Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

Baseline Characteristics and Representativeness of Participants in the BEST-Fluids Trial: A Randomized Trial of Balanced Crystalloid Solution Versus Saline in Deceased Donor Kidney Transplantation.

Delayed graft function (DGF) is a major complication of deceased donor kidney transplantation. Saline (0.9% sodium chloride) is a commonly used intravenous fluid in transplantation but may increase the risk of DGF because of its high chloride content. Better Evidence for Selecting Transplant Fluids (BEST-Fluids), a pragmatic, registry-based, double-blind, randomized trial, sought to determine whether using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce DGF. We sought to evaluate the generalizability of the trial cohort by reporting the baseline characteristics and representativeness of the trial participants in detail. Methods: We compared the characteristics of BEST-Fluids participants with those of a contemporary cohort of deceased donor kidney transplant recipients in Australia and New Zealand using data from the Australia and New Zealand Dialysis and Transplant Registry. To explore potential international differences, we compared trial participants with a cohort of transplant recipients in the United States using data from the Scientific Registry of Transplant Recipients. Results: During the trial recruitment period, 2373 deceased donor kidney transplants were performed in Australia and New Zealand; 2178 were eligible' and 808 were enrolled in BEST-Fluids. Overall, trial participants and nonparticipants were similar at baseline. Trial participants had more coronary artery disease (standardized difference [d] = 0.09; P = 0.03), longer dialysis duration (d = 0.18, P < 0.001), and fewer hypertensive (d = -0.11, P = 0.03) and circulatory death (d = -0.14, P < 0.01) donors than nonparticipants. Most key characteristics were similar between trial participants and US recipients, with moderate differences (|d| ≥ 0.2; all P < 0.001) in kidney failure cause, diabetes, dialysis duration, ischemic time, and several donor risk predictors, likely reflecting underlying population differences. Conclusions: BEST-Fluids participants had more comorbidities and received slightly fewer high-risk deceased donor kidneys but were otherwise representative of Australian and New Zealand transplant recipients and were generally similar to US recipients. The trial results should be broadly applicable to deceased donor kidney transplantation practice worldwide.

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.

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.