Everolimus in Kidney Transplantation: HERAKLES trial

Many studies have been conducted with the intention of reducing exposure to calcineurin inhibitors. Avoiding calcineurin inhibitors is expected to improve long term graft outcome by avoiding CNI nephrotoxicity. MTOR inhibitors (everolimus and sirolimus) have been used to minimize CNI exposure. Most studies reveal an improvement in GFR when comparing patients on MTOR inhibitors to those on CNIs at 1-3 years. One such study was the ZEUS trial where patients on cyclosporine and mycophenolate were randomized at 4.5 months to switch to either everolimus or continue CNI-based therapy. The HERAKLES trial, presented by Dr. Zeier from Nuremberg Germany, is a similar trial comparing utilizing everolimus.

In this trial 499 patients who were transplanted with basiliximab induction and cyclosporine (CSA), prednisone and mycophenolate (MPA) were randomized at 3 months to either continue CSA-based therapy, convert to everolimus and MPA (CNI free) or everolimus and low dose CSA. Patients had preserved GFR, were low risk, and had less than 1gm of proteinuria. At 1 year post transplant kidney function was better in the CNI free group compared to the other two groups. This difference persisted at 24 months (4.8 mL higher at 24 months follow-up). There was no significant difference between death or graft loss between groups. Biopsy proven acute rejection occurred in 12% of the standard CSA group, 14% of the CSA free group, and 12% of the low dose CSA/everolimus group. There was also no difference in adverse effects and infections (including BK virus infection).

So the data looks pretty good for an everolimus CNI free regime. Problems with the trial however include relatively short follow up, and frequent conversion to tacrolimus in all groups. Of note, a per protocol analysis was not presented. Finally, as the chair of the session noted, it is still not clear if the improved GFR in the everolimus group is simply due to the loss of CSA’s hemodynamic effect on GFR or a paranchymal difference. Only studies looking at renal histology or those measuring the slopes of GFR over long-term follow-up can answer these questions.

Post written by Dr. Vinay Nair, eAJKD Advisory Board member.

Check out all of eAJKD’s coverage of the 2013 American Transplant Congress.