Steroid use in Kidney Transplantation - The Hope of Harmony

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