genberg.qxp 9/7/07 10:00 am Page 57
Kidney Transplantation
(Novartis International AG, Basel, Switzerland)
36
and FK778 (Astellas
Figure 2: Malignancies in Renal Transplantation – an Unmet
Pharma Inc, Tokyo, Japan)
37
both failed in early clinical trials.
38,39 Medical Need
Consequently, no clinically realistic alternative to the two CNIs
Cancer
cyclosporine and tacrolimus is currently available. Several studies
Cardiac
comparing cyclosporine and tacrolimus have been conducted, generally
Infection
showing equal efficacy of the two drugs. In a meta-analysis performed by
Other
the Cochrane library
40
in 2005, the conclusion was that tacrolimus
Vascular
50
Social
resulted in better graft function and fewer rejections, but on the other
hand was associated with an increased risk of post-transplant diabetes,
compared with cyclosporine.
40
c
ipients (%)
A major drawback when using CNIs is their dose-dependent
30
nephrotoxicity. They cause both acute afferent arteriolar vaso-
constriction, resulting in a decreased glomerular filtration rate (GFR),
and chronic vascular and tubulointerstitial damage.
41
In focus today is 20
c
e of death in transplant re
c
iden
…less immunogenic humanised
In
10
antibodies have been developed. The
0
field has expanded rapidly over the past
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
decade, and monoclonal humanised
Source: Dantal J et al., 2007
25
by permission of Oxford University Press.
antibodies now constitute the fastest-
growing class of drugs.
with the IL-2 receptor antagonists, on the other hand, is very well
tolerated and associated with fewer side effects compared with other,
therefore the development of low-toxicity protocols. In a recently commonly used antibodies. Use of these antagonists is approved for
completed trial, the Symphony study, which so far is the largest clinical induction therapy. However, although they form part of the
trial in transplantation (n=1,645), low-dose tacrolimus + daclizumab immunosuppressive protocol at numerous transplant centres, as well as
yielded a superior calculated GFR at one year and a reduced incidence in many clinical trials, the clinical benefit of these antibodies is not fully
of acute rejection compared with normal-dose cyclosporine, low-dose established. In a Cochrane analysis, a reduced incidence of acute
cyclosporine + daclizumab and low-dose sirolimus + daclizumab. All rejection was observed, but without any significant effect on patient or
study regimens also included mycophenolate mofetil and graft survival.
46
corticosteroids.
42
Newer depleting antibodies used in kidney transplantation, although
Antibody Therapeutics primarily developed for the treatment of haematological malignancies,
As induction or antirejection therapy, polyclonal rabbit and horse are rituximab (Mabthera
®
and Rituxan
®
, registered in 1997), directed at
antibodies have been in use in transplantation for several decades. These CD20 on B-lymphocytes, and the CD52 antibody alemtuzumab
include antithymocyte globulin (ATG) and antilymphocyte globulin (ALG). (Campath-1H
®
, and MabCampath
®
, registered in 1999), directed at
Although very effective, these antibodies are immunogenic, and mononuclear cells. Off-label use is widespread. Both agents induce a
treatment with them is associated with severe infusion-related reactions.
43
rapid and sustained elimination of cells expressing the target molecule
With the emergence of modern recombinant techniques, less (see Figure 3). These depleting antibodies have gained much interest.
immunogenic humanised antibodies have been developed. The field has Although the approved indication for rituximab treatment is limited to B-
expanded rapidly over the past decade, and monoclonal humanised cell lymphoma and rheumatoid arthritis, rituximab has been explored as
antibodies now constitute the fastest growing class of drugs.
44
a therapeutic option for virtually all autoimmune diseases and is used for
various indications in transplantation.
47
It is generally well tolerated and
Three monoclonal antibodies (mAbs) have been approved for use in serious side effects are rare, which in part explains its popularity. There
transplantation: the blocking interleukin-2 (IL-2) receptor antagonists are several ongoing randomised, controlled trials evaluating rituximab in
basiliximab (Simulect
®
, a chimeric mAb registered in 1998) and kidney transplantation. They include trials on rituximab as induction
daclizumab (Zenapax
®
, a humanised mAb registered in 1999) and the therapy in the treatment of rejection and in highly sensitised patients
anti-CD3 murine T-cell-depleting antibody muromonab-CD3 (Orthoclone awaiting renal transplantation as a means to reduce HLA antibodies. The
OKT3
®
, registered in 1989). other antibody, alemtuzumab, is a very potent immunosuppressive
agent
48
and depletes most mononuclear cells for a sustained period of
Muromonab-CD3 has been approved for the treatment of acute time. Its use in transplantation is rapidly increasing but has so far been
rejection. The drug is highly potent but associated with an acute and limited. Alemtuzumab is primarily used as induction therapy. Two
severe influenza-like syndrome and, at a later stage, increased risk of randomised trials have been conducted
49,50
indicating that alemtuzumab
lymphoma.
45
Its use in kidney transplantation today is limited. Treatment induction enables a reduction in maintenance immunosuppression. Other
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