Multicentre randomised controlled trial: protocol for Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO)

Abstract

IntroductionAcute electrolyte and acid–base imbalance is experienced by many children following kidney transplantation. When severe, this can lead to complications including seizures, cerebral oedema and death. Relatively large volumes of intravenous fluid are administered to children perioperatively in order to establish perfusion to the donor kidney, the majority of which are from living and deceased adult donors. Hypotonic intravenous fluid is commonly used in the post-transplant period due to clinicians’ concerns about the sodium, chloride and potassium content of isotonic alternatives when administered in large volumes.Plasma-Lyte 148 is an isotonic, balanced intravenous fluid that contains sodium, chloride, potassium and magnesium with concentrations equivalent to those of plasma. There is a physiological basis to expect that Plasma-Lyte 148 will reduce the incidence of clinically significant electrolyte and acid–base abnormalities in children following kidney transplantation compared with current practice.The aim of the Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO) trial was to determine whether the incidence of clinically significantly abnormal plasma electrolyte levels in paediatric kidney transplant recipients will be different with the use of Plasma-Lyte 148 compared with intravenous fluid currently administered.Methods and analysisPLUTO is a pragmatic, open-label, randomised controlled trial comparing Plasma-Lyte 148 to current care in paediatric kidney transplant recipients, conducted in nine UK paediatric kidney transplant centres.A total of 144 children receiving kidney transplants will be randomised to receive either Plasma-Lyte 148 (the intervention) intraoperatively and postoperatively, or current fluid. Apart from intravenous fluid composition, all participants will receive standard clinical transplant care.The primary outcome measure is acute hyponatraemia in the first 72 hours post-transplant, defined as laboratory plasma sodium concentration of <135 mmol/L. Secondary outcomes include symptoms of acute hyponatraemia, other electrolyte and acid–base imbalances and transplant kidney function.The primary outcome will be analysed using a logistic regression model adjusting for donor type (living vs deceased donor), patient weight (<20 kg vs ≥20 kg pretransplant) and transplant centre as a random effect.Ethics and disseminationThe trial received Health Research Authority approval on 20 January 2020. Findings will be presented to academic groups via national and international conferences and peer-reviewed journals. The patient and public involvement group will play an important part in disseminating the study findings to the public domain.Trial registration numbers2019-003025-22 and 16586164.

Multicenter Validation of a Urine CXCL10 Assay for Noninvasive Monitoring of Renal Transplants

“…The MSD assay was selected as the comparator for its analytical characteristics (monoclonal antibody pair, Table 1), demonstration of clinical validity in multicenter observational studies, 11 and current use in 2 RCTs evaluating the clinical utility of urine CXCL10 monitoring (NCT03140514 and NCT03206801). 26 Within this context, the Luminex assay was rigorously evaluated by multiple technicians in multiple laboratories, and it demonstrated precision, accuracy, and reproducibility. There was a high degree of correlation with the existing MSD assay in independent cohorts, which was additionally refined after the assay conversion was characterized and independently validated.…”

“…The decision to randomize to biopsy is based on 2 consecutive elevated urine CXCL10 values above the threshold, thereby simulating a clinical decision to biopsy based on a serial CXCL10 values. 26 Therefore, the final net reclassification was defined as whether a patient transitioned from unrandomized to randomized, or vice versa, with randomization acting as a surrogate for the clinical decision to biopsy. This was evaluated using within-patient ≥2 sequential urines ≤28 d apart (236 urines from 85 patients).…”

“…This is anticipated because they quantify CXCL10 using different reagents, monoclonal antibodies, and detection systems. Therefore, we sought to define the mathematical conversion between assays to optimize interchangeability of CXCL10 measurement because prior multicenter observational studies demonstrating clinical validity 11 and current kidney transplant RCTs (NCT03140514 and NCT03206801) 26 use the MSD assay. The TMCT04 cohort was divided into an independent test and validation set and a linear mixed-effects model was fit (trained) in the test set, with random patient-specific intercepts and slopes to account for repeated samples taken from some patients.…”

“…16,[22][23][24][25] Taken together, these data suggest that urine CXCL10 monitoring may enhance the noninvasive detection of rejection and can also be used for biomarkerenriched trial designs for TCMR. 10,26 Notably, a single-and a multicenter randomized controlled trial (RCT) are underway to determine whether the early treatment of rejection as detected by urine CXCL10 will improve 12-mo transplant outcomes (NCT03140514 and NCT03206801). 26 A major barrier to implementing urine CXCL10 monitoring has been the lack of a robust and reproducible monoclonal antibody pair-based quantitative assay accessible to clinical HLA laboratories.…”

Potential utility of urinary chemokine CCL2 to creatinine ratio in prognosis of 5‐year graft failure and mortality post 1‐year protocol biopsy in kidney transplant recipients

“…CXL10 has been proved to be associated with T‐cell‐mediated rejection and antibody‐mediated rejection 22,23 . Currently, a multicenter randomized controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients is being performed 24 …”