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Transplantation
immunosuppression has been evaluated using T-cell-depleting polyclonal Glucocorticoids freely cross the cell membrane and bind to cytoplasmic
antibodies (Thymoglobulin) or an anti-CD52 monoclonal antibody specific receptors that migrate to the nucleus, where they regulate the
(Campath-1H) combined with sirolimus but not CNIs. Unfortunately, transcription of numerous responsive genes. Glucocorticoids inhibit the
these studies have demonstrated high incidence of acute rejections and, transcription of several cytokines mediated by the nuclear factor-kB (NF-
in the patients treated with Campath, a high incidence of early humoral kB).
30
Furthermore, at a high dose they induce apoptosis of activated
rejection, suggesting that a regimen with Campath induction and T and B cells.
sirolimus does not protect from humoral rejection. The authors
concluded that CNIs could be a good option as a maintenance High-dose metilprednisolone is used as induction therapy during kidney
immunosuppressant to use following intense T-cell depletion.
26
transplant surgery with gradual tapering to a maintenance dose
(5–10mg/day) at six months. The numerous side effects – including
As sirolimus is free of nephrotoxicity it is increasingly used to replace CNIs insulin resistance, diabetes, cataracts, hypertension, hyperlipidaemia,
in patients with chronic allograft nephropathy. A meta-analysis osteoporosis and growth retardation in children – have prompted new
performed by Mulay et al.,
27
who considered five randomised and 25 immunosuppression approaches to steroid withdrawal. There have so far
non-randomised trials with a total of 2,017 patients, found that been two approaches: early and late withdrawal. Early steroid withdrawal
conversion to sirolimus was associated with improvement in renal protocols have been very successful but require antibody induction
function, probably due to CNI withdrawal, but with a high rate of therapy with daclizumab, basiliximab, alentuzumab or thymoglobuline.
31
discontinuation and side effects. There are no large clinical studies on the This is not the case for late steroid withdrawal. In fact, several studies
use of everolimus for maintenance therapy in renal transplantation. have demonstrated increased chronic allograft nephropathy and graft
However, preliminary results from a study in progress show that it may loss at three to five years after glucocorticoid cessation.
32
Thus, late
be useful in association with a reduced dose of cyclosporine as there is steroid withdrawal should be carried out carefully and only after having
no evidence of increased risk of acute rejection. Sirolimus and everolimus carefully considered the risks and benefits.
share the same common side effects: hyperlipidaemia, hyper-
triglyceridaemia, thrombocytopoenia, delayed wound healing and Conclusions
leukopoenia. Less common side effects include oral ulcers, peripheral During the last two decades immunosuppressive drug therapy for
facial oedema and non-infectious interstitial pneumonitis. kidney transplantation has evolved rapidly. Clinicians may now choose
from a variety of immunosuppressive drugs and tailor the
Corticosteroids immunosuppressive regimen to individual patients. Although CNIs and
Although largely criticised for their numerous side effects, tacrolimus remain the cornerstone of current immunosuppressive
glucocorticoids have been the mainstay of long-term immuno- therapy, newer approaches incorporating minimisation or withdrawal
suppression. Furthermore, they still have a central role in the treatment of steroids and CNIs will gradually reduce long-term complications and
of borderline to moderate acute cellular rejection (Banff grade 0–2B). preserve allograft function. ■
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