Better Evidence for Selecting Transplant Fluids

Study Overview
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Brief Summary
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End-stage kidney disease (ESKD) is a significant, expensive health problem. Kidney transplantation improves survival, quality of life, and is much cheaper than dialysis treatment for ESKD. However sometimes kidney transplants from a deceased donor function poorly after surgery, and a period of continued dialysis is needed, a condition known as delayed graft function (DGF). In addition to complicating recovery, DGF can adversely affect long-term kidney function and the health of the recipient. Intravenous fluids given during and after transplantation (usually 0.9% sodium chloride or saline) are critical to preserve kidney transplant function, but there is evidence that 0.9% saline may not be the safest fluid to use due to its high chloride content. BEST Fluids is a randomised controlled trial that aims to find out whether using a balanced low-chloride solution - Plasma-Lyte 148® - as an alternative to normal saline in deceased donor kidney transplantation, will improve kidney transplant function, reduce the impact of DGF, and improve long-term outcomes for patients.

Detailed Description
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End-stage kidney disease is a significant public health problem worldwide, and its treatment imposes a high healthcare burden and cost. Kidney transplantation is considered the best treatment for ESKD, offering improved survival and quality of life at significantly lower cost that dialysis. However, many kidney transplants fail prematurely due in part due to injury sustained at the time of transplantation. Delayed graft function (DGF), i.e. the requirement for dialysis early after transplantation, affects approximately 30% of deceased donor kidney transplants, and increases the risk of graft failure and mortality. Intravenous fluids are a critical, albeit inexpensive, aspect of care that impacts early transplant function with normal (0.9%) saline the current standard care at most centres. However, normal saline may in fact be harmful in the setting of kidney transplantation due to its high chloride content relative to plasma, causing metabolic acidosis, acute kidney injury and thus potentially increasing the risk of DGF. Utilising a balanced low-chloride crystalloid solution such as Plasma-Lyte 148® (Plasmalyte) as an alternative to 0.9% saline may therefore improve outcomes after kidney transplantation. The BEST-Fluids study is an investigator-initiated, pragmatic, registry-based, multi-centre, double -blind randomised, controlled trial. The primary objective of the study is to evaluate the effect in deceased donor kidney transplant recipients of intravenous therapy with Plasmalyte versus 0.9% saline, commencing pre-operatively and continuing until intravenous fluids are no longer required or 48 hours post-transplant (whichever is earliest), on DGF, defined as the requirement for dialysis in the first seven days post-transplant. Patients admitted for a deceased donor kidney transplant at participating centres will be invited to participate in the study prior to transplant surgery. Following informed consent, participants will be randomised to receive either blinded Plasmalyte or blinded 0.9% saline for all intravenous fluid therapy purposes until 48 hours post-transplant. The volume and rate of fluid therapy will be determined by treating clinicians; all other treatments will be as per local standard of care. Participants will be enrolled, randomised and followed up using ANZDATA, the Australia & New Zealand Dialysis & Transplant Registry. The trial was prospectively registered with Australia New Zealand Clinical Trials Registry (ANZCTR) on 08/03/2017 (ACTRN12617000358347).

Official Title
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An Investigator-initiated, Pragmatic, Registry-based, Multi-centre, Double-blind, Randomised Controlled Trial Evaluating the Effect of Plasmalyte Versus 0.9% Saline on Early Kidney Transplant Function in Deceased Donor Kidney Transplantation

Conditions
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End Stage Kidney Disease, Delayed Graft Function, Kidney Transplant; Complications

Intervention / Treatment
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* Drug: Plasma-Lyte 148 (approx. pH 7.4) IV Infusion
* Drug: 0.9% SODIUM CHLORIDE 9g/L injection BP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult or child with End-Stage Kidney Disease, of any cause, on maintenance dialysis, or who has pre-dialysis stage 5 chronic kidney disease with an estimated Glomerular Filtration Rate of <15 mL/min/1.73m2, AND Planned deceased donor kidney transplant from a brain-death (DBD) or circulatory-death (DCD) organ donor within 24 hours, AND Written informed consent, or consent given by their parent or guardian (if age <18), or other authorised person Exclusion Criteria: Planned live donor kidney transplant (except where this is cancelled in favour or transplantation from a deceased donor) Planned multi-organ transplant (dual or en-bloc kidney transplants are not excluded) Children of weight <20 kg, or a child that the treating physician believes should not be included in a study of blinded fluids due to their small body size Known hypersensitivity to the trial fluid preparations or packaging
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasma-Lyte 148 (approx. pH 7.4) IV Infusion<br>Plasma-Lyte 148 (approx. pH 7.4) IV Infusion intravenous fluid therapy will be used for all maintenance, replacement and resuscitation purposes from randomization onwards until 48 hours post-transplant, or until fluid therapy is no longer required, if earlier. | Drug: Plasma-Lyte 148 (approx. pH 7.4) IV Infusion<br>* Plasma-Lyte 148 (approx. pH 7.4) IV Infusion is a sterile, clear, non-pyrogenic isotonic solution and when administered intravenously is a source of water, electrolytes and calories. Plasma-Lyte 148 intravenous infusion is indicated as a source of water & electrolytes or as an alkalinising agent.<br>* Other names: Balanced crystalloid solution;|
| Active Comparator: 0.9% SODIUM CHLORIDE 9g/L injection BP<br>0.9% saline intravenous fluid therapy will be used for all maintenance, replacement and resuscitation purposes from randomization onwards until 48 hours post-transplant, or until fluid therapy is no longer required, if earlier. | Drug: 0.9% SODIUM CHLORIDE 9g/L injection BP<br>* Sodium chloride (0.9% saline) infusion is a sterile, non-pyrogenic solution of sodium chloride in Water for Injections. The concentration of sodium chloride is 154mmol/L. Sodium chloride (0.9%) intravenous infusion is indicated for extra-cellular fluid replacement and in the management of metabolic alkalosis in the presence of fluid loss, and for restoring or maintaining the concentration of sodium and chloride ions.<br>* Other names: Isotonic saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants with Delayed Graft Function | Delayed Graft Function defined as receiving treatment with any form of dialysis in the first seven days after transplant | 7 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early Kidney Transplant Function | Early Kidney Transplant Function, a ranked composite of Duration of Delayed Graft Function Description: Participants who require dialysis within seven days post-transplant, the time from transplant to the final dialysis treatment in days (up to 84 days/12 weeks) will be ranked from best to worst (longer times are worse). Rate of recovery of kidney transplant graft function Description: for participants who do not require dialysis, graft function assessed using the creatinine reduction ratio on post-transplant day two (CRR2) will be ranked from best to worst (smaller reductions are worse). | a. Duration of Delayed Graft Function - 12 Weeks; b. Rate of recovery of kidney transplant graft function - 2 Days | 
| Number of dialysis sessions | The number of dialysis sessions | First 28 days post-transplant | 
| Total duration of dialysis | The total duration of dialysis in days | 12 Weeks | 
| Creatinine reduction ratio from day 1 to day 2 post-transplant | Creatinine reduction ratio from day one to day two measured using serum assay, for those who do not require dialysis within the first 7 days | Day 1 to Day 2 post-transplant | 
| Reduction in serum creatinine of greater than or equal to 10% | The proportion of subjects with a reduction in serum creatinine of greater than or equal to 10% on three consecutive days in the first 7 days post-transplant | First 7 days post-transplant | 
| Serum creatinine trends over 52 weeks | Serum creatinine trends measured over 52 weeks | 12 months | 
| Incidence of serum potassium greater than or equal to 5.5 mmol/L | Serum potassium greater than or equal to 5.5 mmol/L measured by serum assay | First 48 hours post-transplant | 
| Peak potassium level | Peak potassium level, measured by serum assay | First 48 hours post-transplant | 
| Treatment for hyperkalaemia | Treatment for hyperkalaemia with dialysis, Ca2+-gluconate, insulin, beta-agonists, sodium bicarbonate or ion exchange resins in the first 48 hours post-transplant | First 48 hours post-transplant | 
| Incidence of significant fluid overload | Incidence of significant fluid overload defined as >5% weight gain | Baseline to day 2 | 
| Aggregate urine output | Aggregate urine output until day 2 post-transplant | Until day 2 post-transplant | 
| Requirement for inotropic support (use of vasopressors or other drugs to maintain adequate blood pressure) | Requirement for inotropic support both intra- and post-operatively to Day 2 | Intra- and post-operatively to Day 2 | 
| Number of acute rejection episodes | Number of acute rejection episodes in the first 52 weeks as reported by ANZDATA routine data capture and as assessed by treating physicians | 12 months | 
| Number of renal transplant biopsies | Number of renal transplant biopsies performed in the first 28 days post-transplant | First 28 days post-transplant | 
| Death from all causes | Death from all causes up to 52 weeks | Up to 52 weeks | 
| Graft survival | Graft survival and death-censored graft survival as reported by ANZDATA and assessed by treating physician | 12 months | 
| Graft function | Graft function (estimated glomerular filtration rate; eGFR) at 4, 12, 26 and 52 weeks | 4, 12, 26 and 52 weeks | 
| Health-related quality of life | Health-related quality of life measured using EuroQol EQ-5D-5L for adults, and EQ-5D-Y in children under 18 years. EQ-5D has descriptive and visual analogue scale (VAS). Descriptive system consists of five dimensions mobility, self-care, usual activities, pain/discomfort and anxiety/depression. VAS records patient's self-rated health on vertical visual analogue scale with endpoints best to worst health with 0 being worst and 100 being best health. | Baseline, day 7, day 28, week 12, week 26, and week 52 | 
| Length of hospital stay | Length of hospital stay over 12 months using linked data state and country based health data | 12 months | 
| Healthcare resource use | Healthcare resource use over 12 months using linked data state and country based health data | 12 months | 
| Cost-effectiveness | Cost-effectiveness over 12 months using linked data state and country based health data | 12 months |