Early experience of a new national lung allocation scheme in the UK based on clinical urgency.

INTRODUCTION: A new UK Lung Allocation Scheme (UKLAS) was introduced in 2017, replacing the previous geographic allocation system. Patients are prioritised according to predefined clinical criteria into a three-tier system: the super-urgent lung allocation scheme (SULAS), the urgent lung allocation scheme (ULAS) and the non-urgent lung allocation scheme (NULAS). This study assessed the early impact of this scheme on waiting-list and post-transplant outcomes. METHODS: A cohort study of adult lung transplant registrations between March 2015 and November 2016 (era-1) and between May 2017 and January 2019 (era-2). Outcomes from registration were compared between eras and stratified by urgency tier and diagnostic group. RESULTS: During era-1, 461 patients were registered. In era-2, 471 patients were registered (19 (4.0%) SULAS, 82 (17.4%) ULAS and 370 (78.6%) NULAS). SULAS patients were younger (median age 35 vs 50 and 55 for urgent and non-urgent, respectively, p=0.0015) and predominantly suffered from cystic fibrosis (53%) or pulmonary fibrosis (37%). Between eras 1 and 2, the odds of transplantation within 6 months of registration were increased (OR=1.41, 95% CI 1.07 to 1.85, p=0.0142) despite only a 5% increase in transplant activity. Median time-to-transplantation during era-1 was 427 days compared with waiting times in era-2 of 8 days for SULAS, 15 days for ULAS and 585 days for NULAS patients. Waiting-list mortality (15% era-1 vs 13% era-2; p=0.5441) and post-transplant survival at 1 year (81.3% era-1 vs 83.3% era-2; p=0.6065) were similar between eras. CONCLUSION: The UKLAS scheme prioritises the critically ill and improves transplantation odds. The true impact on waiting-list mortality and post-transplant survival requires further follow-up.

The impact of severe acute kidney injury requiring renal replacement therapy on survival and renal function of heart transplant recipients - a UK cohort study.

Severe acute kidney injury (AKI), defined as requiring renal replacement therapy (RRT), is associated with higher mortality postheart transplantation, but its long-term renal consequences are not known. Anonymized data of 3365 patients, who underwent heart transplantation between 1995 and 2017, were retrieved from the UK Transplant Registry. Multivariable binary logistic regression was performed to identify risk factors for severe AKI requiring RRT, Kaplan-Meier analysis to compare survival and renal function deterioration of the RRT and non-RRT groups, and multivariable Cox regression model to identify predicting factors of mortality and end-stage renal disease (ESRD). 26.0% of heart recipients received RRT post-transplant. The RRT group has lower survival rates at all time points, especially in the immediate post-transplant period. However, conditional on 3 months survival, older age, diabetes and coronary heart disease, but not post-transplant RRT, were the risk factors for long-term survival. The predicting factors for ESRD were insulin-dependent diabetes, renal function at transplantation, eGFR decline in the first 3 months post-transplant, post-transplant severe AKI and transplantation era. Severe AKI requiring RRT post-transplant is associated with worse short-term survival, but has no impact on long-term mortality. It also accelerates recipients' renal function deterioration in the long term.

PREDICTA: A Model to Predict Primary Graft Dysfunction After Adult Heart Transplantation in the United Kingdom.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of morbidity and mortality post-heart transplantation. The rates of PGD across Europe are higher than North America possibly because of the increasing use of extended criteria donors because of organ shortage. Our aim was to derive a novel scoring system based on data collected nationally in the UK over a 3-year period. We compared this scoring system to a previously validated (RADIAL) score in a contemporary cohort of patients. METHODS: Medical records of all adult patients who underwent heart transplantation between October 1, 2012 and September 30, 2016 in the 6 UK heart transplant centers were analyzed. Preoperative donor and recipient characteristics, intraoperative details and post-transplant complications were compared between the PGD and non-PGD groups using the International Society of Heart and Lung Transplant definition. Multivariable logistic regression was used to build the predictive model. An area under receiver operating characteristics curve was used to test the novel scoring system (PREDICTA) versus the RADIAL score. RESULTS: Six hundred and thirteen heart transplants were included in the study. There were 233 patients who had PGD. The variables included in the model were recipient diabetes mellitus, preoperative mechanical circulatory support (short-term ventricular assist devices/extracorporeal membrane oxygenation), implant time, donor age, and bypass time >180 minutes. The C statistic of the PREDICTA score was 0.704 versus 0.547 for the RADIAL score indicating an acceptable discriminatory value. CONCLUSION: The PREDICTA score is a novel scoring tool with improved ability to predict the development of PGD compared with the RADIAL score. Its application in the prevention and early management of PGD needs further evaluation.

Renal function and cardiovascular outcomes after living donor nephrectomy in the UK: quality and safety revisited.

OBJECTIVE: To determine renal function and cardiovascular outcomes after living donor nephrectomy (LDN). Living donor kidney transplantation has become established as the treatment of choice for end-stage renal failure. Benefits to the recipient have to be balanced against perioperative and long-term health risks to the donor. SUBJECTS/PATIENTS AND METHODS: The UK Transplant Registry (UKTR) was used to identify 4586 living donors who had donated a kidney for transplantation in the UK between 2001 and 2008. This study was conducted with the consent and support of the NHS Blood and Transplant (NHSBT) Kidney and Pancreas Research Group. RESULTS: The mean glomerular filtration rate (GFR) fell from 103 mL/min/1.73 m(2) before LDN to 58 mL/min/1.73 m(2) 1 year after LDN. At 1 year after LDN 60% of donors had a GFR of <60 mL/min/1.73 m(2). A GFR of <60 mL/min/1.73 m(2) after LDN was associated with older age, females, lower GFR before LDN, White ethnicity, earlier LDN period, unrelated donor type and body mass index of >25 kg/m(2). Over a 2-year period after LDN there was an overall mortality rate of 0.39%, cardiovascular death in one patient (mortality rate of 0.02%) and a major cardiovascular event rate of 0.44%. CONCLUSION: In this study we show that mild renal dysfunction is common after LDN; however, due to the short duration of follow-up we are unable to comment on whether this subsequently leads to an increased risk of developing of cardiovascular disease.

Group consultations for menopause: A way forward if we can encourage women to join?

The number of patients presenting to primary care requiring support with menopause symptoms is increasing and the number of available appointments in general practice is reducing. In attempt to improve access new ways of engaging with these patients may be beneficial. Group consultations could be a solution. Here I describe my experience of setting up group consultations in a GP practice.

A national pilot of donation after circulatory death (DCD) heart transplantation within the United Kingdom.

BACKGROUND: The United Kingdom (UK) was one of the first countries to pioneer heart transplantation from donation after circulatory death (DCD) donors. To facilitate equity of access to DCD hearts by all UK heart transplant centers and expand the retrieval zone nationwide, a Joint Innovation Fund (JIF) pilot was provided by NHS Blood and Transplant (NHSBT) and NHS England (NHSE). The activity and outcomes of this national DCD heart pilot program are reported. METHODS: This is a national multi-center, retrospective cohort study examining early outcomes of DCD heart transplants performed across 7 heart transplant centers, adult and pediatric, throughout the UK. Hearts were retrieved using the direct procurement and perfusion (DPP) technique by 3 specialist retrieval teams trained in ex-situ normothermic machine perfusion. Outcomes were compared against DCD heart transplants before the national pilot era and against contemporaneous donation after brain death (DBD) heart transplants, and analyzed using Kaplan-Meier analysis, chi-square test, and Wilcoxon's rank-sum. RESULTS: From September 7, 2020 to February 28, 2022, 215 potential DCD hearts were offered of which 98 (46%) were accepted and attended. There were 77 potential donors (36%) which proceeded to death within 2 hours, with 57 (27%) donor hearts successfully retrieved and perfused ex situ and 50 (23%) DCD hearts going on to be transplanted. During this same period, 179 DBD hearts were transplanted. Overall, there was no difference in the 30-day survival rate between DCD and DBD (94% vs 93%) or 90 day survival (90% vs 90%) respectively. There was a higher rate of ECMO use post-DCD heart transplants compared to DBD (40% vs 16%, p = 0.0006), and DCD hearts in the pre pilot era, (17%, p = 0.002). There was no difference in length of ICU stay (9 DCD vs 8 days DBD, p = 0.13) nor hospital stay (28 DCD vs 27 DBD days, p = 0.46). CONCLUSION: During this pilot study, 3 specialist retrieval teams were able to retrieve DCD hearts nationally for all 7 UK heart transplant centers. DCD donors increased overall heart transplantation in the UK by 28% with equivalent early posttransplant survival compared with DBD donors.

The introduction of a super-urgent heart allocation scheme in the UK: A 2-year review.

BACKGROUND: In response to a growing number of patients on the UK urgent heart transplant waiting list, the UK donor heart allocation scheme was revised in October 2016 with the introduction of a new super-urgent category. Patients with temporary mechanical circulatory support (tMCS) became eligible for super-urgent registration. The aim of this study was to compare activity, indications, and outcomes before and after the change. METHODS: Data on adult (aged ≥16 years) heart transplant registrations and recipients in the 2 years before (Era 1: July 1, 2014-June 30, 2016) and after (Era 2: January 2017-December 2018) the introduction of the new scheme were extracted from the UK Transplant Registry and analyzed using competing risks analysis, Kaplan-Meier analysis, and Cox proportional-hazards regression. RESULTS: There were 525 waiting-list registrations in Era 1 and 594 in Era 2, including 14% super-urgent registrations, with 90% having some form of tMCS. Median waiting time to transplant was 41 days for all urgent registrations in Era 1 compared with 17 days for super-urgent registrations and 71 days for urgent registrations in Era 2. Numbers of non-urgent transplants were not affected. Deaths on the waiting list significantly decreased from 5% to 2% at 6 months between Era 1 and Era 2 (adjusted hazard ratio = 0.29, 95% CI = 0.13-0.62). In addition, total number of patients with tMCS were not different between both eras, suggesting no significant change in this area of clinical decision making. Post-transplant survival at 1 year for super-urgent recipients was not significantly different from post-transplant survival at 1 year for other categories. CONCLUSIONS: The Introduction of a super-urgent heart allocation scheme in the UK reduces waiting time to transplant for the sickest patients, with comparable post-transplant survival while reducing deaths on the waiting list.

ISHLT Primary Graft Dysfunction Incidence, Risk Factors, and Outcome: A UK National Study.

BACKGROUND: Heart transplantation (HTx) remains the most effective long-term treatment for advanced heart failure. Primary graft dysfunction (PGD) continues to be a potentially life-threatening early complication. In 2014, a consensus statement released by International Society for Heart and Lung Transplantation (ISHLT) established diagnostic criteria for PGD. We studied the incidence of PGD across the United Kingdom. METHODS: We analyzed the medical records of all adult patients who underwent HTx between October 2012 and October 2015 in the 6 UK heart transplant centers Preoperative donor and recipient characteristics, intraoperative details, and posttransplant complications were compared between the PGD and non-PGD groups using the ISHLT definition. Multivariable analysis was performed using logistic regression. RESULTS: The incidence of ISHLT PGD was 36%. Thirty-day all-cause mortality in those with and without PGD was 31 (19%) versus 13 (4.5%) (P = 0.0001). Donor, recipient, and operative factors associated with PGD were recipient diabetes mellitus (P = 0.031), recipient preoperative bilateral ventricular assist device (P < 0.001), and preoperative extracorporeal membranous oxygenation (P = 0.023), female donor to male recipient sex mismatch (P = 0.007), older donor age (P = 0.010), and intracerebral haemorrhage/thrombosis in donor (P = 0.023). Intraoperatively, implant time (P = 0.017) and bypass time (P < 0.001) were significantly longer in the PGD cohort. Perioperatively, patients with PGD received more blood products (P < 0.001). Risk factors identified by multivariable logistic regression were donor age (P = 0.014), implant time (P = 0.038), female: male mismatch (P = 0.033), recipient diabetes (P = 0.051) and preoperative ventricular assist device/extracorporeal membranous oxygenation support (P = 0.012). CONCLUSIONS: This is the first national study to examine the incidence and significance of PGD after HTx using the ISHLT definition. PGD remains a frequent early complication of HTx and is associated with increased mortality.

Durable left ventricular assist device support as a bridge to heart transplant candidacy†.

OBJECTIVES: Left ventricular assist devices are funded in the UK exclusively as a bridge to transplant (BTT). However, patients who potentially could receive a transplant may develop reversible contraindications to transplant. Bridge to candidacy (BTC) has sometimes been controversial, given the uncertain clinical efficacy of BTC and the risk that reimbursement could be denied. We analysed the UK ventricular assist device database to understand how common BTC was and to assess patient survival rates and incidences of transplants. METHODS: We identified BTC implants in patients with pulmonary hypertension, chronic kidney disease and obesity using the UK guidelines for heart transplants. RESULTS: A total of 306 of 540 patients had complete data and 157 were identified as BTC (51%). Overall, there was no difference in survival rates between patients designated as BTC and those designated at BTT (71.9 vs 72.9% at 1 year, respectively; P = 0.82). However, the survival rate was lower at all time points in those with an estimated glomerular filtration rate (eGFR) <40 and in patients with a body mass index (BMI) >32 up to 1-year postimplant. There were no significant differences in the incidence of transplant between patients who were BTC and BTT or for any subgroup up to 5 years. However, we noted a diverging trend towards a lower cumulative incidence of transplant for patients with a BMI >32. CONCLUSIONS: BTC is common in the UK and appears clinically effective, given that the survival rates and the incidence of transplants were comparable with those for BTT. Patients with a high BMI have a worse survival rate through to 1 year and a trend for a lower incidence of a transplant. Patients with a low eGFR also have a worse survival rate, but a similar proportion received transplants.

Patient survival and therapeutic outcome in the UK bridge to transplant left ventricular assist device population.

OBJECTIVE: To study the survival and patient outcome in a population of UK patients supported by an implantable left ventricular assist device (LVAD) as a bridge to heart transplantation. METHODS: Data on all adult patients (n=342) who received a HeartMate II or HVAD as a first long-term LVAD between January 2007 and 31 December 2013 were extracted from the UK Ventricular Assist Device (VAD) Database in November 2015. Outcomes analysed include survival on a LVAD, time to urgent listing, heart transplantation and complications including those needing a pump exchange. RESULTS: 112 patients were supported with the Thoratec HeartMate II and 230 were supported with the HeartWare HVAD. Median duration of support was 534 days. During the study period, 81 patients required moving to the UK urgent waiting list for heart transplantation. Of the 342 patients, 85 (24.8%) received a heart transplant, this included 63 on the urgent list. Thirty-day survival was 88.9%, while overall patient survival at 3 years from LVAD implant was 49.6%. 156 patients (46%) died during LVAD support; the most common cause of death on a VAD was a cerebrovascular accident. There was no significant difference between the two devices used in any outcome. CONCLUSIONS: In a population of patients with advanced heart failure, who have a very poor prognosis, support with an implantable LVAD allowed a quarter to receive a heart transplant in a 3-year period. Overall survival of the cohort was about 50%. With improvement in technology and in post-LVAD management, it is likely that outcomes will improve further.

The interval between brainstem death and cardiac assessment influences the retrieval of hearts for transplantation.

OBJECTIVES: The optimum time after brainstem death (BSD) at which to assess the function of donor hearts is unknown. We hypothesized that a longer interval may be associated with a higher transplantation rate due to improved function. METHODS: Data were obtained from the UK Transplant Registry for the period between April 2010 and March 2015. The time when fixed dilated pupils were first noted in the donor was considered as the time of BSD. Retrieval was defined as the time when the abdominal organs were surgically perfused. RESULTS: BSD to retrieval duration was available for 1947 donors, of which 458 (24%) donated their heart. In the univariable analysis (not adjusting other donor risk factors), evidence was available to suggest that the BSD to cardiac assessment duration had a non-linear association with heart utilization (P < 0.0001). Adjusting for donor risk factors, the relationship remained with longer intervals being associated with increased transplantation (P = 0.0056). The modelled probability of heart utilization had a similar pattern to the observed rate of heart utilization. However, the probability of heart donation began to plateau after approximately 48 h. The analysis of the subset of donors attended by a cardiothoracic retrieval team showed a similar pattern. CONCLUSIONS: These data suggest that time interval from BSD to organ retrieval influences the heart retrieval rate. When the sole reason for declining a donor heart is poor function, a period of further observation and optimization up to 2 days should be considered.

Strategies for expanding the UK pool of potential intestinal transplant donors.

BACKGROUND: The pool of suitable donors and listed recipients for intestinal transplantation is small, resulting in difficulties in donor-to-recipient matching and significant mortality on the waiting list. This study aims to help define the pool of potential donors for intestinal transplantation and propose methods for an increased utilization of donor bowels in the United Kingdom. METHODS: Data on bowel offering from 657 donors after brain stem death (DBD) and on 46 patients on the active intestinal transplant list over 12 months from 14 April 2011 were obtained from the UK Transplant Registry. RESULTS: Family consent for bowel donation was lower than for the other transplantable organs. Only 57% of bowels from DBD donors with consent and meeting the bowel offering criteria were offered for transplantation. A lack of suitable recipients was the most common reason cited for not offering. Only 10% of offered bowels were accepted and transplanted by centers. Donor size discrepancy and human leukocyte antigen incompatibility were common reasons for declining offers of the bowel. There was a scarcity of young and small donors compared with the number of young and small patients requiring a transplant. Two patients who were on the active list during the time period died. CONCLUSIONS: An increased awareness of bowel donation is needed to improve the low offering rate of bowels from DBD donors. A more robust UK bowel allocation system and a formalized European-wide intestinal donor organ sharing program should lead to an increased utilization of available donor bowels and a lower waiting list mortality rate.

Trends in the indications for corneal graft surgery in the United Kingdom: 1999 through 2009.

OBJECTIVE: To examine trends in the indications for corneal graft surgery in the United Kingdom. METHODS: National Health Service Blood and Transplant data were analyzed for keratoplasty operations performed in the United Kingdom between April 1, 1999, and March 31, 2009, distinguishing the type of graft and the surgical indication. RESULTS: The total number of annual keratoplasty operations increased from 2090 in 1999-2000 to 2511 in 2008-2009. Among these, the annual number of grafts performed for endothelial failure increased from 743 (35.6%) in 1999-2000 to 939 (37.4%) in 2008-2009. The performance of penetrating keratoplasty (PK) for endothelial failure decreased from 98.3% of all grafts in 1999-2000 to 46.6% of all grafts in 2008-2009, while the performance of endothelial keratoplasty increased from 0.3% of all grafts in 1999-2000 to 51.2% of all grafts in 2008-2009. The annual number of grafts performed for keratoconus increased from 514 (24.6%) in 1999 to 564 (22.5%) in 2008-2009. The performance of PK for keratoconus decreased from 88.4% of all grafts in 1999-2000 to 57.1% of all grafts in 2008-2009, while the performance of deep anterior lamellar keratoplasty increased from 8.8% of all grafts in 1999-2000 to 40.1% of all grafts in 2008-2009. The number of annual regraft operations increased from 249 (11.9%) in 1999-2000 to 401 (16.0%) in 2008-2009, most commonly for endothelial failure. In 2008-2009, PK regrafts (78.1%) far outnumbered endothelial keratoplasty regrafts (17.0%). CONCLUSIONS: Endothelial failure is the most common indication for keratoplasty in the United Kingdom, and endothelial keratoplasty is performed more commonly than PK for this indication. The number of grafts performed for pseudophakic bullous keratopathy has remained stable, while the number of grafts performed for Fuchs endothelial dystrophy is likely to continue increasing. Keratoconus is the second most common indication for keratoplasty, and deep anterior lamellar keratoplasty numbers are approaching those for PK. Regraft surgery is the third most common indication for keratoplasty, required in most cases because of endothelial failure.

Trends in corneal graft surgery in the UK.

AIMS: The aims of this study were to examine trends over time and regional variation in rates of corneal graft surgery in the UK. METHODS: The hospital in-patient enquiry (HIPE) and hospital episode statistics (HES) were analysed for keratoplasty admissions in England from 1971 to 2006. NHS Blood and Transplant (NHSBT) data were analysed for keratoplasty operations in the UK from 1999 to 2009. RESULTS: Annual rates of penetrating keratoplasty (PK) under HIPE and HES increased from 0.7 per 100,000 population (1971) to 3.9 (1992), then decreased to 3.1 (2006). Rates of lamellar keratoplasty (LK) increased from 0.1 (1971) to 0.9 (2006). Annual PK operations under NHSBT decreased from 1901 (1999/00) to 1473 (2008/9). Over the same period, deep anterior lamellar keratoplasty operations increased from 91 to 327 per year, while endothelial keratoplasty operations increased from 2 to 569 per year. Geographical analysis showed a wide variation across local authority areas in rates of keratoplasty around 1998-2004, especially for LK. CONCLUSION: The total number of corneal graft operations performed in the UK has increased slowly over the past decade. The proportion of lamellar versus penetrating keratoplasty has increased, with LK performed at the highest rates in specialist centres distributed across the UK.

Stromal niche cells protect early leukemic FLT3-ITD+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors.

Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34(+) progenitors from patients with FLT3-ITD(+) or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD(+) and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD(+) and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD(+) but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD(+) AML. Further, we defined a specific interaction between FLT3-ITD(+) progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone.

Characterization of sugar binding by the mannose receptor family member, Endo180.

Members of the mannose receptor family, the mannose receptor, the phospholipase A(2) receptor, DEC-205, and Endo180, contain multiple C-type lectin-like domains (CTLDs) within a single polypeptide. In addition, at their N termini, all four family members contain a cysteine-rich domain similar to the R-type carbohydrate recognition domains of ricin. However, despite the common presence of multiple lectin-like domains, these four endocytic receptors have divergent ligand binding activities, and it is clear that the majority of these domains do not bind sugars. Here the functions of the lectin-like domains of the most recently discovered family member, Endo180, have been investigated. Endo180 is shown to bind in a Ca(2+)-dependent manner to mannose, fucose, and N-acetylglucosamine but not to galactose. This activity is mediated by one of the eight CTLDs, CTLD2. Competition assays indicate that the monosaccharide binding specificity of Endo180 CTLD2 is similar to that of mannose receptor CTLD4. However, additional experiments indicate that, unlike the cysteine-rich domain of the mannose receptor, the cysteine-rich domain of Endo180 does not bind sulfated sugars. Thus, although Endo180 and the mannose receptor are now both known to be mannose binding lectins, each receptor is likely to have a distinct set of glycoprotein ligands in vivo.