Newstead_EU_Renal.qxp 8/2/08 03:23 Page 68
Transplantation
Figure 3: Cadaver Kidney Recipients
AB
Graft surviving Patients surviving
C
Functional surviving
100 100 100
90 90 90
80 80 80
70 70 70
60 60 60
Surviving after study entry (%)
50 50 50
0 0 0
01234567 01234567 01234567
Years Years Years
Study patients (n=1,015) Controls (n=3,045)
Seven-year graft (A), patient (B) and functional graft (C) survival in renal transplant recipients after steroid withdrawal (study patients) or steroid continuation (matched controls).
19
widely adopted in clinical practice. The extrapolation from surrogate end- the development of diabetes mellitus. This is a dose-dependent risk that
points is tenuous, with those relating to graft survival – such as acute in non-renal transplant recipients rises from a relative risk of 1.77 for
rejection rate and glomerular filtration rate (serum creatinine) – favouring those receiving up to 10mg daily of prednisolone to 10.3 increased
TOR-Is, and those relating to patient survival – such as bone marrow relative risk for those receiving over 30mg of prednisolone per day.
15
suppression and dyslipidaemia – worsened by TOR-Is. Many groups have attempted to reduce the toxicity associated with
steroid use. The (late) withdrawal of prednisolone from immuno-
Of particular interest is the possibility that sirolimus substituted for suppressive regimens in renal transplantation was examined in an
ciclosporin early post-renal transplant can reduce the risk of cancer.
14
In influential review in 2000.
16
In this meta-analysis of 10 studies there was
this open-label study 430 patients – whose initial therapy was a statistically significant increased risk of graft loss (relative risk 1.38) as
prednisolone, ciclosporin and sirolimus – were randomised at three well as acute rejection (1.14%) post-steroid withdrawal. The need to
months post-grafting to have the ciclosporin withdrawn and sirolimus balance a 38% increased risk of graft loss and a 14% risk of acute
levels increased or to continue on triple therapy. At forty-eight months, rejection – and to explain that to the usually stable patient – against the
confining analysis to those in the on-treatment group, a clinically undoubted morbidity of ongoing steroid therapy has led to conservatism
significant difference in the first skin carcinoma was seen – at 5% in the in clinical practice. As with all meta-analyses, it relies on the quality of
group on sirolimus and prednisolone and 10% in those receiving the papers that were available to be studied. Critically, in only two of the
ciclosporin, sirolimus and prednisolone. By forty-eight months only studies were patients taking the antimetabolite mycophenolate as
approximately 50% of these recipients were still on this original therapy. opposed to the older agent azathioprine. In a more recent review in
If this effect is shown to be of clinical utility, the selection of TOR-Is for a 2004, six studies, all of which included mycophenolate, four with
subgroup at special risk of immunosuppressive-induced malignancy – ciclosporin and two with tacrolimus, were analysed.
17
Of note is that,
which is usually individuals who have received long-term immuno- although randomised, in no study were patients and staff blinded to the
suppression to treat glomerular disease or those who have developed steroid withdrawal. The summary risk ratio for acute rejection was 2.28
renal failure as a consequence of calcineurin inhibitor treatment (95% confidence interval 1.65–3.16). This indicates that the proportion
for another solid organ transplant or because of a now-failed renal of patients with acute rejection after prednisolone withdrawal was
allograft – is an obvious tactic in this difficult situation. significantly higher compared with those who remained on
prednisolone. However, the relative risk for graft failure in this analysis
Since the advent of renal transplantation, prednisolone has been a near- had a confidence interval that embraced zero, showing that the
constant feature of chemotherapeutic regimens, originally alone in proportion of patients with graft failure after withdrawal was not
massive doses and then in smaller doses in combination with a variety of significantly different from that observed in controls.
immunosuppressive drugs. The beneficial drug effects for transplantation
are multiple and include immunosuppression by reducing the activity and There remains caution regarding steroid withdrawal, in part because of
volume of the lymphatic system. In addition, they are powerfully anti- the results of the largest placebo-controlled study, which evaluated the
inflammatory, suppressing the migration of polymorphonuclear outcomes of 523 stable transplant recipients who, at day 90 post-renal
leukocytes and reducing the increased capillary permeability. These anti- transplant, were randomly assigned to receive either a placebo or
inflammatory effects are important and are not seen with other agents alternate-day prednisolone.
18
Importantly, poorer allograft survival
used for immunosuppression. associated with total corticosteroid withdrawal was not clear until follow-
up at five years. The difference in survival – at 73% in those withdrawn
Steroids are, however, responsible for many of the most undesirable side from prednisolone and receiving placebo and 85% in those on
effects of these drug combinations. Of particular concern is the risk of prednisolone – is both statistically and clinically significant.
68 EUROPEAN RENAL DISEASE 2007
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