SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study.

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.

Barriers to living donor kidney transplantation in the United Kingdom: a national observational study.

BACKGROUND: Living donor kidney transplantation (LDKT) provides more timely access to transplantation and better clinical outcomes than deceased donor kidney transplantation (DDKT). This study investigated disparities in the utilization of LDKT in the UK. METHODS: A total of 2055 adults undergoing kidney transplantation between November 2011 and March 2013 were prospectively recruited from all 23 UK transplant centres as part of the Access to Transplantation and Transplant Outcome Measures (ATTOM) study. Recipient variables independently associated with receipt of LDKT versus DDKT were identified. RESULTS: Of the 2055 patients, 807 (39.3%) received LDKT and 1248 (60.7%) received DDKT. Multivariable modelling demonstrated a significant reduction in the likelihood of LDKT for older age {odds ratio [OR] 0.11 [95% confidence interval (CI) 0.08-0.17], P < 0.0001 for 65-75 years versus 18-34 years}; Asian ethnicity [OR 0.55 (95% CI 0.39-0.77), P = 0.0006 versus White]; Black ethnicity [OR 0.64 (95% CI 0.42-0.99), P = 0.047 versus White]; divorced, separated or widowed [OR 0.63 (95% CI 0.46-0.88), P = 0.030 versus married]; no qualifications [OR 0.55 (95% CI 0.42-0.74), P < 0.0001 versus higher education qualifications]; no car ownership [OR 0.51 (95% CI 0.37-0.72), P = 0.0001] and no home ownership [OR 0.65 (95% CI 0.85-0.79), P = 0.002]. The odds of LDKT varied significantly between countries in the UK. CONCLUSIONS: Among patients undergoing kidney transplantation in the UK, there are significant age, ethnic, socio-economic and geographic disparities in the utilization of LDKT. Further work is needed to explore the potential for targeted interventions to improve equity in living donor transplantation.

Organ Transplants From Deceased Donors With Primary Brain Tumors and Risk of Cancer Transmission.

Importance: Cancer transmission is a known risk for recipients of organ transplants. Many people wait a long time for a suitable transplant; some never receive one. Although patients with brain tumors may donate their organs, opinions vary on the risks involved. Objective: To determine the risk of cancer transmission associated with organ transplants from deceased donors with primary brain tumors. Key secondary objectives were to investigate the association that donor brain tumors have with organ usage and posttransplant survival. Design, Setting, and Participants: This was a cohort study in England and Scotland, conducted from January 1, 2000, to December 31, 2016, with follow-up to December 31, 2020. This study used linked data on deceased donors and solid organ transplant recipients with valid national patient identifier numbers from the UK Transplant Registry, the National Cancer Registration and Analysis Service (England), and the Scottish Cancer Registry. For secondary analyses, comparators were matched on factors that may influence the likelihood of organ usage or transplant failure. Statistical analysis of study data took place from October 1, 2021, to May 31, 2022. Exposures: A history of primary brain tumor in the organ donor, identified from all 3 data sources using disease codes. Main Outcomes and Measures: Transmission of brain tumor from the organ donor into the transplant recipient. Secondary outcomes were organ utilization (ie, transplant of an offered organ) and survival of kidney, liver, heart, and lung transplants and their recipients. Key covariates in donors with brain tumors were tumor grade and treatment history. Results: This study included a total of 282 donors (median [IQR] age, 42 [33-54] years; 154 females [55%]) with primary brain tumors and 887 transplants from them, 778 (88%) of which were analyzed for the primary outcome. There were 262 transplants from donors with high-grade tumors and 494 from donors with prior neurosurgical intervention or radiotherapy. Median (IQR) recipient age was 48 (35-58) years, and 476 (61%) were male. Among 83 posttransplant malignancies (excluding NMSC) that occurred over a median (IQR) of 6 (3-9) years in 79 recipients of transplants from donors with brain tumors, none were of a histological type matching the donor brain tumor. Transplant survival was equivalent to that of matched controls. Kidney, liver, and lung utilization were lower in donors with high-grade brain tumors compared with matched controls. Conclusions and Relevance: Results of this cohort study suggest that the risk of cancer transmission in transplants from deceased donors with primary brain tumors was lower than previously thought, even in the context of donors that are considered as higher risk. Long-term transplant outcomes are favorable. These results suggest that it may be possible to safely expand organ usage from this donor group.

The Global Impact of COVID-19 on Solid Organ Transplantation: Two Years Into a Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has had a major global impact on solid organ transplantation (SOT). An estimated 16% global reduction in transplant activity occurred over the course of 2020, most markedly impacting kidney transplant and living donor programs, resulting in substantial knock-on effects for waitlisted patients. The increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk and excess deaths in transplant candidates has resulted in substantial effort to prioritize the safe restart and continuation of transplant programs over the second year of the pandemic, with transplant rates returning towards prepandemic levels. Over the past 2 y, COVID-19 mortality in SOT recipients has fallen from 20%-25% to 8%-10%, attributed to the increased and early availability of SARS-CoV-2 testing, adherence to nonpharmaceutical interventions, development of novel treatments, and vaccination. Despite these positive steps, transplant programs and SOT recipients continue to face challenges. Vaccine efficacy in SOT recipients is substantially lower than the general population and SOT recipients remain at an increased risk of adverse outcomes if they develop COVID-19. SOT recipients and transplant teams need to remain vigilant and ongoing adherence to nonpharmaceutical interventions appears essential. In this review, we summarize the global impact of COVID-19 on transplant activity, donor evaluation, and patient outcomes over the past 2 y, discuss the current strategies aimed at preventing and treating SARS-CoV-2 infection in SOT recipients, and based on lessons learnt from this pandemic, propose steps the transplant community could consider as preparation for future pandemics.

Real-world Effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S Vaccines Against SARS-CoV-2 in Solid Organ and Islet Transplant Recipients.

BACKGROUND: The clinical effectiveness of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunosuppressed solid organ and islet transplant (SOT) recipients is unclear. METHODS: We linked 4 national registries to retrospectively identify laboratory-confirmed SARS-CoV-2 infections and deaths within 28 d in England between September 1, 2020, and August 31, 2021, comparing unvaccinated adult SOT recipients and those who had received 2 doses of ChAdOx1-S or BNT162b2 vaccine. Infection incidence rate ratios were adjusted for recipient demographics and calendar month using a negative binomial regression model, with 95% confidence intervals. Case fatality rate ratios were adjusted using a Cox proportional hazards model to generate hazard ratio (95% confidence interval). RESULTS: On August 31, 2021, it was found that 3080 (7.1%) were unvaccinated, 1141 (2.6%) had 1 vaccine dose, and 39 260 (90.3%) had 2 vaccine doses. There were 4147 SARS-CoV-2 infections and 407 deaths (unadjusted case fatality rate 9.8%). The risk-adjusted infection incidence rate ratio was 1.29 (1.03-1.61), implying that vaccination was not associated with reduction in risk of testing positive for SARS-CoV-2 RNA. Overall, the hazard ratio for death within 28 d of SARS-CoV-2 infection was 0.80 (0.63-1.00), a 20% reduction in risk of death in vaccinated patients (P = 0.05). Two doses of ChAdOx1-S were associated with a significantly reduced risk of death (hazard ratio, 0.69; 0.52-0.92), whereas vaccination with BNT162b2 was not (0.97; 0.71-1.31). CONCLUSIONS: Vaccination of SOT recipients confers some protection against SARS-CoV-2-related mortality, but this protection is inferior to that achieved in the general population. SOT recipients require additional protective measures, including further vaccine doses, antiviral drugs, and nonpharmaceutical interventions.

Changes in quality of life (QoL) and other patient-reported outcome measures (PROMs) in living-donor and deceased-donor kidney transplant recipients and those awaiting transplantation in the UK ATTOM programme: a longitudinal cohort questionnaire survey with additional qualitative interviews.

OBJECTIVE: To examine quality of life (QoL) and other patient-reported outcome measures (PROMs) in kidney transplant recipients and those awaiting transplantation. DESIGN: Longitudinal cohort questionnaire surveys and qualitative semi-structured interviews using thematic analysis with a pragmatic approach. SETTING: Completion of generic and disease-specific PROMs at two time points, and telephone interviews with participants UK-wide. PARTICIPANTS: 101 incident deceased-donor (DD) and 94 incident living-donor (LD) kidney transplant recipients, together with 165 patients on the waiting list (WL) from 18 UK centres recruited to the Access to Transplantation and Transplant Outcome Measures (ATTOM) programme completed PROMs at recruitment (November 2011 to March 2013) and 1 year follow-up. Forty-one of the 165 patients on the WL received a DD transplant and 26 received a LD transplant during the study period, completing PROMs initially as patients on the WL, and again 1 year post-transplant. A subsample of 10 LD and 10 DD recipients participated in qualitative semi-structured interviews. RESULTS: LD recipients were younger, had more educational qualifications and more often received a transplant before dialysis. Controlling for these and other factors, cross-sectional analyses at 12 months post-transplant suggested better QoL, renal-dependent QoL and treatment satisfaction for LD than DD recipients. Patients on the WL reported worse outcomes compared with both transplant groups. However, longitudinal analyses (controlling for pre-transplant differences) showed that LD and DD recipients reported similarly improved health status and renal-dependent QoL (p<0.01) pre-transplant to post-transplant. Patients on the WL had worsened health status but no change in QoL. Qualitative analyses revealed transplant recipients' expectations influenced their recovery and satisfaction with transplant. CONCLUSIONS: While cross-sectional analyses suggested LD kidney transplantation leads to better QoL and treatment satisfaction, longitudinal assessment showed similar QoL improvements in PROMs for both transplant groups, with better outcomes than for those still wait-listed. Regardless of transplant type, clinicians need to be aware that managing expectations is important for facilitating patients' adjustment post-transplant.

Recipient Comorbidity and Survival Outcomes After Kidney Transplantation: A UK-wide Prospective Cohort Study.

BACKGROUND: Comorbidity is increasingly common in kidney transplant recipients, yet the implications for transplant outcomes are not fully understood. We analyzed the relationship between recipient comorbidity and survival outcomes in a UK-wide prospective cohort study-Access to Transplantation and Transplant Outcome Measures (ATTOM). METHODS: A total of 2100 adult kidney transplant recipients were recruited from all 23 UK transplant centers between 2011 and 2013. Data on 15 comorbidities were collected at the time of transplantation. Multivariable Cox regression models were used to analyze the relationship between comorbidity and 2-year graft survival, patient survival, and transplant survival (earliest of graft failure or patient death) for deceased-donor kidney transplant (DDKT) recipients (n = 1288) and living-donor kidney transplant (LDKT) recipients (n = 812). RESULTS: For DDKT recipients, peripheral vascular disease (hazard ratio [HR] 3.04, 95% confidence interval [CI]: 1.37-6.74; P = 0.006) and obesity (HR 2.27, 95% CI: 1.27-4.06; P = 0.006) were independent risk factors for graft loss, while heart failure (HR 3.77, 95% CI: 1.79-7.95; P = 0.0005), cerebrovascular disease (HR 3.45, 95% CI: 1.72-6.92; P = 0.0005), and chronic liver disease (HR 4.36, 95% CI: 1.29-14.71; P = 0.018) were associated with an increased risk of mortality. For LDKT recipients, heart failure (HR 3.83, 95% CI: 1.15-12.81; P = 0.029) and diabetes (HR 2.23, 95% CI: 1.03-4.81; P = 0.042) were associated with poorer transplant survival. CONCLUSIONS: The key comorbidities that predict poorer 2-year survival outcomes after kidney transplantation have been identified in this large prospective cohort study. The findings will facilitate assessment of individual patient risks and evidence-based decision making.

Variations in the assessment practice for renal transplantation across the United Kingdom.

BACKGROUND: To investigate whether there are any variations in the evaluation of adult candidates for cadaveric renal transplantation among transplant centers in the United Kingdom. METHODS: An online survey of transplant units in the United Kingdom, including nephrologists, surgeons, and transplant coordinators, measured differences in the assessment process and evaluation of patient's age, body mass index (BMI), cardiovascular comorbidity, and viral serology. RESULTS: A response was received from 20 out of the 23 centers (87%). These centers perform 90% of all renal transplants in the United Kingdom. In 30% of the units, there is no formal transplant assessment clinic. There is no cutoff age limit for assessment across the United Kingdom, but 12 centers (60%) exclude patients with a high BMI, with a median cutoff BMI of 35. Eight out of the 20 centers do not give cytomegalovirus (CMV)-negative patients the option to receive kidneys from a CMV-positive donor. Hepatitis C antibody-positive donors are not used in 50% of the units. There is considerable variation in the investigation of cardiovascular disease and exclusion criteria based on cardiovascular status of the patients. Five units have no consistent policy of re-evaluating patients once they are listed. CONCLUSIONS: There is evidence, from this study, of significant variations in the assessment of patients for renal transplantation across the United Kingdom. Further research and better-defined guidelines are required for a uniform assessment process and to ensure equity of access to the renal transplant waiting list.

Commercially available recombinant sonic hedgehog up-regulates Ptc and modulates the cytokine and chemokine expression of human macrophages: an effect mediated by endotoxin contamination?

The Sonic hedgehog (Shh) signalling pathway plays an important role in developmental patterning and proliferation. Recent evidence suggests that Shh also plays a role in the development of the immune system. Here, we demonstrate that components of the Shh signalling pathway are expressed in human macrophages and that the receptor for Shh, Ptc, is up-regulated by a commercially available recombinant preparation of Shh (CArShh). Further, we report that the addition of CArShh up-regulates the production of IL-6, IL-8, MCP-1, IP-10, MIG and RANTES by macrophages, an effect enhanced by the presence of fetal calf serum in the culture medium. In contrast, TGF-beta, TNF-alpha, IL-1b, IL-12 and IL-10 production were not modulated by CArShh and VEGF was minimally up-regulated even in the presence of serum. The up-regulation of these cytokines and chemokines was abrogated by CD14 inhibition and polymixin B, but not reliably inhibited by the specific Shh pathway inhibitor cyclopamine. These results suggest that, although components of the Shh signalling pathway are expressed in macrophages, the modulation of macrophage cytokine and chemokine effector function seen in response to commercially available rShh results from low levels of endotoxin contained within the CArShh preparations employed to explore the effects of Shh in vitro.

Renal transplantation in the United Kingdom for patients from ethnic minorities.

BACKGROUND: To investigate any differences in access to transplant and post-transplant outcomes for ethnic minority patients in the United Kingdom, national data on ethnicity of patients on the waiting list, those receiving a transplant, and deceased donors were analyzed. METHODS: Adult patients and donors were included. Ethnic origin was classified as white, Asian, black, or "other." National data were analyzed, and 2001 U.K. National census data were used for comparative purposes. Median waiting times to transplant were obtained from Kaplan-Meier estimates for patients registered 1998-2000. Transplant survival was estimated for patients transplanted from 1998 to 2003. RESULTS: A total of 92% of the U.K. population was white, compared with 77% of waiting list patients, 88% of transplant recipients, and 97% of deceased donors. Median waiting time to transplantation for white patients was 719 days (95% confidence interval 680-758) compared with 1368 (1131-1605) days for Asian patients and 1419 (1165-1673) days for black patients. The degree of human leukocyte antigen matching achieved was inferior for Asian and black patients. There is some evidence of inferior 3-year transplant survival for black patients compared with white and Asian patients (P=0.03). CONCLUSIONS: There are imbalances in the ethnic make up of the waiting list, the donor pool, and renal transplant recipients. There are significant differences in both post-transplant outcomes and time to transplantation between patients of different ethnic origin. Waiting times are influenced by allocation schemes, and the 2006 U.K. National Kidney Allocation Scheme is designed to achieve greater equity of access to transplant for all patients, regardless of geography, blood group, or ethnicity.

The use of marginal heart beating donor livers for transplantation in the United kingdom.

BACKGROUND: This study investigated the use of deceased heart-beating donor livers offered for transplantation during a 10-year period, during which there has been an increasing disparity between organ supply and demand in the United Kingdom. METHODS: Summary data from the National Transplant Database were analyzed on all 7107 heart-beating cadaveric donor livers offered for transplantation in the United Kingdom between 1996 and 2006, with particular attention to livers that were not retrieved, not transplanted, or that subsequently failed to function after transplantation. RESULTS: The difference between the number of patients registered for liver transplantation in the United Kingdom and those transplanted increased from 132 in 1996 to 333 in 2006, leading to a 77% increase in the number of waiting list deaths. Mean donor age increased by 6.1 (5.7-6.6) years during the period studied, in part because of a reduction in the proportion of donors arising from road fatalities. Despite this, the rate of primary nonfunction remained low (1.7% during 1996-2006). The absolute risk increase of primary nonfunction arising from receipt of a moderately as opposed to mildly steatotic organ was 2.6%, which translates to a "number needed to harm" of 41 patients. CONCLUSIONS: The decline in both the number and the quality of livers offered for transplantation in the United Kingdom during the past 10 years has not been associated with a change in the rate of primary nonfunction. In these times of acute donor shortage, these data may justify a more liberal use of marginal grafts.

Patient preferences, knowledge and beliefs about kidney allocation: qualitative findings from the UK-wide ATTOM programme.

OBJECTIVE: To explore how patients who are wait-listed for or who have received a kidney transplant understand the current UK kidney allocation system, and their views on ways to allocate kidneys in the future. DESIGN: Qualitative study using semistructured interviews and thematic analysis based on a pragmatic approach. PARTICIPANTS: 10 deceased-donor kidney transplant recipients, 10 live-donor kidney transplant recipients, 12 participants currently wait-listed for a kidney transplant and 4 participants whose kidney transplant failed. SETTING: Semistructured telephone interviews conducted with participants in their own homes across the UK. RESULTS: Three main themes were identified: uncertainty of knowledge of the allocation scheme; evaluation of the system and participant suggestions for future allocation schemes. Most participants identified human leucocyte anitgen matching as a factor in determining kidney allocation, but were often uncertain of the accuracy of their knowledge. In the absence of information that would allow a full assessment, the majority of participants consider that the current system is effective. A minority of participants were concerned about the perceived lack of transparency of the general decision-making processes within the scheme. Most participants felt that people who are younger and those better matched to the donor kidney should be prioritised for kidney allocation, but in contrast to the current scheme, less priority was considered appropriate for longer waiting patients. Some non-medical themes were also discussed, such as whether parents of dependent children should be prioritised for allocation, and whether patients with substance abuse problems be deprioritised. CONCLUSIONS: Our participants held differing views about the most important factors for kidney allocation, some of which were in contrast to the current scheme. Patient participation in reviewing future allocation policies will provide insight as to what is considered acceptable to patients and inform healthcare staff of the kinds of information patients would find most useful.

"Dirty little secrets"--endotoxin contamination of recombinant proteins.

The identification of Toll-like receptors has revolutionised our understanding of innate immunity. TLR4 transduces the LPS signal and that of a number of structurally and functionally unrelated agonists. However, recent evidence adds to longstanding concerns that endotoxin contamination of bacterially derived recombinant TLR4 agonists is responsible for effects attributed to these molecules. We highlight key factors in differentiating specific agonist effects from those of endotoxin and emphasize why conventional methods of detecting and eliminating LPS may lead to erroneous results. We propose that considerable caution is needed in the investigation of TLR4 agonists, particularly when using proteins produced in a bacterium that also houses the most ideal TLR4 agonist, LPS.

Logistical Factors Influencing Cold Ischemia Times in Deceased Donor Kidney Transplants.

BACKGROUND: Prolonged cold ischemia time (CIT) is associated with a significant risk of short- and long-term graft failure in deceased donor kidney transplants across the world. The aim of this prospective longitudinal study was to determine the importance of logistical factors on CIT. METHOD: Data on 1763 transplants were collected prospectively over 14 months from personnel in 16 transplant centers, 19 histocompatibility and immunogenetics laboratories, transport providers, and National Health Service Blood and Transplant. RESULTS: The overall mean CIT was 13.8 hours, with significant center variation (P < 0.0001). Factors that significantly reduced CIT were donation after circulatory death (P = 0.03), shorter transport time (P = 0.0002), use of virtual crossmatch (XM) (P < 0.0001), and use of donor blood for pretransplant XM (P < 0.0001). The CIT for transplants that went ahead with a virtual XM was 3 hours shorter than those requiring a pretransplant XM (P < 0.0001). There was a mean delay of 3 hours in starting transplants despite organ, recipient, and pretransplant XM result being ready, suggesting that theater access contributes significantly to increased CIT. DISCUSSION: This study identifies logistical factors relating to donor, transport, crossmatching, recipient, and theater that impact significantly on CIT in deceased donor renal transplantation, some of which are modifiable; attention should be focussed on addressing all of these.

Incentives to promote organ donation.

The worldwide shortage of organs has led to the development of incentives to promote organ donation. These incentives vary widely in nature ranging from financial remuneration to preferential access to conditional donation. Such strategies to increase organ donation present a variety of ethical dilemmas challenging traditional concepts of justice and equity of access. In addition, there are legal and logistic considerations that must be discussed. The case is made that schemes using incentives to promote organ donation must meet the requirements of society for justice, equity of access, and avoidance of racial or other bias.

Does a kidney-sharing alliance have to sacrifice cold ischemic time for better HLA matching?

BACKGROUND: The Scotland-Northern Ireland Kidney Allocation Alliance was created in August 1998. The purpose was to optimize the transplant service through increased regional exchange, higher quality matched kidneys, and better organ distribution. METHODS: An analysis was performed on prospectively collected data regarding retrieval and transplant activity. The degree of HLA matching, the cold ischemic time (CIT), the balance of exchange, and graft survival were analyzed for a 2-year period after the introduction of the new alliance and compared with the last year before alliance. RESULTS: There was a 17.7% increase in the number of transplants performed. In the 2-year period, 78% of kidneys were exported from the retrieving center compared with 55% in the prealliance year, (P<0.05, chi2). The proportion of 000 mismatched transplants and other favorable matches increased from 9.5 to 21% and from 52.5 to 61%, respectively. There was no significant difference between the CIT for the three study periods, nor between the CIT for locally used kidneys versus those exchanged within the Alliance (P>0.05, Student's t test). The largest center was a net importer of kidneys, whereas small and medium-sized centers balanced their exchange within the 2-year period. The 1-year transplant survival rate improved from 81.5% in the prealliance year to 88.4% at the end of the second year. CONCLUSIONS: The introduction of a regional kidney allocation alliance has improved the degree of HLA matching and increased the exchange of organs, without a significant increase in the CIT and any detrimental effect on graft survival.

Human leukocyte antigen and the allocation of kidneys from cadaver donors in the United Kingdom.

The national scheme currently used for the allocation of cadaver kidneys in the United Kingdom includes factors demonstrated to improve transplant outcome and promote equity in organ allocation. Introduced in 1998, the scheme is based on human leukocyte antigen matching, gives priority to children and highly sensitized patients, and incorporates features to assist transplantation in patients who are difficult to match. The scheme is open and transparent and subject to continuous audit and review to address any inequities in access to transplant that become apparent.