Steroid use in Kidney Transplantation – The Hope of Harmony

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Presently, death with a
functioning graft is one of the most important causes of kidney transplant
failure with the leading cause of death being from cardiovascular events.
Withdrawing or avoiding steroids to improve cardiovascular outcomes is a
controversial issue.
Most patients receiving a renal
transplant will have long term immunosuppression regimes including tacrolimus,
mycophenolate and corticosteroids, as per the ELITE-Symphony
trial.  Corticosteroids
have been used since the beginning of organ transplantation to reduce the risk
of acute rejection. However their use is well known to cause insulin resistance
and increasing cardiovascular risk and clearly there is a balance to be struck.
Avoidance or early cessation of corticosteroids post-transplant is an
attractive option. A trial
of 386 patient randomized to withdrawal at 7 days or continuation of steroids
showed improved metabolic parameters (triglycerides, gained less weight) at the
expense of more acute rejection and more worryingly, chronic allograft injury.
A Cochrane
review
published in 2016 concluded that both avoidance and early withdrawal
of steroids substantially increases the risk of acute rejection by 58% and 77%
respectively, without long term benefits in mortality or side effects, such as
infection or diabetes. The review therefore concluded that steroids should be
part of long term immunosuppression in all but specific subgroups of patients.
The HARMONY
trial, published in January 2017, cast the spotlight on this subject again.
This open-label, European, randomised controlled trial was set up and powered
to investigate whether induction therapy with rabbit Anti-Thymocyte Globulin
(ATG) was superior to basiliximab with respect to frequency of biopsy proven
acute rejection rates in the situation of rapid steroid withdrawal. Patients were
predominantly on their first transplant and had low immunological risk.  The study had three arms with patients
randomly assigned to:
  •        Basiliximab,
    tacrolimus, MMF and steroid maintenance
  •        Basiliximab,
    tacrolimus, MMF and steroid withdrawal on day 8
  •        Rabbit
    ATG, tacrolimus, MMF and steroid withdrawal on day 8.

Acute rejection rates were low
(10-11%) and comparable between all three study arms at 12 months. The study
therefore concluded that rapid steroid withdrawal was possible without ATG
induction in this low risk setting. Furthermore, there was significantly lower
rates of NODAT in the two rapid steroid withdrawal groups; Arm A 39.%, Arm B
23.9%, Arm C 22.7% [p=0.0004]. It has to be noted that the rates of NODAT in
the control group were considerably higher than those found in the
ELITE-Symphony trial and probably reflects the active investigation for NODAT
in this trial as opposed to the self-reporting method used in ELITE-Symphony
(see NephJC
coverage of HARMONY).

It has yet to be seen whether
these results translate into longer term reduced cardiovascular risk and
mortality. Also as follow-up was only 1 year and late graft injury is a concern
with steroid withdrawal, we eagerly await the longer term results of this
trial. For now this trial has challenged previous evidence and provided hope
that steroid free immunosuppression is possible, and perhaps beneficial, in a
low risk setting.
Post by Anna Kolb, Nephrology Fellow at Royal Infirmary of
Edinburgh

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