Steroid avoidance may reduce death and diabetes after kidney transplant but raises rejection risk

Rationale Steroid‐sparing strategies aim to reduce the adverse effects associated with steroid use. The main concern has been a potential increase in the risk of rejection, as reported in previous systematic reviews. In recent years, improvements in immunosuppressive regimens and a significant decline in the incidence of acute rejection have renewed interest in steroid‐sparing strategies. More contemporary trials suggest that reducing steroid exposure might be safe. This is an updated review, previously published in 2009 and 2016. Objectives To evaluate the benefits and harms of steroid withdrawal or avoidance for kidney transplant recipients. Search methods We searched the Cochrane Kidney and Transplant Specialised Register, CENTRAL, MEDLINE, Embase and two trials registers up to 29 April 2025. Eligibility criteria All randomised and quasi‐randomised controlled trials that evaluated steroid avoidance or withdrawal after kidney transplantation. Outcomes Critical outcomes were all‐cause death, graft loss and biopsy‐proven acute rejection. Important outcomes were post‐transplant diabetes mellitus, cardiovascular events, infection, malignancy, and kidney function measures. Risk of bias Risk of bias was assessed with the Cochrane RoB 1 tool. Synthesis methods Assessment of risk of bias and data extraction were performed independently by at least two authors, and disagreements were resolved through discussion. Statistical analyses were performed using the random‐effects model, and dichotomous outcomes were reported as risk ratios (RRs) and continuous outcomes as mean differences (MDs) with 95% confidence intervals (CIs). The certainty of the evidence was assessed using the GRADE approach. Included studies This updated review includes 53 studies (261 reports, 8317 randomised kidney transplant recipients). Of these, three studies were conducted in children (204 randomised participants). Synthesis of results The overall certainty of the evidence of the included studies was low, ranging from moderate to very low. Factors downgraded on GRADE were primarily risk of bias and imprecision. Over 50% of the included studies did not adequately report random sequence generation or allocation concealment. Only five of 53 studies blinded participants and investigators. Incomplete outcome data was judged to be low in 26 studies, and 41 were free of selective reporting. Studies in adult kidney transplant recipients Steroid avoidance versus steroid maintenance The evidence is very uncertain about the effect of steroid avoidance on all‐cause death up to one year (RR 0.84, 95% CI 0.51 to 1.39; 13 studies, 2126 participants; very‐low‐certainty evidence). Steroid avoidance may reduce death by one to five years (RR 0.61, 95% CI 0.39 to 0.96; 9 studies, 1607 participants; low‐certainty evidence), and has little to no effect on graft loss censored for death up to one year (RR 0.95, 95% CI 0.62 to 1.46; moderate‐certainty evidence). Steroid avoidance may increase the risk of biopsy‐proven acute rejection up to one year (RR 1.58, 95% CI 1.11 to 2.25; 10 studies, 1845 participants; low‐certainty evidence), although subgroup analysis showed no increase in risk when steroid avoidance was used in combination with tacrolimus, an antimetabolite and induction therapy. Steroid avoidance may reduce the risk of post‐transplant diabetes mellitus up to five years (RR 0.70, 95% CI 0.59 to 0.84; 13 studies, 2390 participants; low‐certainty evidence), but may have little to no effect on cardiovascular events (RR 0.73, 95% CI 0.46 to 1.18; 6 studies, 1417 participants; low‐certainty evidence), infection (all) (RR 0.96, 95% CI 0.87 to 1.05; 11 studies, 2426 participants; low‐certainty evidence), and probably has little to no effect on cytomegalovirus (CMV) infection (RR 1.01, 95% CI 0.80 to 1.27; 9 studies, 2155 participants; moderate‐certainty evidence). Steroid withdrawal versus steroid maintenance Compared to steroid maintenance, steroid withdrawal may have little to no effect on all‐cause death up to one year (RR 0.69, 95% CI 0.35 to 1.37; 9 studies, 1884 participants; low‐certainty evidence) or one to five years (RR 1.17, 95% CI 0.67 to 2.03; 8 studies, 1189 participants; low‐certainty evidence), and probably has little to no effect on graft loss censored for death up to one year (RR 1.19, 95% CI 0.72 to 1.96; 8 studies, 1854 participants; moderate‐certainty evidence). Steroid withdrawal may have little to no effect on biopsy‐proven acute rejection up to one year (RR 1.41, 95% CI 0.89 to 2.23; 5 studies, 1406 participants; low‐certainty evidence). Steroid withdrawal probably has little to no effect on post‐transplant diabetes mellitus up to five years (RR 0.82, 95% CI 0.55 to 1.21; 8 studies, 1647 participants; moderate‐certainty evidence), and may have little to no effect on cardiovascular events up to five years (RR 0.91, 95% CI 0.42 to 1.97; 3 studies, 712 participants; low‐certainty evidence) or infection (all) up to five years (RR 1.06, 95% CI 0.83 to 1.36; 6 studies, 1924 participants; low‐certainty evidence). Steroid withdrawal probably has little to no effect on CMV infection up to five years (RR 1.10, 95% CI 0.85 to 1.43; 7 studies, 1956 participants; moderate‐certainty evidence). Steroid avoidance versus steroid withdrawal The evidence is very uncertain regarding the effects of steroid avoidance compared with steroid withdrawal (4 studies, 466 randomised participants). Studies in paediatric kidney transplant recipients The evidence is very uncertain regarding the effects of steroid‐sparing regimens in paediatric kidney transplant recipients (3 studies, 204 randomised participants). Authors' conclusions There was no evidence to suggest a difference in patient death or graft loss up to one year after transplantation with steroid avoidance or withdrawal compared to maintenance, but steroid avoidance may reduce patient death at five years in adult kidney transplant recipients. Steroid avoidance may increase the risk of biopsy‐proven acute rejection, but the risk may be similar when steroid avoidance is paired with tacrolimus, antimetabolite and induction therapy. The risk of biopsy‐proven acute rejection in steroid withdrawal regimens may be similar to steroid maintenance regimens. We found no evidence to suggest differences in cardiovascular events or infection, but steroid avoidance compared to steroid maintenance may reduce the risk of post‐transplant diabetes mellitus. Funding LO is supported by a Río Hortega predoctoral fellowship from the Instituto de Salud Carlos III. Registration Protocol and previous versions available via https://doi.org/10.1002/14651858.CD005632, https://doi.org/10.1002/14651858.CD005632.pub2, and https://doi.org/10.1002/14651858.CD005632.pub3. PICOs PICOs Population Intervention Comparison Outcome