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Successful kidney transplantation involves rigorous evaluation of both
donor and recipient. This results in immunologic categorization as either
a high-risk or low-risk transplant and determines the immunosuppressive
regimen an individual recipient should receive. The majority of these
patients will receive combination therapy, which includes a calcineurin
inhibitor, an antiproliferative agent, and a corticosteroid.
Induction therapy is used in most kidney transplant cases. Rabbit
antithymocyte globulin, alemtuzumab, and basiliximab are common
agents. Differences among these agents include dosing regimen and
side effect profile. Rabbit antithymocyte globulin and alemtuzumab are
often used in high-risk patients, including those with delayed graft
function, whereas basiliximab is frequently used in low-risk recipients.
Immunosuppressive combination therapy is directed at prevention of
whereas B-cell-mediated rejection is much more resistant. Despite
success in reducing acute rejections, chronic rejection and chronic graft
dysfunction are major causes of graft loss.
Cyclosporine is a calcineurin inhibitor with a complex pharmacokinetic
profile associated with multiple adverse effects and requires therapeutic
drug monitoring (TDM). Its use has significantly declined since the
The mTOR inhibitors, sirolimus and everolimus, have complex
pharmacokinetic profiles, significant adverse effects, and require TDM.
These agents appear to be most useful in minimizing or avoiding the use
of calcineurin inhibitors or other agents.
The calcineurin inhibitors cyclosporine and tacrolimus and steroids have
significant toxicity profiles, particularly with chronic long-term use.
Calcineurin inhibitor-induced nephrotoxicity is a major problem. Steroids
have a negative impact on the cardiovascular, bone, and endocrine
system. Severalstrategies have been developed in an attempt to either
avoid or minimize these adverse effects.
Cardiovascular complications, including hypertension, hyperlipidemia, and Case 34-5 (Questions 1–4)
diabetes, are prevalent among kidney transplant recipients. These
contribute to poor patient survival and graft loss. Other complications
such as osteoporosis are frequently observed. Monitoring and treatment
of these complications, which may be drug-induced, are an important
part of the post-transplant care plan.
BK polyomavirus is almost exclusively seen in kidney transplantation and
is associated with graft loss. The best approach to reducing its
occurrence is viralsurveillance. If it is present, then reduction of
immunosuppression appears to be the most effective treatment.
Liver transplantation is considered the treatment of choice for patient
with end-stage liver disease. Common early post-transplant
complications include surgical (biliary leaks and bleeding), neurologic
(continued hepatic encephalopathy, drug toxicity), and infectious
(pneumonias, urinary tract infections, and biliary bacteremias).
Tacrolimus is considered the cornerstone of the immunosuppressant
regimen for the vast majority of solid organ transplant recipients. It has
complex pharmacokinetics and therefore requires close TDM for
optimal use. Tacrolimus is a potent agent that has significantly reduced
acute rejection rates; additionally, compared to cyclosporine, tacrolimus
has fewer cosmetic side effects (hirsutism, gingival hyperplasia), fewer
effects on serum lipoproteins and blood pressure, but has more severe
effects on serum glucose levels and more pronounced neurotoxicities.
Acute rejection of the transplanted liver is a common, but usually
reversible, consequence after this surgery. It is usually asymptomatic,
but can be identified early through serial monitoring of serum
transaminases and bilirubin, and definitively diagnosed only through liver
biopsy. Treatment usually consists of pulse-dose corticosteroids,
followed by a taper, or the use of rabbit antithymocyte globulin for more
severe rejections or those refractory to steroid therapy.
Mycophenolate is considered the adjuvant agent of choice in solid organ
transplantation and is used to reduce calcineurin inhibitor exposure or
augment immunosuppressant regimen potency. TDM is not common
and has yet to prove effective in optimizing therapy. Common side
effects with this agent include gastrointestinal issues (nausea, vomiting,
and diarrhea) and cytopenias (leukopenia and thrombocytopenia).
Drug interactions with immunosuppressants are numerous and are
commonly encountered clinical dilemmas in the transplant recipient.
Pharmacists should prospectively screen for these interactions and,
depending on their magnitude, may need to prospectively adjust
medication regimens. Closer TDM or clinical monitoring is always
warranted when adding or removing an interacting medication to a
Infections, including opportunistic infections, are common complications
after transplant. Prophylaxis with antimicrobial agents is critical for the
most common and severe pathogens. Hepatitis B and hepatitis C are
problematic after liver transplant and require immunoprophylaxis or
treatment in certain circumstances.
Cytomegalovirus is the most common and debilitating opportunistic
infection after solid organ transplantation. Reactivation or new infection
with this virus can lead to severe tissue invasive disease and potentially
death. Indirect effects include acute rejection, chronic rejection, graft
loss, and potentially, lymphoma. Prophylaxis with potent antivirals
(ganciclovir or valganciclovir) is the cornerstone of prevention.
Treatment involves a long course of antiviral therapy usually in
conjunction with reductions in immunosuppression.
Post-transplant lymphoproliferative disorder (PTLD), which is usually a
B-cell lymphoma, is the most common cancer encountered after organ
transplant. Early PTLD is generally responsive to reductions in
immunosuppression; advanced PTLD is usually not responsive to this
nor to traditional chemotherapy. The use of rituximab, a monoclonal
antibody directed against B cells, has shown promise for treatment of
INTRODUCTION TO TRANSPLANTATION
Solid organ transplantation, adult and pediatrics, is an established therapeutic option
for patients with end-stage kidney, liver, heart, and lung disease. For many of these
patients, it is the only option. One-year patient and graft survival for these major
organs is between 85% and 98%.
1 Pancreas or combined pancreas–kidney
transplantation is available as a treatment for diabetic patients with end-stage renal
Unfortunately, many more patients are in need of transplantation than there are
organs available. In 2014, about 30,000 organ transplants were performed, whereas
130,000 people were waiting for all organs and 60,000 for kidneys. Consequently, a
significant number of candidates die while on the waiting list.
During the 1960s, azathioprine, prednisone, antilymphocyte serum, and
antilymphocyte globulin made the success of kidney transplantation possible. In the
1980s, the introduction of cyclosporine had a remarkable impact on solid organ
transplantation, and the first monoclonal antibody approved for human use, OKT3,
was introduced, but is no longer available.
Since the 1990s, a number of other agents have been approved. These include
tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus (formerly
rapamycin), and everolimus; monoclonal antibodies, such as basiliximab; a
polyclonal antibody, antithymocyte globulin (rabbit antithymocyte globulin); and
belatacept. More recently, several agents, such as alemtuzumab, intravenous
immunoglobulins (IVIGs), rituximab, eculizumab, and bortezomib, are incorporated
into transplant protocols. Several new agents are undergoing investigation.
Although transplantation has a significant positive impact on the quality of life in
most patients, rehospitalizations, retransplantation because of graft failure or disease
recurrence, donation source (living-related and unrelated organs), and costs to
individuals, insurers, and society are major issues. For example, the average
Medicare cost during the first year after kidney transplantation is $83,000 and during
the second year is $25,000. After liver transplantation, first-year average Medicare
cost is $190,000 and second year $30,000.
2 The ability of transplant recipients to pay
for their medications or insurance denial or termination of coverage is another major
The goal of immunosuppressive therapy is to prevent organ rejection, prolong graft
and patient survival, and improve quality of life. Short-term (i.e., 1–2 years) survival
after transplantation has improved dramatically. Long-term survival also has
improved, but not to the same degree.
3 As patients live longer after transplantation,
the focus of therapy has shifted to survival and management of long-term
complications. Immunosuppressive agents are associated with significant long-term
complications. These include nephrotoxicity, hypertension, hyperlipidemia,
osteoporosis, diabetes, infection and malignancy, as well as graft loss secondary to,
recurrence of primary disease, nonadherence and rejection. Many patients also have
several pre- and post-transplant comorbidities and complicated drug regimens,
which must be evaluated and managed. Pharmacists play an important role in these
4 Although acute rejection rates are significantly lower, this
remains a problem, along with chronic rejection and/or chronic allograft injury and
long-term outcomes. The search for safer and more effective immunosuppressive
regimens continues, along with a better understanding of optimal long-term
5 This chapter addresses the immunology of transplantation and
rejection, indications for kidney and liver transplantation, appropriate use of
immunosuppressive agents, and the management of postoperative and long-term
complications in these patients. Many of these issues are similar for the various types
of solid organ transplantations, but there can also be significant differences as well.
This chapter addresses some of these issues as they relate to kidney and liver
Successful organ transplantation has evolved from a greater understanding and
application of pharmacology, microbiology, molecular and cellular biochemistry and
biology, genetics, and immunology. Suppression of the host’s immune system and
prevention of rejection are vital for host acceptance of the transplanted organ. The
ultimate goal is permanent acceptance or tolerance, a situation in which the new
organ is seen as “self” by the host’s immune system. In general, the currently used
immunosuppressive drugs provide a nonpermanent form of tolerance and lifelong
immunosuppression is required. A basic understanding of the immune system and the
mechanisms of rejection is key to the effective use of immunosuppressive drugs in
Major Histocompatibility Complex and Human
The degree to which allogeneic grafting (e.g., donor and recipient from same
species) is successful depends on the genetic similarities or differences between the
donor organ and the recipient’s immune system. The recipient recognizes the
transplanted graft as either self or foreign. This recognition is based on the
recipient’s reaction to alloantigens or antigens (i.e., substances that initiate an
immune response that can lead to rejection of the transplanted organ). These
substances, also known as histocompatibility antigens, play a very important role in
organ transplantation. The ABO blood group system of red blood cells is also
important and, in most cases, the donor and recipient should be ABO compatible;
otherwise, immediate graft destruction can occur because of antibodies directed
Histocompatibility antigens are glycoproteins that are located on the surface of
cell membranes. These are encoded by the major histocompatibility complex (MHC)
genes located on the short arm of chromosome 6. In humans, the MHC is called the
human leukocyte antigen (HLA). The gene products encoded on the HLA are divided
into classes I, II, and III based on their tissue distribution, antigen structure, and
function. Class I antigens (HLA-A, HLA-B, and HLA-C) are present on all nucleated
cell surfaces and are the primary targets for cytotoxic T-lymphocyte reactions against
(B cells), monocytes, activated T lymphocytes (T cells), dendritic cells, and some
endothelial cells, all of which can act as antigen-presenting cells (APCs). Individual
HLA loci are extensively polymorphic. Each transplant recipient possesses two A,
B, and DR antigens, one from each parent. This is called a haplotype. Recognition of
these polymorphic loci by recipient T cells appears to account for rejection events.
Class III antigens (C4, C2, and Bf) are part of the complement system.
Rejection of a transplanted organ is the outcome of the natural response of the
immune system, innate and adaptive immunity, to a foreign substance, or antigen, and
is a complex process, the understanding of which continues to evolve. This process
involves an array of interactions between antigens, T cells, macrophages, cytokines
(soluble mediators secreted by lymphocytes, also called lymphokines [the
interleukins]), adhesion molecules (also referred to as costimulatory molecules), and
immune response, but it is predominantly T-cell-mediated. This process can be
divided into several important steps, which include antigen presentation, T-cell
recognition, activation, proliferation, and differentiation of the various components of
the immune response. For foreign antigens to interact with recipient T cells and B
cells, they must be prepared for presentation by APCs. These APCs usually are
recipient macrophages or dendritic cells (indirect pathway of allorecognition),
although initially donor cells—dendritic cells or passenger leukocytes and graft
endothelial cells—also can serve as APCs (direct pathway of allorecognition). This
phase takes place within the blood, lymph nodes, spleen, and the transplanted organ.
primary site for this to occur is at the CD3–T-cell receptor (TCR) complex on
[CD]) on their surfaces that, along with CD3, recognize and respond to different
types of antigens. These T cells are known as CD4
+ cells (TH, helper or inducer T
+ cells (TC, cytotoxic or suppressor T cells). CD4
+ cells interact with class I antigens.
In addition (signal two), proteins known as adhesion molecules or costimulatory
molecules promote T-cell signaling and activation. For T-cell activation to occur,
binding of these costimulatory molecules as well as binding of the TCR with the
presented antigen and MHC is required. Examples of these molecules include
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