Update on the ethical, legal and technical challenges of translating xenotransplantation.

This manuscript reports on a landmark symposium on the ethical, legal and technical challenges of xenotransplantation in the UK. King's College London, with endorsement from the British Transplantation Society (BTS), and the European Society of Organ Transplantation (ESOT), brought together a group of experts in xenotransplantation science, ethics and law to discuss the ethical, regulatory and technical challenges surrounding translating xenotransplantation into the clinical setting. The symposium was the first of its kind in the UK for 20 years. This paper summarises the content of the expert lectures showcasing the progress which has been made in xenotransplantation including-the history of xenotransplantation, advances in gene edited animals and progress towards clinical xenotransplantation. We then set out the ethical and legal issues still to be resolved. Finally, we report the themes of the roundtable discussion highlighting areas of consensus and controversy. While the detail of the legal discussion was directed towards the UK, the principles and summary reported here are intended to be applicable to any jurisdiction seeking to implement clinical xenotransplantation.

Propensity Score and Instrumental Variable Techniques in Observational Transplantation Studies: An Overview and Worked Example Relating to Pre-Transplant Cardiac Screening.

Inferring causality from observational studies is difficult due to inherent differences in patient characteristics between treated and untreated groups. The randomised controlled trial is the gold standard study design as the random allocation of individuals to treatment and control arms should result in an equal distribution of known and unknown prognostic factors at baseline. However, it is not always ethically or practically possible to perform such a study in the field of transplantation. Propensity score and instrumental variable techniques have theoretical advantages over conventional multivariable regression methods and are increasingly being used within observational studies to reduce the risk of confounding bias. An understanding of these techniques is required to critically appraise the literature. We provide an overview of propensity score and instrumental variable techniques for transplant clinicians, describing their principles, assumptions, strengths, and weaknesses. We discuss the different patient populations included in analyses and how to interpret results. We illustrate these points using data from the Access to Transplant and Transplant Outcome Measures study examining the association between pre-transplant cardiac screening in kidney transplant recipients and post-transplant cardiac events.

A propensity score-matched analysis indicates screening for asymptomatic coronary artery disease does not predict cardiac events in kidney transplant recipients.

Screening for asymptomatic coronary artery disease prior to kidney transplantation aims to reduce peri- and post-operative cardiac events. It is uncertain if this is achieved. Here, we investigated whether pre-transplant screening with a stress test or coronary angiogram associated with any difference in major adverse cardiac events (MACE) up to five years post-transplantation. We examined a national prospective cohort recruited to the Access to Transplant and Transplant Outcome Measures study who received a kidney transplant between 2011-2017, and linked patient demographics and details of cardiac screening investigations to outcome data extracted from the Hospital Episode Statistics dataset and United Kingdom Renal Registry. Propensity score matched groups were analyzed using Kaplan-Meier and Cox survival analyses. Overall, 2572 individuals were transplanted in 18 centers; 51% underwent screening and the proportion undergoing screening by center ranged from 5-100%. The incidence of MACE at 90 days, one and five years was 0.9%, 2.1% and 9.4% respectively. After propensity score matching based on the presence or absence of screening, 1760 individuals were examined (880 each in screened and unscreened groups). There was no statistically significant association between screening and MACE at 90 days (hazard ratio 0.80, 95% Confidence Interval 0.31-2.05), one year (1.12, 0.51-2.47) or five years (1.31, 0.86-1.99). Age, male sex and history of ischemic heart disease were associated with MACE. Thus, there is no association between screening for asymptomatic coronary artery disease and MACE up to five years post-transplant. Practices involving unselected screening of transplant recipients should be reviewed.

Do routine hospital data accurately record comorbidity in advanced kidney disease populations? A record linkage cohort study.

BACKGROUND: Routine healthcare datasets capturing clinical and administrative information are increasingly being used to examine health outcomes. The accuracy of such data is not clearly defined. We examine the accuracy of diagnosis recording in individuals with advanced chronic kidney disease using a routine healthcare dataset in England with comparison to information collected by trained research nurses. METHODS: We linked records from the Access to Transplant and Transplant Outcome Measures study to the Hospital Episode Statistics dataset. International Classification of Diseases (ICD-10) and Office for Population Censuses and Surveys Classification of Interventions and Procedures (OPCS-4) codes were used to identify medical conditions from hospital data. The sensitivity, specificity, positive and negative predictive values were calculated for a range of diagnoses. RESULTS: Comorbidity information was available in 96% of individuals prior to starting kidney replacement therapy. There was variation in the accuracy of individual medical conditions identified from the routine healthcare dataset. Sensitivity and positive predictive values ranged from 97.7 and 90.4% for diabetes and 82.6 and 82.9% for ischaemic heart disease to 44.2 and 28.4% for liver disease. CONCLUSIONS: Routine healthcare datasets accurately capture certain conditions in an advanced chronic kidney disease population. They have potential for use within clinical and epidemiological research studies but are unlikely to be sufficient as a single resource for identifying a full spectrum of comorbidities.

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.

Changes in quality of life, health status and other patient-reported outcomes following simultaneous pancreas and kidney transplantation (SPKT): a quantitative and qualitative analysis within a UK-wide programme.

We examined quality of life (QoL) and other patient-reported outcome measures (PROMs) in 95 simultaneous pancreas and kidney transplant (SPKT) recipients and 41 patients wait-listed for SPKT recruited to the UK Access to Transplantation and Transplant Outcome Measures (ATTOM) programme. Wait-listed patients transplanted within 12 months of recruitment (n = 22) were followed 12 months post-transplant and compared with those still wait-listed (n = 19) to examine pre- to post-transplant changes. Qualitative interviews with ten SPKT recipients 12 months post-transplant were analysed thematically. Cross-sectional analyses showed several better 12-month outcomes for SPKT recipients compared with those still wait-listed, a trend to better health utilities but no difference in diabetes-specific QoL or diabetes treatment satisfaction. Pre- to post-transplant, SPKT recipients showed improved treatment satisfaction, well-being, self-reported health, generic QoL and less negative impact on renal-specific QoL (ps < 0.05). Health utility values were better overall in transplant recipients and neither these nor diabetes-specific QoL changed significantly in either group. Pre-emptive transplant advantages seen in 12-month cross-sectional analyses disappeared when controlling for baseline values. Qualitative findings indicated diabetes complications, self-imposed blood glucose monitoring and dietary restrictions continued to impact QoL negatively post-transplant. Unrealistic expectations of SPKT caused some disappointment. Measuring condition-specific PROMs over time will help in demonstrating the benefits and limitations of SPKT.

Limited health literacy is associated with reduced access to kidney transplantation.

Limited health literacy is common in patients with chronic kidney disease (CKD) and has been variably associated with adverse clinical outcomes. The prevalence of limited health literacy is lower in kidney transplant recipients than in individuals starting dialysis, suggesting selection of patients with higher health literacy for transplantation. We investigated the relationship between limited health literacy and clinical outcomes, including access to kidney transplantation, in a prospective UK cohort study of 2,274 incident dialysis patients aged 18-75 years. Limited health literacy was defined by a validated Single Item Literacy Screener (SILS). Multivariable regression was used to test for association with outcomes after adjusting for age, sex, socioeconomic status (educational level and car ownership), ethnicity, first language, primary renal diagnosis, and comorbidity. In fully adjusted analyses, limited health literacy was not associated with mortality, late presentation to nephrology, dialysis modality, haemodialysis vascular access, or pre-emptive kidney transplant listing, but was associated with reduced likelihood of listing for a deceased-donor transplant (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.51-0.90), receiving a living-donor transplant (HR 0.41; 95% CI 0.19-0.88), or receiving a transplant from any donor type (HR 0.65; 95% CI 0.44-0.96). Limited health literacy is associated with reduced access to kidney transplantation, independent of patient demographics, socioeconomic status, and comorbidity. Interventions to ameliorate the effects of low health literacy may improve access to kidney transplantation.

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft-versus-host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor-specific tolerance results in improved outcomes remains unanswered. We collected follow-up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper-matched living-donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 µmol/l (interquartile range [IQR] 72-99) in the tolerant cohort and 118 µmol/l (IQR 99-143) in the control group. Mixed linear-model showed around 29% lower average creatinine levels throughout follow-up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long-term immunosuppression for many years, suggesting permanent donor-specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.

Health literacy and patient outcomes in chronic kidney disease: a systematic review.

Background: Limited health literacy affects 25% of people with chronic kidney disease (CKD), and may reduce self-management skills resulting in poorer clinical outcomes. By disproportionately affecting people with low socio-economic status and non-white ethnicity, limited health literacy may promote health inequity. Methods: We performed a systematic review of quantitative studies of health literacy and clinical outcomes among adults with CKD. Results: A total of 29 studies (13 articles; 16 conference abstracts) were included. One included non-USA patients. Of the 29 studies, 5 were cohort studies and 24 were cross-sectional. In all, 18 300 patients were studied: 4367 non-dialysis CKD; 13 202 dialysis; 390 transplant; 341 unspecified. Median study size was 127 [interquartile range (IQR) 92-238)], but 480 (IQR 260-2392) for cohort studies. Median proportion of non-white participants was 48% (IQR 17-70%). Six health literacy measures were used. Outcomes included patient attributes, care processes, clinical/laboratory parameters and 'hard' clinical outcomes. Limited health literacy was significantly, independently associated with hospitalizations, emergency department use, missed dialysis sessions, cardiovascular events and mortality (in cohort studies). Study quality was high (1 study), moderate (3 studies) and poor (25 studies), limited by sampling methods, variable adjustment for confounders and reduced methodological detail given in conference abstracts. Conclusions: There is limited robust evidence of the causal effects of health literacy on patient outcomes in CKD. Available evidence suggests associations with adverse clinical events, increased healthcare use and mortality. Prospective studies are required to determine the causal effects of health literacy on outcomes in CKD patients, and examine the relationships between socio-economic status, comorbidity, health literacy and CKD outcomes. Intervention development and evaluation will determine whether health literacy is a modifiable determinant of poor outcomes in CKD.

Kidney transplant outcomes from older deceased donors: a paired kidney analysis by the European Renal Association-European Dialysis and Transplant Association Registry.

As the median age of deceased kidney donors rises, updated knowledge of transplant outcomes from older deceased donors in differing donor-recipient age groups is required. Using ERA-EDTA Registry data we determined survival outcomes of kidney allografts donated from the same older deceased donor (55-70 years), and transplanted into one recipient younger and one recipient of similar age to the donor. The recipient pairs were divided into two groups: group 1; younger (median age: 52 years) and older (60 years) and group 2; younger (41 years) and older (60 years). A total of 1410 adults were transplanted during 2000-2007. Compared to the older recipients, the mean number of functioning graft years at 10 years was 6 months longer in the group 1 and group 2 younger recipients (P < 0.001). Ten-year graft survival was 54% and 40% for the group 1 younger and older recipients, and 60% and 49% for the group 2 younger and older recipients. Paired Cox regression analyses showed a lower risk of graft failure (group 1 younger; adjusted relative risk [RRa]:0.57, 95% CI:0.41-0.79, and group 2 younger; RRa:0.63, 95% CI:0.47-0.85) in younger recipients. Outcomes from older deceased donor allografts transplanted into differing donor-recipient age groups are better than previously reported. These allografts remain a valuable transplant resource, particularly for similar-aged recipients.

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.

Estimating Health-State Utility Values in Kidney Transplant Recipients and Waiting-List Patients Using the EQ-5D-5L.

OBJECTIVES: To report health-state utility values measured using the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) in a large sample of patients with end-stage renal disease and to explore how these values vary in relation to patient characteristics and treatment factors. METHODS: As part of the prospective observational study entitled "Access to Transplantation and Transplant Outcome Measures," we captured information on patient characteristics and treatment factors in a cohort of incident kidney transplant recipients and a cohort of prevalent patients on the transplant waiting list in the United Kingdom. We assessed patients' health status using the EQ-5D-5L and conducted multivariable regression analyses of index scores. RESULTS: EQ-5D-5L responses were available for 512 transplant recipients and 1704 waiting-list patients. Mean index scores were higher in transplant recipients at 6 months after transplant surgery (0.83) compared with patients on the waiting list (0.77). In combined regression analyses, a primary renal diagnosis of diabetes was associated with the largest decrement in utility scores. When separate regression models were fitted to each cohort, female gender and Asian ethnicity were associated with lower utility scores among waiting-list patients but not among transplant recipients. Among waiting-list patients, longer time spent on dialysis was also associated with poorer utility scores. When comorbidities were included, the presence of mental illness resulted in a utility decrement of 0.12 in both cohorts. CONCLUSIONS: This study provides new insights into variations in health-state utility values from a single source that can be used to inform cost-effectiveness evaluations in patients with end-stage renal disease.

Long-term graft outcomes and patient survival are lower posttransplant in patients with a primary renal diagnosis of glomerulonephritis.

Glomerulonephritis (GN) is the primary diagnosis in 20% to 40% of patients receiving a renal transplant. Here we studied patient survival and graft outcomes in patients with GN transplanted in the UK. UK Renal Registry data were used to analyze patient survival and graft failure in incident transplant patients between 1997 to 2009 who had a diagnosis of primary GN, in comparison to patients transplanted with adult polycystic kidney disease (APKD) or diabetes. Multivariable regression analysis adjusted for age, sex, donor type, ethnicity, donor age, time on dialysis, human leukocyte antigen mismatch, cold ischemic time, and graft failure (for patient survival). Patients were followed up through December 2012. Of 4750 patients analyzed, 2975 had GN and 1775 APKD. Graft failure was significantly higher in membranoproliferative glomerulonephritis (MPGN) type II (hazard ratio: 3.5, confidence interval: 1.9-6.6), focal segmental glomerulosclerosis (2.4, 1.8-3.2), MPGN type I (2.3, 1.6-3.3), membranous nephropathy (2.0, 1.4-2.9), and IgA nephropathy (1.6, 1.3-2.0) compared to APKD. Survival was significantly reduced in patients with MPGN type II (4.7, 2.0-10.8), and those with lupus nephritis (1.8, 1.1-2.9). Overall graft failure for patients with GN was similar to those with diabetes. Thus, in comparison to outcomes in APKD, graft survival is significantly lower in most GNs, with variation in outcomes between different GNs. This information should assist in pretransplant counseling of patients. Further study is required to understand the reduced survival seen in lupus nephritis and MPGN type II, and to improve overall graft outcomes.

Limited health literacy in advanced kidney disease.

Limited health literacy may reduce the ability of patients with advanced kidney disease to understand their disease and treatment and take part in shared decision making. In dialysis and transplant patients, limited health literacy has been associated with low socioeconomic status, comorbidity, and mortality. Here, we investigated the prevalence and associations of limited health literacy using data from the United Kingdom-wide Access to Transplantation and Transplant Outcome Measures (ATTOM) program. Incident dialysis, incident transplant, and transplant wait-listed patients ages 18 to 75 were recruited from 2011 to 2013 and data were collected from patient questionnaires and case notes. A score >2 in the Single-Item Literacy Screener was used to define limited health literacy. Univariate and multivariate analyses were performed to identify patient factors associated with limited health literacy. We studied 6842 patients, 2621 were incident dialysis, 1959 were wait-listed, and 2262 were incident transplant. Limited health literacy prevalence was 20%, 15%, and 12% in each group, respectively. Limited health literacy was independently associated with low socioeconomic status, poor English fluency, and comorbidity. However, transplant wait-listing, preemptive transplantation, and live-donor transplantation were associated with increasing health literacy.

Predicting patient survival after deceased donor kidney transplantation using flexible parametric modelling.

BACKGROUND: The influence of donor and recipient factors on outcomes following kidney transplantation is commonly analysed using Cox regression models, but this approach is not useful for predicting long-term survival beyond observed data. We demonstrate the application of a flexible parametric approach to fit a model that can be extrapolated for the purpose of predicting mean patient survival. The primary motivation for this analysis is to develop a predictive model to estimate post-transplant survival based on individual patient characteristics to inform the design of alternative approaches to allocating deceased donor kidneys to those on the transplant waiting list in the United Kingdom. METHODS: We analysed data from over 12,000 recipients of deceased donor kidney or combined kidney and pancreas transplants between 2003 and 2012. We fitted a flexible parametric model incorporating restricted cubic splines to characterise the baseline hazard function and explored a range of covariates including recipient, donor and transplant-related factors. RESULTS: Multivariable analysis showed the risk of death increased with recipient and donor age, diabetic nephropathy as the recipient's primary renal diagnosis and donor hypertension. The risk of death was lower in female recipients, patients with polycystic kidney disease and recipients of pre-emptive transplants. The final model was used to extrapolate survival curves in order to calculate mean survival times for patients with specific characteristics. CONCLUSION: The use of flexible parametric modelling techniques allowed us to address some of the limitations of both the Cox regression approach and of standard parametric models when the goal is to predict long-term survival.