Delayed initiation or reduced initial dose of calcineurin-inhibitors for kidney transplant recipients at high risk of delayed graft function

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BACKGROUND: Kidney transplantation is the preferred therapy for many patients with kidney failure. Delayed graft function (DGF) is more common in donors after cardiac death (DCD), especially those with older age, longer cold ischemia time, or higher creatinine levels. Currently, there is no agreement on the optimal immunosuppressive approach for patients at increased risk of DGF. Strategies include delaying the introduction of calcineurin inhibitors (CNI) or using an initial low dose of CNI. OBJECTIVES: To evaluate the benefits and harms of delayed initiation of CNI or reduced CNI dose as initial immunosuppression therapy for kidney transplant recipients at high risk of DGF. SEARCH METHODS: The Cochrane Kidney and Transplant Register of Studies was searched up to 11 December 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs evaluating delayed versus early initiation of CNI or reduced versus standard initial dose of CNI in kidney transplant recipients at high risk of DGF. DATA COLLECTION AND ANALYSIS: Three authors independently assessed study eligibility, and two assessed the risk of bias, certainty of evidence, extracted the data, and performed the analysis. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and as mean difference (MD) with 95% CI for continuous outcomes. Statistical analysis was performed using the random-effects model. Risk of bias was assessed with the Cochrane risk of bias assessment tool 1.0, and the certainty of the evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods, which are presented in the summary of findings tables. MAIN RESULTS: We included 12 studies (2230 randomised participants). All studies were performed in Europe. Around 60% of the participants were males, reflecting the expected proportion in the population on kidney replacement therapy in Europe. Most studies had insufficient information to judge adequate random sequence generation and, or allocation concealment. All studies were unblinded, and judged as high risk of bias for DGF if the definition was based on need for dialysis, and for acute rejection if the diagnosis did not require a biopsy. Overall, the level of certainty was low, and reasons to downgrade were mainly due to risk of bias and imprecision. Delayed versus early initiation of CNI There may be little or no difference in DGF between the groups (6 studies, 905 recipients: RR 0.92, 95% CI 0.76 to 1.12; low certainty evidence) or in acute rejection (8 studies, 1295 recipients: RR 1.02, 95% CI 0.75 to 1.40; low certainty evidence). Delaying the initiation of CNI probably makes little or no difference to eGFR (6 studies, 851 recipients: MD -0.81 mL/min, 95% CI -3.33 to 1.72; moderate certainty evidence). Delaying the initiation of CNI may make little or no difference to graft loss censored for death (8 studies, 1295 recipients: RR 1.58, 95% CI 0.68 to 3.65; very low certainty evidence) or to all-cause death (8 studies, 907 recipients: RR 1.08, 95% CI 0.54 to 2.14; very low certainty evidence) although the evidence is very uncertain. There is probably little or no difference in all infections between the groups (6 studies, 1226 recipients: RR 1.10, 95% CI 0.97 to 1.25; moderate certainty evidence). Low versus standard initial dose of CNI There may be little or no difference to DGF between the groups (5 studies, 983 recipients: RR 1.16, 95% CI 0.90 to 1.50; low certainty evidence) or in acute rejection (5 studies, 947 recipients: RR 0.83, 95% CI 0.52 to 1.30; low certainty evidence). Starting CNI at a lower dose may make little or no difference to eGFR (5 studies, 935 recipients: MD 4.06 mL/min, 95% CI -1.36 to 9.48, low certainty evidence). Starting CNI at a lower dose may make little or no difference to graft loss censored for death, although the evidence is very uncertain (5 studies, 983 recipients: RR 1.05, 95% CI 0.64 to 1.71; very low certainty evidence), or to all-cause death (4 studies, 521 recipients: RR 1.01, 95% CI 0.41 to 2.47; low certainty evidence). There is probably little or no difference in all infections between the groups (4 studies, 828 recipients: RR 0.87, 95% CI 0.71 to 1.07; moderate certainty evidence). AUTHORS' CONCLUSIONS: There may be little or no difference in DGF or acute rejection when delaying the start of CNI or when starting it at a lower dose in kidney transplant recipients at high risk of DGF. The available data are of low certainty.

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