Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy

Abstract

HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m , P < .001) or low CNI (difference 7.6 mL/min/1.73 m , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m and 10.1 mL/min/1.73 m , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account.

Early conversion to a CNI-free immunosuppression with SRL after renal transplantation—Long-term follow-up of a multicenter trial

“…For those patients who had remained "on therapy" GFR was even better with 66.00 ± 15.25 ml/min/1.73 m 2 . This is in accord with other publications which report that patients seem to benefit in particular when they remain "on therapy" [21,49,50]. In contrast, GFR had significantly deteriorated under CsA.…”

“…In contrast, GFR had significantly deteriorated under CsA. Although difficult to compare for existing differences regarding the mTOR-I used, medication plan and study duration, these results appear similar to other trials with "longer" follow-ups, such as the ZEUS-or HERAKLES-5-yr extension trials [21,49]. Interestingly, decrease of transplant function under CNIs seems to occur well beyond the first 5 years [33,50].…”

“…Many trials exist comparing the effects of an early switch to mTOR-Is with a CNI-based immunosuppression [18][19][20][21][22][23][24][25][26]. Irrespective of the type of the mTOR-I, most of these trials confirm an improved renal function especially in those patients who remain "on therapy" [20,21] and an efficacy rate in terms of acute rejection, graft and patient survival which is similar to that of CNIs. Besides, the rate of certain malignant and viremic diseases is reduced [27,28].…”

Pathological Characteristics of Periodontal Disease in Patients with Chronic Kidney Disease and Kidney Transplantation

“…There might be a bias in the patient selection in the study. ERL is used for CNI minimization or corticosteroid elimination due to protection from CNI nephrotoxicity or various side effects of steroid therapy, which might affect long-term graft survival or patient survival [95,96,97]. Tac has similar adverse effects as CsA because both drugs share the same pharmacological mechanism of calcineurin inhibition.…”

Infektionen unter Immunsuppression nach Nierentransplantation

“…In der Harmony-Studie zeigte sich im ersten Jahr post transplantationem kein Unterschied zwischen Rejektionsraten und Patientenüberleben zwischen steroidenthaltender und steroidfreier Basisimmunsuppression [15] Auch eine mTORi-enthaltende Basisimmunsuppression, entweder anstelle des CNIs oder anstelle des Antimetaboliten, ist möglich. Eine immunsuppressive Therapie bestehend aus einem mTORi gemeinsam mit einem niedrigdosierten CNI wurde in der Herakles- [18] und aktueller in der Transform-Studie [19] untersucht. Aufgrund einer antiviralen Wirksamkeit stellen mTORi-basierte Kombinationstherapien in bestimmten klinischen Konstellationen eine gute Option dar, worauf im weiteren Verlauf des Artikels noch eingegangen wird.…”