Articles

Balanced crystalloid solution versus saline in deceased donor

kidney transplantation (BEST-Fluids): a pragmatic,
double-blind, randomised, controlled trial
Michael G Collins*, Magid A Fahim*, Elaine M Pascoe, Carmel M Hawley, David W Johnson, Julie Varghese, Laura E Hickey, Philip A Clayton,
Kathryn B Dansie, Rachael C McConnochie, Liza A Vergara, Charani Kiriwandeniya, Donna Reidlinger, Peter F Mount, Laurence Weinberg,
Colin J McArthur, P Toby Coates, Zoltan H Endre, David Goodman, Kirsten Howard, Martin Howell, Jagadish S Jamboti, John Kanellis,
Jerome M Laurence, Wai H Lim, Steven J McTaggart, Philip J O’Connell, Helen L Pilmore, Germaine Wong, Steven J Chadban†, on behalf of the
BEST-Fluids Investigators‡ and the Australasian Kidney Trials Network

Summary
Background Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Lancet 2023; 402: 105–17
Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise Published Online
graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high June 18, 2023
https://doi.org/10.1016/
chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution S0140-6736(23)00642-6
(Plasma-Lyte 148) instead of saline would reduce the incidence of DGF.
See Comment page 80
*Joint first authors
Methods BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at
†Senior author
16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney
‡Members listed in the
transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. appendix p 4
Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced
Central Northern Adelaide
crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids Renal and Transplantation
were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The Service, Royal Adelaide
primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who Hospital, Adelaide, SA,
Australia (M G Collins PhD,
consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety
P A Clayton PhD,
was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether Prof P T Coates PhD);
or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, Department of Renal Medicine
(ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). (M G Collins PhD,
Prof H L Pilmore MD) and
Department of Critical Care
Findings Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid Medicine (R C McConnochie MN,
(n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant C J McArthur MBChB), Auckland
in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid City Hospital, Auckland, New
Zealand; Faculty of Health and
group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of Medical Sciences, University of
404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk Adelaide, Adelaide, SA,
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, Australia (M G Collins PhD,
numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of P A Clayton PhD,
K B Dansie MBiostats,
406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted Prof P T Coates PhD);
risk difference –0·5%, 95% CI –1·8 to 0·9; p=0·48). Australasian Kidney Trials
Network, Centre for Health
Interpretation Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced Services Research, University of
Queensland, Brisbane, QLD,
crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the Australia (M G Collins PhD,
standard-of-care intravenous fluid used in deceased donor kidney transplantation. M A Fahim PhD,
E M Pascoe MBiostats,
Funding Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Prof C M Hawley MMedSc,
Prof D W Johnson PhD,
Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter. J Varghese BHMS, L E Hickey BSc,
L A Vergara PhD,
Copyright © 2023 Published by Elsevier Ltd. All rights reserved. C Kiriwandeniya BScEng,
D Reidlinger MPH); Department
of Kidney and Transplant
Introduction more.1–3 DGF is associated with inferior outcomes, Services, Princess Alexandra
Patients who receive a kidney transplant from a deceased including increased health-care costs, driven primarily Hospital, Brisbane, QLD,
donor are at risk of delayed graft function (DGF), defined by requirement for dialysis and prolongation of hospital Australia (M A Fahim PhD,
Prof C M Hawley MMedSc,
as the requirement for dialysis within the first week after stay, and increased risks of acute rejection, graft failure,
Prof D W Johnson PhD);
transplantation due to poor kidney function.1 DGF occurs and death.4–8 Translational Research
as a consequence of ischaemia-reperfusion injury of the The type of intravenous fluid administered during and Institute, Brisbane, QLD,
transplanted kidney and affects 30–50% of recipients or after surgery could contribute to the risk of acute kidney Australia

www.thelancet.com Vol 402 July 8, 2023 105

 Articles
(Prof C M Hawley MMedSc,
Prof D W Johnson PhD);
Australia and New Zealand
Dialysis and Transplant
(ANZDATA) Registry, South
Australian Health and Medical
Research Institute
(SAHMRI),Adelaide, SA,
Australia (P A Clayton PhD,
K B Dansie MBiostats);
Department of Nephrology
(P F Mount PhD) and
Department of Anaesthesia
(Prof L Weinberg PhD), Austin
Health, Melbourne, VIC,
Australia; Department of
Medicine (Austin)
(P F Mount PhD) and
Department of Critical Care
(Prof L Weinberg PhD),
University of Melbourne,
Melbourne, VIC, Australia;
Department of Nephrology,
Prince of Wales Hospital,
Sydney, NSW, Australia
(Prof Z H Endre PhD); Prince of
Wales Clinical School,
University of New South Wales,
Sydney, NSW, Australia
(Prof Z H Endre PhD);
Department of Nephrology,
St Vincent’s Hospital,
Melbourne, VIC, Australia
(D Goodman PhD); School of
Public Health, Faculty of
Medicine and Health
(Prof K Howard PhD,
M Howell PhD,
Prof G Wong PhD), Menzies
Centre for Health Policy and
Economics (Prof K Howard PhD,
M Howell PhD), Institute of
Academic Surgery, Royal Prince
Alfred Hospital, University of
Sydney, NSW, Sydney
(J M Laurence PhD), Centre for
Transplant and Renal Research,
Westmead Institute for
Medical Research
(Prof P J O’Connell PhD,
Prof G Wong PhD), and Kidney
Node, Charles Perkins Centre
(Prof S J Chadban PhD),
University of Sydney, Sydney,
NSW, Australia; Department of
Nephrology and Renal
Transplantation, Fiona Stanley
Hospital, Murdoch, WA,
Australia (J S Jamboti DM);
School of Medicine, University
of Western Australia, Perth,
WA, Australia (J S Jamboti DM,
Prof W H Lim PhD); Department
of Nephrology, Monash Health,
Melbourne, VIC, Australia
(Prof J Kanellis PhD); Centre for
Inflammatory Diseases,
Department of Medicine,
Monash University, Melbourne,
VIC, Australia
(Prof J Kanellis PhD);
106
Research in context
Evidence before this study
Two systematic reviews and meta-analyses of balanced low-
chloride solutions versus saline in kidney transplantation had
been published before the report of this trial. Before this study,
one of us (PFM) and two colleagues (Wan S, Roberts MA, and
Mount P, 2016) published a Cochrane systematic review and
meta-analysis of six randomised controlled trials after
searching MEDLINE, Embase, and the Cochrane Central
Register of Controlled Trials from database inception to
Nov 26, 2015, using the terms “kidney transplantation”, “fluid
therapy”, “isotonic solutions”, “sodium chloride”, “saline”,
“Lactated Ringer”, “Hartmann”, “Plasmalyte”, and “acid-base
equilibrium”. This review found that there might be little or no
difference in the risk of delayed graft function (DGF) between
balanced crystalloids and saline solutions, based on low
certainty evidence (three trials, 298 participants, relative risk
1·03, 95% CI 0·62–1·7, I²=0%). In 2021, Jahangir and colleagues
published an updated systematic review and meta-analysis
with the same conclusion, again based upon low certainty
evidence (five trials, 400 participants, odds ratio
0·98, 95% CI 0·56–1·69, I²=0%). In these trials, only
202 participants had received a deceased donor kidney
transplant; the remaining 50% were recipients of live donor
kidneys and were therefore at very low risk of DGF. In all but
one study (n=49 participants), randomly assigned fluids were
limited to those given in the operating room, and
postoperative fluid use was not controlled. All trials were
single centre, small (only one had >100 participants), and were
in general of low overall quality with unclear or high risk
of bias. Overall, the certainty of evidence comparing the effect
of balanced crystalloids with saline on the risk of DGF was low.
injury and DGF after kidney transplantation.9,10 Saline
(0·9% sodium chloride) is the most commonly used fluid
in clinical practice,10,11 but due to its supraphysiological
chloride concentration (154 mmol/L), might cause
hyperchloraemic metabolic acidosis, which can lead to
reduced kidney perfusion and acute kidney injury.12–14
Balanced crystalloid solutions have chloride
concentrations that approximate human plasma,
potentially mitigating this risk of kidney injury.9,15,16
However, balanced crystalloids also contain potassium
(4–5 mmol/L), which could exacerbate hyperkalaemia
with associated risks of cardiac arrhythmias,
haemodynamic instability, and the need for acute dialysis,
particularly in the setting of poor kidney transplant
function.17
Balanced crystalloids have been associated with a lower
risk of DGF compared with saline in observational
studies. 9,10 A Cochrane systematic review and meta-
analysis15 of six randomised controlled trials that included
477 recipients of kidneys from living or deceased donors
found moderate certainty evidence that balanced
crystalloids reduced the risk of hyperchloraemic
Added value of this study
BEST-Fluids was a large, rigorously conducted trial that
investigated the effect of intravenous balanced low-chloride
solution versus saline on the risk of DGF, defined as the
requirement for dialysis within 7 days after transplantation.
This trial included 808 recipients of deceased donor kidney
transplant. We found a significant reduction in the incidence of
DGF with the balanced crystalloid solution Plasma-Lyte
148 compared with saline. This effect appeared consistent in
most subgroups of DGF risk, including recipients of kidneys
from donors after brain death or circulatory death, different
categories of kidney donor risk, and shorter and longer
ischaemic times. There were no significant safety concerns with
the use of balanced crystalloids compared with saline, and there
was no evidence of a difference in the risk of hyperkalaemia
with either fluid. Although urine output was greater with
balanced crystalloids, there were no differences in other
creatinine-based measures of renal recovery between the
groups. At 1 year, graft function was similar between the
groups, and there were no differences in graft failure or
mortality, although the numbers of these events were small.
Implications of all the available evidence
Patients receiving a kidney transplant from a deceased donor
are at lower risk of delayed graft function if they receive
intravenous fluid therapy with balanced crystalloid solution
rather than saline, with approximately one case of DGF
prevented for every ten patients treated. Use of balanced
crystalloids do not increase the risk of serious adverse events or
hyperkalaemia. The available evidence suggests that balanced
crystalloid solution should be the standard of care intravenous
fluid in deceased donor kidney transplantation.
metabolic acidosis compared with saline, but uncertain
effects on the risks of DGF and hyperkalaemia. An
updated meta-analysis18 that included three additional
trials and a matched cohort study (n=726 participants)
found lower risks of both acidosis and hyperkalaemia
with balanced crystalloids than with saline, but had
similar uncertainty regarding DGF and effects on graft
function. Of these, only three trials (n=202 participants)
included recipients of deceased donor kidneys at
substantial risk of DGF,18 and only one trial involved
fluids given intra-operatively as well as postoperatively.16
All trials were single centre, small (all but one had
100 participants or fewer), and were of variable quality.
Thus, whether using balanced crystalloids instead of
saline in deceased donor kidney transplantation improves
kidney function and is safe remains unknown.
We conducted the Better Evidence for Selecting
Transplant Fluids (BEST-Fluids) trial to test the hypothesis
that, compared with saline, intravenous fluid therapy with
a balanced crystalloid solution, Plasma-Lyte 148, would
reduce the incidence of DGF in recipients of deceased
donor kidney transplants.
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Methods
Study design
BEST-Fluids was a pragmatic, investigator-initiated,
registry-based, double-blind, randomised, controlled trial
conducted at 16 hospitals in Australia (12 sites) and New
Zealand (four sites). The trial was sponsored and
coordinated by the Australasian Kidney Trials Network
(AKTN; University of Queensland, QLD, Australia). The
trial protocol, 19 which was approved by human research
ethics committees for all participating sites, and the
statistical analysis plan, 20 have been published, and are
also available in the appendix (pp 52–267).
Participants
Adults and children of any age with kidney failure admitted
to a participating hospital for a deceased donor kidney
transplant were eligible. Patients were excluded if they
were receiving a multi-organ transplant, were a child
weighing less than 20 kg, or were considered by their
physician to be too small for a blinded fluid study. Written
informed consent was obtained before enrolment from all
patients, or from a parent or guardian for children.
Randomisation and masking
Participants were randomly assigned (1:1) to either
balanced crystalloid solution (Plasma-Lyte 148, Baxter
Healthcare; Old Toongabbie, Sydney, NSW, Australia) or
saline (0·9% sodium chloride) using an adaptive
minimisation algorithm. The minimisation factors were:
transplant centre, deceased donor type (donation after
brain death [DBD] or circulatory death [DCD]), use of
hypothermic machine perfusion, and Kidney Donor Risk
Index (KDRI) tertile, using the Australian KDRI. 21
Randomisation was performed before transplantation
using a centralised web-based randomisation system
accessed through the Australian and New Zealand
Dialysis and Transplant (ANZDATA) Registry web
platform. Trial fluids were supplied in identical 1000 mL
bags and patients, clinical staff, outcome assessors,
investigators, trial coordinating centre staff, and
ANZDATA Registry staff were masked to group
assignments.
Procedures
After randomisation, participants received the assigned
trial fluid for all maintenance, replacement, and
resuscitation purposes during and after surgery until
48 h after transplantation or cessation of intravenous
fluids, whichever occurred first. Plasma-Lyte 148 used in
this trial consisted of an isotonic buffered crystalloid
solution containing sodium (140 mmol/L), potassium
(5 mmol/L), magnesium (1·5 mmol/L), chloride
(98 mmol/L), acetate (27 mmol/L), and gluconate
(23 mmol/L) in sterile water, balanced to a pH of
7·4. Saline consisted of a solution of 154 mmol/L
of sodium and 154 mmol/L of chloride in sterile water.
The compositions of these trial fluids were identical to
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Articles
those used in clinical practice. The volume and rate Department of Renal Medicine,
of fluids, as well as decisions to cease fluids, were Sir Charles Gairdner Hospital,
Perth, WA, Australia
determined by treating clinicians. Further details of the (Prof W H Lim PhD); Child and
interventions and guidance for concomitant care are Adolescent Renal Service,
included in the appendix (pp 12–16) and the trial Queensland Children’s
protocol.19 Hospital, Brisbane, QLD,
Australia (S J McTaggart PhD);
Data for this trial were collected by research staff at Department of Renal and
each site from medical records and were entered into Transplantation Medicine,
the ANZDATA Registry web platform. Data collected Westmead Hospital, Sydney,
included those routinely recorded in the registry on NSW, Australia
(Prof P J O’Connell PhD,
demographics, clinical characteristics, acute rejection, Prof G Wong PhD);
graft function, graft survival, and patient survival. Data Department of Medicine,
on the sex of participants was based on self-report or University of Auckland,
physician reporting. Additional trial-specific data, Auckland, New Zealand
(Prof H L Pilmore MD);
including trial fluid volumes, open-label fluid use, urine Department of Renal Medicine,
volume, bodyweight, and laboratory measures, were Kidney Centre, Royal Prince
collected using a bespoke module added for the purpose Alfred Hospital, Sydney, NSW,
Australia (Prof S J Chadban PhD);
of the trial. Data on serum creatinine were collected from
the medical record: we did not assign specific values or Correspondence to:
Dr Michael G Collins, Central
exclude data from participants on the basis whether they Northern Adelaide Renal and
had dialysis treatment or not. Data on deceased donor Transplantation Service, Royal
characteristics were obtained from the Australia and Adelaide Hospital, Port Road,
New Zealand Organ Donation Registry. Safety data and Adelaide, SA 5000, Australia
michael.collins@sa.gov.au
protocol deviations were collected using a REDCap
See Online for appendix
database.22
Outcomes
The primary outcome was DGF, defined as receiving
treatment with any form of dialysis in the first 7 days
after transplantation. Participants who died or had early
graft failure before 7 days after transplantation were
considered to have had DGF for the purposes of the
primary outcome analysis.
In the original version of the trial protocol approved
in 2017, the primary outcome was defined as a ranked
composite of the duration of DGF in days for patients
who received dialysis, and a biochemical measure of
graft function recovery (creatinine reduction ratio on
day 2) for participants not requiring dialysis. 23 This
ordinal outcome had been proposed as a useful measure
of the effect of DGF and increased the efficiency of the
trial (for details see the original version of the protocol
and appendix p 25), but concerns were expressed by
some peer reviewers of the protocol that this outcome
might be difficult to interpret and of insufficient
importance to justify a change in clinical practice. After
a review of recruitment and the event rate of DGF
(conducted without unblinding) after 5 months of
recruitment with 113 participants enrolled, the primary
outcome was changed in 2018 to the incidence of DGF
defined as dialysis within 7 days of transplantation.19 This
change was made to make the trial outcome more
meaningful and relevant to clinicians and patients, and
to be consistent with published guidance from the US
Food and Drug Adminstration.24 This amendment
necessitated an increase in the sample size from
574 to 800 participants (appendix p 25).
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Secondary outcomes (appendix pp 17–19) included the

1350 patients assessed for eligibility number of dialysis treatments (to day 28) and duration of
494 excluded
95 did not meet eligibility criteria dialysis in days (to week 12); a ranked composite of DGF
90 had a multi-organ transplant
4 unable to consent
duration and creatinine reduction ratio on day 2 (the
1 other reason original primary outcome); creatinine reduction ratio on
55 declined to participate day 2 and creatinine reduction of 10% or more in the
344 excluded for other reasons
61 had recruitment on hold at site first 3 days; post-transplantation hyperkalaemia
58 had a competing trial (≥5·5 mmol/L), treatment required for hyperkalaemia,
55 for whom medical staff did not
seek consent
and peak potassium; fluid overload (>5% weight gain by
52 had recruitment suspended postoperative day 2); urine output to postoperative day 2;
(COVID-19) use of inotropes or vasopressors during and after surgery;
34 staff unavailability at site due
to weekend or after hours acute rejection; the number of kidney transplantation
transplant biopsies performed; mortality; graft survival; graft func­
20 had insufficient time for consent
20 had no staff availability
tion measured using estimated glomerular filtration rate
10 had transplant surgery cancelled (eGFR; appendix p 19); and duration of the index
before randomisation hospitalisation. Quality-of-life measures were also
34 excluded for other reasons
856 randomly assigned reported by site* collected but will be reported elsewhere.
Site investigators reported any serious adverse events
between baseline and day 7 after transplantation that were
considered potentially related to study treatment. Data
427 assigned to balanced crystalloid 429 assigned to Saline were also collected on specific adverse events of particular
interest associated with the index hospitalisation using
discharge codes (appendix pp 20–24).
22 did not receive a kidney transplant† 24 did not receive a kidney transplant†
1 withdrawn as did not consent 1 withdrawn due to invalid consent
Statistical analysis
We estimated that a sample size of 722 participants
404 received a kidney transplant 404 received a kidney transplant
would provide 80% power at a 5% two-sided α level to
show an absolute difference of 10% (41% vs 31%) between
9 discontinued trial 10 discontinued trial the groups for the incidence of DGF, corresponding to
0 before day 7 3 before day 7 a relative risk for balanced crystalloid versus saline
9 week 2 to 52 2 died
8 died 1 withdrew consent‡ of 0·76. We considered this effect size to be both clinically
1 lost to follow-up 7 week 2 to 52 meaningful and within the range of biological plausibility
6 died
1 withdrew consent
for the association between balanced crystalloid solution
versus saline with the risk of DGF. 9,16,19 We adjusted
the sample size to 800 participants to allow for 1% loss
395 completed trial follow-up to 394 completed trial follow-up to to follow-up, and up to 4% non-adherence (drop in or
week 52 week 52
drop out).
All randomised and consented participants who
404 included in primary analysis 403 included in primary analysis received a kidney transplant were included in the primary
and secondary analyses. The safety analysis included all
Figure 1: Trial profile randomised and consented participants whose surgery
*Other reasons for exclusion included: no translator (n=7), medical reasons (n=5), patient was resident in another started and who received trial fluids, whether or not they
country and admitted to participating hospital for transplant surgery only (n=5), developmental delay or
intellectual disability (n=4), physician decision (n=4), patient anxiety (n=3), transplantation was done at a
received a kidney transplant. The primary outcome was
participating hospital for another non-participating hospital during the COVID-19 pandemic (n=2), assessment analysed using a log-binomial regression model, with
was done for safety reasons only (due to being given study fluids but not enrolled or randomised; n=1), interstate fixed effects for treatment group, three minimisation
logistics (n=1), non-adherence of the patient (n=1), and transplantation was done at another hospital (n=1). variables (deceased donor type, machine perfusion,
†48 patients (23 in the balanced crystalloid group vs 25 in the saline group) were excluded after randomisation
because their surgery was cancelled (20 vs 19), surgery was started but they did not actually receive a kidney
KDRI tertiles), and ischaemic time. Due to intractable
(two vs five; these patients were included in the safety analysis), or because of missing or invalid consent convergence issues with generalised mixed models, we
(one vs one). Reasons that transplantation surgery was cancelled after randomisation included that deceased accounted for clustering at study centres by using a
donation did not proceed (eg, when a potential donor did not reach asystole after withdrawal of life support generalised estimating equation (GEE) approach with an
within established timeframes for organ donation, or became medically unstable before organ retrieval), the donor
kidney was deemed unsuitable to transplant after retrieval, or the recipient had surgery cancelled for medical exchangeable correlation structure and robust standard
reasons. Reasons that surgery was started but a kidney was not transplanted included donor kidneys being deemed errors. In prespecified sensitivity analyses, we used a
unsuitable for transplantation by the recipient surgeon intra-operatively, or when a recipient was found to have no best-worst and worst-best imputation approach to assess
vessels suitable for the transplant vascular anastomosis. ‡This participant was not included in the primary analysis. the effect of missing data on the primary outcome. We
also conducted prespecified subgroup analyses of the
primary outcome by donor type, machine perfusion,
KDRI tertiles, and ischaemic time.

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Secondary outcomes measured on a single occasion

were analysed using statistical models with the same Balanced Saline (n=404) Total (n=808)
fixed effects as per the primary outcome model and, crystalloid (n=404)
except for time-to-event outcomes, the same approach to Age, years 55 (45–62) 54 (43·5–63) 55 (45–63)
clustering by study centre. The ordinal composite ranked Sex
outcome was analysed with a proportional odds logistic Female 144 (36%) 152 (38%) 296 (37%)
regression model. Binary outcomes were analysed as for Male 260 (64%) 252 (62%) 512 (63%)
the primary outcome. Count outcomes were analysed
Child aged <16 years 1 (<1%) 3 (1%) 4 (<1%)
with Poisson regression models, or negative binomial
Ethnicity*
models if there was evidence of overdispersion. Time-to-
Asian 40/397 (10%) 37/399 (9%) 77/796 (10%)
event outcomes were analysed with Cox regression, and
Australian Aboriginal or Torres Strait 26/397 (7%) 22/399 (6%) 48/796 (6%)
Fine and Gray regression for the analysis of graft failure Islander
with a competing risk of death. Continuous outcomes New Zealand Māori 25/397 (6%) 21/399 (5%) 46/796 (6%)
measured on a single occasion were analysed using GEE Pacific Islander 27/397 (7%) 35/399 (9%) 62/796 (8%)
linear models and those measured repeatedly were White or European 228/397 (57%) 243/399 (61%) 471/796 (59%)
analysed using linear mixed models. For the analyses of Other 51/397 (13%) 41/399 (10%) 92/796 (12%)
the secondary outcomes of number of dialysis treatments
BMI, kg/m²† 27 (23–33) 27 (23–33) 27 (23–33)
to day 28, and the duration of dialysis in days (to week 12),
Cause of kidney failure‡
the statistical analysis plan prespecified that these
Diabetic nephropathy 77/387 (20%) 91/391 (23%) 168/778 (22%)
analyses would be limited to participants who received
Hypertension 35/387 (9%) 37/391 (9%) 72/778 (9%)
dialysis and was therefore not an intention-to-treat
Glomerulonephritis 146/387 (38%) 159/391 (41%) 305/778 (39%)
analysis. We conducted additional post-hoc analyses for
Reflux nephropathy 25/387 (6%) 20/391 (5%) 45/778 (6%)
these outcomes on an intention-to-treat basis including
Polycystic kidney disease 53/387 (14%) 50/391 (13%) 103/778 (13%)
all participants (ie, assigning zero values to those who
Other 51/387 (13%) 34/391 (9%) 85/778 (11%)
did not receive dialysis) using the same analytical
Diabetes 114 (28%) 119 (29%) 233 (29%)
approach as for the prespecified analysis.
Coronary artery disease 89 (22%) 103 (25%) 192 (24%)
We did not adjust for multiplicity; therefore, all sec­
Peripheral vascular disease 40 (10%) 49 (12%) 89 (11%)
ondary analyses were considered hypothesis-generating.
A two-sided p value of less than 0·05 was considered Chronic lung disease 37 (9%) 54 (13%) 91 (11%)

statistically significant. All analyses were performed Cerebrovascular disease 24 (6%) 23 (6%) 47 (6%)

using SAS version 9·4 or Stata version 17. Previous kidney transplant 46 (11%) 51 (13%) 97 (12%)
An independent data and safety monitoring board Dialysis duration before transplantation, 30 (16–52) 31 (17–55) 31 (17–53)
months
monitored safety and operational data throughout the
Dialysis modality before transplantation
trial. No interim analyses for efficacy were performed.
Haemodialysis 265 (66%) 285 (71%) 550 (68%)
The study was registered with the Australian New Zealand
Peritoneal dialysis 130 (32%) 112 (28%) 242 (30%)
Clinical Trials Registry, (ACTRN12617000358347) and at
None (pre-emptive transplant) 9 (2%) 7 (2%) 16 (2%)
ClinicalTrials.gov (NCT03829488).
Peak panel reactive antibody

Role of the funding source 0 257/402 (64%) 262 (65%) 519/806 (64%)

The funders of the study had no role in study design, 1–98% 134/402 (33%) 128 (32%) 262/806 (33%)

data collection, data analysis, data interpretation, or ≥99% 11/402 (3%) 14 (3%) 25/806 (3%)
writing of the report. Number of HLA mismatches‡
0 18/402 (4%) 10 (2%) 28/806 (3%)
Results 1–2 93/402 (23%) 126 (31%) 219/806 (27%)
Between Jan 26, 2018, and Aug 10, 2020, 1350 patients 3–4 133/402 (33%) 123 (30%) 256/806 (32%)
were assessed for eligibility, of whom 494 were excluded: 5–6 158/402 (39%) 145 (36%) 303/806 (38%)
95 did not meet eligibility criteria, 55 declined to Total ischaemic time, h§ 10 (7–13) 10 (7–14) 10 (7–13)
participate, and 344 had other reasons (figure 1). A total of Immunosuppression: induction¶
856 patients were randomly assigned to a study group, Any induction 398 (99%) 400 (99%) 798 (99%)
of whom 46 were excluded (22 in the balanced crystalloid Basiliximab 364 (90%) 355 (88%) 719 (89%)
group and 24 in the saline group) because they did not T-cell depletion 45 (11%) 51 (13%) 96 (12%)
receive a transplant. Two additional patients were excluded Immunosuppression: maintenance¶
because of missing or invalid consent (one in each group). Glucocorticoid 401 (99%) 399 (99%) 800 (99%)
Thus, a total of 808 participants (404 in the balanced Ciclosporin 65 (16%) 53 (13%) 118 (15%)
crystalloid group and 404 in the saline group) were Tacrolimus 335 (83%) 345 (85%) 680 (84%)
enrolled in the trial. One participant in the saline group (Table 1 continues on next page)
withdrew consent before day 7, leaving 807 participants

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[SD 4077] vs 7180 mL [3448]; appendix p 43). Non-trial

Balanced Saline (n=404) Total (n=808)
crystalloid (n=404) fluids were given to 508 (63%) of 807 participants (255
(Continued from previous page) [63%] of 404 in the balanced crystalloid group vs 253
Mycophenolic acid derivative 397 (98%) 394 (98%) 791 (98%) [63%] of 403 in the saline group). Open-label saline was
Sirolimus or everolimus 5 (1%) 5 (1%) 10 (1%)
given to 186 (46%) of 404 participants in the balanced
Azathioprine 0 1 (<1%) 1 (<1%)
crystalloid group (mean 484 mL [SD 646]) and 182 (45%)
Donor age, years 49 (34–58) 48 (35–58) 48 (34–58)
of 403 participants in the saline group (612 mL [1102])
during the intervention period, predominantly for
Deceased donor type
medication administration. Use of other open-label
Donation after brain death 305 (75%) 302 (75%) 607 (75%)
crystalloids was infrequent. Blood product use was
Donation after circulatory death 99 (25%) 102 (25%) 201 (25%)
similar in both groups (appendix pp 34–36, 43).
Expanded criteria donor 117 (29%) 111 (27%) 228 (28%)
Compared with the saline group, the balanced crystalloid
Donor cause of death
group had lower mean serum chloride and sodium
Cerebrovascular infarct or 155 (38%) 159 (39%) 314 (39%)
haemorrhage concen­ trations and higher mean serum bicarbonate
Other 249 (62%) 245 (61%) 494 (61%)
concentrations and blood pH from transplantation to
Donor history of hypertension 90 (22%) 86 (21%) 176 (22%)
postoperative day 2 (figure 2). Mean serum concen­
Donor terminal serum creatinine, 68 (54–91) 69·5 (57–89·5) 68·5 (56–91)
trations of potassium, urea, and haemoglobin did not
µmol/L|| differ between the groups. Mean serum creatinine
KDRI score** 1·26 (0·99–1·61) 1·23 (1·00–1·60) 1·24 (1·00–1·61) concentrations measured up to day 7 were similar in
KDRI tertile†† both groups (figure 2).
First 137 (34%) 141 (35%) 278 (34%) The primary outcome of DGF occurred in 121 (30%) of
Second 145 (36%) 144 (36%) 289 (36%) 404 participants in the balanced crystalloid group and
Third 122 (30%) 119 (29%) 241 (30%) 160 (40%) of 403 participants in the saline group (adjusted
Machine perfusion of donor kidney‡‡ 11 (3%) 9 (2%) 20 (2%)
relative risk [RR] 0·74, 95% CI 0·66–0·84; p<0·0001),
representing an adjusted risk difference of 10·1% (95% CI
Data are median (IQR), n (%), and n/N (%). Note that denominators have been added to cells when the number of
participants for whom data were available did not match the total number of participants; if the cell contains no
3·5–16·6; table 2; appendix p 37). Results were similar in
denominator, then no data were missing for that group and variable. KDRI=Kidney Donor Risk Index. *Ethnicity was prespecified sensitivity analyses (appendix p 38).
categorised as recorded in the Australian New Zealand Dialysis and Transplant Registry; ethnicity was either self- In prespecified subgroup analyses (figure 3;
reported or clinician-reported. †Data were missing for one patient in the balanced crystalloid group and one patient in
appendix p 39), the point estimates for the effects of
the saline group. ‡Number of HLA mismatches between the donor and recipient for HLA loci at A, B, and DR. §Data
were missing for two patients in the saline group. ¶The different categories of immunosuppression are not mutually balanced crystalloid versus saline on DGF consistently
exclusive. ||To convert the values for serum creatinine to mg/dL, multiply by 0·01131222. **Calculated using the favoured balanced crystalloids in all subgroups. There
Australian modification of this score (appendix p 10). ††Cutoffs for the KDRI tertiles were calculated using KDRI values was evidence of effect modification by donor type, with a
for all eligible Australian and New Zealand deceased donor kidney transplant recipients during the period of trial
recruitment from January, 2018, to August, 2020.25 ‡‡Hypothermic machine perfusion was only used at one hospital greater effect seen in recipients of a kidney from a donor
during the trial. after circulatory death than from a donor after brain
death (pinteraction=0·0072). The most frequent indications
Table 1: Participant characteristics at baseline
for dialysis reported by investigators were volume con­
trol, uraemia, and hyperkalaemia (appendix p 40).
In post-hoc intention-to-treat analyses, there were
(404 in the balanced crystalloid group and 403 in the saline significant differences in both the number of dialysis
group) who were included in the intention-to-treat sessions and the duration of dialysis in favour of balanced
primary analysis (figure 1). Two participants in the saline crystalloid, consistent with the findings for the primary
group died before day 7; one had had dialysis before death, outcome (table 2; figure 4; appendix p 40). In the
the other had not but per the statistical analysis plan was prespecified analyses limited to the subgroup of
classified as having DGF in the primary analysis. One participants who required dialysis (121 in the balanced
participant in the saline group had graft loss before day 7, crystalloid group and 159 in the saline group), there were
and was also classified as having DGF. no differences in the number of dialysis sessions to day 28
Baseline characteristics were well balanced between or total duration of dialysis between the groups (table 2).
the groups (table 1; appendix pp 26–32). Trial participants There was no significant difference between the
were representative of recipients of deceased donor two groups with respect to the ranked composite outcome
kidney transplants across Australia and New Zealand of duration of DGF and creatinine reduction ratio on
(appendix p 33).25 day 2 (table 2). Creatinine reduction ratio on day 2,
The assigned trial fluid was administered to 402 (>99%) creatinine reduction of 10% or more in the first 3 days,
of 404 people in the balanced crystalloid group and post-transplant hyperkalaemia (≥5·5 mmol/L), treatment
400 (99%) of 403 people in the saline group. During the required for hyperkalaemia, peak potassium, incidence
period from randomisation to 48 h after transplantation, of fluid overload, treatment with inotropic or vasopressor
the balanced crystalloid group received a greater mean drugs, acute rejection, number of kidney transplant
volume of trial fluid than the saline group (8143 mL biopsies performed, mortality, graft survival to 52 weeks,

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Chloride Bicarbonate Blood pH Sodium

Balanced crystalloid
106 26 7·40 138
Saline
104

Bicarbonate (mmol/L)
24 137
Chloride (mmol/L)

Sodium (mmol/L)
102 7·35

Blood pH
100 22 136
98 7·30
20 135
96
94 18 7·25 134
After Day 1 Day 2 After Day 1 Day 2 After Day 1 Day 2 After Day 1 Day 2
surgery surgery surgery surgery
Number of participants
Balanced crystalloid 392 390 389 393 394 368 319 164 109 401 403 403
Saline 395 388 389 399 399 376 312 158 100 401 403 402

Potassium Urea Haemoglobin Bodyweight

5·2 20 110 88

5·0 19 105 86
Potassium (mmol/L)

Haemoglobin (g/L)
Urea (mmol/L)

18

Weight (kg)
4·8 100 84
17
4·6 95 82
16
4·4 15 90 80

4·2 14 85 78
After Day 1 Day 2 After Day 1 Day 2 After Day 1 Day 2 Baseline Day 2
surgery surgery surgery
Number of participants
Balanced crystalloid 401 403 403 396 403 397 399 403 399 404 373
Saline 400 401 402 396 402 397 397 401 399 403 370

Urine output Serum creatinine

Total urine output to 48 h
Balanced crystalloid: 6011 mL (SD 4917)
Saline: 4948 mL (SD 4235)
Adjusted mean difference:
1022 mL (95% CI 459–6234)
3000 800
Creatinine (μmol/L)

600
Urine output (mL)

2000
400
1000
200

0 0
After surgery to Day 1 to day 2 Day 2 to 48 h After Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
day 1 surgery
Number of participants Number of participants
Balanced crystalloid 403 403 402 Balanced crystalloid 394 404 403 404 403 400 399 398
Saline 401 401 402 Saline 389 403 402 403 402 403 397 388

Figure 2: Changes in laboratory measures, bodyweight, urine output, and serum creatinine following deceased donor kidney transplantation
Datapoints are mean values and error bars are 95% CI. Baseline measurements were those measured at baseline, before transplantation. After surgery refers to
measurements taken on arrival in the recovery room after transplantation. Day 1 refers to measurements taken between 0500 h and 0900 h on the day after surgery.
Day 2 refers to measurements taken 24 h (±2 h) after day 1. 48 h refers to measurements taken 48 h since completion of transplantation.

graft function (eGFR at 12, 26, and 52 weeks), and that fewer participants were admitted to an intensive
duration of the initial hospitalisation were also not care unit for continuous ventilatory support in the
significantly different between the groups (table 2; balanced crystalloid group versus the saline group
appendix pp 41, 44–50). Mean urine output during the (table 3).
first 48 h after transplantation was higher with balanced
crystalloid solution than with saline (figure 2). Discussion
The incidence of investigator-reported serious adverse In this pragmatic, randomised clinical trial involving
events, and adverse events of particular interest (based 808 participants, intravenous fluid therapy with the
on discharge coding) were similar in both groups, except balanced crystalloid solution Plasma-Lyte 148 significantly

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reduced the incidence of DGF compared with saline in

Balanced crystalloid Saline Estimate
(n=404) (n=403) (95% CI) recipients of a deceased donor kidney transplant. This
finding was robust in sensitivity analyses and appears
Primary outcome
consistent across prespecified subgroups of deceased
Delayed graft function 121/404 (30%) 160/403 (40%) RR 0·74 (0·66 to 0·84)*;
p<0·0001 donor deceased donor type, KDRI, and ischaemic time.
Secondary outcomes Among participants who developed DGF, the duration
Dialysis†, n 121 159 ··
and number of dialysis treatments required were similar
Number of dialysis 3·7 (3·40) 3·8 (3·28) IRR 0·95 (0·64 to 1·43)*
between the groups. As DGF was more frequent in
sessions up to day 28‡ participants receiving saline, this group received an
Duration of dialysis up 6 (2–11) 7 (3–10) HR 0·95 (0·72 to 1·26)§ additional 190 dialysis sessions compared with the
to day 84, days balanced crystalloid group. Postoperative urine output
Ranked composite of duration of DGF and creatinine reduction ratio on day 2¶ was greater with balanced crystalloid than with saline, but
Rank 390 (223) 415 (241) OR 0·84 (0·65 to 1·07)|| secondary outcome measures of kidney functional
Decile of rank 5·3 (2·76) 5·6 (2·96) OR 0·85 (0·65 to 1·10)|| recovery based on serum creatinine, including the ordinal
Graft function recovery**, 282 243 ·· ranked composite outcome, did not differ between the
n groups. Other secondary outcomes including hyper­
Creatinine reduction 24% (21·9) 27% (22·6) MD –1·8 (–6·8 to 3·2)* kalaemia, graft function from 12 to 52 weeks, graft failure,
ratio on day 2, %
mortality, and length of hospital stay also did not
Creatinine reduction 228/282 (81%) 206/242 (85%) RR 0·96 (0·89 to 1·03)*
≥10% within 3 days of
differ between the groups. Adverse events were overall
transplantation infrequent and similar in both groups, although a higher
Post-transplant hyperkalaemia within 48 h of transplantation rate of intensive care unit admission requiring ventilation
Any serum potassium 228/404 (56%) 228/403 (57%) RR 1·00 (0·90 to 1·11)* was observed in the saline group than in the balanced
concentration crystalloid group.
≥5·5 mmol/L Our results are consistent with those of earlier
Treatment for 188/404 (47%) 184/403 (46) RR 1·01 (0·87 to 1·17)* observational studies9,10 that compared balanced crystalloids
hyperkalaemia††
with saline in recipients of kidney transplants. The effects
Peak potassium 5·7 (0·88) 5·6 (0·89) MD 0·02 (–0·08 to 0·11)*
concentration, mmol/L
seen are greater than those seen in systematic reviews
Fluid overload‡‡, weight 152/373 (41%) 154/369 (42%) RR 0·96 (0·83 to 1·11)*
of randomised trials that included recipients of both
gain >5% by day 2 living and deceased donor kidneys,15,18 in which the risk of
Urine output from surgery until 48 h after transplantation, mL DGF was much lower,15,18 and a previous single-centre
Mean (SD) 6011 (4917) 4948 (4235) MD 1022 (459 to 6324)* randomised trial in 49 participants by Weinberg and
Median (IQR) 5295 (2335–8482) 4364 (1199–7398) ·· colleagues16 restricted to deceased donor transplants, which
Treatment with inotropic 194/404 (48%) 211/403 (52%) RR 0·92 (0·83 to 1·02)* reported differences in some biochemical measures of
drugs§§ kidney function, but did not find a difference in the rate of
Acute rejection, number 0·24 (0·53) 0·18 (0·47) IRR 1·28 (0·94 to 1·76)* DGF (for which the study was underpowered). Unlike that
of episodes per participant previous trial and the most recent meta-analysis,16,18 we did
to week 52
not observe a higher incidence of hyperkalaemia with
Number of transplant 0·55 (1·06) 0·65 (1·15) IRR 0·86 (0·74 to 1·01)*
saline. It is conceivable that any differences in potassium
biopsies per participant to
day 28 were confounded by the greater use of dialysis with saline,
Mortality up to 52 weeks 8/404 (2%) 8/403 (2%) HR 1·06 (0·39 to 2·85)¶¶ although potassium was not higher at any timepoint
Graft failure including immediately following surgery. Nevertheless,
Graft failure (including 18/404 (4%) 20/403 (5%) HR 0·91 (0·55 to 1·49)¶¶ avoidance of balanced crystalloids in transplantation due
death) up to 52 weeks to safety concerns about their potassium content resulting
Graft failure censored 11/404 (3%) 15/403 (4%) HR 0·73 (0·48 to 1·11)¶¶ in hyperkalaemia now appears unjustified.
for death up to Consistent with the hypothesis that balanced crystalloid
52 weeks
use would lead to a reduction in DGF via avoidance of the
Graft failure up to 11/404 (3%) 15/403 (4%) HR 0·73 (0·48 to 1·10)||||
hyperchloraemic metabolic acidosis that frequently
52 weeks with death as
a competing risk complicates the use of saline,12–14 we observed lower serum
Graft function, estimated glomerular filtration rate, mL/min/1·73 m² chloride concentrations, and higher bicarbonate and pH,
12 weeks 53·6 (20·5) 53·8 (21·7) MD –0·14 (–2·74 to 2·46)* in the balanced crystalloid group compared with the saline
26 weeks 53·8 (19·3) 53·4 (21·3) MD 0·47 (–2·11 to 3·04)* group. Urine output was also higher with balanced
52 weeks 54·0 (20·4) 54·8 (21·6) MD –0·84 (–3·46 to 1·79)* crystalloid than with saline. These findings are consistent
(Tabe 2 continues on next page) with experimental data that suggest hyperchloraemia can
induce kidney vasocon­ striction and consequent
ischaemia, and a resultant reduction in urine output.12–14
We also observed that the balanced crystalloid group
received a greater total volume of fluid, particularly

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postoperatively (appendix p 43), which might reflect a
clinical practice of basing intravenous fluid infusion rates
on recipient urine volumes. Our hypothesis suggests that
use of other balanced crystalloids that have a physiological
chloride concentration, such as Lactated Ringer’s
solution, Sterofundin, or Elomel Isoton, could be as
protective as Plasma-Lyte 148. Plasma-Lyte 148 was
selected as the preferred balanced crystalloid for this
study for various reasons including its isotonicity
(compared with Lactated Ringers, which is hypotonic),
because it does not contain lactate (a commonly measured
clinical biomarker) or calcium (which affects compatibility
with blood products), and because it is readily available in
Australia and New Zealand as well as other countries
(appendix p 42).26 Further studies of the effects of Plasma-
Lyte 148 and other balanced crystalloids on kidney
transplant perfusion are needed to establish whether the
mechanism of reduced DGF is entirely explained by
the avoidance of saline-induced hyperchloraemia, or
whether other mechanisms specific to the compos­
ition of Plasma-Lyte 148 play a substantial role.
We did not find differences in secondary outcome
measures of renal functional recovery based on
post-transplant changes in serum creatinine, or in the
ordinal ranked composite outcome that incorporated
both a change in creatinine and the duration of DGF.
These creatinine-based measures were probably
confounded by the different rates of DGF and dialysis
treatment between the groups, with the effect dialysis has
on serum creatinine reducing the value of such measures
as indicators of kidney ischaemia-reperfusion injury. 1,24
In post-hoc intention-to-treat analyses, consistent with
findings of the primary outcome, there were significantly
fewer dialysis treatments in the group who received
balanced crystalloid than in those who received saline. In
prespecified analyses restricted to participants with DGF,
the burden of dialysis treatment was similar in both
groups, indicating that the greater incidence of DGF with
saline did not appear to reflect a milder form of kidney
injury. Despite these differences, the length of hospital
stay was not significantly different between the groups;
the reasons are uncertain but might reflect the increasing
use of outpatient dialysis and clinic follow-up for
otherwise clinically stable patients with DGF. 27
Despite finding a substantial reduction in DGF with
the balanced crystalloid solution Plasma-Lyte
148 compared with saline, we did not observe differences
in graft function from week 12 to 52, graft failure, or
mortality. Although the trial was not designed or
powered for graft failure or mortality outcomes, the
absence of an association between DGF and measures of
graft function at 1 year after transplantation was
somewhat unexpected. We observed that the reduction
in DGF with balanced crystalloids appeared to have been
greater in recipients of a DCD kidney than in recipients
of a DBD kidney. In an ANZDATA registry analysis
comparing DCD kidney pairs from the same donor who
www.thelancet.com Vol 402 July 8, 2023
Articles
Balanced crystalloid Saline (n=403) Estimate (95% CI)
(n=404)
(Continued from previous page)
Length of stay for index or 6 (5–8) 6 (5–8) HR 1·05 (0·88 to 1·26)†††
transplant
hospitalisation***, days
Post-hoc analyses
Dialysis (intention to 404 403 ··
treat), n
Total number of dialysis 406 596 ··
sessions, per group
Number of dialysis 1·0 (2·09) 1·5 (2·73) IRR 0·75 (0·59 to 0·95)†††
sessions to day 28‡‡‡
Duration of dialysis§§§ 0 (0–2) 0 (0–6) HR 1·10 (1·03 to 1·16)§
up to day 84, days
Data are n (number of participants), n/N (%), mean (SD), and median (IQR), unless otherwise specified. DGF=delayed
graft function. HR=hazard ratio. IRR=incidence rate ratio. KDRI=kidney donor risk index. MD=mean difference.
RR=relative risk. *Adjusted for donor type (donation after circulatory death or brain death), KDRI tertile, machine
perfusion, ischaemic time, and clustering by centre. †Restricted to the subgroup of participants who required dialysis in
the first 7 days. ‡Analysed using a zero-truncated negative binomial regression model; the use of a zero-truncated
model was not prespecified in the statistical analysis plan but is the most appropriate approach given the absence of
zeros in the dialysis session data. §Adjusted for donor type, KDRI tertile, machine perfusion, and ischaemic time.
¶The ranked composite (ordinal) outcome included the duration of DGF (in days) for patients who received dialysis,
and graft function recovery as measured by the creatinine reduction ratio on day 2 for those who did not require
dialysis within 7 days; higher ranks (larger deciles) represent worse outcomes. ||Ordinal logistic regression model,
adjusted for donor status, KDRI tertile, machine perfusion and ischaemic time; the standard errors are adjusted for
clustering by centre; an OR of <1 suggests that the odds of having a larger rank (being in a higher decile group) are
lower for balanced crystalloids relative to saline. **Analyses restricted to participants who did not have dialysis in the
first 7 days (ie, not the intention-to-treat population); data were missing for one participant in the balanced crystalloid
group, and one participant in the saline group. ††Treatment for hyperkalaemia with any one or more of dialysis,
intravenous calcium, insulin, β agonists, sodium bicarbonate, or ion exchange resins. ‡‡Data were missing for
66 participants (65 due to missing day 2 weight values): 31 in the balanced crystalloid group and 35 in the saline
group. §§Defined as any use of inotropic drugs or vasopressors during or after surgery. ¶¶Adjusted for donor type,
KDRI tertile, machine perfusion, and ischaemic time. ||||Subdistribution HR from Fine and Gray competing risk analysis;
adjusted for donor type, KDRI tertile, machine perfusion, and ischaemic time. ***In this time-to-event analysis, a
shorter time to hospital discharge is favourable, and thus an HR >1 favours balanced crystalloid versus saline. Three
participants in the saline group died before discharge and were assigned the longest stay of 53 days (1 day more than
the longest calculated stay); nine participants (three in the balanced crystalloid group and six in the saline group) had
missing discharge data and were excluded (none died or had graft failure and all except one in the saline group
completed the study). †††Adjusted for donor type, KDRI tertile, machine perfusion, and ischaemic time, with robust
sandwich covariance estimates for clustered data. ‡‡‡Analysed using a zero-inflated negative binomial regression
model. §§§In this time-to-event analysis, a shorter duration of dialysis is favourable, so an HR >1 favours balanced
crystalloid versus saline.
Table 2: Trial outcomes
did and did not have DGF, graft function (eGFR) was
similar in both groups at 12 months, but by 3 years,
patients with DGF had significantly lower graft function
and a higher risk of graft loss,5 suggesting that the
deleterious effects of DGF might not yet be evident in
analyses restricted to the first year after transplantation,
as in this trial. Some studies28,29 have questioned the
relevance of the accepted definition of DGF (dialysis
within the first week after transplantation) and its effect
on long-term outcomes, especially when DGF is of short
duration, or follows DCD transplan­tation. However, not
only does the need for dialysis represent a costly,
burdensome, and uncomfortable treat­ment for patients
during their postoperative recovery,30 registry studies4,5
and meta-analyses6,31 have also consis­tently found that
DGF defined in this way is associated with significantly
increased risks of graft failure and mortality.
113
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Balanced crystalloid Saline Relative risk (95% CI) pinteraction

Overall <0·0001
All patients 121/404 (30·0%) 160/403 (39·7%) 0·74 (0·66–0·84)
Donor type 0·0072
DCD 44/99 (44·4%) 70/102 (68·6%) 0·65 (0·54–0·78)
DBD 77/305 (25·3%) 90/301 (29·9%) 0·88 (0·74–1·04)
KDRI tertile 0·96
First 29/137 (21·2%) 38/140 (27·1%) 0·76 (0·52–1·12)
Second 48/145 (33·1%) 64/144 (44·4%) 0·75 (0·63–0·89)
Third 44/122 (36·1%) 58/119 (48·7%) 0·76 (0·68–0·85)
Machine perfusion 0·50
No 119/393 (30·3%) 156/394 (39·6%) 0·75 (0·66–0·86)
Yes 2/11 (18·2%) 4/9 (44·4%) 0·71 (0·17–2·91)
Ischaemic time 0·57
<10 h 42/175 (24·0%) 58/178 (32·6%) 0·71 (0·55–0·91)
≥10 h 79/229 (34·5%) 102/225 (45·3%) 0·77 (0·66–0·90)
Ischaemic time 0·94
<14 h 91/314 (29·0%) 113/298 (37·9%) 0·76 (0·63–0·92)
≥14 h 30/90 (33·3%) 47/105 (44·8%) 0·75 (0·61–0·92)

0·5 1·0 1·5 2·0

Favours balanced crystalloid Favours saline

Figure 3: Subgroup analysis of delayed graft function

Note that the pinteraction values have not been adjusted for multiple testing (appendix p 39). DCD=donation after circulatory death. DBD=donation after brain death.
KDRI=Kidney Donor Risk Index.

100 Raw counts of haemodialysis by group However, two other large, multicentre, randomised
double-blind trials (PLUS and BaSICS) reported no
Balanced crystalloid: 406 treatments (n=404)
Saline: 596 treatments (n=403) differences in kidney outcomes, including requirement for
80
Difference: 190 treatments dialysis, between saline and Plasma-Lyte 148. 34,35 The use of
IRR* 0·75 (95% CI 0·59–0·95)
substantially lower volumes of intravenous fluids
Participants (%)

60
Time to dialysis independence (up to week 12)†
Hazard ratio* 1·10 (95% CI 1·03–1·16)
40
20
0 between these trials and our findings.
0 1 2 3 4 5 ≥6
Number of haemodialysis treatments
Figure 4: Number of haemodialysis treatments to day 28 by treatment group
DGF=delayed graft function. HR=hazard ratio. IRR=incidence rate ratio. *Intention-
to-treat analysis, adjusted for donor type, machine perfusion, Kidney Donor Risk
Index tertile, ischaemic time, and clustering by centre.†Dialysis duration to
week 12 was analysed using a Cox proportional hazards model for time to dialysis
independence. Shorter times are considered favourable, thus an HR of more than
1·0 favours balanced crystalloid. The dotted vertical line separates no DGF (dialysis
count=0) from DGF (counts of 1 or more).
Several large, well conducted trials in hospital inpatient
and intensive care settings have examined the effect of
balanced crystalloids versus saline on the risk of acute
kidney injury in more heterogeneous populations than
this trial but have yielded inconsistent results. Two large,
single-centre, cluster randomised, open-label trials
(SALT-ED and SMART) found balanced crystalloids
(predominantly Lactated Ringers) achieved a modest
reduction in a composite of major adverse kidney events.32,33
(reducing the potential harm from saline), receipt of open-
label fluids, particularly saline, before trial enrolment
(resulting in contamination of any benefit from balanced
crystalloids),36 and less kidney ischaemic injury in critical
care settings compared with recipients of kidney
transplants might explain the apparent discrepancy
This trial has several strengths. It was a multicentre,
double-blind, investigator-initiated trial, which used
a pragmatic, registry-embedded design that facilitated
enrolment of a representative population of kidney
transplant recipients with minimal selection bias. We
enrolled 37% of all eligible patients who received a
transplant in Australia and New Zealand during the trial
period, and a comparison of trial participants with other
patients in Australia and New Zealand, and in the USA,
indicated that our results were broadly generalisable.25
Randomisation occurred before transplantation, thereby
avoiding contamination due to open-label fluid use.
Adherence to the intervention was high and there were
negligible missing data for the primary outcome.
Although registry-based data capture was used to
enhance the efficiency of enrolment and data capture,
the data were collected and entered into the registry by
hospital research staff and audited by the trial sponsor,
thus ensuring data accuracy and completeness.

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for the effect of balanced crystalloid versus saline in the

Balanced Saline Risk difference p value
crystalloid (n=409) (95% CI)* machine perfusion subgroup (RR 0·71, 95% CI 0·17–2·91).
(n=406) Our findings might therefore not be generalisable to
Investigator-reported adverse events transplantations in which machine perfusion is used.
Serious adverse 3 (<1%) 5 (1%) –0·5% 0·48 DGF is a common and increasing problem in deceased
events† (–1·8 to 0·9) donor kidney transplantation, driven by greater use of
Adverse events from discharge codes (ICD-10 and ACHI)‡ kidneys from older, increasingly multimorbid donors and
Ischaemic 8 (2%) 3 (1%) 1·2% 0·13 DCD kidneys.2,3 Intravenous fluid therapy is an
cardiac event§ (–0·4 to 2·8) inexpensive, yet critical part of the treatment given to all
Arrhythmia 5 (1%) 7 (2%) –0·5% 0·57 recipients of kidney transplantations. Because of the
(any)§ (–2·1 to 1·2)
substantial morbidity and costs associated with DGF and
Atrial 2 (<1%) 3 (1%) –0·2% 0·66 subsequent need for dialysis, our finding of a substantial
arrhythmia§ (–1·3 to 0·8)
benefit for balanced crystalloid solution over saline
Ventricular 3 (<1%) 4 (1%) –0·2% 0·71
arrhythmia§ (–1·5 to 1·0) without any concerning signals for harm provides a strong
Other 11 (3%) 13 (3%) –0·5% 0·70 justification for a change to clinical practice. Kidney
cardiovascular (–2·8 to 1·9) transplantation is practised in countries across the full
event§ spectrum of income status.38 The low cost and wide
Electrolyte 0 0 ·· ·· availability of balanced crystalloids make this intervention
disturbance §¶
readily implementable at transplantation centres globally.
Admission to 1 (<1%) 12 (3%) –2·7% 0·0015
In conclusion, among patients receiving a deceased
ICU requiring (–4·4 to –1·0)
ventilation|| donor kidney transplant, intravenous fluid therapy with
the balanced crystalloid solution Plasma-Lyte 148 during
Data are numbers of participants who had one or more of the listed events (%),
unless otherwise specified. ACHI=Australian Classification of Health Interventions. and after surgery reduced the incidence of DGF, defined as
ICD-10=International Statistical Classification of Diseases and Related Health the need for dialysis within 7 days, compared with saline.
Problems, tenth revision (Australian modification). ICU=intensive care unit.
Contributors
*Exact confidence limits for the balanced crystalloid group minus the saline group.
MGC proposed the trial concept. MGC, SJC, MAF, EMP, CMH, DWJ,
†WHO definition; only eight serious adverse events were reported, so we have not
provided a breakdown by category. ‡See appendix pp 20–24 for a listing of the
JV, LEH, and LAV designed the trial, wrote the protocol, and had
ICD-10 and ACHI codes. §Data were missing for one participant in the balanced oversight over trial conduct. PAC, KBD, RCM, DR, PFM, LW, CJM,
crystalloid group (denominator 405). ¶There were no ICD-10 codes for electrolyte ZHE, KH, MH, CK, JML, WHL, SJM, HLP, and GW contributed to trial
disturbance reported in the listing of discharge codes for any of the participants. design and oversight. MGC, MAF, SJC, PFM, LW, PTC, ZHE, DG, JSJ,
||Data were missing for four participants in the balanced crystalloid group and JK, WHL, SJM, PJO, and GW enrolled participants and oversaw all
three in the saline group (denominators 402 and 406, respectively). clinical follow-up and data collection at their site. PAC and KDB oversaw
data collection processes at the ANZDATA registry. JV, EMP, LEH, LAV,
Table 3: Adverse events and CK oversaw central data management and quality assurance.
The manuscript was initially drafted by MGC with input from SJC, DWJ,
CMH, EMP and MAF. All authors contributed to data interpretation,
Balanced against these strengths, there were several critical review, and revisions of the manuscript. EMP and MGC have
accessed and verified the trial data. EMP oversaw the statistical analysis
limitations. As a pragmatic trial, data collection was and vouches for the fidelity of this report to the trial protocol and
generally limited to that routinely recorded in clinical care. statistical analysis plan. All authors had full access to the study data and
We limited mandatory serious adverse event reporting by had final responsibility for the decision to submit for publication.
investigators to events deemed to be related to the trial Declaration of interests
fluids; the difference in intensive care unit admissions for MGC has received research support from Baxter Healthcare, the
ventilation between the groups seen in discharge coding manufacturer of Plasma-Lyte 148, via a Baxter Investigator-Initiated
Research grant that provided fluids for the BEST-Fluids trial (commercial
data suggests that some important events might not have value of US$36 270). DWJ has received consultancy fees, research grants,
been captured with this strategy. We also do not have data speaker’s honoraria, and travel sponsorships from Baxter Healthcare and
on the reasons for intensive care unit admissions, so are Fresenius Medical Care; consultancy fees from AstraZeneca and AWAK;
speaker’s honoraria and travel sponsorships from ONO; and travel
unable to establish the reasons for this difference
sponsorships from Amgen. DR, LEH, LAV, EMP, CK, and JV are
(eg, whether it was due to iatrogenic fluid overload or due employees of the sponsor, The University of Queensland. KBD’s salary
to other reasons). There were missing data on some was funded by a Better Evidence and Translation in Chronic Kidney
laboratory measures, and, except for creatinine, these were Disease (BEAT-CKD) grant‚ and she is an employee of the ANZDATA
Registry. PAC is the Deputy Executive Officer of the ANZDATA Registry.
only collected until day 2 after transplantation. We did not
CMH has received fees for research committee activities from Janssen
collect the results of laboratory tests taken before and GlaxoSmithKline paid to her institution; personal fees from Otsuka;
transplantation. We did not collect data on haemodynamic research grants from Fresenius, Shire, and PKD Australia outside the
variables, such as blood pressure, residual urine submitted work; and research grants from Baxter and the National
Health and Medical Research Council of Australia related to the current
output, drug dosing, or therapeutic drug monitoring,
project. LW works in the Department of Anaesthesia at Austin Health,
or surgical anastomosis time. In addition, machine which has received funding from Baxter Healthcare for investigator-
perfusion of kidneys before transplantation, which can initiated clinical research. PFM has received honoraria for presentations
have a clinically significant effect on the rate of DGF,37 was on behalf of AstraZeneca and consultancy fees from Vifor. LW has
received honoraria from Baxter Healthcare for consulting activities.
infrequent (2%), as shown by the wide confidence interval

www.thelancet.com Vol 402 July 8, 2023 115

 Articles
All LW’s fluid-related research, including study design, execution, data
collection, analysis, and reporting, has been conducted independently of
Baxter Healthcare and other commercial entities. ZHE has received
consultancy fees and travel sponsorships from AstraZeneca. WHL has
received honoraria from Alexion and education or research grants from
Astellas. SJC has received research support, travel support, speaker fees,
or honoraria from AstraZeneca, Bayer, CSL-Behring, Novartis, and
Takeda. All other authors declare no competing interests.
Data sharing
Individual participant data that underlie the results reported in this
publication, after de-identification (text, tables, figures, and appendices)
will be available for individual participant data meta-analysis. Proposals
can be submitted beginning 2 years and ending 5 years after main
publication. After 5 years, the data will be available from a designated
data warehouse but without investigator support other than deposited
metadata. An independent review board will assess proposals from bona
fide investigators on the basis of the following criteria: sound science,
benefit–risk balancing, and research team expertise.
Acknowledgments
The BEST-Fluids trial was funded by an Australian Government Medical
Research Future Fund (MRFF) Rare Cancers, Rare Diseases and Unmet
Needs Grant 2018 (application ID 1152390), and a Health Research
Council of New Zealand Project Grant 2017 (17/414). Additional support
was received via allocation of funds from the National Health and Medical
Research Council of Australia Program Grant 2014 held by the BEAT-CKD
group of investigators (Chief Investigator A: Jonathan Craig, application
ID 1092957). MGC was supported by Royal Australasian College of
Physicians Jacquot Research Establishment Fellowship Grants awarded
in 2017 and 2018. The trial was also supported by the manufacturer of
Plasma-Lyte 148, Baxter Healthcare (Deerfield, IL, USA), who provided in
kind support via a Baxter Investigator Initiated Research Grant
(Medication Delivery) 2017 to provide 930 boxes of trial fluid. Additional
fluids required to complete the trial (380 boxes) were purchased under
standard commercial agreements from Baxter Healthcare (Australia). We
thank all the patients who generously agreed to participate in the BEST-
Fluids trial. We are also very grateful to the many clinical staff (medical,
nursing, theatre staff, and many others) at participating hospitals who
supported the conduct of this trial. We thank the staff at the Australia and
New Zealand Dialysis and Transplant Registry who helped to develop and
manage the trial-specific module within ANZDATA, and who worked
closely with us to collect and extract the trial data: Stephen McDonald,
Kylie Hurst, Matilda Antoine, and Maneesha Kandamby. We thank the
staff at the NHMRC Clinical Trials Centre who developed the
randomisation module, and the staff at Baxter Healthcare who assisted
the trial by manufacturing, blinding, supplying, and distributing the trial
fluids. We are especially grateful to Elizabeth Broadbent (University of
Auckland), for her assistance with reviewing and providing feedback on
the original drafts of the patient information sheets and consent forms,
and to Julian Singer (University of Sydney) who created the forest plot
figure (figure 3). We also thank Peta-Anne Paul-Brent and Stephanie
Smith (AKTN, University of Queensland) for their contributions to
developing the protocol, Justin Scott (QCIF Bioinformatics, University
of Queensland) for statistical support, and Ross Francis (Princess
Alexandra Hospital, Brisbane) and Katherine Barraclough (Royal
Melbourne Hospital, Melbourne) who contributed to the development of
the study design as members of the AKTN Transplant Working Group.
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