Nephrol Dial Transplant (2001) 16 wSuppl 6x: 153–155
Immunosuppressive regimens for renal transplantation
J. D. Briggs
Renal Unit, Western Infirmary, Glasgow, UK
Introduction
The choice of immunosuppressive drugs now available
is much greater than a decade ago. This gives us
the opportunity to vary the regimen depending on the
risk of rejection and predisposition to side-effects.
A number of regimens will be discussed later in this
review but first comments will be made about the
commonly used drugs.
Available drugs
Azathioprine
Although less potent than mycophenolate mofetil,
azathioprine still has a useful role in regimens for
patients with a lower risk of rejection. Relatively high
doses in the early post-transplant period will lessen the
risk of acute rejection in comparison with lower doses
but close haematological monitoring is required w1x.
Steroids
High dose i.v. prednisolone usually in a dose of
500 mg on three successive days is well established for
the treatment of acute rejection.
The need for maintenance steroid therapy is
more controversial. There are clear advantages to
a steroid free or steroid withdrawal. On the other
hand acute rejection episodes or deterioration in renal
function have been documented following steroid
withdrawal w2x.
Cyclosporin
This drug continues to have an important role in
maintenance therapy. It has numerous side-effects.
Recent studies have shown that using AUC0–4 h to
monitor the cyclosporin dose results in much lower
early acute rejection rates when compared with
Correspondence and offprint requests to: Dr J. D. Briggs, 48 Kings-
borough Gardens, Glasgow G12 9NL, UK.
# 2001 European Renal Association–European Dialysis and Transplant Association
measurement of trough levels w3x and also that
a single cyclosporin blood level at 2 h post-dose
correlates well with the AUC0–4 h w4x. Thus, a change
to 2-h post-dose cyclosporin monitoring should lessen
acute rejection rates and may give this drug a ‘new
lease of life’ in maintenance immunosuppressive
regimens.
Tacrolimus
This drug is similar to cyclosporin in its efficacy and
side-effects as well as in its mode of action in that they
are both calcineurin inhibitors. The main difference
in the side-effect profile is that tacrolimus does not
cause hirsutism or gum hypertrophy and has a lesser
tendency than cyclosporin to raise the serum choles-
terol. However, it is more likely than cyclosporin to
precipitate diabetes and it may cause tremor. Most
reports suggest that its use is associated with a lower
frequency of acute rejection but similar graft survival
to cyclosporin w5x. However, almost all the published
comparisons have involved sandimmun which is less
effective than the currently used microemulsion
(Neoral) and with cyclosporin monitoring by means
of trough levels rather than the recently advocated 2-h
post-dose level. Only preliminary data is available
comparing tacrolimus with Neoral and this has shown
no difference between these two drugs in the frequency
of acute rejection episodes w6x.
Mycophenolate mofetil (MMF)
This is a potent immunosuppressive agent which has to
a considerable extent replaced azathioprine in triple
drug regimens. Multicentre studies have shown an
acute rejection incidence of just under 20% in MMF
treated patients compared with a figure of around 40%
among patients receiving azathioprine w7x. Although
MMF has a reputation for a high incidence of gastro-
intestinal side-effects, the rate of withdrawal of MMF
resulting from adverse events has been only marginally
higher than in azathioprine-treated patients when
a daily dose of 2 g of MMF was used w7x. MMF
probably has a number of roles. The main one is
in a maintenance triple therapy regimen. However
154
it will probably be increasingly used as the mainstay
of immunosuppression following the withdrawal of
cyclosporin or tacrolimus in the setting of calcineurin
inhibitor nephrotoxicity or chronic allograft nephro-
pathy of less well defined cause w8x. Also, it has been
demonstrated that MMF may reduce the risk of
patients developing chronic allograft nephropathy
independent of its effect in reducing the incidence of
acute rejection w9x but this observation has still to be
confirmed. A further role could be as an adjunct to
prednisolone in the treatment of acute rejection
episodes and here initial observations have been
encouraging w10x. One study has suggested that by
monitoring MPA AUC one can detect patients with
an inadequate dose w11x.
IL-2 receptor antagonists
Polyclonal antibody preparations such as ATG and
ALG are now needed much less for acute rejection
prophylaxis and OKT3 also less in its treatment.
However the newer monoclonal antibodies which
are directed against the IL-2 receptor (IL-2R) have
a potentially useful role in prophylaxis. The prepara-
tions now available are either chimeric such as
Basiliximab or humanized such as Daclizumab. Both
have the same level of efficacy with an acute rejection
rate between 30 and 40% less than in control groups
w12,13x. Experience so far suggests that adverse effects
are uncommon.
Rapamycin
This drug binds to the protein ‘mammalian target
of rapamycin’ (mTOR) and the end result is inhibi-
tion of both T and B cells by means of a number of
pathways. Prospective studies, such as the one con-
ducted by the Rapamune US Study Group have shown
a substantial reduction in the frequency of acute
rejection when rapamycin has been compared with
azathioprine in patients also receiving cyclosporin
w14x. With a 2-mg daily dose of rapamycin, the acute
rejection rate was 43% lower and with a 5-mg dose,
60% lower. When rapamycin has been given instead of
cyclosporin in triple drug regimens containing also
steroids and azathioprine or steroids and MMF, the
frequency of acute rejection episodes has not been
significantly less in the rapamycin groups w15x. How-
ever, renal function was superior in the rapamycin-
treated patients. The main toxic effect of rapamycin
reported so far has been hyperlipidaemia but this effect
would seem to lessen with time and at the end of the
first year in one study the serum triglyceride and
cholesterol levels were not significantly higher than in
the cyclosporin-treated group w15x. Its other reported
adverse effects include myelosuppression which has so
far been uncommon in clinical practice and the risk of
over-immunosuppression. It would seem highly likely
that rapamycin will become established as an effective
immunosuppressive agent. What is less certain is how
it can best be used.
J. D. Briggs
Maintenance immunosuppression regimens
The number of drugs now available allows us to
choose different regimens depending on the clinical
setting such as the degree of risk of rejection and we
can also more effectively change the regimen in the
post-transplant period as circumstances demand.
I have arbitrarily divided the risk of rejection into
low, medium, and high, and I have also recommended
regimens for rescue therapy in acute rejection and for
patients with chronic allograft nephropathy.
Low-risk recipients
Included in this group would be patients of older age,
i.e. over 60 years, those with good renal function and
freedom from rejection several years post-transplant,
and recipients of HLA identical sibling kidneys.
A suitable regimen for such patients would consist
of azathioprine and cyclosporin, with prednisolone
withdrawal for the established transplant.
Medium-risk recipient
These would include recipients of one haplotype match
live donor kidneys and cadaver transplants with a
good HLA match in recipients who are not sensitized
to HLA antigens. A suitable regimen for such patients
would consist of low dose prednisolone, MMF and
cyclosporinutacrolimus.
High-risk recipient
These would include patients who are ‘highly
sensitized’ patients receiving a third or subsequent
transplant and recipients of unrelated live donor
kidneys. A suitable regimen for such patients would
consist of low-dose prednisolone, MMF and
tacrolimus with or without an IL-2R inhibitor.
‘Rescue’ therapy for acute rejection
In cyclosporin-treated patients, it is often helpful to
switch to tacrolimus should an acute rejection episode
prove severe or steroid resistant. Alternatively, if MMF
is not already part of the regimen, the addition of this
drug may be worthwhile w10x. A final step, should these
measures prove ineffective, would be to give a course
of OKT3.
Chronic allograft nephropathy
There is not yet clear evidence that any immuno-
suppressive regimen is effective in this setting. How-
ever, there is always the possibility that nephrotoxicity
is contributing to the renal dysfunction in patients
diagnosed as having chronic nephropathy. Thus,
until our knowledge of this condition improves, a
Immunosuppressive regimens for renal transplantation
reasonable policy is to substitute MMF or rapamycin
for cyclosporin or tacrolimus.
Finally I have not attempted to assign a role for
rapamycin in the various regimens outlined above as
I do not think we yet have enough experience of the
drug to know in what circumstances it is most useful.
In conclusion, the availability of a variety of drugs
enables different choices in order to improve both graft
and patient survival.
References
1. Bergan S, Rugstad HE, Bentdal O et al. Monitored high-dose
azathioprine treatment reduces acute rejection episodes after
renal transplantation. Transplantation 1998; 66: 334–339
2. Ratcliffe PJ, Dudley CRK, Higgins RM, Fifth JD, Smith B,
Morris PJ. Randomised controlled trial of steroid withdrawal in
renal transplant recipients receiving triple immunosuppression.
Lancet 1996; 348: 643–648
3. Mahalati K, Belitsky P, Sketris I, West K, Panek R. Neoral
monitoring by simplified sparse sampling area under the
concentration-time curve. Transplantation 1999; 68: 55–62
4. Cantarovich M, Barkun JS, Tchervenkov JI, Besner J-G,
Aspeslet L, Metrakos P. Comparison of Neoral dose monitor-
ing with cyclosporin trough levels versus 2-hr postdose levels in
stable liver transplant patients. Transplantation 1998; 66:
1621–1627
5. Knoll GA, Bell RC. Tacrolimus versus cyclosporin for
immunosuppression in renal transplantation: meta-analysis of
randomized trials. Br Med J 1999; 318: 1104 –1107
6. Morris-Stiff G, Ostrowski K, Balaji V et al. Prospective random-
ised study comparing tacrolimus (Prograf ) and cyclosporin
155
(Neoral) as primary immunosuppression in cadaveric renal
transplants at a single institution: interim report of the first 80
cases. Transplant Int 1998; 11 wSuppl 1x: S334–S336
7. Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L,
Barker C. Mycophenolate mofetil in renal allograft patients.
Transplantation 1997; 63: 39–47
8. Ducloux D, Fournier V, Bresson-Vautrin C et al. Myco-
phenolate mofetil in renal transplant recipients with cyclo-
sporin-associated nephrotoxicity. Transplantation 1998; 65:
1504 –1506
9. Ojo AO, Meier-Kriesche H-U, Hanson JA et al.
Mycophenolate mofetil reduces late renal allograft loss
independent of acute rejection. Transplantation 2000; 69:
2405–2409
10. Mycophenolate mofetil acute renal rejection study group.
Mycophenolate mofetil for the treatment of a first acute renal
allograft rejection. Transplantation 1998; 65: 235–241
11. van Gelder T, Hilbrands LB, Vanrenterghem Y et al. A
randomized double-blind, multicentre plasma concentration
controlled study of the safety and efficacy of oral myco-
phenolate mofetil for the prevention of acute rejection
after kidney transplantation. Transplantation 1999; 68: 261–266
12. Nashan B, Moore R, Amlot P, Schmidt A-G, Abeywickrama K,
Soulilou J-P. Randomised trial of Basiliximab versus placebo for
control of acute cellular rejection in renal allograft recipients.
Lancet 1997; 350: 1193–1198
13. Vincenti F, Kirkman R, Light S et al. Interleukin-2-receptor
blockade with Daclizumab to prevent acute rejection in renal
transplantation. N Eng J Med 1998; 338: 161–165
14. Kahan BD. Efficacy of sirolimus compared with azathioprine
for reduction of acute renal allograft rejection: a randomised
multicentre study. Lancet 2000; 356: 194–202
15. Morelon E, Mamzer-Bruneel M-F, Peraldi M-N, Kreis H.
Sirolimus: a new promising immunosuppressive drug. Towards
a rationale for use in renal transplantation. Nephrol Dial
Transplant 2001; 16: 18–20