Abstract
BackgroundConversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation.MethodsBiopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids.ResultsAt least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively.ConclusionsThis analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy.Trial registrationClinicalTrials.gov NCT00154310. Date of registration: September 12, 2005.
Highlights
Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR)
Study design and patient population ZEUS was a 12-month multicenter, open-label, parallelgroup trial in which kidney transplant recipients were randomized at 4.5 months post-transplant to convert to everolimus or remain on CsA therapy (NCT00154310)
The 12-month core study was completed by 269 patients (138 everolimus, 131 CsA) and the five-year visit was attended by 232 patients (123 everolimus, 109 CsA) (Additional file 1: Figure S1)
Summary
Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). The graft, is subject to multiple insults which can lead to irreversible nephron loss and progressive dysfunction, but this typically occurs relatively late such that graft function is a poor marker for the severity of histological changes. These include early tubulointerstitial damage from ischemia-reperfusion injury, acute and subclinical rejection, calcineurin inhibitor (CNI)-related nephrotoxicity, and viral infections [1]. IF/TA is associated with reduced survival, in the presence of inflammation [9]
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