Steroid-free immunosuppression in kidney transplantation

Abstract

Background: Steroids have been successfully used in kidney transplantation for six decades as part of different immunosuppressive protocols. To date, the most frequently used regimen is a combination of tacrolimus, mycophenolate mofetil and prednisolone (a steroid drug), preceded by antibody induction. Chronic use of steroids, however, has several serious side effects, such as diabetes mellitus, weight gain, hypertension, hyperlipidemia, associated with increased cardiovascular risk, and negative impact on patient and graft survival. This thesis evaluates whether a steroid-free immunosuppressive regimen reduces the early onset of posttransplantation diabetes mellitus (PTDM) and assesses the long-term efficacy, safety, and sustainability of this approach. Methods: An open-label multicenter randomized controlled trial, the SAILOR trial, compared two immunosuppressive strategies in kidney transplant recipients with low immunologic risk: 1. Steroid avoidance-arm i.e., without prednisolone, based on low-dose tacrolimus and mycophenolate mofetil together with antithymocyte globulin induction; 2. Steroid maintenance-arm with prednisolone, low-dose tacrolimus and mycophenolate mofetil together with basiliximab induction. Paper I detailed the study design and clinical trial protocol of the randomized controlled trial, and provided the theoretical foundation and hypothesis that steroid avoidance could decrease the incidence of PTDM within the first year post-transplantation. The study was designed to validate a novel immunosuppressive regimen centered on steroid avoidance and minimization of calcineurin inhibitor. Paper II presented results from the SAILOR trial, primarily the impact of steroid avoidance on incidence of PTDM, as well as short-term (2 years) efficacy and safety outcomes. Paper III analyzed retrospectively the impact the impact of steroids on mycophenolic acid exposure during co-administration with tacrolimus in participants of the SAILOR trial. Paper IV, the SAILOR follow-up observational study, described long-term outcomes (>7 years post-transplantation) in the SAILOR trial participants, and assessed the feasibility and safety of steroid avoidance strategy. Results: The SAILOR trial demonstrated a comparably low incidence of PTDM, similar incidence of biopsy-proven rejection in both treatment arms, without the steroid-free regimen compromising efficacy and safety at two years. Mycophenolic acid exposure was lower in patients without steroids early post-transplantation, and negatively correlated with body weight. The long-term follow-up showed similar patient survival, death-censored graft survival, kidney function and safety parameters after 7.3 years. Two thirds of participants originally randomized to the steroid avoidance arm remained on steroid-free immunosuppression. Conclusions: Steroid avoidance combined with low-dose tacrolimus and mycophenolate mofetil is feasible, effective, and safe for immunologically low-risk kidney transplant recipients up to 7 years. A broader application of steroid-free immunosuppression might be beneficial in a carefully selected group of kidney transplant recipients to mitigate the long-term adverse effects of steroid use.