Transplantation Immunology.pdf - E-Lib FK UWKS

12 Callaghan and Bradley
Table 4
Adverse Cardiovascular Risk Profiles
of Common Immunosuppressant Medications
Medication Diabetes Hypertension Hyperlipidemia
Corticosteroids +++ ++ +++
Cyclosporine ++ ++ ++
Tacrolimus +++ ++ +
Sirolimus – – +++
Within each of the three main classes of immunosuppressive drugs, the sideeffect
profiles are similar. The calcineurin inhibitors, although chemically unrelated,
are associated with hypertension, hyperlipidemia, and the development of
diabetes to varying degrees (Table 4). Of most concern are the nephrotoxic
effects of calcineurin inhibitors, which can cause permanent renal damage and
contribute to CAN. The antiproliferative agents lead to dose-related nonspecific
bone marrow suppression, and MMF causes gastrointestinal disturbances.
The debilitating side effects of steroids are well known and include osteoporosis,
cataracts, hypertension, adrenal suppression, skin atrophy, neuropsychiatric
changes, and peptic ulceration. Also, the continued use of steroids may be
associated with poorer long-term graft outcome (12). Posttransplant immunosuppressive
protocols have been developed that are entirely steroid-free (63),
but in most centers steroids are given at the time of transplantation and then
slowly tapered to the minimal required dose. In some patients steroids can be
stopped completely, but unfortunately steroid withdrawal can initiate an episode
of acute rejection, especially in black recipients (64).
A new class of immunosuppressants, the mammalian target of rapamycin
(mTOR) inhibitors, was launched in the late 1990s. The first member of the
mTOR inhibitor class to enter clinical practice was rapamycin (sirolimus,
Rapamune ® , Wyeth). The main side effects of sirolimus are hyperlipidemia
and myelosuppression. An advantage of the mTOR inhibitors is their lack of
nephrotoxicity. Cyclosporine withdrawal from a sirolimus–CyA–steroid regimen
has been shown to lead to improved graft function and reduction in hypertension
(65). There is hope that the calcineurin-sparing effects of sirolimus
may lead to decreased rates of CAN in the long-term. At present the optimal
role of sirolimus in renal transplantation is unknown and the long-term results
of trials are awaited (66).
As acute rejection rates have dropped and the number of clinically effective
immunosuppressant agents has increased, the clinical focus has moved towards
optimizing long-term outcomes and tailoring immunosuppressive regimes to