Study Protocol for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a pragmatic, registry-based, multi-center, double-blind, randomized controlled trial evaluating the effect of intravenous fluid therapy with Plasma-Lyte 148 versus 0.9% saline on delayed graft function in deceased donor kidney transplantation

Michael G Collins, Magid A Fahim, Elaine M Pascoe, Kathryn B Dansie, Carmel M Hawley, Philip A Clayton, Kirsten Howard, David W Johnson, Colin J McArthur, Rachael C McConnochie, Peter F Mount, Donna Reidlinger, Laura Robison, Julie Varghese, Liza A Vergara, Laurence Weinberg, Steven J Chadban, BEST-Fluids Investigators and the Australasian Kidney Trials Network, Michael G Collins, Magid A Fahim, Elaine M Pascoe, Kathryn B Dansie, Carmel M Hawley, Philip A Clayton, Kirsten Howard, David W Johnson, Colin J McArthur, Rachael C McConnochie, Peter F Mount, Donna Reidlinger, Laura Robison, Julie Varghese, Liza A Vergara, Laurence Weinberg, Steven J Chadban, BEST-Fluids Investigators and the Australasian Kidney Trials Network

Abstract

Background: Delayed graft function, the requirement for dialysis due to poor kidney function post-transplant, is a frequent complication of deceased donor kidney transplantation and is associated with inferior outcomes and higher costs. Intravenous fluids given during and after transplantation may affect the risk of poor kidney function after transplant. The most commonly used fluid, isotonic sodium chloride (0.9% saline), contains a high chloride concentration, which may be associated with acute kidney injury, and could increase the risk of delayed graft function. Whether using a balanced, low-chloride fluid instead of 0.9% saline is safe and improves kidney function after deceased donor kidney transplantation is unknown.

Methods: BEST-Fluids is an investigator-initiated, pragmatic, registry-based, multi-center, double-blind, randomized controlled trial. The primary objective is to compare the effect of intravenous Plasma-Lyte 148 (Plasmalyte), a balanced, low-chloride solution, with the effect of 0.9% saline on the incidence of delayed graft function in deceased donor kidney transplant recipients. From January 2018 onwards, 800 participants admitted for deceased donor kidney transplantation will be recruited over 3 years in Australia and New Zealand. Participants are randomized 1:1 to either intravenous Plasmalyte or 0.9% saline peri-operatively and until 48 h post-transplant, or until fluid is no longer required; whichever comes first. Follow up is for 1 year. The primary outcome is the incidence of delayed graft function, defined as dialysis in the first 7 days post-transplant. Secondary outcomes include early kidney transplant function (composite of dialysis duration and rate of improvement in graft function when dialysis is not required), hyperkalemia, mortality, graft survival, graft function, quality of life, healthcare resource use, and cost-effectiveness. Participants are enrolled, randomized, and followed up using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry.

Discussion: If using Plasmalyte instead of 0.9% saline is effective at reducing delayed graft function and improves other clinical outcomes in deceased donor kidney transplantation, this simple, inexpensive change to using a balanced low-chloride intravenous fluid at the time of transplantation could be easily implemented in the vast majority of transplant settings worldwide.

Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12617000358347. Registered on 8 March 2017. ClinicalTrials.gov: NCT03829488. Registered on 4 February 2019.

Keywords: Balanced crystalloid; Delayed graft function; End-stage kidney disease; Intravenous fluids; Kidney transplantation; Normal saline; Peri-operative care; Plasma-Lyte 148; Pragmatic trial; Registry trial.

Conflict of interest statement

MC has received research support from Baxter Healthcare Pty Ltd., the manufacturer of Plasmalyte, through a Baxter Investigator Initiated Research grant that provided fluids for this trial (commercial value of US $36,270). DJ has received consultancy fees, research grants, speaker’s honoraria, and travel sponsorships from Baxter Healthcare and Fresenius Medical Care, consultancy fees from Astra Zeneca and AWAK, speaker’s honoraria and travel sponsorships from ONO, and travel sponsorships from Amgen. DR, LR, LV, EP, and JV are employees of the Sponsor, The University of Queensland. KD’s salary is funded by a BEAT-CKD grant and she is an employee of the ANZDATA Registry. PC is the Deputy Executive Officer at the ANZDATA Registry. CH has received fees for research committee activities from Janssen and GlaxoSmithKline paid to her institution, personal fees from Otsuka, research grants from Fresenius, Shire and PKD Australia outside the submitted work, and research grants from Baxter and NHMRC related to the current project. LW works at the Department of Anaesthesia at Austin Health, which has received funding from Baxter Healthcare for investigator-initiated clinical research. LW has received honoraria from Baxter Healthcare for consulting activities. All LW’s fluid-related research, including study design, execution, data collection, analysis, and reporting have been conducted independently of Baxter Healthcare and other commercial entities. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Outline of the BEST-Fluids trial. ESKD, end-stage kidney disease; CKD, chronic kidney disease
Fig. 2
Fig. 2
Pragmatic aspects of trial design. The Pragmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) wheel for the BEST-Fluids trial. Scores in each domain range from 1 (very explanatory) to 5 (very pragmatic) as described in Loudon et al. [26]. This PRECIS-2 wheel was generated using the tool available at www.precis-2.org
Fig. 3
Fig. 3
Participant timeline. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. Enrolment, interventions and assessments. EQ-5D-5L, EuroQol five dimensions, 5 levels questionnaire; EQ-5D-Y, EuroQol five dimensions, Youth questionnaire
Fig. 4
Fig. 4
Masking of study fluid. The printed label design on the study fluid bag does not allow identification of the type of study fluid (right hand image). Two adhesive stickers with the unique study code (treatment pack number) are attached to the exterior protective over-pouch (not shown), one of which is applied to the bag itself, along with a patient label, when the bag is opened by clinical staff (left hand image)

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