Abstract
BackgroundDelayed graft function, or the requirement for dialysis due to poor kidney function, is a frequent complication of deceased donor kidney transplantation that is associated with inferior outcomes. Intravenous fluids with a high chloride content, such as isotonic sodium chloride (0.9% saline), are widely used in transplantation but may increase the risk of poor kidney function. The primary objective of the BEST-Fluids trial is to compare the effect of a balanced low-chloride crystalloid, Plasma-Lyte 148 (Plasmalyte), versus 0.9% saline on the incidence of DGF in deceased donor kidney transplant recipients. This article describes the statistical analysis plan for the trial.Methods and designBEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial. Eight hundred patients (adults and children) in Australia and New Zealand with end-stage kidney disease admitted for a deceased donor kidney transplant were randomised to intravenous fluid therapy with Plasmalyte or 0.9% saline in a 1:1 ratio using minimization. The primary outcome is delayed graft function (dialysis within seven days post-transplant), which will be modelled using a log-binomial generalised linear mixed model with fixed effects for treatment group, minimization variables, and ischaemic time and a random intercept for study centre. Secondary outcomes including early kidney transplant function (a ranked composite of dialysis duration and the rate of graft function recovery), treatment for hyperkalaemia, and graft survival and will be analysed using a similar modelling approach appropriate for the type of outcome.DiscussionBEST-Fluids will determine whether Plasmalyte reduces the incidence of DGF and has a beneficial effect on early kidney transplant outcomes relative to 0.9% saline and will inform clinical guidelines on intravenous fluids for deceased donor kidney transplantation. The statistical analysis plan describes the analyses to be undertaken and specified before completion of follow-up and locking the trial databases.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12617000358347. Prospectively registered on 8 March 2017ClinicalTrials.gov identifier NCT03829488. Registered on 4 February 2019
Highlights
Delayed graft function, or the requirement for dialysis due to poor kidney function, is a frequent complication of deceased donor kidney transplantation that is associated with inferior outcomes
BEST-Fluids will determine whether Plasmalyte reduces the incidence of Delayed graft function (DGF) and has a beneficial effect on early kidney transplant outcomes relative to 0.9% saline and will inform clinical guidelines on intravenous fluids for deceased donor kidney transplantation
Delayed graft function (DGF) in kidney transplantation is the requirement for dialysis due to poor kidney function in the first week post-transplant [1]
Summary
The full SAP, given in Additional file 1, was written and reviewed by the study statistician and clinical investigators from the BEST-Fluids Trial Steering Committee (TSC). Minimization based on three donor characteristics (deceased donor type [donation after brain death, donation after circulatory death], machine perfusion (no, yes), and Australian Kidney Donor Risk Index [KDRI] tertile) and study centre was used to allocate treatments. The main analyses of the primary and secondary outcomes will adjust for these characteristics in addition to ischaemic time. The primary outcome DGF will be analysed using a log-binomial generalised linear mixed model (GLMM) with fixed effects for treatment group, the three minimisation variables based on donor and transplant characteristics (deceased donor type, machine perfusion, KDRI tertile), and ischemic time, and a random intercept for study centre. Should the GLMM log-binomial model fail to converge, model simplifying strategies will be adopted in the first instance: adding very small centres to larger ones based on geographic location, excluding machine perfusion as a fixed effect due to the very small number of participants receiving kidneys stored by this method. In addition to detailed descriptions of planned analyses of primary, secondary, exploratory, and safety outcomes, the SAP details planned subgroup analyses where subgroups are formed by the minimization variables and ischaemic time, a comprehensive approach to addressing missing data on the primary and secondary outcomes, and lists changes to outcomes and analyses since publication of the final version of the trial protocol
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