IMMUNOSUPPRESSION
Recognition of a foreign alloantigen after organ transplantation
triggers an immune response in the host. An immediate goal of immunosuppressive
therapy is to prevent the rejection of grafts from genetically nonidentical donors.
Various immunosuppressive drugs have been developed to diminish the immunologic
attack on grafts and target T-cell activation, which triggers the predominant form
of acute rejection. Individual immunosuppressants inhibit different steps in T-cell
activation, which is a very complex process that can be divided into two stages:
a sensitization phase and an effector stage. The first stage of T-cell activation
involves interaction between antigen-presenting cells of the graft and host T cells,
CD3. The second stage involves participation of costimulatory receptors such as
B7, CD28, and CD40, which also activate the T-cell response, and subsequent secretion
of cytokines by activated T cells. An interaction of intracellular adhesion molecules
and cytokines (e.g., interleukin-2, interferon-γ, and tumor necrosis factor-β)
activates the transcription cascade, which further amplifies T-cell activation through
DNA synthesis and T-cell proliferation and therefore plays a central role in graft
rejection. Graft rejection reactions have various time courses: hyperactive rejection
occurs within the first 24 hours after transplantation, acute rejection reactions
usually begin in the first few weeks after transplantation, and chronic rejection
can occur months to years after transplantation.[421]
[422]
Immunosuppressive drugs are used for the prevention or treatment
of acute and chronic rejection of a transplanted organ. The growing success of organ
transplantation is closely linked to the evolution of immunosuppressive therapy over
the last decades. The first immunosuppressive drug, azathioprine, was introduced
in 1962 and increased the possibilities for successful human transplants while earning
a Nobel Prize for innovative pharmacologic progress. In the last 20 years, important
medical breakthroughs such as tissue typing and the introduction of calcineurin inhibitor-based
immunosuppression have dramatically improved the survival rate of transplant recipients.
In 1983, the "calcineurin inhibitors era" was ushered in after the discovery of
cyclosporine (1979).
Transplantation of extrarenal organs became routine, with excellent outcomes for
liver, pancreas, heart, and even lung transplants.[423]
Immunosuppressive therapy is increasingly being tailored to the specific organs
transplanted and their individual risk factors. For example, patients who are presensitized
or receive a blood group-incompatible organ are from an immunologic point of view
considered to be high-risk patients. They are likely to require more potent, aggressive
immunosuppressive therapy than needed for other transplant patients.[424]
However, frequently, the type of immunosuppressive drug (e.g., calcineurin inhibitors)
or increased doses of immunosuppressive drugs are linked to increased end-organ toxicity
such as neurotoxicity or nephrotoxicity. Therefore, in patients with delayed renal
graft function after transplantation, initial omission of calcineurin inhibitors
is crucial to avoid further renal damage. Immunosuppressive drugs are frequently
combined to take advantage of additive or synergistic immunosuppressive interaction
and limit drug-specific toxicity ( Table
56-7
).[425]
Therapy has to be maintained
lifelong, although isolated cases without graft loss after complete withdrawal of
all immunosuppressive drugs have been reported. A typical regimen consists of different
phases, starting with the induction phase, therapy during hospitalization, the maintenance
phase, and if necessary, antirejection treatment. Each phase may consist of different
drugs or doses and is constantly adjusted as dictated by the medical condition of
the patient. The major limitation of current immunosuppressive drugs is that no
currently available therapy is entirely effective in preventing rejection.[424]
Furthermore, the use of multiple immunosuppressive drugs predisposes
TABLE 56-7 -- Immunosuppressive drugs used in solid organ transplantation and their side
effects
|
Mechanism of Action |
Side Effects |
|
Inhibition of T-Cell Interaction |
|
|
Prednisolone |
As with all steroids: osteoporosis, diabetes mellitus, glaucoma,
infections |
|
Orthoclone (OKT3) |
Fever, lymphoproliferative disease, pulmonary edema, anaphylactic
reaction, neoplasia |
|
15-Deoxyspergualin |
Bone marrow suppression, gastrointestinal syndromes, paresthesia |
|
Inhibition of Adhesion Molecules |
|
|
Rabbit/horse antithymocyte globulin |
Fever, nausea, anaphylactic reaction, higher incidence of cytomegalovirus
and Epstein-Barr virus infection |
|
Antilymphocyte globulin |
Fever |
|
Enlimomab |
Fever, hypertension, chills, nausea, vomiting |
|
OKT4A |
Unknown |
|
Inhibition of Cytokine Synthesis |
|
|
Cyclosporine |
Nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension,
diabetes, hyperlipidemia, hirsutism, tremor, gingival hyperplasia |
|
Tacrolimus (FK506) |
Nephrotoxicity, neurotoxicity, hypertension, hyperlipidemia,
hyperglycemia |
|
Sirolimus (rapamycin) |
Hyperlipidemia, myelosuppression, infections |
|
SDZ-RAD (everolimus) |
Hyperlipidemia, myelosuppression, infections |
|
Inolimomab |
Headache, leukopenia, thrombocytopenia |
|
Basiliximab |
No major adverse effects |
|
Daclizumab |
No major adverse effects |
|
Inhibition of DNA Synthesis |
|
|
Azathioprine |
Myelosuppression, hepatotoxicity, development of malignancy |
|
Mycophenolate mofetil |
Leukopenia, gastrointestinal syndromes |
patients to a host of infectious and malignant complications. Long-term survival
of patients after solid organ transplantation has improved with adequate immunosuppressive
therapy. However, modification of the immune system has also increased the risk
of malignancy, especially types of malignancy involving viruses.[426]
For example, azathioprine has been associated with a significant increase in skin
cancer, as has prolonged cyclosporine administration with Kaposi's sarcoma. Malignancy
is now responsible for substantial morbidity and mortality in this patient population.
With many available immunosuppressant combinations (cyclosporine
+ sirolimus, cyclosporine + mycophenolate mofetil, tacrolimus + sirolimus, tacrolimus
+ mycophenolate mofetil, cyclosporine + everolimus), acute rejection rates are acceptable,
and the focus of interest in transplantation has significantly shifted and expanded
toward tolerability and long-term graft and patient survival. The goals of therapy
for new immunosuppressants drugs should include: (1) prevention of the immune response
(i.e., acute/chronic rejection and vascular remodeling); (2) prevention of the complications
of immunodeficiency, such as opportunistic infections and malignancies; and (3) minimization
of drug-induced toxicity.
Because the therapeutic range of most immunosuppressive drugs
is narrow, perioperative monitoring of drug levels is important. Several immunosuppressives
(e.g., cyclosporine, tacrolimus, and sirolimus) are substrates or modulators (or
both) of cytochrome P4503A and P-glycoprotein.[427]
[428]
P-glycoprotein is a member of the ABC (adenosine
triphosphate [ATP]-binding cassette) transport protein family. It is found in various
tissues,
including the blood-brain barrier, gastrointestinal tract, kidneys, adrenal cortex,
and several more. One of the functions of P-glycoprotein is the energy-dependent
transport of drug acquired from the cytoplasm or plasma membrane into the extracellular
space.[429]
Several other drug classes (e.g., antifungals,
calcium channel blockers, HIV protease inhibitors) administered to transplant patients
are also substrates or modulators (or both) of cytochrome P4503A and P-glycoprotein.
These drugs themselves may interact with drugs commonly administered during the
perioperative period.[430]
[431]
Although interactions between immunosuppressive and anesthetic
drugs are likely to occur, few studies have examined in a prospective randomized
fashion the impact of immunosuppressive drugs on selected anesthetics. In animal
studies, cyclosporine was shown to alter barbiturate, fentanyl, and isoflurane requirements.
[432]
[433]
[434]
[435]
[436]
However,
the clinical relevance of these interactions remains to be investigated. Similarly,
cyclosporine appears to enhance the effects of neuromuscular blockade as demonstrated
in several animal studies and case reports.[437]
[438]
[439]
[440]
[441]
Despite the lack of adequate trials in humans,
it appears to be reasonable to anticipate reduced requirements of nondepolarizing
muscle relaxants in patients taking cyclosporine. Azathioprine, in contrast, produced
a small and transient antagonism to nondepolarizing muscle blockade in patients with
renal failure that was considered clinically insignificant.[442]
An animal study also demonstrated no effect of azathioprine on atracurium requirements.
[443]
The complexity of the immunosuppressive regimen in conjunction
with adjunct therapies makes clinically relevant drug-drug interactions likely.
A detailed preoperative review of the patient's medication should focus on possible
side effects, drug-drug interactions, and potential implications for the anesthetic
plan.[444]
