have improved over the past several decades. Outcomes of solid organ transplants are summarized in Table 20-5. Clinical outcomes of solid organ transplantation are reported as graft survival and patient survival.

The number of patients on waiting lists for solid organ transplants continues to increase. The deaths of patients awaiting kidney transplants increased in 2019 to 3,759 while the death rates for patients awaiting heart and liver transplants in 2019 was 224 and 1,200, respectively. Since 2015, there has been a consistent reduction in number of deaths of heart transplant candidates (from 406 in 2015 to 224 in 2019). This may be due to adoption of new medical innovations such as ventricular assistance device.

Current estimates of HSCTs performed annually are greater than 50,000 worldwide. The annual rate of growth of this procedure has been estimated to between 40% and 50%. Improved HSCT-related healthcare has resulted in less morbidity and lower mortality rates. Historically, HSCTs for hematologic malignancies were undertaken as salvage therapy for refractory cancers, but outcomes are actually better for patients who are treated with HSCT soon after diagnosis or in remission, rather than after multiple relapses of hematologic disease. Outcomes have improved in both autologous and allogeneic HSCTs. There are various reasons that the success of HSCT has improved. In the setting of autologous HSCT, changes in conditioning regimens, hematopoietic growth factors, and the use of peripheral blood stem cells rather than bone marrow stem cells have been credited in part with improving mortality by shortening the duration of neutropenia (and incidence of severe infections) after intensive chemotherapy or radiation. In addition, better supportive care, antibiotic use, and blood product support have all improved outcomes for autologous HSCT. For allogeneic HSCT, CSA was introduced in the 1980s as an immunosuppressive agent limiting the severity of GVHD, making allogeneic donor HSCT practical. Decrease in severe GVHD has improved outcomes in allogeneic HSCT. Additionally, CMV accounted for high rates of mortality seen in patients treated with an allogeneic HSCT. Viral transmission can be limited by using screened “CMV-free” blood products for CMV-negative patients or using leukocyte-reduced blood products for transfusions. CMV-positive patients are treated with a prophylactic or, more recently, “preemptive” strategy using new high-sensitivity assays for CMV reactivation. These procedures have decreased the mortality associated with CMV interstitial pneumonitis. Post-transplantation cell growth factors have also been cited as improving outcomes in allogeneic HSCT patients. In allogeneic HSCT, advances have led to a decrease in overall mortality. The introduction of nonmyeloablative HSCT with RIC regimens allows for faster recovery of blood lineages and fewer complications post transplant. There are many patients who have survived HSCT for 5 years or more, and the future holds even greater promise as various transplantation techniques become further refined.

Outcomes of recipients who have received both bone marrow and solid organ transplantation have also been reviewed. There are many clinical and immunologic considerations that are highlighted by reviewing this unique patient population. Further research regarding the concept of immunologic tolerance/chimerism in patients who have had both a solid organ and an HSCT transplant may provide clues for future studies or for consideration of routine treatment regimens, including HSCT with the transplanted solid organ. Close monitoring of these patients will allow a better understanding of the concept of chimerism and tolerance.

ORAL HEALTH SEQUELAE IN TRANSPLANTATION

Oral complications post transplantation may affect the patient at any time. Some may subside and others may become chronic and be detrimental to patient quality of life. The following section will extend on each oral complication (Box 20-2).