An epitope-based approach of HLA-matched platelets for transfusion: a noninferiority crossover randomized trial.

Platelet transfusion refractoriness results in adverse outcomes and increased health care costs. Managing refractoriness resulting from HLA alloimmunization necessitates the use of HLA antigen-matched platelets but requires a large platelet donor pool and does not guarantee full matching. We report the first randomized, double-blind, noninferiority, crossover trial comparing HLA epitope-matched (HEM) platelets with HLA standard antigen-matched (HSM) platelet transfusions. Alloimmunized, platelet-refractory, thrombocytopenic patients with aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia were eligible. HEM platelets were selected using HLAMatchMaker epitope (specifically eplet) matching. Patients received up to 8 prophylactic HEM and HSM transfusions provided in random order. The primary outcome was 1-hour posttransfusion platelet count increment (PCI). Forty-nine patients were randomized at 14 UK hospitals. For intention to treat, numbers of evaluable transfusions were 107 and 112 for HEM and HSM methods, respectively. Unadjusted mean PCIs for HEM and HSM methods were 23.9 (standard deviation [SD], 15) and 23.5 (SD, 14.1), respectively (adjusted mean difference, -0.1; 95% confidence interval [CI], -2.9 to 2.8). Because the lower limit of the 95% CI was not greater than the predefined noninferiority limit, the HEM approach was declared noninferior to the HSM approach. There were no differences in secondary outcomes of platelet counts, transfusion requirements, and bleeding events. Adequate 1-hour PCI was more frequently observed, with a mean number of 3.2 epitope mismatches, compared with 5.5 epitope mismatches for inadequate 1-hour increments. For every additional epitope mismatch, the likelihood of an adequate PCI decreased by 15%. Epitope-matched platelets should be considered to support HLA alloimmunized patients. This trial was registered at www.isrctn.com as #ISRCTN23996532.

Red cell transfusion in outpatients with myelodysplastic syndromes: a feasibility and exploratory randomised trial.

Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow-up in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ-C30 and EQ-5D-5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85-100 g/l) with liberal thresholds (105 g/l, maintaining 110-125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention-to-treat population was 86% (95% confidence interval 75-94%) and 99% (95-100%) for restrictive and liberal arms respectively. Mean pre-transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient-centred outcomes.

Multiply imputing missing values arising by design in transplant survival data.

In this article, we address a missing data problem that occurs in transplant survival studies. Recipients of organ transplants are followed up from transplantation and their survival times recorded, together with various explanatory variables. Due to differences in data collection procedures in different centers or over time, a particular explanatory variable (or set of variables) may only be recorded for certain recipients, which results in this variable being missing for a substantial number of records in the data. The variable may also turn out to be an important predictor of survival and so it is important to handle this missing-by-design problem appropriately. Consensus in the literature is to handle this problem with complete case analysis, as the missing data are assumed to arise under an appropriate missing at random mechanism that gives consistent estimates here. Specifically, the missing values can reasonably be assumed not to be related to the survival time. In this article, we investigate the potential for multiple imputation to handle this problem in a relevant study on survival after kidney transplantation, and show that it comprehensively outperforms complete case analysis on a range of measures. This is a particularly important finding in the medical context as imputing large amounts of missing data is often viewed with scepticism.

Renal allograft survival rates in kidneys initially declined for paediatric transplantation.

BACKGROUND: The outcome of organs which have been declined for paediatric recipients is not known. This study aimed to determine the outcome of kidneys initially declined for paediatric recipients and establish renal allograft survival in kidneys that were eventually transplanted. METHODS: Data were obtained from the UK Transplant Registry for all donation after brain death (DBD) kidneys offered and declined to paediatric recipients (< 18 years) in the UK from 2009 to 2014. RESULTS: Eighty-two percent (503/615) of kidneys initially declined for paediatric transplantation were eventually transplanted, 7% (46/615) of kidneys went to paediatric recipients and 62% (384/615) of kidneys went to adult (kidney only) recipients. The remainder were used for multiple organ transplants. In the 46 kidneys that went to paediatric recipients, 1 and 3-year renal allograft survivals were 89% (95% CI 75.8-95.3%) and 82% (95% CI 67.1-90.6%), respectively. In the 384 kidneys given to adult kidney-only recipients, 1 and 3-year renal allograft survivals were 96% (95% CI 93.5-97.6%) and 94% (95% CI 90.7-96.1%), respectively. Eighty-four percent of the 204 children who initially had an offer declined on their behalf were eventually transplanted and have a functioning graft at a median 3-year follow-up. CONCLUSIONS: This study reports acceptable short-term renal allograft survival in kidneys that were initially declined for paediatric recipients and subsequently transplanted. Evidence-based guidelines are required to ensure that the most appropriate kidneys are selected for paediatric recipients.

UK Renal Registry 15th annual report: Chapter 9 centre variation in access to renal transplantation in the UK (2006-2008).

BACKGROUND: Renal transplantation is recognised as being the optimal treatment modality for many patients with established renal failure. This analysis aimed to explore inter-centre variation in access to renal transplantation in the UK. METHODS: Transplant activity and waiting list data were obtained from NHS Blood and Transplant, demographic and laboratory data were obtained from the UK Renal Registry. All incident RRT patients starting treatment between 1st January 2006 and 31st December 2008 from 72 renal centres were considered for inclusion. The cohort was followed until 31st December 2010 (or until transplantation or death, whichever was earliest). RESULTS: Age, ethnicity and primary renal diagnosis were associated with both accessing the kidney transplant waiting list and receiving a kidney transplant. A patient starting dialysis in a non-transplanting renal centre was less likely to be registered for transplantation (OR 0.80, 95% CI 0.74-0.87) or receive a transplant from a donor after cardiac death or a living kidney donor (OR 0.69, 95% CI 0.61-0.77) compared with patients cared for in transplanting renal centres. Once registered for kidney transplantation, patients in both transplanting and non-transplanting renal centres had an equal chance of receiving a transplant from a donor after brainstem death (OR 0.92, 95% CI 0.79-1.08). CONCLUSION: There was wide variation in access to kidney transplantation between UK renal centres which cannot be explained by differences in case mix.

UK Renal Registry 16th annual report: chapter 4 demography of patients waitlisted for renal transplantation in the UK: national and centre-specific analyses.

INTRODUCTION: For suitable patients, renal transplantation is considered the optimal modality of renal replacement therapy, with availability of donor organs limiting the number of transplants undertaken. The 2006 kidney allocation policy was developed to ensure equity of allocation to patients on the transplant waiting list, whilst still achieving a good donor/recipient match. This study aims to describe the characteristics of the kidney transplant waiting list and variations in median waiting times. METHODS: Demographics and clinical characteristics of all patients listed for a kidney only transplant in the UK on 1st January 2011 were examined. Renal unit variations were explored. Patients listed between January 2006 and December 2009 were included in analysis of waiting times to transplant. RESULTS: At the beginning of 2011, there were 6,699 patients registered active for kidney only transplant in UK; a prevalence rate of 107 pmp. The median age of prevalent listed patients was 53 years, with 8% aged 70 or above. Of the patients listed, 84% had started renal replacement therapy (RRT), 59% were male, 28% were from ethnic minorities, 50% had blood group type O, 28% were defined as difficult to HLA match and 23% were highly sensitised (calculated HLA antibody reaction frequency 85%). Median waiting time to transplant was 38 months. Waiting time was shorter for White patients (36 months) compared to Asian or Black patients (46 months), and was doubled in highly sensitised compared to un-sensitised patients. CONCLUSIONS: Intercentre variation was observed in the rate of wait-listing and in the proportion of listed patients across different ethnic groups, age, blood groups and level of sensitisation. This may reflect differences in baseline population characteristics as well as individual centre practice patterns. Median waiting times differ significantly across blood groups, degree of sensitisation and ethnic group.

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

INTRODUCTION: Acute 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 ANALYSIS: PLUTO 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 DISSEMINATION: The 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 NUMBERS: 2019-003025-22 and 16586164.

PreImplantation Trial of Histopathology In renal Allografts (PITHIA): a stepped-wedge cluster randomised controlled trial protocol.

INTRODUCTION: Most potential kidney transplant donors in the UK are aged over 60 years, yet increasing donor age is associated with poorer graft survival and function. Urgent preimplantation kidney biopsy can identify chronic injury, and may aid selection of better 'quality' kidneys from this group. However, the impact of biopsy on transplant numbers remains unproven. The PreImplantation Trial of Histopathology In renal Allografts (PITHIA) study will assess whether the introduction of a national, 24 hours, digital histopathology service increases the number, and improves outcomes, of kidneys transplanted in the UK from older deceased donors. METHODS AND ANALYSIS: PITHIA is an open, multicentre, stepped-wedge cluster randomised study, involving all UK adult kidney transplant centres. At 4-monthly intervals, a group of 4-5 randomly selected clusters (transplant centres) will be given access to remote, urgent, digital histopathology (total intervention period, 24 months). The trial has two primary end points: it is powered for an 11% increase in the proportion of primary kidney offers from deceased donors aged over 60 years that are transplanted, and a 6 mL/min increase in the estimated glomerular filtration rate of recipients at 12 months post-transplant. This would equate to an additional 120 kidney transplants performed in the UK annually. Trial outcome data will be collected centrally via the UK Transplant Registry held by NHS Blood and Transplant (NHSBT) and will be analysed using mixed effects models allowing for clustering within centres and adjusting for secular trends. An accompanying economic evaluation will estimate the cost-effectiveness of the service to the National Health Service. ETHICS AND DISSEMINATION: The study has been given favourable ethical opinion by the Cambridge South Research Ethics Committee and is approved by the Health Research Authority. We will present our findings at key transplant meetings, publish results within 4 years of the trial commencing and support volunteers at renal patient groups to disseminate the trial outcome. TRIAL REGISTRATION NUMBER: ISRCTN11708741; Pre-results.

UK National Registry Study of Kidney Donation After Circulatory Death for Pediatric Recipients.

BACKGROUND: Donation after circulatory death (DCD) kidney transplantation has acceptable renal allograft survival in adults but there are few data in pediatric recipients. The aim of this study was to determine renal allograft outcomes for pediatric recipients of a DCD kidney. METHODS: Data were collected from the UK Transplant Registry held by National Health Service Blood and Transplant. Kidney transplants performed for pediatric recipients (age, <18 years) in the United Kingdom from 2000 to 2014 were separated into DCD, donation after brain death (DBD), and living donor (LD) transplants, analyzing 3-year patient and renal allograft survival. RESULTS: One thousand seven hundred seventy-two kidney only transplants were analyzed. Twenty-one (1.2%) of these were from DCD donors, 955 (53.9%) from DBD donors, and 796 (44.9%) from LDs. Patient survival is 100% in the DCD group, 98.7% in the DBD group, and 98.9% in the LD group. Three-year renal allograft survival was 95.2% in the DCD group, 87.1% in the DBD group, and 92.9% in the LD group. There was no significant difference in 3-year renal allograft survival between the DCD and DBD groups (P = 0.42) or DCD and LD groups (P = 0.84). For DCD, the primary nonfunction rate was 5% and delayed graft function was 25%. CONCLUSIONS: Children receiving a DCD kidney transplant have good renal allograft survival at 3-year follow-up, comparable to those receiving a kidney from a DBD donor or a LD. This limited evidence encourages the use of selected DCD kidneys in pediatric transplantation, and DCD allocation algorithms may need to be reviewed in view of this.

Early Outcomes of the New UK Deceased Donor Kidney Fast-Track Offering Scheme.

BACKGROUND: The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012 to identify kidneys at high risk of discard and to rapidly facilitate transplantation. A retrospective analysis of kidneys transplanted through the KFTS was undertaken. METHODS: UK Transplant Registry data were collected on deceased donor kidneys implanted between November 1, 2012, and April 30, 2015, (donation after brain death [DBD] donors) and March 1, 2013, and April 30, 2015 (donation after circulatory death [DCD] donors). Posttransplant outcomes included 1-year estimated glomerular filtration rate and death-censored graft survival (DCGS). RESULTS: Over the study period, 523 deceased donor kidneys were transplanted through the KFTS and 4174 via the standard National Kidney Allocation Scheme (NKAS). Kidneys in the KFTS were more likely to be from older diabetic donors, had a higher frequency of poor ex vivo perfusion, had longer cold ischemic times, and were transplanted into older recipients. One-year DCGS of KFTS and NKAS DBD donor kidneys was similar (94% vs 95%; P = 0.70), but for DCD donor kidneys, DCGS was lower in those allocated via the KFTS (91% versus 95%; P = 0.04). Median 1-year estimated glomerular filtration rate for DBD donor kidneys was lower in those allocated via the KFTS (49 vs 52 mL/min per 1.73 m; P = 0.01), but for DCD kidneys, there was no difference (45 vs 48 mL/min per 1.73 m; P = 0.10). CONCLUSIONS: Although KFTS kidneys have less favorable donor, graft, and recipient risk factors than NKAS kidneys, short-term graft and patient outcomes are acceptable. National schemes that identify and rapidly offer kidneys at high risk of discard may contribute to minimizing the unnecessary discard of organs.

The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants.

BACKGROUND: ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. METHODS: The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. RESULTS: For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. CONCLUSIONS: Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

Living Donation Has a Greater Impact on Renal Allograft Survival Than HLA Matching in Pediatric Renal Transplant Recipients.

BACKGROUND: Living donor (LD) kidney transplantation accounts for around half of all pediatric renal transplant recipients and results in improved renal allograft survival. The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant on all children who received a donation after brain death (DBD) or LD kidney-only transplant between 2000 and 2011. HLA-A, HLA-B and HLA-DR mismatches were categorized into 4 levels and 2 groups. Data were fully anonymized. RESULTS: One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed; 804 (58%) received a DBD donor kidney, 574 (42%) received an LD kidney. Five-year renal allograft survival was superior for children receiving a poorly HLA-matched LD kidney transplant (88%, 95% confidence interval [95% CI], 84-91%) compared with children receiving a well HLA-matched DBD kidney transplant (83%, 95% CI, 80-86%, log rank test P = 0.03). Five-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches (88%, 95% CI, 84-91%) compared with children receiving a DBD kidney with 0 HLA-DR mismatches (83%, 95% CI, 80-86%, log rank test P = 0.03). CONCLUSIONS: In children, poorly HLA-matched LD renal transplant outcomes are not inferior when compared with well HLA-matched DBD renal transplants. It is difficult to justify preferentially waiting for an improved HLA-matched DBD kidney when a poorer HLA-matched LD kidney transplant is available.