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.

Statistical analysis plan for Better Evidence for Selecting Transplant Fluids (BEST-Fluids): a randomised controlled trial of the effect of intravenous fluid therapy with balanced crystalloid versus saline on the incidence of delayed graft function in deceased donor kidney transplantation.

BACKGROUND: 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. 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 DESIGN: BEST-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. DISCUSSION: BEST-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 REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000358347 . Prospectively registered on 8 March 2017 ClinicalTrials.gov identifier NCT03829488 . Registered on 4 February 2019.

Conducting clinical trials during the COVID-19 pandemic-a collaborative trial network response.

The unprecedented demand placed on healthcare systems from the COVID-19 pandemic has forced a reassessment of clinical trial conduct and feasibility. Consequently, the Australasian Kidney Trials Network (AKTN), an established collaborative research group known for conducting investigator-initiated global clinical trials, had to efficiently respond and adapt to the changing landscape during COVID-19. Key priorities included ensuring patient and staff safety, trial integrity and network sustainability for the kidney care community. New resources have been developed to enable a structured review and contingency plan of trial activities during the pandemic and beyond.

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.

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.

Cardiac biomarkers in dialysis.

Cardiovascular disease is the major cause of death, accounting for approximately 40 percent of all-cause mortality in patients receiving either hemodialysis or peritoneal dialysis. Cardiovascular risk stratification is an important aspect of managing dialysis patients as it enables early identification of high-risk patients, so therapeutic interventions can be optimized to lower cardiovascular morbidity and mortality. Biomarkers can detect early stages of cardiac injury so timely intervention can be provided. The B-type natriuretic peptides (Brain Natriuretic peptide [BNP] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and troponins have been shown to predict mortality in dialysis patients. Suppression of tumorigenicity 2 (ST2) and galectin-3 are new emerging biomarkers in the field of heart failure in both the general and dialysis populations. This article aims to discuss the current evidence regarding cardiac biomarker use to diagnose myocardial injury and monitor the risk of major adverse cardiovascular events in patients undergoing dialysis.

N-terminal pro-B-type natriuretic peptide variability in stable dialysis patients.

BACKGROUND AND OBJECTIVES: Monitoring N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful for assessing cardiovascular risk in dialysis patients. However, its biologic variation is unknown, hindering the accurate interpretation of serial concentrations. The aims of this prospective cohort study were to estimate the within- and between-person coefficients of variation of NT-proBNP in stable dialysis patients, and derive the critical difference between measurements needed to exclude biologic and analytic variation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-five prevalent hemodialysis and peritoneal dialysis patients attending two hospitals were assessed weekly for 5 weeks and then monthly for 4 months between October 2010 and April 2012. Assessments were conducted at the same time in the dialysis cycle and entailed NT-proBNP testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they became unstable. RESULTS: This study analyzed 136 weekly and 113 monthly NT-proBNP measurements from 40 and 41 stable patients, respectively. Results showed that 22% had ischemic heart disease; 9% and 87% had left ventricular systolic and diastolic dysfunction, respectively. Respective between- and within-person coefficients of variation were 153% and 27% for weekly measurements, and 148% and 35% for monthly measurements. Within-person variation was unaffected by dialysis modality, hydration status, inflammation, or cardiac comorbidity. NT-proBNP concentrations measured at weekly intervals needed to increase by at least 46% or decrease by 84% to exclude change due to biologic and analytic variation alone with 90% certainty, whereas monthly measurements needed to increase by at least 119% or decrease by 54%. CONCLUSIONS: The between-person variation of NT-proBNP was large and markedly greater than within-person variation, indicating that NT-proBNP testing might better be applied in the dialysis population using a relative-change strategy. Serial NT-proBNP concentrations need to double or halve to confidently exclude change due to analytic and biologic variation alone.

Biological variation of high sensitivity cardiac troponin-T in stable dialysis patients: implications for clinical practice.

BACKGROUND: Changes in high sensitivity cardiac troponin-T (hs-cTnT) concentrations may reflect either acute myocardial injury or biological variation. Distinguishing between these entities is essential to accurate diagnosis, however, the biological variation of hs-cTnT in dialysis population is currently unknown. We sought to estimate the within- and between-person coefficients of variation of hs-cTnT in stable dialysis patients, and derive the critical difference between measurements needed to exclude biological variation with 99% confidence. METHODS: Fifty-five prevalent haemo- and peritoneal-dialysis patients attending two metropolitan hospitals were assessed on 10 consecutive occasions; weekly for 5 weeks then monthly for 4 months. Assessments were conducted at the same dialysis cycle time-point and entailed hs-cTnT testing, clinical review, electrocardiography, and bioimpedance spectroscopy. Patients were excluded if they developed clinical or physiological instability. RESULTS: In total 137 weekly and 114 monthly hs-cTnT measurements from 42 stable patients were analysed. Respective between- and within-person coefficients of variation were 83% and 7.9% for weekly measurements, and 79% and 12.6% for monthly measurements. Within-person variation was unaffected by dialysis modality or cardiac co-morbidity. The bidirectional 99% reference change value was -25% and +33% for weekly measurements, and -37% and +58% for monthly measurements. CONCLUSIONS: The between-person variation of hs-cTnT in the dialysis population is markedly greater than within-person variation indicating that hs-cTnT testing is best applied in this population using a relative change strategy. An increase of 33% or a reduction of 25% in serial hs-cTnT concentrations measured at weekly intervals excludes change due to analytical and biological variation alone with 99% confidence.

Cardiac testing for coronary artery disease in potential kidney transplant recipients.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of coronary artery disease (CAD) and adverse cardiac events. Screening for CAD is therefore an important part of preoperative evaluation for kidney transplant candidates. There is significant interest in the role of non-invasive cardiac investigations and their ability to identify patients at high risk of CAD.  OBJECTIVES: We investigated the accuracy of non-invasive cardiac screening tests compared with coronary angiography to detect CAD in patients who are potential kidney transplant recipients. SEARCH METHODS: MEDLINE and EMBASE searches (inception to November 2010) were performed to identify studies that assessed the diagnostic accuracy of non-invasive screening tests, using coronary angiography as the reference standard. We also conducted citation tracking via Web of Science and handsearched reference lists of identified primary studies and review articles.   SELECTION CRITERIA: We included in this review all diagnostic cross sectional, cohort and randomised studies of test accuracy that compared the results of any cardiac test with coronary angiography (the reference standard) relating to patients considered as potential candidates for kidney transplantation or kidney-pancreas transplantation at the time diagnostic tests were performed.  DATA COLLECTION AND ANALYSIS: We used a hierarchical modelling strategy to produce summary receiver operating characteristic (SROC) curves, and pooled estimates of sensitivity and specificity. Sensitivity analyses to determine test accuracy were performed if only studies that had full verification or applied a threshold of ≥ 70% stenosis on coronary angiography for the diagnosis of significant CAD were included. MAIN RESULTS: The following screening investigations included in the meta-analysis were: dobutamine stress echocardiography (DSE) (13 studies), myocardial perfusion scintigraphy (MPS) (nine studies), echocardiography (three studies), exercise stress electrocardiography (two studies), resting electrocardiography (three studies), and one study each of electron beam computed tomography (EBCT), exercise ventriculography, carotid intimal media thickness (CIMT) and digital subtraction fluorography (DSF). Sufficient studies were present to allow hierarchical summary receiver operating characteristic (HSROC) analysis for DSE and MPS. When including all available studies, both DSE and MPS had moderate sensitivity and specificity in detecting coronary artery stenosis in patients who are kidney transplant candidates [DSE (13 studies) - pooled sensitivity 0.79 (95% CI 0.67 to 0.88), pooled specificity 0.89 (95% CI 0.81 to 0.94); MPS (nine studies) - pooled sensitivity 0.74 (95% CI 0.54 to 0.87), pooled specificity 0.70 (95% CI 0.51 to 0.84)]. When limiting to studies which defined coronary artery stenosis using a reference threshold of ≥ 70% stenosis on coronary angiography, there was little change in these pooled estimates of accuracy [DSE (9 studies) - pooled sensitivity 0.76 (95% CI 0.60 to 0.87), specificity 0.88 (95% CI 0.78 to 0.94); MPS (7 studies) - pooled sensitivity 0.67 (95% CI 0.48 to 0.82), pooled specificity 0.77 (95% CI 0.61 to 0.88)]. There was evidence that DSE had improved accuracy over MPS (P = 0.02) when all studies were included in the analysis, but this was not significant when we excluded studies which did not avoid partial verification or use a reference standard threshold of ≥70% stenosis (P = 0.09).   AUTHORS' CONCLUSIONS: DSE may perform better than MPS but additional studies directly comparing these cardiac screening tests are needed. Absence of significant CAD may not necessarily correlate with cardiac-event free survival following transplantation. Further research should focus on assessing the ability of functional tests to predict postoperative outcome.

Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies.

BACKGROUND: Cardiovascular disease is the leading cause of death after kidney transplant. Screening for coronary artery disease is integral to pretransplant evaluation, although the relative performance of different tests is uncertain. STUDY DESIGN: Systematic review of diagnostic test accuracy studies using hierarchical summary receiver operating characteristic analysis. SETTING & POPULATION: Kidney transplant candidates undergoing pretransplant assessment. SELECTION CRITERIA OF STUDIES: Studies evaluating the accuracy of screening tests for detecting coronary artery disease. INDEX TESTS: Any non- or minimally invasive test used to diagnose coronary artery disease. REFERENCE TEST: Coronary angiography. RESULTS: 11 studies (690 participants) evaluated dobutamine stress echocardiography; 7 (317 participants), myocardial perfusion scintigraphy; 2 (129 participants), exercise stress electrocardiography; and 2 (121 participants), other tests. Dobutamine stress echocardiography had pooled sensitivity of 0.80 (95% CI, 0.64-0.90) and specificity of 0.89 (95% CI, 0.79-0.94). Myocardial perfusion scintigraphy had pooled sensitivity of 0.69 (95% CI, 0.48-0.85) and specificity of 0.77 (95% CI, 0.59-0.89). Head-to-head comparison of dobutamine stress echocardiography and myocardial perfusion scintigraphy (2 studies; 116 participants) showed that dobutamine stress echocardiography had higher specificity and at least equivalent or higher sensitivity. Indirect comparison suggested dobutamine stress echocardiography may have improved accuracy over myocardial perfusion scintigraphy (P = 0.07). LIMITATIONS: Power to detect differences in accuracy between tests is limited due to sparse data. Absence of significant coronary artery disease may not necessarily correlate with cardiac event-free survival after transplant. CONCLUSIONS: Dobutamine stress echocardiography may perform better than myocardial perfusion scintigraphy; however, additional studies directly comparing dobutamine stress echocardiography and myocardial perfusion scintigraphy are needed. Further research should focus on assessing the ability of functional tests to predict postoperative outcome.