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The Ultimate Gift
A
newsletter from the transplant team
at Rhode Island Hospital
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Steroid Withdrawal
by Paul Morrissey, MD
Chronic immunosuppressive therapy places patients at risk for infections,
virally-mediated cancers, skin cancer and drug-related side effects
including hypertension, hypercholesterolemia, bone marrow suppression,
insulin resistance and a host of cosmetic alterations. Recently
interest has grown in the transplant community for steroid withdrawal
(SW) or steroid avoidance (use limited to 0-5 doses after transplantation)
as a means to improve long-term results in renal transplantation.
Unfortunately, the available data do not support this approach as
a means to prolong patient or allograft survival, limit serious
complications or other recipient morbidity. In fact, almost all
studies show a significant risk of acute rejection associated with
steroid withdrawal and some studies have shown a long-term decrement
in renal function in steroid-free patients.
Steroids were introduced into clinical transplantation in
1961 and for 22 years served as the mainstay of maintenance immunosuppression
along with azathioprine. In that era, steroid requirements were
astronomical by today's standards and the typical patient was Cushingoid,
edematous, hypertensive and prone to infectious complications. Those
whose allografts survived beyond the first year (approximately 50%
of patients) were the immunologically advantaged who eventually
required much lower doses of steroids plus azathioprine and grace
our clinics today. The introduction of newer and more powerful immunosuppressive
agents (mycophenolate mofetil (MMF), tacrolimus and cyclosporine
microemulsion (CsA-ME)) have renewed interest in SW under the presumption
that these agents provide better immunosuppression and that allograft
function should be maintained after SW. To date, SW has been evaluated
with CsA-ME/MMF, Tacrolimus/MMF, and sirolimus/CsA-ME. All of the
studies have shown a 10-30% rate of acute rejection related to SW.
A meta-analysis of the data (Kasiske B. JASN 11:1910, 2005) concluded
that SW was unwise given current rates of acute rejection. Arguably
the best of the studies was an NIH sponsored multicenter trial of
SW in stable renal transplant recipients treated with CsA-ME and
MMF. Ninety days after successful transplantation steroids were
slowly tapered to zero. The study achieved a 10% higher incidence
of acute rejection (5% controls versus 15% in SW group) and recruitment
was halted at 276 patients (goal 400 patients) by the Data Safety
Monitoring Board. Three points emerged from the study: (1) the projected
rate of AR after SW at one year was 30%, which is identical to the
rate observed in the CsA/azathioprine era, (2) antibody induction
provided no benefit in SW and (3) black patients comprised a disproportionate
number of patients with AR in the SW arm.
Thus far only one study has reported SW with no attendant AR (ref).
In this report prednisone was tapered by 1mg every 3 months from
10 mg/d. After 30 months 54/54 select patients were weaned from
steroids without AR. No study of steroid withdrawal has investigated
the long-term effects on renal allograft function. The best data
are the 3-year follow-up of SW with maintenance tacrolimus/MMF,
which show a 70% success rate for the strategy and acceptable allograft
survival. Registry data (Opelz European Registry) suggest that patients
weaned from steroids have a higher incidence of late graft loss,
presumably due to chronic allograft nephropathy.
Why are steroids being weaned? They are vastly less expensive
than newer agents and are the only immunosuppressive drug not associated
with malignancy. Steroid withdrawal, I suppose, is driven by the
attendant cosmetic deformities that patients complain of in the
clinic. While obvious initially, these effects disappear over time
and we should reassure patients that these effects are temporary
and well worth a rejection-free course. Our constant admonition
to patients that the "prednisone" is the source of all
their woes, establishes an incorrect belief that any dose of prednisone
is bad. In modern practice, the metabolic benefits of SW are limited
to accelerated growth in children. Improvements in blood pressure
and lipid profiles are minor and not sustained after one year. Changes
in cardiovascular outcomes after SW (MI, stroke, PVD) have not been
demonstrated. Furthermore, there is no evidence in the literature
that steroid elimination is better than low-dose steroids (10 mg
QOD or 5 mg/d). In contrast, it has been shown that there are no
differences in metabolic parameters in renal transplant patients
maintained on low-dose steroids versus successful SW. Furthermore,
cosmetic side effects on low dose steroids (5 mg/d, e.g.) are negligible.
Finally, in renal transplant recipients many of the complications
attributed to steroid use already exist in the patient population
by virtue of their renal failure. Patients with ESRD already have
a high prevalence of hypertension, atherosclerosis and bone disease
(osteodystrophy). These conditions are not impacted significantly
by low-dose steroids and as mentioned are not improved by SW. Steroid
therapy is often unjustly attributed as the etiology of many of
our patient's complications after transplantation.
Maintenance corticosteroids offer several potential benefits after
renal transplantation beyond the avoidance of acute rejection associated
with SW. Not mentioned are the attendant morbidities and expense
associated with the therapy of acute rejection (infections, allograft
damage, risk of chronic rejection, PTLD risk, myopathy, hyperglycemia
and lost time from work, to name a few). Steroids have been implicated
in abrogating indirect recognition (Ag presentation), antifibrotic
properties which may protect against the profibrotic effects of
calcineurin inhibitors and preventing recurrent disease (FSGS, autoimmune
diseases). Long-term effects of low dose steroid therapy, known
from the rheumatology literature, include: (1) thinning of the skin
and purpura (2) cataracts (10%) and (3) osteoporosis. However, these
effects are acceptable or treatable and do not improve significantly
with SW a strategy that places patients with a well functioning
allograft at risk for chronic allograft dysfunction and an eventual
return to hemodialysis.
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