Newstead_EU_Renal.qxp 28/2/08 12:54 Page 66
Transplantation
Current Trends in Immunosuppressive Strategies After Renal Transplantation
a report by
Charles Newstead
Consultant Renal Physician, St James’s Hospital, Leeds
The prognosis for graft survival following renal transplantation in the particular patient. A second general point is that, in the past, as new
modern era is very impressive. This is well illustrated by Figure 1, from immunosuppressive agents were developed the approach was generally
the Collaborative Transplant Study, which is a voluntary registry to add them to existing regimens while reducing the dose of the older
collecting data from participating units across the world. Although agents. Many patients received a calcineurin inhibitor as well as anti-T-cell
there is likely to be some positive selection bias, the number of antibodies, or an antimetabolite as well as prednisolone. Currently,
patients whose data are analysed must mean that the results reflect however, there is substantially more interest in reducing the
current experience. As Figure 1 illustrates, there is a trend of early graft immunosuppressive burden and attempting drug withdrawal.
loss so that by six months post-grafting graft survival is approximately
93%, and after the end of the first year approximately 3% of grafts The introduction of ciclosporin A into clinical practice in the early 1980s
are lost annually. transformed the discipline of transplantation. Its use was coincident with
much improved renal allograft survival and it changed the experience of
This good performance means that it has become increasingly difficult to the early clinical care of recipients from a situation of great uncertainty to
demonstrate any impact of new immunosuppressive agents (or one in which management was much more predictable. The drug in
combination of agents) on graft survival. In part, this is because only a effect allowed heart, lung, heart–lung, pancreas and liver transplantation
proportion of graft losses is due to an immunologically mediated to move from a near-experimental status to a realistic clinical option.
‘rejection process’. It has become necessary to focus on early proxy There was also a substantial impact on haemopoietic cell transplantation
measures that influence either graft survival – such as the rate of acute as well as on a number of non-transplant applications, which have
rejection – or factors such as dyslipidaemia or hypertension, which are subsequently become established as the standard of care.
likely to influence patient survival in the long term. As well as these
quasi-hard end-points, there has been increasing interest in exploring the The other calcineurin inhibitor available is tacrolimus. Unfortunately, both
drug-associated side effects as well as other influences on the patient’s drugs share two particularly troublesome side effects: nephrotoxicity and
compliance with the invariably complex treatment regimens. In the large, hypertension. In common with all immunosuppressive agents, they
pivotal, randomised controlled studies that form the basis for regulatory increase the risk of infection and malignant disease. A number of other
approval of the majority of immunosuppressive drugs used in chronic important side effects are seen more frequently with either ciclosporin or
management, the rate at which patients discontinued the studies tacrolimus. The dose of drug for an individual has to be determined by
because of side effects varied from 3 to 17%.
1–3
These proportions may therapeutic drug-level monitoring and many of the side effects as well as
not reflect current experience as in trials any new symptoms are likely to the efficacy are proportional to the drug levels. This has meant that
be attributed to the ‘trial drug’, and so exaggerate the apparent side- comparing the two agents has been difficult, as target drug levels will
effect profile. However, there is little doubt that morbidity associated critically influence the immunosuppressive efficacy with consequences,
with therapy is considerable. for example, on the rate of acute rejection.
In the rest of this commentary I will draw attention to some of the critical In my opinion the best direct comparison of the two drugs was published
issues currently influencing immunosuppressive strategies in renal in The Lancet in 2002 as the study size was adequate and drug levels
transplant units. I will not cover agents used off-label, nor will I discuss during the first three months – during which virtually all the acute
agents that are not in widespread clinical use. rejection that was seen occurred – was similar to those targeted by the
majority of units, at approximately 12ng/ml for tacrolimus and 250ng/ml
One key theme is that clinicians are now better placed than ever before for ciclosporin.
4
Figure 2 shows the key result of the frequency of biopsy-
to offer evidence-based tailoring of immunosuppressive therapy to fit any confirmed acute rejection against time for patients treated with the two
drugs. As seen in the chart, the rate of acute rejection in the tacrolimus-
treated patients was half that in those treated with ciclosporin.
Charles Newstead has been a Consultant Renal Physician at
St James’s Hospital in Leeds and Honorary Lecturer at the
University of Leeds since 1994. He is also Clinical Director
In 2005, the Cochrane Renal Group published a meta-analysis and meta-
and Head of the Clinical Management Team (Head of
regression analysis of randomised trial data for tacrolimus versus
Service) for Renal Services in the Leeds Teaching Hospitals
Trust. He has been Chair of the Standards Committee of the ciclosporin as primary immunosuppression for renal transplant
British Transplantation Society (BTS) for over a decade.
recipients.
5,6
They included 123 reports from 30 trials (4,102 patients). At
E: chas.newstead@leedsth.nhs.uk six months, graft loss was roughly halved (relative risk 0.56, 95%
confidence interval 0.3–0.86) in tacrolimus- versus ciclosporin A-
66 © TOUCH BRIEFINGS 2007
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