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As SARS-CoV-2 vaccines have started to be rolled out, a key question facing transplant units has been whether listing for transplantation should be contingent on recipients having received a vaccine. We aimed to provide an ethical framework when considering potential transplant candidates who decline vaccination. We convened a working group comprising transplant professionals, lay members and patients and undertook a literature review and consensus process. This group's work was also informed by discussions in two hospital clinical ethics committees. We have reviewed arguments for and against mandating vaccination prior to listing for kidney transplantation and considered some practical difficulties which may be associated with a policy of mandated vaccination. Rather than requiring that all patients must receive the SARS-CoV-2 vaccine prior to transplant listing, we recommend considering vaccination status as one of a number of SARS-CoV-2-related risk factors in relation to transplant listing. Transplant units should engage in individualised risk-benefit discussions with patients, avoid the language of mandated treatments and strongly encourage uptake of the vaccine in all patient groups, using tailor-made educational initiatives.

Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates. OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants. Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report. ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012–004308-36 . Registered on 10 December 2012.

Patients with chronic kidney disease stage 5 and those on immunosuppression are particularly vulnerable and are shielded as per public health strategy. We present our experience of coronavirus disease 2019 (COVID-19) transplant patients in one of the most affected parts of the UK with direct comparison to waitlisted patients.A single-center prospective study of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive waitlisted and transplant patients was undertaken to compare these groups and assess clinical outcomes.A total of 60 consecutive symptomatic SARS-CoV-2 positive patients were identified with 32 active waitlisted patients and 28 functioning renal transplants. Demographics were similar. The incidence of symptomatic COVID-19 in the waitlisted group was 9.9% compared to 1.9% in renal transplant patients (P0.001). Immunosuppression did not influence initial symptomology. Fifteen percent of patients in the waitlisted and 32% in the transplant groups died (P = 0.726). Mortality as proportion of total waitlisted (321 patients) and transplant population (1434 patients) of our centre was 1.5% and 0.6% (P0.001), respectively. C-reactive protein (CRP) at 48 h and peak CRP were associated with mortality in both groups while quick sequential organ failure assessment score at 48 h (P = 0.036) was associated with mortality for transplant patients.Incidence of COVID-19 is higher in the waitlisted population but transplant patients have more severe disease, reflected by higher mortality. CRP at 48 h can be used as a predictive tool. In the absence of effective treatments, the current strategy of shielding is arguably the most important factor in protecting patients while resuming transplantation.

Background The risk of COVID-19 infection in transplant recipients is unknown. Patients on dialysis may be exposed to greater risk of infection due to an inability to isolate. Consideration of these competing risks is important before restarting suspended transplant programs. This study compared outcomes in kidney and kidney/pancreas transplant recipients with those on the waiting list, following admission with COVID-19 in a high prevalence region. Methods Audit data from all 6 London transplant centres were amalgamated. Demographic and laboratory data were collected and outcomes included mortality, intensive care (ITU) admission and ventilation. Adult patients who had undergone a kidney or kidney/pancreas transplant, and those active on the transplant waiting list at the start of the pandemic were included. Results 121 transplant recipients (TR) and 52 waiting list patients (WL) were admitted to hospital with COVID-19. 36 TR died (30%), whilst 14 WL patients died (27% p=0.71). There was no difference in rates of admission to ITU or ventilation. 24% of TR required renal replacement therapy, and 12% lost their grafts. Lymphocyte nadir and D-dimer peak showed no difference in those who did and did not die. No other co-morbidities or demographic factors were associated with mortality, except for age (odds ratio of 4.3 [95% CI 1.8 - 10.2] for mortality if aged over 60 years) in TR. Conclusions Transplant recipients and waiting list patients have similar mortality rates after hospital admission with COVID-19. Mortality was higher in older transplant recipients. These data should inform decisions about transplantation in the COVID era.

BACKGROUND: Patients with chronic kidney disease stage 5 and those on immunosuppression are particularly vulnerable and are shielded as per public health strategy. We present our experience of coronavirus disease 2019 (COVID-19) transplant patients in one of the most affected parts of the UK with direct comparison to waitlisted patients. METHODS: A single-center prospective study of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive waitlisted and transplant patients was undertaken to compare these groups and assess clinical outcomes. RESULTS: A total of 60 consecutive symptomatic SARS-CoV-2 positive patients were identified with 32 active waitlisted patients and 28 functioning renal transplants. Demographics were similar. The incidence of symptomatic COVID-19 in the waitlisted group was 9.9% compared to 1.9% in renal transplant patients (P < 0.001). Immunosuppression did not influence initial symptomology. Fifteen percent of patients in the waitlisted and 32% in the transplant groups died (P = 0.726). Mortality as proportion of total waitlisted (321 patients) and transplant population (1434 patients) of our centre was 1.5% and 0.6% (P < 0.001), respectively. C-reactive protein (CRP) at 48 h and peak CRP were associated with mortality in both groups while quick sequential organ failure assessment score at 48 h (P = 0.036) was associated with mortality for transplant patients. CONCLUSIONS: Incidence of COVID-19 is higher in the waitlisted population but transplant patients have more severe disease, reflected by higher mortality. CRP at 48 h can be used as a predictive tool. In the absence of effective treatments, the current strategy of shielding is arguably the most important factor in protecting patients while resuming transplantation.

Introduction The benefit of administering chemical thromboprophylaxis to chronic kidney disease patients undergoing renal transplantation is unclear and no previous systematic review has addressed this as reflected by variations in national guidelines. Methods A literature search was performed using MEDLINE, Embase, Cochrane, CINAHL, World Health Organisation (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov databases to December 2019. Studies included participants undergoing renal transplantation only with no contra-indication to thromboprophylaxis, no history/clinical suspicion of acute organ rejection and those describing a form of chemical thromboprophylaxis intervention compared with another form, no intervention or placebo. Results Thirteen studies with 1600 patients were included. There was wide variation concerning type of thromboprophylaxis, time of onset, dosing and duration. Reports of symptomatic/asymptomatic venous thromboembolism and mortality were limited. Seven studies reported on renal allograft thrombosis. When comparing thromboprophylaxis to no intervention, there was no evidence of difference for thrombosis risk (risk ratio 0.2; [95% CI 0.01–4.63]), however all studies were underpowered to answer this question. Six studies reported on major bleeding but type of intervention, timing of onset and duration of thromboprophylaxis varied significantly, making it difficult to pool data for further analysis. Conclusion There is insufficient evidence to advise on efficacy and safety of chemical thromboprophylaxis in patients undergoing renal transplantation or to determine whether one chemical thromboprophylaxis is better than another thromboprophylaxis.

It is well recognised that kidney transplant recipients have an increased risk of cancers compared with the age and gender matched general population. Malignancy is one of the commonest causes of death among this cohort after cardiovascular disease. This increased risk is largely attributable to the effect of immunosuppression, which impairs T cell function, immunosurveillance and the immunological control of oncogenic viral infections. Cancer related mortality rates are also higher in solid organ transplant recipients compared with the general population. While early diagnosis may improve outcomes in these patients, cancer screening is debatable given the lack of randomised controlled trials in this cohort, and treatment is often challenging. This article reviews the epidemiology and risk factors for the development of malignancy in the post-transplant setting, as well as screening guidelines for specific malignancies of which patients are at particular risk.

There are over 12,000 people with sickle cell disease (SCD) in the UK, and 4-12% of patients who develop Sickle Cell Nephropathy (SCN) progress to End Stage Renal Disease (ESRD). Renal transplantation offers the best outcomes for these patients with but their access to transplantation is often limited. Regular automated exchange blood transfusions (EBT) reduce the complications of SCD and may improve outcomes. However, concerns over alloimmunisation limit its widespread implementation. In this retrospective multicenter study, data were collected on 34 SCD patients who received a kidney transplant across 6 London Hospitals between 1997 and 2017. 20/34 patients were on an EBT program, pre or post renal transplantation. Overall patient and graft survival were inferior to contemporaneous UK data in the ESRD population as a whole, a finding which is well-recognised. However, patient survival (CI 95%, p = 0.0032), graft survival and graft function were superior at all time-points in those who received EBT versus those who did not. 4/20 patients (20%) on EBT developed de novo donor specific antibodies (DSAs). 3/14 patients (21%) not on EBT developed de novo DSAs. The incidence of rejection in those on EBT was 5/18 (28%), as compared with 7/13 (54%) not on EBT. In conclusion, our data, while limited by an inevitably small sample size and differences in the date of transplantation, do suggest that long-term automated EBT post renal transplant is effective and safe, with improvement in graft and patient outcomes and no increase in antibody formation or graft rejection.

OBJECTIVES Posttransplant anemia affects 30% to 45% of kidney transplant recipients and is associated with increased morbidity. However, there is lack of evidence about safe hemoglobin levels after erythropoietin treatment. Studies are needed to better understand the potential benefits and risks, as well as to define safe target hemoglobin ranges in these patients. MATERIALS AND METHODS In this single-center exploratory, open-label randomized controlled trial, kidney trans-plant recipients with anemia 3 months posttransplant were either treated with epoetin beta to a hemoglobin target level of 11.5 to 13.5 g/dL (n = 28) or given no treatment (n = 27). Treatment effects on graft function and health quality of life were assessed. RESULTS After 2 years, hemoglobin concentrations were significantly higher in the epoetin beta treatment group than in the no treatment group (12.3 ± 0.18 vs 9.99 ± 0.22 g/dL; P < .0001). Estimated glomerular filtration rate, calculated by Modified Diet in Renal Disease 7, declined by 1.7 mL/min (interquartile range, -6 to 4.24) in the epoetin treatment group and by 4.16 mL/min (interquartile range, -12.42 to 2.78) in the no treatment group (P = .32). Rate of progression, determined by estimated glomerular filtration rate slope, was not significantly different between groups (-0.09 ± 0.1 vs -0.12 ± 0.15 mL/min for treated vs not treated; P = .78). Moreover, we observed no significant differences in proteinuria and blood pressure. Treated patients had greater improvements in the vitality and mental health domains of the Medical Outcomes Short Form Health Survey quality of life scores. CONCLUSIONS Treatment of anemia in kidney transplant recipients to a hemoglobin level of 11.5 to 13.5 g/dL with erythropoietin improves some quality of life scores. The treatment was safe and not associated with adverse outcomes. There were no changes in rate of decline of graft function.

Background Low clearance transplant clinics (LCTCs) are recommended for the management of recipients with a failing kidney transplant (RFKT) but data to support their use is limited. We conducted a retrospective study to assess management of RFKT at 2 transplant centers, 1 with a LCTC (center A) and 1 without (center B). Methods Patients who transitioned to an alternative form of renal replacement therapy (RRT) between January 1, 2012, and November 30, 2016, were included. Patients with graft failure within a year of transplantation or due to an unpredictable acute event were excluded. Clinical data were collected after review of medical records. Results One hundred seventy-nine patients (age, 48.6 ± 13.4 years, 99 [55.3%] male, and mean transplant duration 10.3 ± 7.8 years) were included. RRT counseling occurred in 79 (91%) and 68 (74%) patients at centers A and B (P = 0.003), at median 135 (61-319) and 133 (69-260) days before dialysis after graft loss (P = 0.92). Sixty-one (34.1%) patients were waitlisted for retransplantation; 18 (32.7%) nonwaitlisted patients were still undergoing workup at center A compared with 37 (58.7%) at center B (P = 0.028). Preemptive retransplantation occurred in 4 (4.6%) and 5 (5.4%) patients at centers A and B (P = 0.35). At 1 year after initiation of dialysis after graft loss, 11 (15.3%) and 11 (17.2%) patients were retransplanted (P = 0.12), and mortality was 6.6% overall. Conclusions A dedicated LCTC improved RRT counseling and transplant work-up but did not lead to improved rates of retransplantation. Earlier consideration of retransplantation in LCTCs is required to improve RFKT outcomes.

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.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Introduction. Delayed graft function (DGF) has a major impact on long-term renal transplant survival. However, it is a diagnosis made retrospectively with little opportunity to modify treatment protocols. A classification based on creatinine reduction ratio between days 1 and 2 (CRR2) suggests that patients with CRR2 less than or equal to 30% (nondialysis requiring DGF [ND-DGF]) have similar outcomes to those with dialysis-requiring delayed graft function (D-DGF). We retrospectively applied this definition in our cohort of patients to examine outcomes. Methods. We studied the association between CRR2 and graft outcomes in all 367 patients transplanted between 1996 and 2004 at our center. Patients were divided into the following three groups: IGF (immediate graft function; CRR2 >30%), D-DGF, and ND-DGF. Mean follow-up was 4.2 years. Results. IGF accounted for 36% of patients, D-DGF for 22%, and ND-DGF for 42%. CRR2 was inversely correlated with serum creatinine on days 7, 30, 90, and 365 (rranging from ―0.65 to ―0.22, P

Background Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients. Methods/Design Recipients >1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate >30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but Discussion We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to feed through to graft survival. This trial will confirm the benefit of routine screening and lead to a greater understanding of how to keep kidney transplants working longer. Trial registration Current Controlled TrialsISRCTN46157828.

BACKGROUND Atrial natriuretic peptide and cyclosporine have opposing effects on renal hemodynamics and excretory function. METHODS Twelve male stable cyclosporine-treated renal transplant recipients received a single 100-mg i.v. dose of the neutral endopeptidase EC 24.11 inhibitor candoxatrilat in a double-blind, placebo-controlled cross-over study. Each study day consisted of 2 hr of baseline and 7 hr of postdose evaluation. RESULTS After administration of candoxatrilat, plasma atrial natriuretic factor rose from 12.8+/-1.6 (mean +/- SEM) to 44.1+/-6.8 pmol/L (P

Passenger lymphocyte syndrome (PLS) is an immune-mediated hemolysis. It occurs following ABO blood group mismatched solid organ and/or bone marrow transplantation between donor and recipient. We report two cases of PLS occurring after renal transplantation. Both recipients received live related kidney transplants; one from his mother and the other from his brother. The direction of blood group transfer, from donor to recipient, was O Rh D+ to A Rh D+ in both cases. Approximately 12 days after transplantation, both recipients showed a rapid fall in their hemoglobin levels with no identifiable bleeding source. DAT positive hemolysis was confirmed and anti-A antibodies were detected in recipient sera, confirming a diagnosis of PLS. Both cases required blood transfusion support to maintain their hemoglobin and both had good renal outcomes. We have identified 99 PLS cases following renal transplant in the English literature. Previous ABO sensitization, donor blood group O to recipient blood group A or B transfer, and ciclosporin treatment have been identified as risk factors for PLS. Clinical outcomes in general are good; nonetheless, cases of graft failure and deaths have been reported. Early diagnosis and appropriate treatment are important in at risk individuals.

A 23-year-old man sero-negative for Epstein-Barr virus (EBV) developed recurrent sore throats 3 and 6 months after a renal transplant from an EBV sero-positive donor. Tonsillar biopsy at 9 months post-transplant showed post-transplant lymphoproliferative disease (PTLD) caused by EBV. Following reduction of immunosuppressive treatment, he developed further signs and symptoms, and serological evidence of infectious mononucleosis followed by resolution of lymphadenopathy. This case emphasizes the difficulty in interpreting EBV serology in immunosuppressed patients and the importance of pre-transplant EBV serology.

Background Blood transfusions are generally avoided for potential renal transplant recipients due to risk of human leukocyte antigen (HLA) allosensitization. Despite the near universal use of erythropoiesis-stimulating agents, there are still occasions when patients require blood transfusions for reasons such as resistance to erythropoiesis-stimulating agents or cardiovascular instability. The risk of allosensitization in renal patients is believed to be lower with leuko-depleted blood. We sought to quantify the risk of blood transfusion per se in male renal patients on the transplant waiting list for their first kidney graft, using sensitive solid phase antibody detection. Method Cross-sectional survey looking at the prevalence of HLA antibody detected using single antigen Luminex beads in male patients awaiting first renal transplantation. Results One hundred sixteen male patients awaiting their first kidney transplant were identified on our waiting list. Seven of the 42 patients (16.7%) who received at least one unit of leuko-depleted blood developed HLA antibody (HLAab). Of the remaining 74 patients without a history of transfusion, 3 (4.1%) were found to have HLAab. All the antibodies identified were directed against class I antigens. A history of blood transfusion gave a relative risk of 4.1 of developing HLAab (P=0.02). Conclusion Male patients awaiting their first organ transplant had a fourfold increased risk of developing HLA antibody if they had been previously transfused when compared with those who did not have a history of a transfusion. Transfusion even in the postleukodepletion era continues to pose a significant risk of sensitization.

Background. The corresponding antigens of alloantibodies identified in patients awaiting kidney transplantation are often listed as unacceptable for transplantation. The use of solid phase testing, being more sensitive and accurate than conventional complement-dependent cytotoxicity (CDC) assays, has resulted in increased identification of alloantibodies. We aimed to study the clinical importance of alloantibodies defined solely by solid phase techniques. Methods. All patients transplanted between 1999 and 2001 at our center with available day-of-transplant sera (D0) were included (121 patients). All had negative CDC crossmatches. Results. Thirty-eight patients (31%) had detectable alloantibodies using high-definition assays with 16 having donorspecific antibodies (DSA) and 22 non-DSA. There were no cases of hyperacute rejection in any of the groups. Biopsyproven acute rejection rates in the DSA and non-DSA were similar to the unsensitized group. Delayed graft function and 1-year graft survival rates were also similar for the three groups as were median 1-year serum creatinine levels. Multivariate analysis, however, showed that DSA were associated with an increased relative risk of longer-term graft failure (relative risk, 6.5; P0.05). Conclusions. These data show that in the context of a CDC-negative crossmatch, the presence of D0 DSA has little impact on any early graft parameters. DSA, however, are associated with poorer longer-term graft outcomes in kidney transplantation.

BACKGROUND Randomized controlled trials and U.S. Registry data have demonstrated that mycophenolate mofetil (MMF) reduces acute rejection rates and improves graft survival. We undertook the first paired kidney analysis comparing the effects of MMF and azathioprine on graft outcome in the United Kingdom. METHODS In all, 238 deceased donors from 1999 to 2002 who donated one kidney to a patient treated with MMF and the other kidney to a patient treated with azathioprine were identified from the national transplant database held by U.K. Transplant. Graft function and rates of change of graft function were compared using multiple linear regression analyses adjusting for covariates on an intention-to-treat basis. Incidence of acute rejection and delayed graft function were studied using logistic regression. Patient and graft survival censored for death were evaluated with Cox regression analyses. RESULTS The MMF-treated patients exhibited a nonsignificant trend towards improved graft function but with increased rejection rates (44% versus 31%, P < 0.01). Treatment with MMF did not reduce delayed graft function rates. Univariate analysis showed that graft survival was inferior in MMF-treated patients (90% versus 95%, log-rank, P = 0.02) but in multivariate Cox regression models, MMF treatment was not a significant factor. Surprisingly, in the first year 32% of patients achieved daily doses of less than 2 g of MMF compared to 18% of patients who received less than 100 mg of azathioprine (P < 0.01). CONCLUSION In this real-life study, there was no difference in patient or graft outcome between MMF and azathioprine treated groups despite increased rejection rates in patients receiving MMF therapy.