Immunosuppressive therapy

The evolution of immunosuppressive regimens over the past few decades has led to considerable improvement in acute rejection rates and short-term graft survival [1]. Patient and graft survival at 1 year post-transplantation now exceed 95% in the case of living donation and 90% after deceased donation. However, the long-term outcomes post kidney transplantation do not show a similar trend of improvement. At 10 years, graft survival remains about 50% after deceased donation in the US and in Europe, with approximately 30% of patients returning to dialysis and one of four patients dying with a functioning graft [1,2]. The lack of improvement in long-term outcomes is further reflected by the fact that the number of re-transplants among adult kidney transplant patients has remained almost unchanged over the last decade [1].
Currently, calcineurin inhibitors (CNIs), cyclosporine, and tacrolimus are the cornerstone of immunosuppressive therapy post kidney transplantation [1]. However, their long-term use may be associated with non-reversible nephrotoxicity, morphologically characterized by striped fibrosis, progressive arteriolar hyalinosis, and ischemic glomerulosclerosis, which is a well-recognised cause of morbidity in transplant patients [3-5]. Chronic allograft injury alone accounts for two-thirds of kidney graft failures [6]. Clinical data has shown that lowering the dose of CNI can improve renal function [5-7]. In this regard, the focus should be on optimising the currently available immunosuppressive regimens with the aim of preserving long-term renal function while maintaining the efficacy [8]. Several studies with a reduced-dose CNI and everolimus regimen have shown that it maintained efficacy and preserved renal function (table 1) [9-33]. In the large randomised A2309 trial, pre-emptive everolimus therapy was associated with a >60% reduction in cyclosporine exposure while preserving renal function with comparable efficacy to mycophenolic acid and standard-exposure cyclosporine in de novo kidney transplant patients [16,17]. In the ASSET study, an everolimus-facilitated tacrolimus minimisation strategy achieved good renal function with an acceptable safety profile without compromising efficacy [23]. Moreover, everolimus exerts other non-immunosuppressive properties, including potential cardioprotective, anti-malignancy, and antiviral effects [34-41]. These non-immunosuppressive benefits further suggest that everolimus-based regimens may be a preferred approach as cardiovascular disease, malignancy, and infections account for nearly four out of the five deaths occurring with functioning grafts [6].
The ATHENA trial is designed to further increase our knowledge and seek answers relating to the use of everolimus in CNI minimisation protocols in de novo kidney transplant patients. The ATHENA study assesses the change in renal function at 12 months post-transplant as the primary objective. The design of the trial is described here.

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