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Immunosuppressive Drugs After Renal Transplant
demonstrated the same efficacy but also the same side effects of interfere with the same signalling pathway involved in the transcription
polyclonal antibodies, including the risk of lymphoproliferative disease of several cytokines. Cyclosporine binds to cyclophyllin protein while
(PTLD).
12
Its use peaked in 1993, when it was the only antibody tacrolimus binds to FK-binding proteins on the same pathway. The
administered for induction in 23% of patients. OKT3 and polyclonal bioavailability of cyclosporine, but not that of tacrolimus, varies
antibodies have been almost completely replaced in clinical practice by markedly between different formulations, although the newer modified
monoclonal IL-2R receptor antibodies. cyclosporine (Neoral) has a better bioavailability. With increasing
evidence of renal injury (leading to reduced renal function) caused by
Interleukin-2 Receptor Antagonist Antibody Therapy cyclosporine, tacrolimus has been used primarily as rescue therapy and
The recognition that interleukin-2 (IL-2) plays a central role in the antigen- later as a first-choice CNI.
19,20
However, apart from side effects such as
specific T-cell clonal proliferation has prompted the development of hyperlipidaemia, hypertension, hyperglycaemia, gingival hyperplasia,
monoclonal antibodies able to bind to the IL-2 receptor also known as hirsutism and tremors, CNIs have been identified as an important non-
CD25. Basiliximab and daclizumab, respectively chimeric and humanised immunological cause of the development of chronic allograft
IL-2R receptor antibodies, proved to be very effective in reducing nephropathy and risk factors for cardiovascular events.
21
These
rejection episodes.
6,7
Patients treated with daclizumab as induction considerations have led to the development of new CNI-free
therapy in association with tacrolimus, mycofenolate mofetil and steroids therapeutic approaches to renal transplantation.
as maintenance therapy demonstrated a very low rejection rate at 18
months.
13
Both monoclonals produced effective immunosuppression, Antiproliferative Agents
sparing recipients the side effects common with polyclonals and reducing Azathioprine (AZA) was the only antimetabolite available in 1993 and
the incidence of complications of immunodeficiency. A major difference was used in combination with steroids and cyclosporine in 86% of kidney
in clinical use between daclizumab and basiliximab is the dose and transplant recipients. By 2002 its use had decreased to 2%.
frequency of administration. Basiliximab is administered in a fixed dose at Mycophenolate mofetil (MMF) and the newer mycophenolic acid have
days zero and four after transplantation, whereas daclizumab is largely replaced AZA in current immunosuppression protocols. Both MMF
administered at 1mg/kg for a total of five doses. This is the major reason and AZA act by inhibiting DNA synthesis. MMF inhibits the de novo
for the limited clinical use of daclizumab. purine synthesis in lymphocytes by blocking the enzyme inosine
monophosphate dehydrogenase (IMPDH). AZA inhibits the same enzyme
Daclizumab and basiliximab have been successfully used as induction and also the synthesis of adenosine monophosphate. Both drugs are used
therapy in immunosuppression regimens that spare steroids and in combination with steroids and CNIs. Common side effects include
minimise calcineurin inhibitors. Borrows et al. withdrew steroids as early leukopoenia and infection. MMF may also induce dose-related
as seven days after kidney transplantation when daclizumab or gastrointestinal symptoms, while AZA may induce hepatitis and
basiliximab induction therapy was added to a regimen including squamous and basal cell skin cancer. The most popular combination
tacrolimus, mycophenolate and steroids in high immunological risk regimen currently utilised in the majority of kidney transplant patients
recipients;
14
excellent results have been reported with the use of IL-2R includes tacrolimus and MMF. This regimen has been shown to be
receptor monoclonal antibodies in regimens minimising or avoiding effective in reducing rejection episodes and preserving renal function in
calcineurin inhibitors.
15,16
several randomised trials.
20,22
Maintenance Immunosuppression Therapy Mammalian Target of Rapamycin Inhibitors
After transplantation the goal is to prevent rejection over the patient’s Sirolimus (rapamycin) and everolimus are mammalian target of rapamycin
lifetime with a combination of immunosuppressive drugs. However, since (mTOR) inhibitors that block signal transduction in the IL-2 pathway from
the leading causes of late graft loss are chronic allograft nephropathy, binding to mTOR protein and inhibiting cell proliferation. Sirolimus has
death with a functioning graft (primarily as a result of post-transplant also been seen to inhibit angiogenesis and smooth muscle cell
cardiovascular disease) and non-compliance with immunosuppressive proliferation effects. This makes the drug useful in preventing
drugs, current immunosuppressive regimens have been designed to atherosclerosis and tumour growth.
23
A multicentre study comparing
minimise or withdraw steroids and calcineurin inhibitors. The large sirolimus/cyclosporine with AZA/cyclosporine or placebo/cyclosporine in
number of immunosuppressive drugs currently available allows the kidney transplant recipients also treated with steroids showed that the
transplant clinician to tailor the immunosuppressive regimen to each addition of sirolimus significantly increased serum creatinine, particularly
patient, decreasing doses and side effects and minimising risk factors. with higher-dose sirolimus.
24
Sirolimus has thus been used in
We will briefly evaluate each of the immunosuppressive drugs currently immunosuppression regimens to replace CNIs. In the sirolimus
used and the different approaches and therapeutic trends. Tricontinental Trial, patients were assigned a triple therapy regimen of
cyclosporine, sirolimus and steroids. At three months patients were
Calcineurin Inhibitors randomly bisected, either continuing the regimen or beginning treatment
In 1993 the majority of patients undergoing kidney transplantation with higher-dose sirolimus and cyclosporine withdrawal. At 36 months
received cyclosporine and only 2% tacrolimus, not yet approved by the renal function was improved and blood pressure was lower in the
US Food and Drug Administration (FDA). Nowadays, the trend has been cyclosporine elimination group. Furthermore, there was no difference in
completely reversed, with cyclosporine down to 30% or less. Most the rate of acute rejection between the groups.
25
In both groups, but
common maintenance regimens consist of a calcineurin inhibitor particularly in the sirolimus/steroid group, there was a high
(cyclosporine or tacrolimus), an antiproliferative agent (mycophenolate, discontinuation rate with several side effects such as abnormal wound
azathioprine or sirolimus) and steroids.
17
CNIs have reduced healing, thrombocytopoenia, hypokalaemia and abnormal liver function
dramatically the incidence of acute cellular rejection.
18
Both CNIs tests. More recently, the possibility of minimising maintenance
EUROPEAN RENAL DISEASE 2007 71
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