Explanation for the choice of comparators {6b}
There is physiological and clinical evidence to support the hypothesis that using a balanced low-chloride solution, such as Plasmalyte, as IV therapy in deceased donor kidney transplantation may reduce the potential for adverse effects, including acute kidney injury and DGF, which could occur due to the high-chloride content of 0.9% saline. Available low-chloride solutions that could be utilized as IV crystalloid therapy in transplantation include Plasmalyte, Hartmanns or Ringers Lactate, and Elomel Isoton (Fresenius Kabi). Hartmanns/Ringers Lactate has been used intra-operatively in trials involving transplant recipients, but has the disadvantage of being a hypotonic solution (osmolality 254 mOsm/kg), increasing the risk of post-operative hyponatremia, especially when used in significant volumes as occurs in transplantation. Elomel Isoton, which has been used in a trial of deceased donor transplant recipients, is similar to Plasmalyte, except that acetate is the sole buffer (Plasmalyte contains both acetate and gluconate buffers); however, it is not currently licensed in Australia and New Zealand. Plasmalyte is licensed in Australia, New Zealand, and many other countries, is readily available and already in use at many centers, and was recently evaluated for safety and potential efficacy in a small trial involving deceased donor kidney transplant recipients [29]. Thus, Plasmalyte was selected as the experimental low-chloride crystalloid fluid therapy for this trial.
Numerous observational studies in the surgical setting have associated the use of 0.9% saline with an increased risk of acute kidney injury [19, 22, 23, 30,31,32,33]. However, as with all observational studies, these findings may be affected by selection bias and residual confounding, making causal inferences problematic. Two prospective pilot studies (the SPLIT-ICU and SALT trials) in the intensive care setting [34, 35] evaluating the effects of buffered crystalloid solutions versus 0.9% saline reported no differences between patient groups in the rate of major adverse kidney events. More recently, in two large multiple crossover cluster trials involving > 20,000 non-critically ill and critically ill adult patients, the use of Hartmann’s solution or Plasmalyte resulted in a lower rate of major adverse kidney events when compared to 0.9% saline [20, 21]. Importantly, these studies did not discriminate between patients undergoing kidney transplant and other patients and did not involve individual blinding of the treatment assignments.
In the context of major surgery, the effects of restricting peri-operative use of IV chloride on kidney injury were examined in the LICRA and SOLAR trials [36, 37]. In both studies, there was no clinically meaningful difference in the risk of a composite of in-hospital mortality and major post-operative complications, including acute kidney injury. Patients undergoing kidney transplantation were excluded. Accordingly, there are no current guidelines on which crystalloid solution should be used in deceased donor kidney transplantation.
Currently, IV therapy with 0.9% saline is the standard of care at the majority of transplant centers in Australia and New Zealand. In a 2016 survey of 22 renal transplant centers conducted by several of the authors (MC, MF, DR, CH, and SC), 64% reported using 0.9% saline intra-operatively and 87% reported using it post-operatively (unpublished observations), which is similar to published studies from other countries [14]. Hence, 0.9% saline was chosen as the standard of care to use as the control therapy in this trial.
Intervention description {11a}
Participants will be randomized to one of two blinded fluid-therapy groups:
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1.
Plasmalyte: low-chloride, balanced crystalloid solution, Plasma-Lyte 148 (approx. pH 7.4) IV Infusion (Baxter Healthcare, Toongabbie, NSW, Australia) or
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2.
0.9% Saline: isotonic Sodium Chloride (0.9%) IV Infusion BP (Baxter Healthcare, Toongabbie, NSW, Australia).
The allocated trial fluid is administered blinded as the routine IV fluid therapy for all maintenance, replacement, and resuscitation purposes. The fluid is administered from randomization onwards pre-operatively, intra-operatively, and post-operatively, until either IV fluid therapy is no longer required or until 48 h post-transplant, whichever is earliest. The rate and volume of fluid administration are not mandated by the study protocol and are prescribed by treating physicians according to usual center practice.
Participants are each allocated an individual box containing 12 × 1000 mL bags of blinded trial fluid labelled with a unique 4-digit study code (treatment pack number). The treatment pack number is provided by the randomization system (accessed via ANZDATA), corresponding with an available box at the study site. The box of allocated fluids remains physically with the participant during their hospital stay, and is transported with them to the operating theatre and other hospital locations as required. A further two boxes of 12 × 1000 mL fluid bags can be allocated by the randomization system prior to 48 h post-transplant, allowing up to 36 L of trial fluid to be used per participant if required. Each uniquely labelled box can be allocated to one participant only.
Criteria for discontinuing or modifying allocated intervention {11b}
Blinded trial fluids may be temporarily or permanently discontinued by the treating clinician or investigator at any time if (1) the IV fluids are no longer indicated or required, (2) there is an indication for a specific open-label fluid that cannot be co-administered with study fluids, (3) a serious adverse event occurs that may be related to fluid therapy, (4) continuation is deemed not to be in the participant’s best interests, or (5) if requested by the treating physician or participant.
Once the 48-h post-transplant timepoint is reached, participants who continue to require IV fluids may be continued on trial fluids beyond 48 h, until the stock of fluid bags within a previously allocated box is exhausted. Alternatively, participants may be converted to open-label fluids prescribed by the treating physician at their discretion.
Strategies to improve adherence to interventions {11c}
A face-to-face initiation meeting was held prior to the commencement of the trial at each site. Site investigators and research staff engaged with their multidisciplinary teams and provided training and tailored local resources to support adherence to the intervention, including checklists, trial alert notices in the medical records, handover documents affixed to the patient’s hospital bed, and trial fluid accountability logs. Presentations on the trial were typically given by site investigators at meetings of clinicians involved in transplant peri-operative care, including transplant and anesthesia departments, to maximize awareness and engagement. Monitoring visits by the staff from the trial coordinating center are conducted periodically to evaluate risk mitigation strategies and confirm adequate study fluid supplies, training, and resources to meet site needs.
Relevant concomitant care permitted or prohibited during the trial {11d}
The use of other non-trial fluids, such as blood products, are permitted as per routine clinical care and treating physician discretion. The use of non-trial open-label crystalloids is permitted in specific circumstances (e.g. hypotonic solutions for hypernatremia, or for administration of IV medications), but is otherwise discouraged in the absence of a compelling clinical indication.
All participants receive usual transplant management as per the local standard of care. This includes peri-operative anesthesia and invasive monitoring, circulatory support, surgical care, immunosuppression, routine prophylactic measures, the management of fluid overload, hyperkalemia and other electrolyte disturbances, and other complications. Hyperkalemia is treated as per standard practice and local protocols. Dialysis is performed for standard clinical indications, as determined by treating clinicians. Further details of protocol recommendations for concurrent participant management, including the use of open-label crystalloids and other fluid therapy, are outlined in Additional file 3.
Provisions for post-trial care {30}
Following completion of the trial intervention at 48 h post-transplant, participants are followed up until 12 months post-transplant. All post-transplant care is provided by the hospital where the transplant takes place or other local hospital, as per routine practice. The Sponsor has indemnity insurance to cover those who suffer from potential harm due to participation in the trial. New Zealand participants are eligible to apply for compensation from the New Zealand Accident Compensation Corporation (ACC) for treatment-related injuries that occur due to participation in the trial.
Outcomes {12}
Primary outcome measure
The primary outcome is the proportion of participants with DGF, defined as those receiving treatment with any form of dialysis in the first 7 days after transplant.
Secondary outcome measures
The secondary outcome measures include the following:
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1.
Early Kidney Transplant Function, measured using a ranked composite of (a) the duration of delayed graft function in days for the participants requiring dialysis, and (b) the rate of transplant graft function recovery measured by creatinine reduction ratio on day 2 (CRR2) [38] for the participants who do not receive dialysis. CRR2 (%) = ([creatinineday 1-creatinineday 2]*100)/creatinineday1 (see Additional file 4 for further details).
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2.
The number of dialysis sessions (in the first 28 days), and the total duration of dialysis in days (from transplant to the final dialysis treatment).
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3.
Creatinine reduction ratio on day 2 post-transplant, and the proportion of participants with a decrease in serum creatinine of ≥ 10% on 3 days consecutively in the first 7 days post-transplant.
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4.
Serum creatinine trends over 52 weeks.
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5.
Incidence of serum potassium ≥ 5.5 mmol/L and peak potassium level in the first 48 h post-transplant.
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6.
Treatment for hyperkalemia with dialysis, IV calcium, insulin, β-agonists, sodium bicarbonate, or ion exchange resins in the first 48 h post-transplant.
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7.
Incidence of significant fluid overload, defined as > 5% weight gain (baseline to day 2).
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8.
Aggregate urine output until day 2 post-transplant.
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9.
Requirement for inotropic support, both intra-operatively and post-operatively, to day 2.
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10.
Number of acute rejection episodes in the first 52 weeks.
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11.
Number of renal transplant biopsies performed in the first 28 days post-transplant.
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12.
Mortality up to 52 weeks.
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13.
Graft survival and death-censored graft survival at 52 weeks.
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14.
Graft function (eGFR derived from serum creatinine using the CKD-EPI equation [27] (adults) or the bedside Schwartz equation [28] (children) at 4, 12, 26, and 52 weeks.
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15.
Health-related quality of life, as measured by the EuroQol five dimensions questionnaire (EQ-5D-5 L) for adults and by the EuroQol five dimensions Youth questionnaire (EQ-5D-Y) for children aged < 18 years.
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16.
Length of hospital stay, healthcare resource use and cost-effectiveness over 12 months.
Participant timeline {13}
Participants are followed up in the study from randomization until 52 weeks after transplant surgery. Figure 3 shows the schedule of enrolment, interventions, and assessments. Data collection occurs at baseline, post-operatively (on arrival to the post-anesthetic recovery unit after transplant surgery), on days 1, 2, 7, and 28, and on weeks 12, 26, and 52 (see Additional file 5 for further details).
Sample size {14}
The sample size for the BEST-Fluids trial (800 participants) is based on a comparison between two independent groups of the proportions of participants experiencing the primary outcome measure of DGF. The effect size, or minimum clinically important difference, was determined by considering that a relative risk (RR) reduction of approximately 25% (RR of 0.75) for the incidence of the primary outcome would be both clinically meaningful and within the range of biological plausibility for the association between DGF and Plasmalyte versus 0.9% saline. The latter is based on trends observed in (1) the Weinberg trial [29]: RR of dialysis within 48 h post-transplant of 0.78 (95% confidence interval (CI) 0.47 to 1.28) and (2) a recently published before-and-after non-randomized interventional study [39]: RR for dialysis within 48 h of 0.3 (95% CI 0.10 to 0.97; adjusted odds ratio 0.14; 95% CI 0.03 to 0.48), as the most current and relevant data available.
A sample size of 722 participants (361 per group) will have 80% power at a 5% two-sided significance level to show an estimated absolute difference between the groups of 10% (41% versus 31%), with an estimated overall incidence of DGF of 36% and RR for Plasmalyte versus 0.9% saline of 0.76. Allowing for 4.0% non-adherence (estimated 2% drop-out from the Plasmalyte group and 2% drop-in) and up to 1% loss to follow up for the primary outcome measure (e.g. due to death or withdrawal of consent within 7 days), an adjusted sample size of 792 participants is required. To allow for fluctuations in these estimates, a total of 800 participants will be recruited.
While the target recruitment allows for 1% loss to follow up, it is expected that loss to follow-up in this study for both the primary outcome (7 days) and secondary outcomes (up to 12 months) will be close to zero due to (1) the very close clinical follow up that renal transplant recipients routinely receive, (2) the short timeframe for ascertainment of the primary outcome (7 days post-transplant), and (3) the fact that transplant recipients are highly motivated patients who typically maintain strong engagement with their care providers.
Recruitment {15}
BEST-Fluids is being conducted at 13 adult hospitals and 3 children’s hospitals that perform kidney transplants in Australia and New Zealand. Collectively these hospitals performed more than 500 deceased donor kidney transplants annually in the year prior to trial commencement; thus, approximately 50–55% of eligible patients overall need to be enrolled to meet the target sample size of 800 over 3 years.
Strategies have been implemented to achieve optimal participant enrolment: comprehensive site engagement with members of the multi-disciplinary clinical team prior to initiation of the trial, a pragmatic trial design with broad eligibility criteria, recruitment of participants by clinical staff who usually undertake the pre-operative assessments prior to transplant at each site, consent forms written in plain English (with interpreters available where required), a simple, rapid randomization process accessed online using ANZDATA, and the alignment of trial processes and the study intervention with usual clinical care. Each site has been provided with training on and resources for the trial, including short online randomization training videos to familiarize them with the ANZDATA Registry web-based platform used for enrolment. With few exceptions, participants are already being treated with dialysis and are registered in the ANZDATA Registry prior to being admitted for transplant, which greatly simplifies the process of enrolment. On-call 24-h telephone support is provided to clinical staff who are enrolling participants, with the ability to access assistance for enrolment and randomization from an investigator on the coordinating committee.
