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CHAPTER 115: The Transplant Patient 1089

■ CALCINEURIN INHIBITORS AND RELATED COMPOUNDS have the same potential to cause renal failure. However, sirolimus has

(CYCLOSPORINE, TACROLIMUS, AND SIROLIMUS) been associated with an increased risk of hepatic artery thrombosis and
11
The introduction of cyclosporine was one of the most revolutionary subsequent allograft loss in liver transplant recipients. There have also
been reports of interstitial pneumonitis associated with sirolimus.
12-15
events in the field of transplant medicine, and the drug remains an Sirolimus is not recommended in the early postoperative period fol-
3
important component of immunosuppressive regimens used by many lowing lung transplantation, as it has been associated with bronchial
institutions. In recent decades, some centers have switched to tacroli- anastomotic dehiscence. 16,17
mus, which has surpassed cyclosporine in certain centers as the agent
of choice given evidence of greater efficacy in certain organ trans- ■ PROLIFERATION INHIBITORS (AZATHIOPRINE,
plants. Sirolimus, a newer immunosuppressive, is generally not used as MYCOPHENOLATE MOFETIL)
commonly given its side-effect profile. All three agents provide effective
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inhibition of T-cell activation by interfering with a receptor on T cells The proliferation inhibitors block DNA and RNA synthesis by interfer-
that involves a calcium-dependent signal transduction pathway. ing with normal purine metabolism. Since lymphocytes are unable to
Cyclosporine binds to intracellular cyclophilin, and this complex salvage purine as efficiently as most other cells, these drugs effectively
interacts with calcineurin. Calcineurin is crucial for normal lympho- inhibit lymphocyte proliferation and clonal expansion of lymphocytes.
kine gene activation, and its inhibition by cyclosporine consequently Azathioprine is a purine analogue that is converted in the liver to
interferes with the production of interleukins-2, -3, and -4 (IL-2, IL-3, 6-mercaptopurine and compromises synthesis of DNA and RNA. Its
and IL-4), tumor necrosis factor-α (TNF-α), and other important most important side effect is marrow suppression, which may result in a
mediators of inflammation. In turn, specific and potent inhibition of profound leukopenia. Other important toxicities include hepatotoxicity
T-cell activation (especially CD4 cells) is achieved. The most frequently and rarely fulminant hepatic failure, acute pancreatitis, skin malignan-
encountered problem is nephrotoxicity, and in many patients cyclospo- cies, and increased susceptibility to infections.
rine causes a rise in serum creatinine level and a reduction of glomerular Mycophenolate mofetil (MMF) interferes with purine metabolism
filtration rate (GFR). The mechanism of this toxicity is felt to be related as a reversible inhibitor of inosine monophosphate dehydrogenase. It
3
to vasoconstriction of the afferent glomerular arteriole. Neurologic also blocks clonal expansion of T lymphocytes. Important side effects
complications may be encountered in up to 20% of patients, and of MMF include marrow depression (especially leukopenia and throm-
include tremor, paresthesias, headache, confusion, seizures, and even bocytopenia) and diarrhea. Less common problems include esophagitis,
coma. Other complications include hypertension (which often requires gastritis, and gastrointestinal bleeding. MMF may have an advantage
treatment), hyperkalemia, tremor, hirsutism, gingival hyperplasia, and over azathioprine in preventing acute rejection. 18
glucose intolerance. Cyclosporine is metabolized by cytochrome P450-3A4 Both azathioprine and MMF are now used predominantly as an
(CYP450-3A4) enzymes. Therefore inhibitors of cytochrome P450 (eg, adjunct to corticosteroid therapy in the maintenance phase of immu-
erythromycin, fluconazole, diltiazem, and verapamil) will increase nosuppression. The major advantage of these drugs is that their use will
serum cyclosporine levels, whereas inducers of these enzymes (eg, often enable the doses of corticosteroids and even of the calcineurin
phenobarbital, phenytoin, rifampin, and trimethoprim) will decrease inhibitor to be reduced, thus avoiding some of the potential dose-related
the serum levels. Previously, trough drug concentrations were used to toxicity associated with these other agents.
on the use of peak cyclosporine levels to monitor the adequacy of ■ ANTILYMPHOCYTE ANTIBODIES
guide therapy. However, more recent recommendations have focused
immunosuppression. Ideally the dose of cyclosporine should be Antibodies directed against lymphocytes were first introduced as an
4
titrated using a biological assay or an assessment of the downstream immunosuppressive therapy as antilymphocyte globulin (ALG). This
effect of the drug on immune effector function. Such assays are under therapeutic agent was created by immunizing animals with human lym-
investigation. phocytes and subsequently purifying the antibody-containing globulin
Tacrolimus (formerly FK506) is a macrolide antibiotic with powerful fraction. ALG is very effective at depleting lymphocytes in the peripheral
immunosuppressive properties. Its mechanism of action is similar to circulation, and quickly became an important component of regimens
cyclosporine, but with enhanced potency. Tacrolimus binds to a recep- used for induction of immunosuppression and for the treatment of
tor known as FK-binding protein (FKBP), and suppresses calcineurin- acute rejection. However, it was subsequently largely replaced by OKT3,
dependent T-cell signaling. Two controlled trials comparing tacrolimus a murine monoclonal preparation directed against T lymphocytes,
5
to cyclosporine in liver transplant recipients demonstrated that tacroli- which could be used in much smaller doses because of its increased
mus reduces the incidence of acute rejection, refractory rejection, and purity. OKT3 binds to the CD3-ε chain present on all human T cells, and
6,7
chronic rejection with similar patient and graft survival. However, the causes a rapid clearance of peripheral T cells. Interestingly, it initially
drug has important toxicities. As with cyclosporine, nephrotoxicity is causes activation of T cells and the subsequent release of several lympho-
the most troublesome side effect. Important neurotoxicity (seizures, kines, including IL-2, IL-6, γ-interferon, and TNF. Rabbit antithymocyte
tremor, psychoses, posterior reversible encephalopathy syndrome, and globulin and to a lesser extent equine antithymocyte globulin are cur-
coma) may also occur with its use. Both tacrolimus and cyclosporine rently the antilymphocyte antibody preparations used most frequently
decrease insulin secretion and can lead to hyperglycemia. Interestingly, by most centers. 1
8,9
however, in renal transplant recipients who were converted from cyclo- The antilymphocyte preparations are used primarily in the induc-
sporine to tacrolimus, there was an improvement in other cardiovascular tion phase, and they have been shown to have higher success rates than
10
19
risk factors such as blood pressure and lipid profile. The gingival steroids for the treatment of acute rejection. However, these prepara-
hyperplasia and hirsutism commonly seen with cyclosporine do not tions have significant toxicity. Fever is almost always observed at the
occur with tacrolimus. Tacrolimus is also metabolized by CYP450-2A4 time of infusion. Nonetheless, the importance of careful surveillance for
enzymes, and the clinician must be cognizant of the effects other drugs infectious complications cannot be understated, as these therapies sig-
will have on its metabolism. nificantly attenuate the normal host immune response. The inflamma-
Sirolimus (rapamycin) is a drug related to tacrolimus that binds to tory response due to lymphokine production that is often seen with the
FKBP. However, in contrast to tacrolimus it does not interfere with cal- initiation of therapy usually responds to corticosteroids, antihistamines,
cineurin activity and consequently does not interfere with the activation and acetaminophen. Serum sickness has been observed with repeated
20
of cytokine genes. Its main effects are the inhibition of IL-2 produc- use of these preparations. Furthermore, when these agents (especially
tion and the suppression of T-cell proliferation. Side effects include OKT3) are administered more than once, the patient may develop anti-
thrombocytopenia, hypercholesterolemia, and hypertriglyceridemia. bodies directed against the globulin preparation that can substantially
Compared to cyclosporine and tacrolimus, the drug does not appear to limit its efficacy. Long-term use is also associated with increased risk

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