Newstead_EU_Renal.qxp 8/2/08 03:22 Page 67
Current Trends in Immunosuppressive Strategies After Renal Transplantation
treated recipients. At one year, tacrolimus-treated patients had less acute
Figure 1: Early Graft Survival for Renal Transplants
rejection (relative risk 0.69, 0.60–0.79) and less steroid-resistant rejection
(relative risk 0.49, 0.37–0.64). In the direct comparison shown in the
100 Transplant year
Kidney transplants
Marguerita study, hypertension, hirsutism and gum hyperplasia were
90
significantly more common in ciclosporin-treated patients and tremor in
the tacrolimus-treated group.
4
De novo insulin-treated diabetes was more 80
common at five of 286 patients in the tacrolimus group compared with
al %
70
two of 271 patients in the ciclosporin-treated group – not a statistically
significant result but one that is clinically significant. The Cochrane review
60
Graft surviv
reinforces this, with insulin-requiring diabetes (relative risk 1.86,
1.11–3.09) as well as diarrhoea, dyspepsia and vomiting significantly
50
2001–2005 (n=62,156)
1996–2000 (n=69,038)
more common in tacrolimus-treated patients. Constipation and ‘cosmetic
1991–1995 (n=74,166)
0 1985–1990 (n=80,856)
side effects’ were more common in those treated with ciclosporin A. The
0123456
Cochrane review summarises by calculating that treating 100 patients
Years
with tacrolimus instead of ciclosporin would avoid 12 suffering acute A striking improvement in performance is seen with time. Data published February 2007.
rejection and two losing their graft, but would cause an extra five to
Figure 2: Proportion of Patients Free from Biopsy-confirmed
become insulin-requiring diabetics.
Acute Rejection
4
Full T-cell activation leads to the calcineurin-mediated stimulation of the
100
transcription translation of secretion of interleukin-2 (IL-2). This is an
p<0.0001
90
autocrine growth factor that induces further T-cell proliferation.
80
Blocking the IL-2 surface receptor on lymphocytes is therefore a very 70
attractive therapeutic strategy. There are two available monoclonal
60
antibodies directed against the IL-2 receptor: daclizumab and
50
basiliximab. They are administered intravenously peri-operatively and
40
acute rejection (%)
30
then at intervals in the early post-transplant period. They have a
20
substantial advantage compared with all of the other immuno-
Proportion free from biopsy-confirmed
10
suppressive agents in that they are extremely well tolerated. Because of
0
the route of administration they have the additional advantage that
0 728 61 91 183
compliance with therapy is guaranteed. The two agents have no
Time since transplantation (days)
Number at risk
important difference in performance, with an absolute reduction in the
Tacrolimus 286 259 229 220 214 204
Ciclosporin 271 227 164 152 415 141
risk of (early) acute cellular rejection of 15% (16% for daclizumab and
Tacrolimus Ciclosporin microemulsion
14% for basiliximab) with 95% confidence intervals of 24–28% and
20–29%, respectively. The odds ratio for acute rejection was reduced
Note rate of rejection approximately half in the tacrolimus-treated group compared with the
by 50% so, in effect, this was halved by the agents, with confidence
ciclosporin-treated group.
intervals of approximately 35–65%.
7–10
there was no difference in acute rejection when TOR-Is were substituted
There are two drugs – sirolimus and everolimus – currently used in for calcineurin inhibitors. However, serum creatinine was lower, indicating
transplantation practice that are target-of-rapamycin inhibitors better renal function. Relative risks and odds ratios were used to present
(TOR-Is). These drugs bind to an intracellular immunophilin, the same one dichotomous variables – such as presence or absence of rejection – and
as tacrolimus. However, instead of inhibiting calcineurin, this drug weighted mean for continuous variables – such as serum creatinine. The
receptor complex then binds to proteins known as ‘mammalian targets of weighted mean difference was an improved serum creatinine of
rapamycin’. This causes inhibition of a papillary functional serine- 18.3µmol/l (95%, confidence interval 3.1–5.7) in those treated with
threonine kinase, thus – critically – preventing both DNA and protein sirolimus/everolimus compared with a calcineurin inhibitor. This would be
synthesis, resulting in arrest of the cell cycle. It has been hard to define considered by most to be a clinically significant improvement in
satisfactorily the best use of this novel class of drugs. Of particular interest performance. However, the bone marrow was more suppressed, with
was the early concept that these agents would be non-nephrotoxic. This leucopoenia at a relative risk of 2.02 (1.12–3.66); thrombocytopoenia at a
has subsequently been shown not to be the case, with the agents relative risk of 6.97 (2.97–16.36); and, particularly clinically significant,
certainly contributing at least to the prolongation of delayed graft anaemia at a relative risk of 1.67 (1.2–2.20).
function. However, the level and degree of nephrotoxicity is less
profound than that seen with the calcineurin inhibitors.
11
When TOR-Is replaced antimetabolites – mycophenolate and
azathioprine – acute rejection (relative risk 0.84, 0.71–0.99)
The Cochrane Renal Group has again carried out a relatively recent review and cytomegalovirus (CMV) infection (relative risk 0.49, 0.37–0.65) was
of all randomised and quasi-randomised controlled trials involving TOR-Is reduced, but hypercholesterolaemia increased (relative risk 1.65,
in the immediate post-transplant period in renal recipients.
12,13
Thirty-three 1.32–2.06). The authors attempted to summarise the results of varying
trials with just over 7,000 patients examined the replacement of TOR-Is the dose of both TOR-Is and calcineurin inhibitors, but the results of these
with calcineurin inhibitor, and one of the studies – with only studies are, in my view, very difficult to evaluate and it is striking that
28 participants – directly compared sirolimus with everolimus. Overall, these combinations (at whatever dose regimen) have not, to date, been
EUROPEAN RENAL DISEASE 2007 67
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