Kristine S. Schonder and Heather J. Johnson
KEY CONCEPTS
A combination of two to four immunosuppressive drugs is used to target different levels of the immune cascade to prevent allograft rejection and allow lower doses of the individual agents to minimize their toxicity.
Calcineurin inhibitors (CNIs), such as cyclosporine and tacrolimus, which inhibit interleukin (IL)-2 and thus block T-cell activation are the backbone of immunosuppressive regimens. However, they are associated with significant adverse effects, namely, nephrotoxicity and neurotoxicity.
CNI-induced nephrotoxicity is one of the most common side effects observed in transplant recipients and is the leading cause of renal dysfunction in nonrenal transplant patients. Therapeutic drug monitoring is used in an attempt to optimize the use of CNIs.
Corticosteroids are a key component of immunosuppressive regimens because they block the initial steps in allograft rejection. However, the adverse effects associated with their long-term use have prompted the investigation of corticosteroid-free immunosuppressive protocols. Corticosteroids remain the cornerstone of the treatment of allograft rejection.
Antimetabolites agents such as azathioprine and mycophenolate inhibit T-cell proliferation by altering purine synthesis to prevent acute rejection. Bone marrow suppression is the most significant adverse effect associated with these agents.
The proliferation signal inhibitors (PSI) sirolimus and everolimus exert their activity by inhibiting the mammalian target of rapamycin (mTOR) receptor, which alters T-cell response to IL-2. The adverse effects associated with sirolimus include thrombocytopenia, anemia, and hyperlipidemia.
Antibody preparations that target specific receptors on T cells are classified as depleting or nondepleting. Most lymphocyte-depleting antibodies are associated with significant infusion-related reactions.
Long-term allograft and patient survival is limited by chronic rejection, cardiovascular disease, and long-term immunosuppressive complications such as malignancy.
INTRODUCTION
Solid-organ transplantation provides a lifesaving treatment for patients with end-stage cardiac, kidney, liver, lung, and intestinal disease. Over 300 U.S. hospitals offer transplant services, and pharmacists are often an integral part of the transplant team. The Centers for Medicare and Medicaid Services regulations require that transplant programs have a multidisciplinary team including individuals with experience in pharmacology. While the regulations do not specifically state that each center must have a pharmacist, a pharmacist would certainly provide the desired expertise in transplant pharmacotherapy that the regulations mandate.1
With the success of transplantation, an increasing number of transplant recipients are in our communities. By the end of 2009 there were nearly 200,000 people living with a solid-organ transplant in the United States, which has doubled over the previous decade.1 In 2011, 28,537 solid-organ transplants were performed. Kidney transplants remain the most common; 11,043 were from cadaveric donors and 5,770 from living donors. The next most frequently transplanted organ was the liver, with 6,095 from cadaveric donors and 247 from living donors. Heart and pancreas (or combined kidney–pancreas) transplants account for over 2,300 and almost 1,100 transplants, respectively; over 1,800 lung transplants were performed as well.1 While the demand for transplantation continues to grow, the number of cadaveric donors has remained relatively stable during the last decade. In 2012, more than 115,000 persons in the United States were waiting for a transplant (over 93,000 people were awaiting a kidney, 16,000 a liver, and 3,000 were on the list for a heart transplant). Median waiting time for a cadaveric kidney is more than 3.5 years. For liver transplantation the median time to transplant is about 1 year, whereas for heart transplantation it is approximately 6 months. For heart, liver, and lung transplantation clinical status is an important factor affecting waiting times, with the sickest patients receiving priority for available organs.1
To increase the number of organs available for transplantation, several strategies have been employed in the last several years. The use of living donors for renal transplantation represents over one third of all kidney transplants, more than any other organ. Living-donor transplantation is also becoming increasingly important for those with end-stage liver and lung disease. Efforts to expand the cadaveric donor pool have included relaxation of age restrictions, development of better preservation solutions, use of “extended-criteria” and non–heart-beating donors, and, in the case of liver transplants, the transplantation of one liver to more than one recipient or implantation of only a segment of a liver. Although very controversial, others advocate the creation of a regulated system for compensating individuals in a monetary fashion for the “donation” of a kidney.
Clinical Controversy…
Several strategies have been used to increase the number of available organs for transplant. Some centers will use extended-criteria deceased donors, including older donors, donors with less than perfect organ function, and donors whose hearts have stopped beating for a period of time before organ harvest, all of which may increase the potential for delayed graft function. Strategies to increase the living donor pool include using plasmapheresis before transplant to remove antibodies to allow for transplanting organs that are not ABO-compatible with the recipient or organs into recipients with donor-specific antibodies.
Despite all these efforts, patients continue to die awaiting transplantation. In 2009, more than 7,000 people who were on transplantation waiting lists died. In all areas, efforts have been made to improve organ allocation by moving toward allocation based primarily on “medical necessity” versus time on the waiting list. Although dialysis can be used for an extended period of time to partially replace the function of the kidneys, such options are not readily available for most liver and heart transplantation candidates. Left ventricular assist devices are now used commonly as a bridge to transplantation for many heart transplantation candidates; however, hepatocyte transplantation and artificial liver support remain investigational alternatives or bridges to liver transplantation.2
Patient and graft survival rates following transplantation have improved significantly over the past 30 years as a result of advances in pharmacotherapy, surgical techniques, organ preservation, and the postoperative management of patients (Table 70-1). The half-life of transplanted kidneys has also continued to improve, but is lower for kidneys from deceased donors compared to living donors, 14.7 years and 26.6 years, respectively. Similarly, the half-life of the transplanted livers and hearts has improved to 10 years for livers from deceased donors and 14.9 years for hearts.1 In this chapter, the epidemiology of end-stage kidney, liver, and heart disease is briefly reviewed, the pathophysiology of organ rejection is reviewed, the pharmacotherapeutic options for individualized immunosuppressive regimens are critiqued, and the unique complications of these regimens along with the therapeutic challenges they present are discussed.
TABLE 70-1 Organ-Specific Patient and Graft Survival Rates 1
EPIDEMIOLOGY AND ETIOLOGY
The epidemiology and etiology associated with solid-organ transplant is specific to the type of organ transplant.
Kidney
Renal transplantation is the preferred long-term therapeutic option for most patients with end-stage renal disease (ESRD) because it provides patients with the greatest potential improvement in quality of life. Dialysis catheter-related infections, peritoneal dialysis-associated peritonitis, and scheduled dialysis treatments are avoided, and dietary restrictions are fewer. Patients who receive a renal transplant before the initiation of dialysis have markedly improved quality of life and prolonged life expectancy.3 The use of living-donor transplantation has made this increasingly possible. Although the analysis of quality of life is complex, patients generally report improved quality of life following transplantation as compared with patients on maintenance dialysis.4
Diabetes mellitus, hypertension, and glomerulonephritis are the three leading causes of ESRD leading to kidney transplantation and account for more than 70% of patients (see Chap. 29).5 Patients with medical conditions such as unstable cardiac disease or recently diagnosed malignancy, for whom the risk of surgery or chronic immunosuppression would be greater than the risks associated with chronic dialysis, are generally excluded from consideration for transplantation.
Liver
Noncholestatic cirrhosis (hepatitis C, alcoholic cirrhosis, hepatitis B, nonalcoholic steatohepatitis, and autoimmune hepatitis) is the primary cause of end-stage liver disease and more than 70% of liver transplant recipients have been diagnosed with one of these conditions.1 Livers are allocated based on a United Network for Organ Sharing-adapted, Model for End-stage Liver Disease (MELD) score.6 This score, based on serum creatinine concentration, total serum bilirubin concentration, international normalized ratio, and etiology of cirrhosis, has been demonstrated to be a useful tool to predict impending mortality.
The few absolute contraindications to liver transplantation are active alcohol or substance abuse. Although hepatitis B and C can recur in the transplanted liver, these are not absolute contraindications to liver transplantation.2,7
Heart
Cardiac transplant candidates are typically patients with end-stage heart failure who have New York Heart Association class III or IV symptoms despite maximal medical management and have an expected 1-year mortality risk of 50% or greater without a transplant.8 Idiopathic cardiomyopathy and ischemic heart disease account for heart failure in more than 90% of heart transplantation recipients.1 Other etiologies include valvular disease, retransplantation for graft atherosclerosis or dysfunction, and congenital heart disease. The role of heart transplantation as a therapeutic option for patients with heart failure is discussed in Chapter 4.
Absolute contraindications to orthotopic cardiac transplantation include the presence of an active infection (except in the case of an infected ventricular assist device, which is an indication for urgent transplantation) or the presence of other diseases (e.g., malignancy) that may limit survival and/or rehabilitation and severe, irreversible pulmonary hypertension.
PHYSIOLOGIC CONSEQUENCES OF TRANSPLANTATION
Transplantation is truly lifesaving for heart, liver, and lung transplantation recipients, whereas renal transplantation is associated with improved quality of life and survival when compared with dialysis.9 Most heart transplantation patients return to New York Heart Association functional class I following transplantation. Although not all return to work, 89.9% of patients consider themselves to have no activity limitations at 1-year follow-up.10 The specific physiologic consequences of kidney, liver, and heart transplantation are discussed below.
Kidney Transplantation
The glomerular filtration rate (GFR) of a successfully transplanted kidney may be near normal almost immediately after transplantation. In some patients, however, the concentration of standard biochemical indicators of renal function, such as serum creatinine and blood urea nitrogen, may remain elevated for several days. Standard formulas used to predict drug dosing rely on a stable serum creatinine and may be inaccurate immediately following transplantation (see eChap. 18 and Chap. 33).
Although the allograft is able to remove uremic toxins from the body, it may take several weeks for other physiologic complications of ESRD, such as anemia, calcium and phosphate imbalance, and altered lipid profiles, to resolve. The renal production of erythropoietin and 1-hydroxylation of vitamin D may return toward normal early in the postoperative period. Because the onset of physiologic effects may be delayed, continuation of the patient’s pretransplantation vitamin D, calcium supplementation, and/or phosphate binders may be warranted. The duration of therapy will depend on how rapidly kidney function improves. Patients should be monitored for hypophosphatemia and hypercalcemia for the first few days to weeks after kidney transplantation.
Primary nonfunction of a renal allograft or delayed graft function (DGF) is characterized by the need for dialysis in the first postop week or the failure of the serum creatinine to fall by 30% of the pretransplantation value. The incidence of DGF in cadaveric renal transplantation ranges from 8% to 50% and results in a slower return of the kidney’s excretory, metabolic, and synthetic functions. DGF is associated with prolonged hospital stays, higher costs, difficult management of immunosuppressive therapy, slower patient rehabilitation, and poor graft survival. Other early causes of renal dysfunction such as urethral obstruction or arterial or venous stenosis or thrombosis should be distinguished from DGF.
The primary cause of DGF is acute tubular necrosis (ATN). The incidence of ATN is higher when kidneys are harvested from donors who recently experienced a cardiac arrest, those who were hypotensive or on vasopressors, or older donors (age >55 years). While cyclosporine and tacrolimus have been implicated in the prolongation of ATN, a clear cause-and-effect relationship has not been established. Nonetheless, most clinicians will decrease calcineurin inhibitor (CNI) doses in patients with ATN. DGF predisposes patients to acute rejection, possibly as a consequence of decreased CNI levels and a resultant reduction in the level of immunosuppression.
Clinical Controversy…
Some clinicians feel that deceased donor kidney allografts should be allocated such that younger recipients receive organs from younger donors, while older recipients receive organs from older donors or kidneys with less than optimal function. Other clinicians feel that kidneys should be allocated based solely on waiting time, such that the recipient who has waited on the list the longest receives the first available kidney allograft, regardless of recipient or donor age or the function of the kidney.
Liver Transplantation
The physiologic consequences of liver transplantation are complex, involving changes in both metabolic and synthetic function. Postoperatively, the liver transplant recipient will likely have many fluid, electrolyte, and nutritional abnormalities. Biliary tract dysfunction may alter the absorption of fats and fat-soluble drugs.11 Poor absorption of the lipid-soluble drug cyclosporine improves after successful liver transplantation and reestablishment of bile flow. Vitamin E deficiency and its neurologic complications in liver failure patients are reversed after successful liver transplantation. In stable adult liver transplant patients, the concentrations of retinol and tocopherol are similar to those seen in normal healthy subjects, indicating recovery of transplanted liver production and excretion of bile salts needed for fat-soluble vitamin absorption. Table 70-2 summarizes the effects of liver transplantation on metabolism and renal elimination that are seen in the immediate postoperative period. Most of these changes resolve as liver function normalizes.
TABLE 70-2 Perioperative Changes in Drug Disposition and Elimination Following Liver Transplantation
The newly transplanted liver fails to function in 10% to 15% of recipients as the result of several different mechanisms. Early graft failure can result from preexisting disease in the donor, and even coagulation defects have been acquired through donor organs. The technical complexity of the operation can produce flaws in revascularization that also lead to graft nonfunction. Surgical complications include portal vein or hepatic artery thrombosis and bile duct leaks. Ischemic injury can also result in early graft dysfunction. While hyperacute rejection in liver transplantation rarely occurs, graft failure in the first two postoperative weeks may indicate antibody-mediated graft destruction.
Heart Transplantation
The orthotopically transplanted heart is denervated and no longer responds to physiologic stimuli and pharmacologic agents in a normal manner (Table 70-3).9 In situations requiring an increased heart rate such as exercise or hypotension, the denervated heart is unable to acutely increase heart rate but instead relies on increasing the stroke volume. Later in the course of exercise or hypotension, heart rate increases in response to circulating catecholamines. While the maximum exercise capacity of heart transplant recipients is below normal, most patients are able to resume normal lifestyles and reasonably vigorous activity levels. Partial reinnervation may occur over time, thereby facilitating more normal physiologic and pharmacologic responses and better exercise capacity.10
TABLE 70-3 Altered Responses to Cardiac Drugs in the Denervated Transplanted Heart
A number of autoregulatory, anatomic, and physiologic responses present in the normal heart are interrupted or blunted for the first 6 weeks after transplantation. The donor sinus node function may be impaired by preservation injury, direct surgical trauma at excision, the presence of long-acting antiarrhythmics (e.g., amiodarone) taken prior to transplant by the recipient, and a lack of “conditioning” responsiveness to catecholamines.10 Consequently, the transplanted heart generally requires chronotropic support with either milrinone or pacing in the perioperative period to maintain a heart rate of 90 to 110 beats per minute and satisfactory hemodynamics (i.e., blood pressure, urine output, and tissue perfusion). Approximately 10% to 20% of transplant patients will have persistent chronotropic incompetence requiring either short courses of medications, such as terbutaline or theophylline, or permanent cardiac pacing.
Right ventricular function is frequently impaired, presumably as a result of preservation injury and elevated pulmonary vascular resistance. A “restrictive” hemodynamic pattern may be present initially but usually improves in 6 weeks following transplantation. Donor–recipient size mismatch may contribute to early posttransplantation hemodynamic abnormalities characterized by higher right and left ventricular end-diastolic pressures. Supraventricular arrhythmias are usually transient and may result from over vigorous use of catecholamines or milrinone. If this type of arrhythmia occurs after the perioperative period, the astute clinician should consider the possibility of acute rejection.
Myocardial depression frequently occurs and generally requires inotropic support with agents such as dobutamine, milrinone, and epinephrine. On occasion, intra- or postoperative administration of vasodilators, including nitric oxide, and inotropic agents may be necessary to treat right-sided failure in the transplant patient; milrinone and isoproterenol are preferred in this setting.
Persistent abnormalities of diastolic function are often noted in the transplanted heart such that intracardiac pressures increase in an exaggerated fashion in response to exercise and/or volume infusion.10 These abnormalities are due in part to denervation, but also to acute rejection or to the scarring secondary to previously treated rejection episodes, hypertension, or cardiac allograft vasculopathy.
Hypertension may occur following surgery secondary to the effect of elevated catecholamine levels and systemic vascular resistance as the residual effects of end-stage heart failure on the healthy heart. Systolic blood pressure should be maintained at 110 to 120 mm Hg to enhance cardiac function. In the acute posttransplantation period, IV nitroprusside or nitroglycerin may be needed, whereas oral angiotensin-converting enzyme inhibitors (ACEIs) and/or amlodipine are commonly used once the patient can ingest oral medications.
PATHOPHYSIOLOGY OF REJECTION
Rejection of the transplanted tissue can take place at any time following surgery and is classified clinically as hyperacute rejection, acute cellular rejection (ACR), humoral rejection, and chronic rejection.
General Concepts
Rejection of any transplanted organ is primarily mediated by activation of alloreactive T cells and antigen-presenting cells such as B lymphocytes, macrophages, and dendritic cells. Acute allograft rejection is caused primarily by the infiltration of T cells into the allograft, which triggers inflammatory and cytotoxic effects on the graft. Complex interactions between the allograft and cellular cytokines, cell-to-cell interactions, CD4+ and CD8+ T cells, and B cells ultimately lead to chronic rejection and graft loss if adequate immunosuppression is not maintained.12
The sequence of events that underlies graft rejection is recognition, via major histocompatibility complex (MHC) class I and II antigens, of the donor’s histocompatibility differences by the recipient’s immune system, recruitment of activated lymphocytes, initiation of immune effector mechanisms, and finally graft destruction. The specifics of this immune cascade of organ rejection are discussed in eChapter 20. The complex nature of cytokine interactions makes it very difficult to design drugs with exclusive actions (Fig. 70-1).
FIGURE 70-1 Stages of CD4 T-cell activation and cytokine production with identification of the sites of action of different immunosuppressive agents. Antigen major histocompatibility complex (MHC) II molecule complexes are responsible for initiating the activation of CD4 T cells. These MHC–peptide complexes are recognized by the T-cell recognition complex (TCR). A costimulatory signal initiates signal transduction with activation of second messengers, one of which is calcineurin. Calcineurin removes phosphates from the nuclear factors (NFAT-P) allowing them to enter the nucleus. These nuclear factors specifically bind to an interleukin (IL)-2 promoter gene facilitating IL-2 gene transcription. Interaction of IL-2 with the IL-2 receptor (IL-2R) on the cell membrane surface induces cell proliferation and production of cytokines specific to the T cell. (APC, antigen-presenting cells; MMF, mycophenolate mofetil.) (Reprinted from Mueller XM. Drug immunosuppressive therapy for adult heart transplantation. Part I. Immune response to allograft and mechanism of action of immunosuppressants. Ann Thorac Surg 2004;77:354–362, Copyright © 2004, with permission from Elsevier.)
Efforts are made to allocate well-matched kidneys, according to human leukocyte antigens (HLA)-A, -B, and -DR, to minimize rejection and enhance survival. However, the benefit of having no recipient donor mismatches may be negated by excessive cold ischemia time (>36 hours) and donor age older than 60 years. HLA tissue matching is not performed routinely before transplantation for livers and hearts because organ availability is more limited and the optimal cold ischemia time is shorter. However, if the potential recipient’s blood is reactive against a panel of random donor blood samples (i.e., panel reactive antibody [PRA] >10% to 20%), a negative T-cell crossmatch is required prior to transplantation. Transplanted organs must be matched for ABO blood group compatibility with the recipient as ABO mismatching will result. Liver transplantation may be carried out in emergency situations across ABO blood groups, but survival is lower.
Hyperacute Rejection
Hyperacute rejection may be evident within minutes of the transplantation procedure when preformed donor-specific antibodies are present in the recipient at the time of the transplant. Hyperacute rejection can also be induced by immunoglobulin G antibodies that bind to antigens on the vascular endothelium, such as class I MHC, ABO, and vascular endothelial cell antigens. Tissue damage can be mediated through antibody-dependent, cell-mediated cytotoxicity, or through activation of the complement cascade. The ischemic damage to the microvasculature rapidly results in tissue necrosis.
Hyperacute rejection has become uncommon in kidney and heart transplants. A positive crossmatch presents a serious risk for graft failure even if hyperacute rejection does not occur. A negative lymphocytotoxicity crossmatch does not entirely rule out the possibility of hyperacute rejection because non-MHC antigens on the vascular endothelium can serve as targets of donor-specific antibodies. Early graft dysfunction is treated with supportive care and retransplantation if possible. The reason for the rarity of hyperacute rejection in liver transplantation is not fully understood, but the local release of cytokines may alter the immunologic reaction in the liver.
Acute Cellular Rejection
Acute rejection is most common in the first few months following transplantation but can occur at any time during the life of the allograft. ACR is mediated by alloreactive T-lymphocytes that appear in the circulation and infiltrate the allograft through the vascular endothelium. After the graft is infiltrated by lymphocytes, the cytotoxic cells specifically target and kill the functioning cells in the allograft. At the same time, local release of lymphokines attracts and stimulates macrophages to produce tissue damage through a delayed hypersensitivity-like mechanism. These immunologic and inflammatory events lead to nonspecific signs and symptoms including pain and tenderness over the graft site, fever, and lethargy.
Kidney
Acute rejection, which may affect up to 20% of patients during the first 6 months following transplantation, is evidenced by an abrupt rise in serum creatinine concentration of ≥30% over baseline. A specific histologic diagnosis can be obtained via biopsy of the allograft and is often used to guide therapy for rejection. A biopsy specimen with a diffuse lymphocytic infiltrate is consistent with ACR. After the diagnosis of rejection has been confirmed, the potential risks and benefits of specific antirejection therapies must be evaluated. Hypertension often worsens during an episode of rejection, and edema and weight gain are common as a result of sodium and fluid retention. Symptomatic azotemia may also develop in severe cases.
Liver
The liver is more likely to promote immunologic tolerance than the other vascularized organs. Approximately 18% of liver transplantation recipients will experience a rejection episode in the first posttransplant year. The clinical signs of ACR include leukocytosis and a change in the color or quantity of bile for those who still have an external drainage tube in place. A serum bilirubin 50% over baseline or increases in hepatic transaminases to values more than three times the upper limit of normal are sensitive markers of rejection. Although a liver biopsy provides definitive evidence of the diagnosis of rejection, a prompt response to antirejection medication has also proven useful as a means to differentiate rejection from other causes of hepatic dysfunction.
Heart
Approximately 16% of heart transplantation recipients will experience at least one episode of acute rejection during the first year.13 Because rejection of the cardiac allograft is not necessarily accompanied by overt clinical signs or symptoms and because the incidence of acute rejection is highest during the first year posttransplant, endomyocardial biopsies are often performed at regularly scheduled intervals following transplantation.14 A typical biopsy schedule would be weekly for the first postoperative month, biweekly for the next 2 months, and monthly to bimonthly through the remainder of the first posttransplant year. Nonspecific symptoms, including low-grade fever, malaise, mild reduction in exercise capacity, heart failure, or atrial arrhythmias may also be evident and if present are reflective of a more severe rejection episode.
Antibody-Mediated Rejection
Antibody-mediated rejection (AMR), sometimes referred to as vascular or humoral rejection, is characterized by the presence of antibodies directed against HLA antigens present on the donor vascular endothelium. The antibodies activate complement, which creates a membrane attack complex that directly damages the organ tissue and further attracts inflammatory cells to the allograft. The resultant damage is histologically distinct from cellular rejection that involves microvascular injury, often to the peritubular capillaries.15 Definitive diagnosis of AMR is based on the presence of three criteria: presence of donor-specific antibodies, immunofluorescence staining of C4d deposits in the peritubular capillaries, and evidence of allograft dysfunction.16 Circulating immune complexes often precede humoral rejection. This form of rejection is less common than cellular rejection and generally occurs in the first 3 months after transplantation. It is associated with an increased fatality rate and appears to be more common when antilymphocyte antibodies are used for rejection prophylaxis. An increased risk of humoral rejection is associated with female gender, elevated PRA, cytomegalovirus (CMV) seropositivity, a positive crossmatch, and prior sensitization to OKT3 (muromonab-CD3).17 Strategies to reverse humoral rejection include plasmapheresis, often in combination with IV immunoglobulin, high-dose IV corticosteroids, antithymocyte globulin (ATG), cyclophosphamide, rituximab, and mycophenolate mofetil.
Chronic Rejection
Chronic rejection is a major cause of graft loss. It presents as a slow and indolent form of ACR, in which the involvement of the humoral immune system and antibodies against the vascular endothelium appear to play a role. Persistent perivascular and interstitial inflammation is a common finding in kidney, liver, and heart transplantation. As a result of the complex interaction of multiple drugs and diseases over time, it is difficult to delineate the true nature of chronic rejection. Unlike acute rejection, chronic rejection is not reversible with any immunosuppressive agents currently available.
Kidney
Advances in the management of acute rejection during the last decade have increased the duration of functioning grafts from living and cadaveric donors by more than 70%.18 Chronic allograft nephropathy remains the most common cause of graft loss in the late posttransplantation period (>1 year). The syndrome is characterized in histological terms as interstitial fibrosis and tubular atrophy (IFTA) of unknown etiology. Structural changes are seen in as many as 50% of kidney transplantation patients within a year after transplantation and may present as early as 3 months.19 Hypertension, proteinuria, and a progressive decline in renal function represent the classic clinical triad of chronic allograft nephropathy. Factors that contribute to the development of chronic allograft nephropathy include CNI nephrotoxicity, polyomavirus infection, hypertension, donor-related factors including ischemia time and undetected kidney disease in the donor kidney, and recurrence of the primary kidney disease in the recipient.
Liver
Approximately 3% to 5% of transplant livers are affected by chronic rejection, which is characterized by an obliterative arteriopathy and the gradual loss of bile ducts, often referred to as the vanishing bile duct syndrome. Initially patients experience an asymptomatic rise in the alkaline phosphatase and α-glutamyl transpeptidase. As levels of bilirubin increase, patients become jaundiced and may experience itching.
Heart
Cardiac allograft vasculopathy, characterized by accelerated intimal thickening or development of atherosclerotic plaques, is the leading cause of graft failure and death in heart transplant recipients.20Endothelial injury, caused by both cell-mediated and humoral responses, is the first step in the process. Vasculopathy is restricted to the transplanted allograft. Routine surveillance with coronary angiography, intravascular ultrasound, or other procedures can aid in the diagnosis of vasculopathy. Evidence of cardiac allograft vasculopathy can be seen in as many as 14% of patients within 1 year of transplantation and in as many as 50% of patients within 5 years.20 While chronic rejection of the kidney or liver allograft is generally not amenable to treatment, 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors and ACEIs have been used to decrease the incidence of vasculopathy in the heart allograft.20 More recently, sirolimus and everolimus have been shown to reduce the incidence and slow progression of cardiac allograft vasculopathy.20 Percutaneous transluminal coronary angioplasty and coronary artery bypass grafting have been used in severe cases of vasculopathy; these procedures, however, are limited by significantly increased mortality compared with the general population.20
TREATMENT
Immunosuppresion can be achieved with a variety of agents and the accepted regimens for most solid organs are usually comprised of two or more agents.
Desired Outcomes
Immediately following surgery, the primary goal of therapy is to prevent hyperacute and acute rejection. The high doses of immunosuppressants required to achieve this goal, if maintained long term, may result in serious complications such as nephrotoxicity, infection, thrombocytopenia, and drug-induced diabetes. Therefore, rapid dosage reductions are frequently used to minimize these effects. Transplant immunosuppression must be balanced to optimize both graft and patient survival.
General Approach to Treatment
A multidrug approach is rational from an immunomechanistic viewpoint because the many agents have overlapping and potentially synergistic mechanisms of action. Furthermore, the use of a multidrug immunosuppression regimen may allow the use of lower doses of individual agents, thus reducing the severity of dose-related adverse effects (Fig. 70-2). The protocols and individual drug regimens tend to be medical center specific. Although induction therapy may not be uniformly used, in almost every setting, patients receive IV methylprednisolone intraoperatively. Patients may also receive a descending dose of methylprednisolone over the first 5 to 7 postoperative days before beginning oral prednisone. Protocols generally combine a drug from two or three of the following classes: calcineurin inhibitors (CNIs), antimetabolites or proliferation signal inhibitors (PSIs), and corticosteroids.
FIGURE 70-2 General approach to solid-organ transplant immunosuppression. (BUN, blood urea nitrogen; CNI, calcineurin inhibitor; CSA, cyclosporine; IL2RA, interleukin-2 receptor antagonist; LFTs, liver function tests; MPA, mycophenolic acid; OKT3, muromonab-CD3; RATG, rabbit antithymocyte immunoglobulin; Scr, serum creatinine; SRL, sirolimus; TAC, tacrolimus.)
If rejection is suspected, a biopsy can be done for definitive diagnosis or the patient may be empirically treated for rejection. Empiric treatment generally involves administration of high-dose corticosteroids, usually 500 to 1,000 mg of methylprednisolone IV for one to three doses. If signs and symptoms of rejection are resolved with empiric therapy, the maintenance immunosuppressive regimen is generally modified to provide a greater level of overall immunosuppression. If rejection is confirmed by biopsy, treatment may be based on the severity of rejection with polyclonal and monoclonal antibodies being reserved for moderate-to-severe rejections or those that have not responded to a course of corticosteroids.
Induction Therapy
Induction therapy provides a high level of immunosuppression, at the time of transplantation, with or without the immediate introduction of cyclosporine or tacrolimus (see Fig. 70-2). Two perioperative immunosuppressive strategies have been predominantly utilized to achieve this goal: (a) the provision of a highly intense immunosuppression, often on the basis of patient-specific risk factors such as age and race, or (b) the use of antibody therapy to provide enough immunosuppression to delay the initiation of therapy with the nephrotoxic CNIs. The rationale for delayed CNI administration varies slightly depending on the type of transplant. In renal transplantation, the newly transplanted kidney is very susceptible to nephrotoxic injury, whereas in liver and heart transplantation, the idea is to protect patients with preexisting renal insufficiency from further insults during the perioperative period. Additionally, CNI dosage adjustment to maintain target concentrations may be difficult in the perioperative period secondary to fluctuation of GI motility and enteral intake.
Acute Rejection
The primary goal of acute rejection therapy is to minimize the intensity of the immune response and prevent irreversible injury to the allograft. The available options include (a) increasing the doses of current immunosuppressive drugs, (b) “pulse” corticosteroids with subsequent dose taper, (c) addition of another immunosuppressant indefinitely, or (d) short-term treatment with a polyclonal or monoclonal antibody. The treatment of acute rejection almost always begins with “pulse” corticosteroid therapy for several days (oral or IV). However, African American kidney transplant recipients may not respond as well to corticosteroids; thus ATG may be preferable for this patient population.21
Cytolytic agents are often reserved for those with corticosteroid-resistant rejection, signs of hemodynamic compromise (heart), or more severe rejections. Other innovative forms of therapy for persistent or intractable rejection have been investigated, including mycophenolate mofetil, tacrolimus, low-dose methotrexate, sirolimus, total lymphoid irradiation, and plasmapheresis and IV immunoglobulin. Prophylactic agents such as valganciclovir, nystatin, trimethoprim–sulfamethoxazole, H2-receptor antagonists or proton-pump inhibitors, and/or antacids may be added to minimize adverse effects associated with these intensive immunosuppression regimens.
Maintenance Therapy
The goal of maintenance immunosuppression is to prevent acute and chronic rejection while minimizing drug-related toxicity. As patients progress through the posttransplant course, the risk of acute rejection decreases, thus allowing the clinician to gradually reduce the doses of immunosuppressants or in some cases totally withdraw them over a period of 6 to 12 months. Transplant organ and type (cadaveric vs. living-donor), the degree of HLA mismatch, time after transplantation, posttransplantation complications (including the number of acute rejections), previous immunosuppressive adverse reactions, compliance, and financial considerations are among the patient-specific factors considered in individualizing maintenance immunosuppression. CNIs are generally a central component in most maintenance regimens, although CNI-free immunosuppression remains a future goal because of the significant nephrotoxicity associated with these agents. Ideally, immunosuppression should be optimized to prevent acute rejection episodes, minimize the occurrence of chronic rejection, and prevent long-term toxicities.
Calcineurin Inhibitors
Cyclosporine and tacrolimus are the two CNIs currently used for most solid-organ transplant recipients. With the exception of heart transplant recipients (69%), more than 80% of transplant recipients receive tacrolimus as part of their immunosuppressive regimen.1
Pharmacology/Mechanism of Action
CNIs block T-cell proliferation by inhibiting the production of IL-2 and other cytokines by T cells (see Fig. 70-1). Cyclosporine and tacrolimus bind to unique cytoplasmic immunophilins cyclophilin and FK-binding protein-12 (FKBP12), respectively. The drug–immunophilin complex inhibits the action of calcineurin, an enzyme that activates the nuclear factor of activated T cells, which is, in turn, responsible for the transcription of several key cytokines necessary for T-cell activity, including IL-2. IL-2 is a potent growth factor for T cells and ultimately is responsible for activation and clonal expansion.
Pharmacokinetics
The CNIs are highly lipophilic compounds, with variable but generally low bioavailability of approximately 30% (range, 5% to 60%). Unlike tacrolimus, cyclosporine depends on bile for intestinal absorption, which lends to more interpatient and intrapatient variability. Liver recipients with a T-tube for diversion of bile may thus experience incomplete and erratic absorption of cyclosporine.
Because of the significant variability in absorption of cyclosporine, peak concentrations are reached within 2 to 6 hours of oral administration. To overcome the pharmacokinetic problems of cyclosporine, a microemulsion formulation was developed. Both forms are available commercially in the United States and are referred to as “cyclosporine, USP” and “cyclosporine, USP [MODIFIED].” The two formulations are not bioequivalent and should not be used interchangeably. The microemulsion formulation is self-emulsifying and forms a microemulsion spontaneously with aqueous fluids in the GI tract, making it less dependent on bile for absorption. The result is a significantly greater rate and extent of absorption and decreased intraindividual variability in pharmacokinetic parameters. Bioavailability is enhanced owing to better dispersion and absorption and does not require bile excretion. The relative bioavailability of the microemulsion formulation is 60%. Peak concentrations are generally reached within 1.5 to 2 hours after oral administration. Tacrolimus, on the other hand, has a more predictable absorption pattern, reaching peak concentrations within 1 to 3 hours.
Following oral absorption, both cyclosporine and tacrolimus are highly protein bound. Ninety percent of cyclosporine is bound to lipoproteins in the blood. In contrast, 99% of tacrolimus is bound primarily to albumin and α1-acid glycoprotein. Cyclosporine is distributed widely into tissue and body fluids, resulting in a large and variable volume of distribution, ranging from 3 to 5 L/kg. Because of the high concentration of FKBP12 that is found in red blood cells, tacrolimus is distributed primarily in the vasculature, with a volume of distribution of 0.8 to 1.9 L/kg. Both drugs are extensively metabolized by the cytochrome P450 3A4 (CYP3A4) system in both the gut and the liver, which accounts for both the poor bioavailability and numerous drug interactions (see eChap. 6).
Efficacy
The introduction of the CNIs significantly improved the outcomes of solid-organ transplantation in terms of patient and graft survival, with 1-year graft survival improving from 75% to 87% for cadaveric grafts.18 Both cyclosporine and tacrolimus are currently approved for prophylaxis of organ rejection in kidney, liver, and heart transplantations. When compared with the standard formulation, the microemulsion formulation of cyclosporine has demonstrated equivalent or superior efficacy in kidney, liver, and heart transplantation recipients. Studies comparing tacrolimus with either formulation of cyclosporine as primary immunosuppression demonstrate equivalent efficacy between the two agents in all transplantation situations.
Monotherapy with CNIs has been described.22 The avoidance of long-term corticosteroids is the primary advantage of CNI monotherapy, whereas the primary disadvantage is the higher incidence of rejection. As a result, CNIs are rarely used as monotherapy.
Adverse Effects
Table 70-4 summarizes the adverse effects of CNIs, cyclosporine and tacrolimus, and other immunosuppressants. The nephrotoxic potential of both drugs is equal and is often related to the dose and duration of exposure. Neurotoxicity typically manifests as tremors, headache, and peripheral neuropathy; occasionally, however, seizures have been observed. Tacrolimus may be associated with an increased occurrence of neurologic complications compared with cyclosporine.
TABLE 70-4 Comparison of Common Adverse Effects of Maintenance Immunosuppressants
Cyclosporine appears to have a greater propensity to cause or worsen hypertension and hyperlipidemia compared with tacrolimus.23–26 On the other hand, hyperglycemia is more common with tacrolimus than with cyclosporine but is often reversible when doses of tacrolimus and/or corticosteroids are reduced.24 Cyclosporine is associated with cosmetic effects, such as hirsutism and gingival hyperplasia, which may be managed by converting from cyclosporine to tacrolimus or by proper hygiene in patients who cannot be switched to tacrolimus. Tacrolimus, in contrast, has been reported to cause alopecia, which is usually self-limiting and reversible.
Calcineurin Inhibitor Nephrotoxicity 
Two types of nephrotoxicity can occur with CNIs. Acute nephrotoxicity is frequently seen early and is dose-dependent and reversible, but chronic nephropathy is more common. Clinical manifestations of CNI nephrotoxicity include elevated serum creatinine and blood urea nitrogen levels, hyperkalemia, hyperuricemia, mild proteinuria, and a decreased fractional excretion of sodium. CNI nephrotoxicity is recognized as the leading cause of renal dysfunction following nonrenal solid-organ transplant.
The predominant mechanism for CNI nephrotoxicity is renal vasoconstriction, primarily of the afferent arteriole, resulting in increased renal vascular resistance, decreased renal blood flow by up to 40%, reduced GFR by up to 30%, and increased proximal tubular sodium reabsorption with a reduction in urinary sodium and potassium excretion. A number of other mechanisms have been implicated, including changes in the renin–angiotensin–aldosterone system, prostaglandin synthesis, nitrous oxide production, sympathetic nervous system activation, and calcium handling.27
Measures to reduce CNI nephrotoxicity include delaying administration immediately postoperatively in patients at high risk for nephrotoxicity (using alternative induction protocols including an IL-2 receptor antagonist or antilymphocyte globulin), monitoring CNI trough blood levels and reducing the CNI dosage if the vasoconstrictive effects are problematic, and avoiding other nephrotoxins (e.g., aminoglycosides, amphotericin B, and nonsteroidal antiinflammatory agents) when possible. Currently, no proven therapies consistently prevent or reverse the nephrotoxic effects of CNIs.
In patients who have received a kidney transplant, it is often difficult to differentiate CNI nephrotoxicity from renal allograft rejection. Because the clinical features of acute renal allograft rejection and CNI nephrotoxicity may overlap considerably, a renal biopsy is necessary to differentiate the two (Table 70-5). However, differentiating between chronic renal allograft rejection and CNI nephrotoxicity may be more difficult because, in addition to clinical signs and symptoms, biopsy findings may also be similar.
TABLE 70-5 Differential Diagnosis of Acute Rejection and Cyclosporine or Tacrolimus Nephrotoxicity
Drug–Drug and Drug–Food Interactions
Drug interactions occur frequently with the CNIs because they are substrates for CYP3A4 and P-glycoprotein.28,29 The most commonly administered drugs that are known to significantly alter cyclosporine and tacrolimus levels are highlighted in Table 70-6. Inhibitors of CYP3A4, such as diltiazem or erythromycin, can increase drug concentrations up to 82%, whereas drugs that induce CYP3A4 activity, such as phenytoin or rifampin, can decrease drug concentrations by 50%.43 Some have taken advantage of these interactions by routinely prescribing CYP3A4 inhibitors to reduce the dosage and cost of CNI therapy while maintaining the same therapeutic concentrations. This strategy seems more beneficial with cyclosporine than with tacrolimus.29–31 While in vitro data suggest that drugs that increase the pH of the GI tract, such as magnesium-, aluminum-, or calcium-containing antacids, sodium bicarbonate, and magnesium oxide, can cause a pH-mediated degradation of tacrolimus by physically adsorbing tacrolimus in the GI tract, this has not been borne out in clinical studies.32 Some clinicians suggest separating such compounds from tacrolimus administration by at least 2 hours to avoid any potential interaction.
TABLE 70-6 Effect of Concomitant Drug Administration on Cyclosporine, Tacrolimus, Sirolimus, and Everolimus
Cyclosporine, and to a lesser extent, tacrolimus, are inhibitors of CYP3A4 and P-glycoprotein.33 The inhibitory effects of cyclosporine and tacrolimus on CYP3A4 can be seen with weaker substrates, such as the HMG-CoA reductase inhibitors (“statins”). Concomitant administration of a CNI with an HMG-CoA reductase inhibitor results in an increase in the HMG-CoA reductase inhibitor levels, which increases the risk of HMG-CoA reductase inhibitor adverse effects, most notably myopathy.34,35 Patients should be monitored for clinical signs of myopathy when receiving HMG-CoA reductase inhibitors in combination with cyclosporine and tacrolimus. The interaction appears to be more pronounced between cyclosporine and HMG-CoA reductase inhibitors due to inhibition of organic anion-transporter proteins (OATP) by cyclosporine.36
Consistency in administration of the CNIs with regard to meals and food intake is important to sustain an effective concentration time profile. High-fat meals can enhance both plasma clearance and the volume of distribution of cyclosporine by more than 60%.37 Food reduces the rate and extent of tacrolimus absorption, and a high-fat meal may further delay gastric emptying and reduce the maximum achieved serum concentration (Cmax), and the area under the concentration–time curve (AUC).30 Furocoumarins, such as quercetin, naringin, and bergamottin, found in grapefruit juice, are potent inhibitors of CYP3A4 and have been reported to increase both cyclosporine and tacrolimus concentrations significantly. The AUC and Cmax of cyclosporine have been reported to be increased by more than 55% and 35%, respectively.38
Dosing and Administration
Initial oral cyclosporine doses range from 8 to 18 mg/kg per day administered every 12 hours. Higher doses of cyclosporine are used more commonly in two-drug regimens, whereas lower doses are part of triple-drug regimens. Oral tacrolimus doses usually are in the range of 0.1 to 0.3 mg/kg per day given every 12 hours. Children require higher doses to maintain therapeutic drug concentrations, up to 14 to 18 mg/kg per day for cyclosporine and 0.3 mg/kg per day for tacrolimus. A once-daily formulation of tacrolimus was recently approved in the United States. After mg:mg conversion based on total daily dose, about one-third of patients required downward dose adjustments on the basis of 24-trough concentrations.39 If oral administration is not possible, both drugs can be administered IV at one third the oral dosage, since administration by this route avoids first-pass metabolism. The usual IV dose of cyclosporine is 2 to 5 mg/kg per day, given as a continuous infusion or as single or twice-daily injection. IV tacrolimus doses range from 0.05 to 0.1 mg/kg per day and must be administered by continuous infusion.
Therapeutic Drug Monitoring
CNI serum concentrations are measured routinely in an attempt to optimize therapy (Table 70-7). The most common and practical method for monitoring CNIs is by measuring trough blood concentrations. Tacrolimus concentrations are most commonly measured by microparticle enzyme immunoassays or enzyme-linked immunoassays. Both drugs can be measured by high-performance liquid chromatography (HPLC), which is recognized as the reference procedure.37 Therapeutic target ranges are assay specific because some quantitate parent plus metabolite concentration, while others only measure the parent compound. Thus, the target concentrations will be lower for the specific assays (HPLC) compared with nonspecific assays (radioimmunoassay [RIA] and microparticle enzyme immunoassays) by approximately 20% to 25%. The specific goal level for both drugs is dependent on transplant type, time after transplantation, concomitant immunosuppression, and transplantation center. One review of the role of tacrolimus in renal transplantation suggests that target 12-hour whole blood concentrations for tacrolimus are 15 to 20 ng/mL (15 to 20 mcg/L; 18.6 to 24.8 nmol/L) (0 to 1 month after transplantation), 10 to 15 ng/mL (10 to 15 mcg/L; 12.4 to 18.6 nmol/L) (1 to 3 months after transplantation), and 5 to 12 ng/mL (5 to 12 mcg/L; 6.2 to 14.9 nmol/L) (>3 months after transplantation).24 Serum drug concentrations should be measured frequently (daily or three times per week) following initiation of the drug and during the stabilization period after transplantation. As the time increases after transplantation, serum concentrations are measured less frequently, usually monthly.
TABLE 70-7 Therapeutic Concentrations of Immunosuppressants by Various Methods
Studies have revealed lack of predictive value of trough cyclosporine concentrations and rejection.40 Alternative strategies, including AUC and peak concentration, have been suggested to better correlate with rejection.37,40Limited sampling techniques using two to five blood samples within the first 4 hours after an oral dose have been used to determine AUC and it was observed that AUC levels >4,400 mcg/L (>3,361 nmol/L) per hour correlated with a reduction in rejection.37,40 Cyclosporine peak concentration (C2) has also been found to correlate with rejection and toxicity. Some transplantation centers have adopted this strategy to manage cyclosporine concentrations because of the convenience and reduced cost associated with the measurement of a single blood concentration. The suggested therapeutic range for C2 cyclosporine levels is 1,500 to 2,000 ng/mL (1,500 to 2,000 mcg/L; 1,248 to 1,664 nmol/L) for the first few months after transplant and 700 to 900 ng/mL (700 to 900 mcg/L; 582 to 749 nmol/L) after 6 to 12 months.40
Corticosteroids
Corticosteroids have been used since the beginning of the modern transplantation era. Despite their many adverse events, they continue to be a cornerstone of immunosuppression regimens in many transplant centers, with 30% and 60% of liver and kidney transplant patients, respectively, receiving corticosteroids for at least the first year after transplantation.1 The most commonly used corticosteroids are methylprednisolone and prednisone.
Pharmacology/Mechanism of Action
Corticosteroids block cytokine activation by binding to corticosteroid response elements, thereby inhibiting IL-1, IL-2, IL-3, IL-6, α-interferon, and tumor necrosis factor-α synthesis (see Fig. 70-1). Additionally, corticosteroids interfere with cell migration, recognition, and cytotoxic effector mechanisms.41
Pharmacokinetics
Prednisone is converted to active prednisolone in the body and has multiple effects on the immune system. Prednisone is very well absorbed from the GI tract and has a long biologic half-life, permitting daily administration.
Efficacy
Corticosteroids became a part of the immunosuppressive regimens used in the first human transplantations42 and continue to be used today. Their efficacy is irrefutable based on the decades of clinical experience. Systematic studies comparing corticosteroid-free immunosuppressive agent combinations with conventional therapy are difficult to perform because of the hundreds of potential combinations that now exist. However, recent studies of corticosteroid-free immunosuppressive agent combinations with newer, more specific immunosuppressants suggest that corticosteroids may in the future have less of a role in maintenance immunosuppression.42,43
Adverse Effects
Adverse effects of prednisone that occur in more than 10% of patients include increased appetite, insomnia, indigestion (bitter taste), and mood changes. Side effects that occur less often but which are seen with high doses or prolonged therapy include cataracts, hyperglycemia, hirsutism, bruising, acne, sodium and water retention, hypertension, bone growth suppression, and ulcerative esophagitis. The adverse effects of corticosteroids are summarized in Table 70-4.
Drug–Drug and Drug–Food Interactions
Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone and thus decrease the effectiveness of prednisone. Prednisone decreases the effectiveness of vaccines and toxoids.41
Dosing and Administration
An IV corticosteroid, commonly high-dose methylprednisolone, is given at the time of transplantation. The dose of methylprednisolone is tapered rapidly and discontinued within days, and oral prednisone is initiated. Prednisone doses are tapered progressively over time, depending on the type of additional immunosuppression and organ function. It is preferable to administer corticosteroids between 7 AM and 8 AM to mimic the body’s diurnal release of cortisol. While conversion to alternate-day regimens or complete withdrawal of prednisone in patients with stable posttransplantation courses has been used with success in some transplantation centers, corticosteroids are often continued for the entire life of the functional graft.
The first-line therapy for the treatment of acute graft rejection is high-dose IV methylprednisolone (250 to 1,000 mg) daily for 3 days or oral prednisone (200 mg). Doses of oral prednisone are then tapered over 5 days to 20 mg/day. Prednisone should be taken with food to minimize GI upset. It is becoming a frequent practice to taper prednisone, with the goal of discontinuation over a period of months. Corticosteroids should never be discontinued abruptly; tapering should be gradual because of suppression of the hypothalamic–pituitary–adrenal axis. Corticosteroids slow the growth rates in children, prompting clinicians to use alternate-day dosing or to withhold corticosteroids until rejection occurs.
Antimetabolites
Antimetabolites have been used since the early days of transplantation because they prevent proliferation of lymphocytes. Azathioprine, long considered a part of the “gold standard” regimen with cyclosporine and corticosteroids, has largely been supplanted by mycophenolic acid (MPA) derivatives as they are more specific in their effects on lymphocytes and have fewer side effects.
Mycophenolic Acid Derivatives
MPA was first isolated from the Penicillium glaucum mold. Two formulations of MPA are currently available in the United States: mycophenolate mofetil is the morpholinoethyl ester of MPA, whereas mycophenolate sodium is available as an enteric-coated formulation of the sodium salt of MPA.
Pharmacology/Mechanism of Action The immunosuppressive effect of MPA is exerted through noncompetitive binding to inosine monophosphate dehydrogenase (IMPDH), the key enzyme responsible for guanosine nucleotide synthesis via the de novo pathway. Inhibition of IMPDH results in decreased nucleotide synthesis and diminished DNA polymerase activity, ultimately reducing lymphocyte proliferation.44 Although MPA inhibits both types of IMPDH: IMPDH I, expressed by all cells in the body, and IMPDH II, which is expressed only in T and B lymphocytes, it is more specific for IMPDH II.44In addition to this, T and B lymphocytes only use the de novo pathway for nucleotide synthesis (see Fig. 70-1), making MPA very specific for these cells. Other cells within the body have a salvage pathway by which they can synthesize nucleotides, making them less susceptible to the actions of MPA and thereby reducing, but not eliminating, the potential for the hematologic adverse effects seen with azathioprine. In addition to decreasing lymphocyte proliferation, MPA may also downregulate activation of lymphocytes.45
Pharmacokinetics Because MPA is unstable in an acidic environment, mycophenolate mofetil acts as a prodrug that is readily absorbed from the GI tract, after which it is rapidly and completely converted to MPA by first-pass metabolism. The enteric coating of mycophenolate sodium protects MPA from the acidic gastric pH and allows for MPA to be released directly into the small intestine for absorption. The absolute bioavailability of MPA when delivered from mycophenolate mofetil and mycophenolate sodium is 94% and 72%, respectively. Peak concentrations of mycophenolate mofetil are reached within 1 to 2 hours following oral administration, while the enteric coating of mycophenolate sodium delays absorption and peak concentrations are not reached until 4 hours after administration.45
MPA is extensively bound (97%) to albumin in the blood. It is eliminated by the kidney and also undergoes glucuronidation in the liver to an inactive glucuronide metabolite (MPAG) that is excreted in the bile and urine. Enterohepatic cycling of MPAG can lead to deconjugation, thereby recirculating MPA into the bloodstream. This can account for 10% to 60% of total MPA exposure and results in a second peak 6 to 12 hours after oral administration.45 The half-life of MPA is 18 hours.
Efficacy Currently, mycophenolate mofetil is approved for use in kidney, liver, and heart transplantations. Mycophenolate sodium was approved in 2004 for use in kidney transplantations only. Early studies comparing mycophenolate to azathioprine in patients receiving cyclosporine and corticosteroids demonstrated a statistically significant improvement in patient and graft survival at 1 and 3 years.46 Subsequent studies have confirmed the efficacy of mycophenolate combined with tacrolimus. Mycophenolate has also demonstrated efficacy in the treatment of acute rejection.47
MPA derivatives are a key component of CNI-sparing protocols. Although MPA monotherapy has been investigated, patients experienced an unacceptable increase in rejection. Combination of MPA with sirolimus, on the other hand, resulted in improved renal function with no change in acute rejection and patient and graft survival.46
Adverse Effects Unlike cyclosporine and tacrolimus, MPA is not associated with nephrotoxicity, neurotoxicity, or hypertension. The most common side effects are related to the GI tract, including nausea, vomiting, diarrhea, and abdominal pain (see Table 70-4), which occur with similar frequency during IV and oral therapy. Strategies to reduce GI symptoms include dose reduction, division of the total daily dose into three or four doses, administration with food, or titration upward from lower doses during initial therapy. MPA also has hematologic effects, such as leukopenia and anemia, particularly with higher doses. Recently, the rare but serious adverse events of progressive multifocal leukoencephalopathy (PML) and pure red cell aplasia have been reported. Because peripheral IV mycophenolate administration is associated with local edema and inflammation, central venous administration may be the preferred route.
Drug–Drug and Drug–Food Interactions Food has no effect on MPA AUC, but it delays the absorption and decreases MPA Cmax by 40% and 33% when mycophenolate mofetil and mycophenolate sodium, respectively, are administered. Administration with aluminum- and magnesium-containing antacids or cholestyramine significantly decreases the AUC of MPA and should be avoided.48 It has been suggested that administration of iron may produce similar results, but this has not been tested. Concomitant administration of mycophenolate mofetil with pantoprazole has been reported to decrease MPA levels by 57% and AUC by 12% in healthy volunteers. The same effect was not observed with mycophenolate sodium.49
Acyclovir, commonly used in renal transplant recipients for the treatment and prevention of viral infections, competes with MPAG for renal tubular secretion. AUCs of both entities are increased with concomitant acyclovir and MPA administration. No pharmacokinetic interaction with other antiviral agents has been demonstrated. However, there is potential for additive pharmacodynamic effects such as bone marrow suppression.
Decreased MPA trough concentrations have been reported when MPA is administered with cyclosporine compared with those achieved when MPA is given with tacrolimus or sirolimus. This interaction is most likely a result of cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP2), which inhibits the enterohepatic recycling of MPAG, resulting in decreased MPA concentrations.45Cyclosporine decreases MPA levels by approximately 40% to 50% compared to tacrolimus.24 To achieve equivalent MPA and MPAG serum concentrations, it may be necessary to administer higher doses of MPA with cyclosporine compared to tacrolimus. Antibiotics may also interfere with enterohepatic recycling of MPAG by decreasing bacterial-mediated deglucuronidation in the colon.45
Dosing and Administration Mycophenolate mofetil is currently available in both oral and IV formulations. Although IV administration of equal doses closely mimics oral administration, the two cannot be considered bioequivalent. Mycophenolate sodium is only available as an oral formulation. To optimize immunosuppression and minimize adverse effects, MPA is administered in two divided doses given every 12 hours. The total daily dose for kidney and liver transplants is typically 2 g/day for mycophenolate mofetil and 1.44 g/day for mycophenolate sodium. A higher level of immunosuppression is required for heart transplants; thus for these patients a total daily dose of 3 g/day for mycophenolate mofetil and 2.16 g/day for mycophenolate sodium is recommended. The recommended pediatric dose is 600 mg/m2for mycophenolate mofetil and 400 mg/m2 for mycophenolate sodium, in two divided doses.
While an increasing body of literature exists, the routine therapeutic drug monitoring of MPA remains controversial. Plasma appears to be the most appropriate medium in which to measure MPA for therapeutic drug monitoring. Numerous studies have demonstrated a relationship between plasma MPA concentrations and improved clinical outcomes in patients receiving concomitant CNIs and corticosteroids. Patients with trough MPA levels between 1 and 3.5 mcg/mL (1 to 3.5 mg/L; 3.1 to 10.9 μmol/L) experienced fewer significant complications. Free (fMPA) concentrations as opposed to total MPA concentrations have been suggested as the relevant measure, especially in patients with liver disease, hypoalbuminemia, and severe infection.50 Trough concentrations may not be accurate in predicting total drug exposure during a 12-hour interval and thus AUC monitoring has been proposed as the most appropriate measure of MPA drug exposure to predict therapeutic outcomes.50 Better outcomes are associated with MPA AUC levels of greater than 42.8 mcg/mL (42.8 mg/L; 134 μmol/L) per hour (by HPLC),51 although a reference range of 30 to 60 mcg/mL (30 to 60 mg/L; 94 to 188 μmol/L) has been proposed. The correlation between MPA AUC levels and adverse effects is low. Further studies are required to determine the best means to evaluate MPA levels, the acceptable targets for each, and the appropriate strategy to monitor MPA levels.51
Azathioprine
Azathioprine, a prodrug for 6-mercaptopurine (6-MP), has been used as an immunosuppressant in combination with corticosteroids since the earliest days of the modern transplantation era. It is associated with substantial toxicities, however, and its use has dramatically declined with the availability of newer immunosuppressants.
Pharmacology/Mechanism of Action Azathioprine is an inactive compound that is converted rapidly to 6-MP in the blood and is subsequently metabolized by three different enzymes. Xanthine oxidase, found in the liver and GI tract, converts 6-MP to the inactive final end product, 6-thiouric acid. Thiopurine S-methyltransferase (TPMT), found in hematopoietic tissues and red blood cells, methylates 6-MP to an inactive product, 6-methylmercaptopurine. Finally, hypoxanthine-guanine phosphoribosyltransferase is the first step responsible for converting 6-MP to 6-thioguanine nucleotides (6-TGNs), the active metabolites, which are incorporated into nucleic acids, ultimately disrupting both the salvage and de novo pathways of DNA, RNA, and protein synthesis. This process is toxic to the cell and renders the cell unable to proliferate (see Fig. 70-1). Eventually, 6-TGNs are catabolized by xanthine oxidase and thiopurine S-methyltransferase to inactive products.52
Pharmacokinetics Oral bioavailability of azathioprine is approximately 40%. Metabolism of 6-MP is primarily by xanthine oxidase to inactive metabolites, which are excreted by the kidneys. The half-life of azathioprine, the parent compound, is very short, approximately 12 minutes. The half-life of 6-MP is longer, ranging from 0.7 to 3 hours. However, it is the activity of the 6-TGNs that determines the pharmacodynamic half-life of the drug. The half-life of 6-TGNs has been estimated to be 9 days.52
Adverse Effects Dose-limiting adverse effects of azathioprine are often hematologic (see Table 70-4). Leukopenia, anemia, and thrombocytopenia can occur within the first few weeks of therapy and can be managed by dose reduction or discontinuation of azathioprine. Other common adverse effects include nausea and vomiting, which can be minimized by taking azathioprine with food. Alopecia, hepatotoxicity, and pancreatitis are less common adverse effects of azathioprine and are reversible on dose reduction or discontinuation. Activity of TPMT can affect the occurrence of adverse effects with azathioprine. Approximately 10% of the population has intermediate TPMT activity and 0.3% has low activity of the enzyme. In both scenarios, the incidence of leukopenia and hepatotoxicity is increased. As a result, TPMT genotyping may be useful to guide dosing of azathioprine to minimize adverse effects.53
Drug–Drug and Drug–Food Interactions The xanthine oxidase inhibitors allopurinol and febuxostat can increase azathioprine and 6-MP concentrations by as much as fourfold.54 The metabolic pathways shift to favor production of 6-TGNs, which ultimately results in increased bone marrow suppression and pancytopenia. Doses of azathioprine should be reduced by 50% to 75% when allopurinol is added.
Dosing and Administration Initial doses of azathioprine are 3 to 5 mg/kg per day IV or orally. Individualization to maintain the white blood cell count between 3,500 and 6,000 cells/mm3 (3.5 × 109 and 6.0 × 109/L) may be accomplished in some with doses as low as 0.25 mg/kg per day. Patients are often instructed to take azathioprine in the evening when initiating or titrating therapy to allow for dose adjustments based on morning determinations of their white blood cell count.
Proliferation Signal Inhibitors
Two PSIs have been approved in the United States for use in transplantation. Sirolimus, also known as rapamycin, is an immunosuppressive macrolide antibiotic that is structurally similar to tacrolimus, and is effective in reducing the risk of acute rejection. Sirolimus is thought to have potential to reduce chronic rejection, but this remains to be proven. Everolimus, a derivative of sirolimus, was approved in the United States in 2009 and was developed to improve the pharmacokinetics of sirolimus. Everolimus has a significantly shorter half-life than sirolimus.
Sirolimus and Everolimus
Pharmacology/Mechanism of Action Sirolimus and everolimus both bind to FKBP12, forming a complex that binds to the mammalian target of rapamycin (mTOR), which inhibits the response to cytokines (see Fig. 70-1). As such, the drugs are commonly referred to as mTOR inhibitors. IL-2 stimulates mTOR to activate kinases that ultimately advance the cell cycle from G1 to the S phase. Thus these drugs reduce T-cell proliferation by inhibiting the cellular response to IL-2 and progression of the cell cycle.55,56
Pharmacokinetics Bioavailability after oral administration is low for both, only 15% to 16%, with peak concentrations being reached within 1 to 2 hours for sirolimus and 0.5 to 4 hours for everolimus.55,56Both have large volumes of distribution, 5.6 to 16.7 L/kg for sirolimus and approximately 110 L for everolimus. Both are metabolized primarily by CYP3A4 both in the gut and in the liver. Likewise, both are also substrates for P-glycoprotein. The half-life for sirolimus is reported to be 60 hours but can be as long as 110 hours in patients with liver dysfunction, while that of everolimus is much shorter, 18 to 35 hours.55,56
Efficacy Sirolimus is only approved for the prevention of rejection in kidney transplant recipients when given in combination with corticosteroids and cyclosporine or after withdrawal of cyclosporine in patients with low-to-moderate immunologic risk. Because of the risks of delayed wound healing sirolimus is usually not started until 3 months after transplantation or later, once the surgical wound has healed. Sirolimus has also been demonstrated to be effective in combination with tacrolimus or mycophenolate in kidney transplants, with patient survival rates >99% and graft survival rates >96%.55 Combination therapy with sirolimus and mycophenolate can be used to avoid the use of CNIs and decrease the risk of nephrotoxicity. Everolimus is approved for use in renal transplantation in combination with basiliximab, cyclosporine, and corticosteroids and for use in liver transplantation in combination with tacrolimus and corticosteroids. Everolimus has also been used with tacrolimus in kidney transplantation with similar results as sirolimus.57 Everolimus appears to have less of an effect on wound healing and thus may potentially be used earlier after transplantation.
Early cyclosporine withdrawal has been studied in patients receiving sirolimus-based immunosuppressive protocols. Ideal candidates are patients who have not had a recent or severe rejection episode and adequate renal function 3 months after transplant. Rejection occurred in 5.6% of patients after discontinuation of cyclosporine, with no difference in graft survival. Long-term follow-up (2 years) showed improved renal function and blood pressure without an increase in acute rejection or graft loss in patients who discontinued cyclosporine.55 Similar results have been demonstrated with everolimus.57
PSIs have demonstrated efficacy to reduce CNI use and nephrotoxicity in liver,58 heart,55 and lung transplant.56 PSIs are also being investigated in liver transplant patients as a means to reduce the recurrence of hepatitis C and hepatocellular carcinoma.58 They may also slow the progression of vaculopathy, which may reduce the incidence of chronic rejection and prolong long-term patient survival after heart transplantation.20 However, the same effects have not been seen with lung transplantation.59
Clinical Controversy…
The benefits of PSIs after liver and lung transplant include decreased CNI-induced nephrotoxicity, anticancer properties, and anti-CMV and anti-HCV activity. Early introduction in these patients has demonstrated increased hepatic artery thrombosis and bronchial anastomotic dehiscence. The optimal timing of initiation of PSIs in these populations is controversial to minimize potential benefits while minimizing serious complications.
Adverse Effects Both everolimus and sirolimus are associated with dose-related myelosuppression. Thrombocytopenia is usually seen within the first 2 weeks of sirolimus therapy but generally improves with continued treatment; leukopenia and anemia are also typically transient.55,56 Sirolimus trough serum concentrations greater than 15 ng/mL (15 mcg/L; 16 μmol/L) have been correlated with thrombocytopenia and leukopenia.55 Hypercholesterolemia and hypertriglyceridemia are also common in patients receiving everolimus or sirolimus. It is postulated that the mechanism of this adverse effect is related to an overproduction of lipoproteins or inhibition of lipoprotein lipase. Peak cholesterol and triglyceride levels are often seen within 3 months of sirolimus initiation but usually decrease after 1 year of therapy and can be managed by reducing the dose, discontinuing sirolimus, or initiating therapy with an HMG-CoA reductase inhibitor or a fibric acid derivative. One study suggests that the dyslipidemia associated with sirolimus is not a major risk factor for early cardiovascular complications following kidney transplantation.55Delayed wound healing and dehiscence could be a result of inhibition of smooth muscle proliferation and intimal thickening.55 Mouth ulcers are reported in as many as 60% of patients treated with sirolimus and appears to be dose-related.55 Reversible interstitial pneumonitis has been described in kidney, liver, and heart–lung transplantation recipients.55 Other adverse effects reported with sirolimus include increased liver enzymes, hypertension, rash, acne, diarrhea, and arthralgia (see Table 70-4).
Drug–Drug and Drug–Food Interactions The major metabolic pathway for everolimus and sirolimus is CYP3A4; thus, the drug interactions mediated by induction or inhibition of the CYP3A4 enzyme system are similar to those seen with cyclosporine and tacrolimus (see Table 70-5). Administration of the microemulsion formulation of cyclosporine with sirolimus significantly increases the AUC and trough sirolimus levels. The same is not seen with the standard formulation of cyclosporine. Conversely, cyclosporine concentrations and AUC are also increased when it is given concomitantly with sirolimus. The mechanism is proposed to be competitive binding to CYP3A4 and P-glycoprotein.55,56 It is recommended that patients separate the dose of sirolimus and cyclosporine by 4 hours to minimize the interaction.55Concomitant administration of tacrolimus does not affect sirolimus levels.55 Although everolimus AUC was increased by the administration of a single dose of cyclosporine modified, no specific recommendations for dose timing are given. It should be expected, however, that any changes in CSA dose may also necessitate a modification of everolimus dose and increased therapeutic drug monitoring is indicated.56
As with cyclosporine and tacrolimus, grapefruit juice increases sirolimus levels. Administration of sirolimus with a high-fat meal is associated with a delayed rate of absorption, decreased Cmax, and increased AUC, indicating an increased drug exposure, whereas the half-life remains unchanged.55 Conversely, administration of everolimus with a high-fat meal decreases both Cmax and AUC.56
Dosing and Administration A fixed sirolimus dosing regimen is approved for concomitant use with cyclosporine that includes a loading dose of 6 or 15 mg followed by 2 or 5 mg daily, respectively. Therapeutic monitoring of sirolimus is advocated using whole-blood concentrations measured by HPLC, which is specific for the parent compound (see Table 70-7). For everolimus a starting dose of 0.75 mg twice daily is indicated in regimens that contain cyclosporine, corticosteroids, and basiliximab. Target concentrations are 3 to 8 ng/mL (3 to 8 mcg/L; 3 to 8 μmol/L).
Costimulatory Signal Inhibitor
Belatacept, derived from abatacept, is the only drug currently approved in the newest class of immunosuppressive agents. Belatacept may replace CNIs in the immunosuppressive regimen, which may abate toxicities associated with CNIs, namely, nephrotoxicity.60 Currently, belatacept is only approved for kidney transplantation.
Belatacept
Pharmacology/Mechanism of Action Belatacept is a selective costimulation blocker that binds costimulatory ligands (CD80 and CD86) on antigen presenting cells, preventing interaction with CD28 on T cells. The interaction of CD80 and CD86 with CD28 is required for the initiation of “signal 2”, the costimulatory signal that produces calcineurin, protein kinases, and nuclear factor-κ β that lead to activation and proliferation of T-cells. Thus, blockade of CD80 and CD86 prevents T-cell activation.60
Pharmacokinetics Belatacept, which is only available as an IV solution, has a volume of distribution of 0.11 L/kg. The half-life of belatacept is approximately 11 days and is not affected by kidney or liver function.60
Efficacy A phase III clinical trial comparing belatacept to cyclosporine in first time kidney transplants demonstrated similar efficacy in terms of both patient and graft survival. In the trial, the cyclosporine group experienced more chronic allograft nephropathy at month 12. However, the belatacept group experienced more frequent and more severe ACR. Despite this, the measured GFR was 13 to 15 mL/min (0.22 to 0.25 mL/s) higher in the belatacept group compared to the cyclosporine group, a trend that persisted for 5 years.60
Studies have also evaluated conversion from CNI-based regimens to belatacept in kidney transplant recipients with stable kidney function. The results show improved GFR from baseline in those converted to belatacept compared to patients who remained on CNIs. However, the difference was not statistically significant as the study was not adequately powered.61 Acute rejection occurred more frequently in patients who switched to belatacept, compared with no acute rejection in the patients who remained on CNIs.60
Early studies with belatacept in liver transplant resulted in increased graft loss and death.62 Therefore, belatacept is not indicated for use in liver transplantation.
Adverse Effects The most common adverse effects of belatacept include anemia, neutropenia, diarrhea, urinary tract infections, headache, and peripheral edema.60 Infusion-related reactions are rare with belatacept. In the clinical trials, patients who were Epstein–Barr virus (EBV) naïve experienced a significantly higher incidence of posttransplant lymphoproliferative disease (PTLD). Most of the cases of PTLD occurred within the first 18 months of treatment and the majority occurred in the CNS. There was no increase in incidence of PTLD in patients who were EBV-seropositive. As a result, belatacept carries a black box warning for PTLD and is contraindicated in patients who are EBV-seronegative. PML was also reported with belatacept.60
Drug–Drug and Drug–Food Interactions No drug or food interactions have been reported with belatacept.
Dosing and Administration Patients for whom belatacept is being considered must first be screened for EBV-serostatus prior to initiation of therapy. Only patients who are EBV-seropositive may receive belatacept due to the increased risk of PTLD in EBV-seronegative patients. The risk evaluation and mitigation strategy (REMS) for belatacept involves screening for symptoms of PTLD and PML with counseling and education related to each prior to each dose of belatacept. As a primary immunosuppressant for first time kidney transplant, belatacept is administered as 10 mg/kg IV over 30 minutes on days 0, 4, 14, 28, and at the end of weeks 8 and 12. Thereafter, the dose is reduced to the maintenance dose of 5 mg/kg administered IV over 30 minutes every 4 weeks beginning at week 16.
When converting to belatacept from a CNI-based regimen, the proposed dosing schedule is 5 mg/kg IV administered every 2 weeks for 5 doses on days 0, 14, 28, 42, and 56, then every 4 weeks thereafter. The CNI dose should be decreased by 50% after the second dose of belatacept, then discontinued after the fourth dose.60
Antibody Agents
Both polyclonal and monoclonal antibody preparations are used in transplantation. These agents can also be differentiated by their level of specificity, that is, particular receptor(s), or their downstream affects. In the following text, the agents are discussed as those that deplete lymphocytic cell lines (depleting antibodies) and those that generally bind to specific receptors but do not result in depletion of the cell to which they bind.
Depleting Antibodies
Antithymocyte Globulin Two antithymocyte globulins are available in the United States: ATG (Atgam, Pfizer, New York, NY), an equine polyclonal antibody, and RATG (Thymoglobulin, Genzyme, Cambridge, MA), a rabbit polyclonal antibody. The rabbit preparation is less immunogenic and may have other advantages over the equine preparation. Both ATG and RATG are often used as induction therapy to prevent acute rejection. In 2009, over 50% of kidney transplant recipients received RATG induction.1
Pharmacology/Mechanism of Action Because of their polyclonal antibody nature, both ATG and RATG exert their immunosuppressive effect by binding to a wide array of lymphocyte receptors (CD2, CD3, CD4, CD8, CD25, CD45, and others). Binding of ATG or RATG to the various receptors results in complement-mediated lysis and subsequent lymphocyte depletion. While T cells are the major lymphocytic target for the compounds, other blood cell components such as B cells and other leukocytes are also affected (see Fig. 70-1). Damaged T cells are subsequently removed by the spleen, liver, and lungs.
Pharmacokinetics ATG is poorly distributed into lymphoid tissue and binds primarily to circulating lymphocytes, granulocytes, and platelets. The terminal half-life of ATG is 5.7 days. RATG has a volume of distribution of 0.12 L/kg, and its terminal half-life in renal transplant recipients is significantly longer than ATG at 30 days.63 Peak plasma concentrations are reached after 5 to 7 days of ATG or RATG infusions. Antiequine antibodies can form in up to 78% of patients who are receiving ATG therapy. Similarly, anti-rabbit antibodies have been reported in up to 68% of patients who are receiving RATG therapy. The effects of preformed antibodies on the efficacy and safety of these preparations have not been studied adequately.
Efficacy ATG and RATG are used most commonly for the treatment of acute allograft rejection or as induction therapy to prevent acute rejection. ATG is currently approved for both indications in kidney transplants. RATG is approved only for the treatment of acute allograft rejection in kidney transplantations. Both drugs have been studied extensively for both indications.
Use of RATG as part of quadruple therapy in liver transplantation is associated with similar rates of patient and graft survival and acute rejection compared with dual therapy. In kidney transplant RATG was associated with improved graft survival at 5 years as compared with equine ATG. Quadruple-drug therapy results in similar rates of patient and graft survival and malignancy in heart transplantations, but a significantly lower rate of acute rejection and infection episodes is seen at 1 year compared with triple-drug therapy. CMV is an adverse effect of this strategy, but recent data indicate that routine prophylaxis is successful in this setting.64
Adverse Effects Most adverse effects reported with ATG and RATG are related to the lack of specificity for T cells owing to their polyclonal nature. Dose-limiting myelosuppression (leukopenia, anemia, and thrombocytopenia) occurs frequently. Other adverse effects include anaphylaxis, hypotension, hypertension, tachycardia, dyspnea, urticaria, and rash. Serum sickness is seen more frequently with ATG than with RATG. Nephrotoxicity has been reported but is rare in the absence of serum sickness. Infusion-related febrile reactions are most common with the first few doses and can be managed by premedicating the patient with acetaminophen, diphenhydramine, and corticosteroids. Finally, as with any immunosuppressive agent, ATG and RATG are associated with an increased risk of infections, particularly viral infections, and malignancy.
Drug–Drug and Drug–Food Interactions No drug or food interactions have been reported with ATG or RATG.
Dosing and Administration ATG doses range from 10 to 30 mg/kg per day as a single dose for 7 to 14 days. RATG is a more potent compound and is administered at doses of 1 to 1.5 mg/kg per day as a single dose for 7 to 14 days for acute rejection or for 5 to 10 days for induction of immunosuppression. It is recommended that both ATG and RATG be administered through a central line or through a high-flow vein with an in-line 0.22-micron filter over at least 4 hours to minimize phlebitis and thrombosis whenever possible.64,65 Literature supports peripheral administration of both agents. However, heparin and hydrocortisone are commonly added to the infusion to minimize phlebitis and thrombosis.66
Alemtuzumab
Alemtuzumab is approved for use in B-cell chronic lymphocytic leukemia. However, its effects on depleting both T and B lymphocytes make it useful in solid-organ transplants. While alemtuzumab is not FDA approved for solid-organ transplantation, it is increasingly recognized as a viable therapeutic option. In 2009, 10% of kidney transplant patients received alemtuzumab at the time of transplant.1 However, in 2012, commercial distribution of alemtuzumab ceased for transplantation and leukemia, requiring centers to enroll in the manufacturer’s distribution program for these indications.
Pharmacology/Mechanism of Action Alemtuzumab is a humanized monoclonal antibody against the CD52 surface antigen found on both T and B lymphocytes, as well as macrophages, monocytes, eosinophils, and natural killer cells. When alemtuzumab binds to the CD52 surface antigen, antibody-dependent lysis occurs, which removes both T and B lymphocytes from the blood, bone marrow, and organs, resulting in complete lymphocyte depletion.67
Pharmacokinetics The pharmacokinetics of alemtuzumab in solid-organ transplantation patients have not been investigated. Data from patients with B-cell chronic lymphocytic leukemia indicate that the volume of distribution of alemtuzumab after repeated dosing is 0.18 L/kg. The mean half-life after the first 30 mg dose was 11 hours, but increased to 6 days after 12 weeks of therapy. The extrapolation of these data to solid-organ transplantation is difficult because of the differences in dosing strategies (single or double doses in solid-organ transplantation vs. weekly to thrice weekly dosing in B-cell chronic lymphocytic leukemia). One or two doses of alemtuzumab result in complete and prolonged lymphocyte depletion. Following administration, B-lymphocyte counts return to normal within 3 to 12 months. T lymphocytes, however, remain depressed for as long as 3 years following administration.67,68
Efficacy Alemtuzumab is effective as induction therapy for the prevention of acute rejection in kidney, liver, pancreas, intestinal, and lung transplants.67 Additionally, alemtuzumab has been used to successfully treat acute rejection following transplantation and is effective for corticosteroid- and antibody-resistant rejection.68,69
Adverse Effects Adverse effects of alemtuzumab are primarily infusion related, hematologic, and infectious. Because alemtuzumab causes complete lymphocyte depletion and associated cytokine release, infusion-related reactions include rigors, hypotension, fever, shortness of breath, bronchospasms, and chills. The potential for developing these reactions can be reduced by administering premedications such as acetaminophen, corticosteroids, and diphenhydramine or by administering smaller doses and escalating the dose gradually. Hematologic effects include pancytopenia, neutropenia, thrombocytopenia, and lymphopenia.
Drug–Drug and Drug–Food Interactions No drug or food interactions have been reported with alemtuzumab.
Dosing and Administration Several dosing regimens have been proposed for alemtuzumab in solid-organ transplantation. The most common dosing strategy for alemtuzumab is 30 mg as a single dose; some centers administer a second dose 1 to 5 days after transplantation.67 Other studied dosing strategies include 0.3 mg/kg per dose, as a single- or multiple-dose regimen, and, finally, two 20-mg doses given on the day of transplantation and the first postoperative day.69
Nondepleting Antibodies
Interleukin-2 Receptor Antagonists Basiliximab, a chimeric monoclonal antibody (25% murine), is the only available IL-2 receptor antagonist in the United States. It is approved for use in kidney transplantation, but is also extensively used in other organ transplants as well.71
Pharmacology/Mechanism of Action Basiliximab exerts its immunosuppressive effect by specifically binding with high affinity to the α-chain (CD25) on the surface of activated T lymphocytes (see Fig. 70-1). Binding of basiliximab to the IL-2 receptor prevents IL-2-mediated activation and proliferation of T cells, a critical step in clonal expansion of T cells and the development of allograft rejection. Saturation of the IL-2 receptor occurs rapidly and confers an immunosuppressive effect that lasts for 4 to 6 weeks after administration.70
Pharmacokinetics Most of the pharmacokinetic data available for basiliximab is in renal transplantation patients. Caution must be used when extrapolating these data to nonrenal transplantation recipients. The volume of distribution is approximately 8 L for basiliximab. Basiliximab saturates CD25 in vivo at serum concentrations of 0.2. Basiliximab has a half-life of approximately 7 days in renal transplant recipients. Clearance of basiliximab is increased in patients who have received a liver transplant, primarily as a consequence of drainage of ascites. It is recommended that patients with greater than 10 L of ascites receive an additional dose of basiliximab on postoperative day 8.71
Efficacy Basiliximab is approved for use in kidney transplantation in combination with cyclosporine and corticosteroids, although induction therapy has also been studied extensively in liver and heart transplantation recipients. In 2009 29.6% of kidney and heart transplant recipients received an IL-2 receptor antagonist at the time of transplant.1 A meta-analysis of basiliximab in renal transplantation concluded that IL-2 receptor antagonists reduced the risk of rejection significantly with no increases in graft loss, infectious complications, malignancy, or death.70 Similar results were seen in liver and heart transplantation.71
IL-2 receptor antagonists offer a reasonable addition to CNI-or corticosteroid-sparing protocols. While CNI therapy cannot be completely avoided in most cases, IL-2 receptor antagonists allow for delayed use or reduced doses of CNIs, thus minimizing the risk of nephrotoxicity in the early posttransplantation period. Similar rates of rejection and corticosteroid-resistant rejection were seen in patients with DGF who received an IL-2 receptor antagonist in conjunction with lower tacrolimus doses compared with patients without DGF who received standard tacrolimus doses and no IL-2 receptor inhibitor induction.70
Adverse Effects Few adverse effects have been reported with basiliximab. In contrast to lymphocyte-depleting agents, basiliximab has not been associated with infusion-related reactions. However, since the marketing of basiliximab, an increased number of hypersensitivity reactions have been reported. Of note, only one patient developed antiidiotypic antibodies to the murine portion during clinical trials.71 The manufacturer of basiliximab reported an increase in mortality in a placebo-controlled trial, which was associated with an increase in severe infections. No increased risk of malignancy has been reported.
Drug–Drug and Drug–Food Interactions Reports of increased cyclosporine and tacrolimus levels in patients receiving concomitant basiliximab were recently published.70 Both authors hypothesized a potential interaction with the cytochrome P450.
Dosing and Administration Basiliximab is administered as two 20-mg IV doses, intraoperatively and again on postoperative day 4. Basiliximab is compatible with both 0.9% sodium chloride and 5% dextrose and can be administered either centrally or peripherally over 20 to 30 minutes in a volume of 50 mL. This regimen results in saturation of the IL-2 receptor for 30 to 45 days.
Investigational Agents
Rituximab
Rituximab is a chimeric monoclonal antibody against the CD20 receptor found on B cells. While it is FDA approved for non-Hodgkin lymphoma and rheumatoid arthritis, it has also been used in various aspects of transplant medicine, including treatment of AMR, suppression of alloantibodies prior to transplantation, and PTLD.72 Rituximab has been shown to improve graft survival in combination with plasmapheresis and IVIG in patients with AMR.16In highly sensitized patients, rituximab administration prior to transplantation has been shown to suppress alloantibodies and even allow transplantation across ABO-incompatibility.72 In PTLD, rituximab is most effective in patients with CD20-positive malignancies.72 The optimal dose of rituximab in transplantation has not been defined.
Bortezomib
Bortezomib, a proteosomal inhibitor that is FDA approved for the treatment of multiple myeloma, has been used in the treatment of AMR. In one series, 20 patients with AMR received four doses of bortezomib 1.3 mg/m2 on days 1, 4, 7, and 11 with plasmapheresis. Bortezomib was effective in lowering donor-specific antibodies by 50%.16 Another series showed benefit of bortezomib over rituximab.16However, bortezomib is associated with significant side effects, namely diarrhea that leads to dehydration, nausea, edema, vomiting, and infections. Side effects led to hospitalizations in one-third of patients in one series.16
Janus Kinase Inhibitors
Janus kinases are important for transduction of intracellular signals in lymphocytes to stimulate proliferation and lymphocyte activity. Tofacitinib is a Janus Kinase 3 (JAK3) inhibitor that has been compared to cyclosporine in combination with mycophenolate mofetil and steroids. Tofacitinib showed similar efficacy to cyclosporine, but was associated with an increased incidence of CMV and BK virus infections.73 Clinical trials continue to evaluate long-term efficacy and safety of JAK3 inhibitors.
EVALUATION OF THERAPEUTIC OUTCOMES
The success of transplantation can be measured in terms of length of graft and patient survival or quality of life. Several donor and recipient factors that have an impact on graft and patient survival have been identified (Table 70-8). The greatest risk to short-term graft survival is acute rejection. Routine surveillance of appropriate biochemical markers and serum drug concentrations are essential to minimize the potential for acute rejection. These parameters should be assessed daily to weekly for the first 1 to 3 months after transplantation. Monitoring should include complete blood counts, serum electrolyte concentrations, serum creatinine and blood urea nitrogen concentrations, and the appropriate serum drug concentrations. Liver function tests should also be evaluated using the same schedule in liver transplantation recipients. Routine biopsies are necessary to monitor for acute rejection in heart transplantation recipients. As the time after transplantation increases, the frequency of monitoring decreases. Once 3 months have elapsed after transplantation, monitoring of these parameters can be reduced to biweekly or monthly for most patients.
TABLE 70-8 Factors Negatively Affecting Allograft and Patient Survival
Long-term graft survival is limited by chronic rejection. Overall survival rates for solid-organ transplantations are described in terms of half-life, or the time after transplantation at which only 50% of transplanted organs are still functioning. Estimated half-lives for kidneys are 26.9 years for HLA-identical grafts and 12.2 and 10.8 years, respectively, for grafts from a sibling or parent who are 1-haplotype matches. The estimated half-life for HLA-matched grafts was 17.3 years while a markedly lower value of 7.8 years has been noted with mismatched kidneys.18 The overall median patient survival time for heart transplantation recipients is 9.8 years, but in these patients surviving the first year after transplantation, the median survival increases to 12 years.1 The highest rate of mortality occurs within the first year after liver transplantation due to the risks of surgery and early postoperative complications. Table 70-9 depicts a typical posttransplantation laboratory monitoring plan.
TABLE 70-9 Laboratory Monitoring after Transplantation as a Function of Time Posttransplant
PERSONALIZED PHARMACOTHERAPY
Individualization of immunosuppression therapy starts with identifying the patient’s risk of rejection prior to transplantation. Most clinicians will use induction therapy with a lymphocyte depleting agent for patients at high risk of rejection, including those patients who are sensitized to more HLA antigens due to previous exposure to blood products or previous transplant, younger patients and African Americans. Similarly, organs associated with a higher risk of rejection, including heart and lung transplants, require higher doses of immunosuppressants as maintenance therapy.
Therapeutic drug monitoring is a key component of individualizing the immunosuppressant regimen to ensure adequate immunosuppression is achieved while minimizing drug-related toxicities. Blood concentrations are routinely monitored for CNIs and PSIs throughout the duration of therapy. Studies are ongoing to determine the correlation between blood concentrations and MPA. Consensus guidelines suggest that MPA monitoring may be warranted when MPA is used as the primary immunosuppressant, CNI doses are reduced or discontinued, the patient has altered liver or kidney function, or medications that interact with MPA are administered concomitantly.51 One study suggests that African Americans may require monitoring of MPA levels due to more rapid clearance of MPA compared to Caucasians.74
Research is ongoing for pharmacogenetic monitoring of immunosuppressive therapies. Cytochrome P450 genetic polymorphisms are important for CNI metabolism. Both cyclosporine and tacrolimus are metabolized by CYP3A5, which contributes to the interpatient variability associated with CNIs. It is estimated that 30% of Caucasians and 50% of African Americans express high levels of CYP3A5 enzymes. Patients who express CYP3A5 require significantly higher doses of CNIs to achieve therapeutic levels.75 CYP3A5 genotyping may help to identify patients who require higher doses of CNIs to optimize immunosuppressive therapy earlier after transplantation and potentially decrease the risk of rejection. However, larger studies are needed to determine the effectiveness of this strategy.
Pharmacodynamic monitoring of immunosuppressants is currently being explored. This involves monitoring the specific targets of immunosuppressants rather than blood concentrations. Research is ongoing to determine the value of monitoring calcineurin activity for CNIs76 and IMPDH activity for MPA.45
Generic Substitution
In recent years, a number of generic versions of immunosuppressants have entered the market. While generic versions of corticosteroids and azathioprine have long been in the marketplace, there are now generic versions of cyclosporine, USP [MODIFIED], tacrolimus, and mycophenolate mofetil, the latter being considered narrow therapeutic index drugs. While these formulations have demonstrated bioequivalence to the innovator product in healthy individuals, bioequivalence testing in transplant patients is not required for approval.77
Although there would be no differences in the action of the molecule once absorbed into the systemic circulation, several potential differences in absorption could result in variability not seen in healthy volunteers. The presence of diabetes may delay gastric emptying, whereas cystic fibrosis may lead to differences in tacrolimus or cyclosporine secondary to fat malabsorption. None of these generic formulations have been studied in pediatric patients.78
As generic medications may offer a significant cost advantage compared with the innovator product, their use will increase over time. Much of the concern with generic substitution for immunosuppressant and other narrow therapeutic index medications relates to the potential for unmonitored changes in formulations. Systems that alert patients and prescribers to changes in formulation (e.g., labels on medications, direct notification to physicians) could trigger clinicians to more closely monitor patients for efficacy and toxicity as well as heightened therapeutic drug monitoring during a switch. However, the extent to which increased monitoring could offset cost savings associated with generic substitution has not been fully delineated.
IMMUNOSUPPRESSION-RELATED COMPLICATIONS
Comorbidities such as cardiovascular disease and malignancy, recurrent disease, drug toxicities (namely nephrotoxicity), and chronic rejection are the primary causes of mortality in patients who have a functioning graft 5 or more years after transplantation.1
Cardiovascular Disease
Cardiovascular disease is a leading cause of morbidity and mortality in transplant patients.79 Preexisting cardiovascular disease, which is common in end-stage organ failure, is not reversed with transplantation. Additionally, hypertension, hyperlipidemia, and diabetes are common complications in transplantation recipients and are independent risk factors that contribute significantly to cardiovascular disease. Chronic rejection has been linked to hypertension80 and hyperlipidemia.81
Hypertension
Corticosteroids, cyclosporine, tacrolimus, and impaired kidney graft function may cause posttransplantation hypertension. The primary mechanism of CNI-associated hypertension in heart transplantation recipients may be related to the CNI-induced stimulation of intact renal sympathetic nerves and the absence of reflex cardiac inhibition of the sympathetic nervous system, but a number of other mechanisms, including decreased prostacyclin and nitric oxide production, have also been proposed.40,82 In addition to the propensity to cause peripheral vasoconstriction, CNIs promote sodium retention, resulting in extracellular fluid volume expansion. Tacrolimus appears to have less potential to induce hypertension following transplantation than cyclosporine.83
Calcium channel blockers have traditionally been the first-line agents to treat hypertension after transplantation.84 Calcium channel blockers may ameliorate the nephrotoxic effects of cyclosporine, improve renal hemodynamics, decrease the incidence of DGF and the development of allograft atherosclerosis, and provide some immunosuppression. Calcium channel blockers, however, may also contribute to gingival hyperplasia that is often associated with cyclosporine-based immunosuppression.
ACEIs and angiotensin II receptor blockers have traditionally been avoided in kidney transplantation recipients, especially in the perioperative phase, because of the potential for hyperkalemia and their potentially negative influence on GFR. ACEIs and angiotensin II receptor blockers are now considered to be an equivalent alternative to calcium channel blockers for the treatment of hypertension in all transplant recipients, and are preferred in patients with proteinuria.84 When ACEIs or angiotensin II receptor blockers are used in patients after transplantation, serum creatinine and potassium levels should be monitored closely. If the increase in serum creatinine is greater than 30% within 1 to 2 weeks after initiating ACEIs or angiotensin II receptor blockers, other alternatives must be considered (see Chap. 3).
Multiple antihypertensive agents are usually necessary to achieve the goal blood pressure in transplant recipients; consequently, the addition of a β-blocker, diuretic, or centrally acting antihypertensive is usually necessary. β-blockers are generally considered to be second-line therapy in solid-organ transplantation recipients because of the potential to worsen metabolic disturbances caused by immunosuppressants, such as hyperkalemia and dyslipidemia. CNI-induced hypertension is often salt-sensitive, making it very responsive to diuretics. Central-acting agents (e.g., clonidine) are used often as adjunctive therapy in transplantation recipients who are unable to achieve blood pressure control with calcium channel blockers or ACEIs.
Hyperlipidemia
Hyperlipidemia may be exacerbated by corticosteroids, CNIs, PSIs, diuretics, and β-blockers.81,84 Corticosteroids promote insulin resistance and a decrease in lipoprotein lipase activity, as well as excessive triglyceride production. The mechanism of CNI-induced hyperlipidemia is not well understood. CNIs may decrease the activity of the low-density lipoprotein (LDL) receptor or lipoprotein lipase, altering LDL catabolism.81 Tacrolimus appears to have less potential than cyclosporine to induce hyperlipidemia.24,26,35,43,81 It is controversial whether the management of hyperlipidemia in transplant recipients should be more aggressive than the current guidelines for the general population established by the National Cholesterol Education Program.84 Aggressive lipid lowering may not only arrest the progress or prevent the complications of atherosclerosis but also promote graft survival in the kidney and heart transplant recipients. Current recommendations suggest monitoring lipid panels 2 to 3 months after transplantation and annually thereafter.84
For most patients, the combination of dietary intervention and an HMG-CoA reductase inhibitor should be considered the treatment of choice. HMG-CoA reductase inhibitors are highly effective in the treatment of hyperlipidemia, especially increased LDL, in transplantation patients. HMG-CoA reductase inhibitors as a class also have immunomodulatory effects on MHC expression and T-cell activation and reduce cardiac allograft rejection.34,35,81
HMG-CoA reductase inhibitors should be used with caution in transplantation recipients because of several reports of rhabdomyolysis when these agents are combined with CNIs.34 Safety measures include using low HMG-CoA reductase inhibitor doses and avoiding inappropriately high cyclosporine or tacrolimus concentrations. Concurrent use of simvastatin and cyclosporine is contraindicated; due to the increased risk of rhabdomyolysis.85 The concurrent use of medications known to increase the risk of myopathy (such as gemfibrozil) should be avoided.81 Patients should be informed of the signs and symptoms of rhabdomyolysis. Baseline and follow-up creatine phosphokinase measurements (every 6 months) have been used to identify patients who develop subclinical rhabdomyolysis when cholesterol-lowering therapy is used. Pravastatin may be preferred as a result of its lower interactive potential with CNIs because it is not metabolized by CYP3A4. The potential for hepatotoxicity from HMG-CoA reductase inhibitors warrants close monitoring of liver function in all transplantation recipients.84
Bile acid-binding resins may be used to lower cholesterol in transplant patients, but adequate doses are difficult to achieve without the development of GI adverse effects. Because the absorption of cyclosporine is dependent on the presence of bile in the GI tract, patients should be instructed to separate dosing of bile acid-binding resins and cyclosporine by at least 2 hours. Bile acid-binding resins should also be separated from other immunosuppressants by at least 2 hours to avoid physical adsorption in the GI tract. For transplant patients who have hypertriglyceridemia refractory to dietary intervention, fish oil and fibric acid derivatives are well-tolerated, effective alternatives (see Chap. 11). Fibric acid derivatives are most effective in lowering serum triglyceride concentrations.
New-Onset Diabetes after Transplantation
Corticosteroids and CNIs can impair glucose control in previously diabetic patients, as well as cause new-onset diabetes after transplantation (NODAT) in 4% to 20% of patients. Corticosteroids induce insulin resistance and impair peripheral glucose uptake, whereas CNIs appear to inhibit insulin production.81 Tacrolimus seems to be more diabetogenic than cyclosporine, although recent studies have failed to show a statistical difference.43 Other possible risk factors that have been identified for NODAT include African American or Hispanic ethnicity, age >40 years, family history, and weight, as well as CMV and hepatitis C virus (HCV) infection.81
Up to 40% of patients with NODAT will require insulin therapy.80 In diabetic patients who can be managed with an oral hypoglycemic agent, glipizide, which is metabolized extensively by the liver, may be preferred over renally eliminated agents such as glyburide. Metformin should be used with extreme caution because of the risk of accumulation and lactic acidosis in those with moderate renal impairment. Regardless of therapy, frequent blood glucose monitoring is imperative in the early postoperative phase both to improve glucose control and to identify those with NODAT. Changes in renal function secondary to CNI nephrotoxicity or DGF or acute rejection in kidney transplant recipients affect the elimination of many hypoglycemic agents, including insulin, and may result in hyper- or hypoglycemia. Dose changes of immunosuppressant drugs also affect glycemic control. Tapering of immunosuppressive medications may result in reduced insulin requirements, whereas corticosteroid pulses for the treatment of rejection may result in increased insulin requirements.
Infection
Increased risk of infection is a natural consequence of therapeutic immunosuppression. Many infections, including CMV and fungal infections, in solid-organ transplant recipients are reviewed in Chapter 100.86
Polyomavirus-associated nephropathy (PVAN) is an important cause of renal dysfunction in kidney transplant recipients. The specific polyomavirus that infects kidney allografts is the BK virus. Primary infection with BK virus occurs in childhood as an asymptomatic infection in 50% to 90% of the general population. The precise mechanism of transmission is not clear but is suspected to be via the oral or respiratory routes. The virus then remains latent primarily in the genitourinary tract. Reactivation of BK virus is limited to people with compromised immune function and is most common in kidney transplant recipients. Reactivation can be detected as the presence of BK virus in the urine of approximately 30% to 40% of kidney transplant recipients, although it does not progress to nephropathy in the majority of patients. However, BK viremia if it develops has been noted to progress to allograft nephropathy in 50% of patients.87 The development of BK virus nephropathy results in graft loss in about 46% of affected patients.87
It has been recommended that all kidney transplant recipients be screened for urinary BK virus replication monthly for the first 3 to 6 months after transplant and every 3 months thereafter for the first year. Screening for BK virus should also occur any time the serum creatinine is elevated without known cause and after treatment of acute rejection.84 Treatment of BK virus should be initiated when plasma concentrations persist above 10,000 copies/mL (10 × 106/L).84 The first line of treatment is to reduce immunosuppressive medications. Other treatment strategies include cidofovir, leflunomide, and fluoroquinolones, although studies with these agents are limited.88
HCV recurs almost universally following liver transplantation and the course of the disease is accelerated. Within 5 years, 10% to 20% of liver transplant recipients with HCV recurrence will progress to cirrhosis requiring retransplantation, compared to the general population where 20% to 30% will develop cirrhosis over 20 to 30 years. Liver donor age over 40 years has been shown to be the primary risk factor for HCV recurrence. Females with HCV recurrence develop more severe disease than the general population. Standard treatment for HCV recurrence includes interferon alfa-2b in combination with ribavirin. However, the virologic response is reduced after liver transplantation compared to the general population. The therapy is further complicated by significant side effects, namely leukopenia and anemia. Administration of hematopoietic growth factors may be needed to allow administration of adequate doses of interferons and ribavirin. Interferon alone shows minimal effect against HCV recurrence after liver transplantation.89 There is no data on the use of the HCV protease inhibitors, boceprevir and telaprevir, after liver transplantation. The potent CYP3A4 inhibition of these drugs, however, will have significant effects on CNI and PSI dosing. One study in healthy volunteers reported telaprevir increased the AUC of cyclosporine by 4.6-fold and tacrolimus by 70-fold.90 The role of these agents after transplantation is currently being investigated to determine the optimal dose adjustments needed for CNIs.89
In the absence of preventative therapy, hepatitis B recurs in approximately 80% of patients after transplantation. Initial studies with short-term IV administration of hepatitis B immunoglobulin (HBIg) showed equally high rates of recurrence upon discontinuation of therapy. However, strategies that employ the long-term administration of HBIg with or without antiviral therapy report much lower recurrence rates, 15% to 30% and 20% to 40%, for nonreplicative and replicative hepatitis B virus, respectively. Common strategies include IV HBIg 10,000 units during the anhepatic phase followed by 10,000 units daily for 6 days. Antihepatitis B surface titer should be monitored weekly to ensure adequate levels for protection as well as to optimize HBIg use. HBIg has been typically dosed to maintain titers >100 to 500 international units/L. Long-term HBIg therapy is extremely costly, estimated at $100,000 for the first postoperative year and $50,000 for each subsequent year. Combination therapy with antiviral agents appears to be synergistic and is the current standard. Lamivudine resistance is a concern with long-term utilization both pre- and posttransplant. The role of newer antiviral agents, including adefovir, entecavir, and tenofovir, remains to be defined. Other strategies that have been investigated and show promise include pretransplant viral load reduction and reduced-dose HBIg. Treatment for active hepatitis B virus graft infection should include HBIg, antiviral therapy, and concomitant reduction in immunosuppression.91
Malignancy
Although advances in immunosuppression have decreased the incidence of acute rejection and increased patient survival, they have also increased the patient’s lifetime exposure to immunosuppression. While the precise mechanism is unclear, posttransplantation malignancy seems to be related to the overall level of immunosuppression, as evidenced by a difference in the rates of malignancy associated with quadruple versus triple versus dual immunosuppressant regimens. The risk of de novo malignancy in transplantation recipients is increased three- to fivefold over the general population. The age-adjusted incidence of lung, breast, colon, and prostate cancers was doubled in renal transplant recipients. A number of cancers that are uncommon in the general population occur with much higher prevalence in transplantation recipients: posttransplantation lymphomas and lymphoproliferative disorders (PTLDs), Kaposi’s sarcoma, renal carcinoma, in situ carcinomas of the uterine cervix, hepatobiliary tumors, and anogenital carcinomas. Skin cancers are the most common tumors. Factors that may predispose transplant recipients to skin cancers include copious sun exposure and therapy with azathioprine.92 While too early to definitively assess the impact of MPA derivatives on malignancy, one analysis showed a lower risk of PTLD with MMF compared with AZA. PSIs have a theoretical benefit in terms of the development of malignancy. In addition to immunosuppressive properties, PSIs also have antiproliferative effects. In fact, a decreased incidence of malignancy was reported in patients receiving PSIs versus CNIs, and conversion to PSIs from CNIs can result in regression of Kaposi’s sarcoma.92
PTLD encompasses a broad spectrum of disorders, ranging from benign polyclonal hyperplasias to malignant monoclonal lymphomas. Factors that predispose patients to PTLD include EBV seronegativity at transplantation and intense immunosuppression, particularly with lymphocyte-depleting agents. Nonrenal transplantation recipients are more likely to develop PTLD secondary to the heavy immunosuppression used to reverse rejection. Administration of ganciclovir or acyclovir preemptively during antilymphocyte therapy may decrease the risk of EBV seroconversion and infection, reducing the eventual risk of PTLD. Treatment of life-threatening PTLD generally includes severe reduction or cessation of immunosuppression. Other options include systemic chemotherapy or rituximab.72
Posttransplantation malignancies appear an average of 5 years after transplantation and increase with the length of follow-up: as many as 72% of patients surviving greater than 20 years may be affected. Malignancy accounts for 11.8% of deaths after cardiac transplantation and is the single most common cause of death in the sixth to the tenth posttransplant years.92
CLINICAL BOTTOM LINE
Transplantation is a lifesaving therapy for several types of end-organ failure. Advances in the understanding of transplant immunology have produced an unprecedented number of choices in terms of immunosuppression. The increasing number of effective immunosuppressive medications and therapies offers clinicians diverse ways to prevent allograft rejection in a patient-specific manner. However, the vast array and efficacy of currently available immunosuppressive agents make it increasingly difficult to evaluate their long-term efficacy. Clinicians must be keenly aware of the adverse effects of immunosuppressive medications and their treatment in order to optimize the care of the transplanted patient.
ABBREVIATIONS
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