Using the GRADE evidence to decision framework to reach recommendations together with ethnic minority community organizations: the example of COVID-19 vaccine uptake in the United Kingdom.

OBJECTIVES: To make recommendations regarding factors that affect COVID-19 vaccine uptake by ethnic minority individuals in the United Kingdom, together with strategies that could be used to increase uptake. STUDY DESIGN AND SETTING: The results of two rapid systematic reviews-one identifying factors that affect respiratory vaccine uptake in ethnic minority adults and the other identifying experimental evaluations of strategies to increase vaccine uptake in ethnic minority adults-were put into Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Evidence to Decision frameworks to support discussion with a panel of ethnic minority community organizations, community-focused small companies, and academics of the relevance of the review findings to the UK COVID context. Aided by the frameworks, the panel made recommendations for factors that need to be addressed to increase vaccine uptake, and for which strategies might be used to increase uptake. RESULTS: Our two reviews contained 31 relevant research studies published in English between 2016 and 2021, all of which were from the United Kingdom (8/31), the United States (20), and Australia (3). We identified six factors-two linked to trust, three linked to information, and one on accessibility-that affected uptake. Strategies that had been evaluated fell into three categories: using trusted messengers, tailoring the message, and increasing convenience. These were put into GRADE Evidence to Decision frameworks and discussed over a series of meetings with individuals from nine ethnic minority community organizations and two community-focused small companies and academics. Community partners provided insight into why ethnic minority individuals in the United Kingdom had lower vaccine uptake, particularly with regard to the impact of nonhealth-related UK Government policy on individuals' heath decision-making. Recommendations included recognizing that trust will be low among some ethnic groups, thinking more broadly as to who messengers should be in a low-trust environment, ensuring that information is tailored to the information needs of specific ethnic groups and working to increase convenience. Our results are at https://www.collaborationforchange.co.uk. CONCLUSION: GRADE Evidence to Decision frameworks could be used more widely to structure discussions of research evidence between researchers, community organizations, and other nonresearch partners.

Sikh and Muslim perspectives on kidney transplantation: phase 1 of the DiGiT project - a qualitative descriptive study.

OBJECTIVES: Kidney transplantation offers patients better quality of life and survival compared with dialysis. The risk of end stage renal disease is higher among ethnic minorities and they experience longer wait times on transplant lists. This inequality stems from a high need for kidney transplantation combined with a low rate of deceased donation among ethnic minority groups. This study aimed to explore the perspectives around living donor kidney transplantation of members of the Sikh and Muslim communities with an aim to develop a digital intervention to overcome any barriers. DESIGN: A qualitative descriptive study using in person focus groups. SETTING: University Teaching Hospital and Transplant Centre. PARTICIPANTS: Convenience sampling of participants from the transplant population. Three focus groups were held with 20 participants, all were of South Asian ethnicity belonging to the Sikh and Muslim communities. METHODS: Interviews were digitally audio-recorded and transcribed verbatim; transcripts were analysed thematically. RESULTS: Four themes were identified: (a) religious issues; (b) lack of knowledge within the community; (c) time; (d) cultural identification with transplantation. CONCLUSIONS: Not only is the information given and when it is delivered important, but also the person giving the information is crucial to enhance consideration of live donor kidney transplantation. Information should be in a first language where possible and overtly align to religious considerations. A more integrated approach to transplantation counselling should be adopted which includes healthcare professionals and credible members of the target cultural group. TRIAL REGISTRATION NUMBER: NCT04327167.

Decisional Needs of People From Minority Ethnic Groups Around Living Donor Kidney Transplantation: A UK Healthcare Professionals' Perspective.

Despite improved patient and clinical outcomes, living donor kidney transplantation is underutilized in the United Kingdom, particularly among minority ethnic groups, compared to deceased donor kidney transplantation. This may in part be due to the way in which kidney services present information about treatment options. With a focus on ethnicity, semi structured interviews captured the views of 19 kidney healthcare professionals from two renal centres in West Yorkshire, about the decisional needs and context within which people with advanced kidney disease make transplant decisions. Data were analysed using thematic analysis. Themes were categorized into three groups: 1) Kidney healthcare professionals: language, cultural awareness, trusted personnel, and staff diversity, 2) Patient information resources: timing and setting of education and suitability of patient-facing information and, 3) People with advanced kidney disease: knowledge, risk perception, and cultural/religious beliefs. To our knowledge, this is the first study in the United Kingdom to investigate in depth, healthcare professionals' views on living donor kidney transplantation decision making. Six recommendations for service improvement/delivery to support decision making around living donor kidney transplantation among minority ethnic groups are described.

Patient information about living donor kidney transplantation across UK renal units: A critical review.

BACKGROUND: Patient information about living donor kidney transplantation is used to supplement conversations between health professionals, people with advanced kidney disease and potential kidney donors. It is not known if the information is designed to support decision-making about renal replacement options and if it helps people discuss living kidney donation with family and friends. OBJECTIVE: Critical review of resources used in outpatient kidney consultations to support patients' decision-making about living kidney donor transplantation. DESIGN: Mixed methods including an audit questionnaire and critical analysis of patient information leaflets. PARTICIPANTS AND MEASUREMENTS: All kidney transplant centres and renal units in United Kingdom received a questionnaire to elicit by whom, how, and when information about living kidney donation is delivered. Copies of leaflets were requested. A coding frame was utilised to produce a quality score for each leaflet. RESULTS: Thirty-nine (54%) units participated. Patients discussed living donor kidney transplantation with nephrologists (100%), living donor nurse (94%), transplant co-ordinator (94%), and predialysis nurse (86%). Twenty-three leaflets were provided and reviewed, mean quality scores for inclusion of information known to support shared decision-making was m = 2.82 out of 10 (range = 0-6, SD = 1.53). Readability scores indicated they were 'fairly difficult to read' (M = 56.3, range = 0-100, SD = 9.4). Few included cultural and faith information. Two leaflets were designed to facilitate conversations with others about donation. CONCLUSIONS: Leaflets are unlikely to adequately support decision-making between options and discussions about donation. Services writing and updating patient leaflets may benefit from our six principles to guide their development.

Isolated Pre-existing HLA-DP Donor-Specific Antibodies are Associated With Poorer Outcomes in Renal Transplantation.

Introduction: The importance of donor-specific antibodies (DSAs) in renal transplantation has long been recognized, but the significance of human leukocyte antigen (HLA)-DP antibodies remains less clear. We performed a retrospective single center study of renal transplants with pre-existing isolated HLA-DP-DSAs to assess clinical outcomes. Methods: Twenty-three patients with isolated HLA-DP-DSAs were compared with 3 control groups as follows: standard immunological risk (calculated reaction frequency [cRF] < 85%, no current or historical DSA, no repeat mismatched antigens with previous transplants, n = 46), highly sensitized (cRF > 85%, n = 27), and patients with HLA-DP antibodies that were not donor-specific (n = 18). Univariate and multivariate analyses were performed comparing antibody-mediated rejection (ABMR)-free and graft survival. Factors in the final multivariable models included patient group, % cRF, B-cell flow crossmatch (BFXM) positivity and regrafts. Results: Over a median follow-up of 1197 days, 65% of HLA-DP-DSA patients had ABMR on indication biopsies, and 30% of HLA-DP-DSA patients lost their graft. Pre-existing HLA-DP DSAs remained the single factor associated with ABMR after multivariable analysis (hazard ratio [HR] = 9.578, P = 0.012). Patients with HLA-DP DSAs had increased microvascular scores (P = 0.0346) and worse transplant glomerulopathy (P = 0.015) on biopsy compared with the standard immunological risk group. Furthermore, flow crossmatch (FXM) positivity did not help inform on the risk of graft failure or ABMR in patients with preformed DP-DSA. Conclusion: Transplants with pre-existing HLA-DP-DSAs should be considered high risk. Routine laboratory tests are unable to further risk stratify these patients. Recipients should be considered for intensified immunosuppression and closely monitored.

Dynamic Behaviour of Donor Specific Antibodies in the Early Period Following HLA Incompatible Kidney Transplantation.

In HLA-incompatible kidney transplantation, monitoring donor-specific antibodies (DSA) plays a crucial role in providing appropriate treatment and increases kidney survival times. This work aimed to determine if early post-transplant DSA dynamics inform graft outcome over and above other predictive factors. Eighty-eight cases were classified by unsupervised machine learning into five distinct DSA response groups: no response, fast modulation, slow modulation, rise to sustained and sustained. Fast modulation dynamics gave an 80% rate for early acute rejection, whereas the sustained group was associated with the lowest rejection rates (19%). In complete contrast, the five-year graft failure was lowest in the modulation groups (4-7%) and highest in the sustained groups (25-31%). Multivariable analysis showed that a higher pre-treatment DSA level, male gender and absence of early acute rejection were strongly associated with a sustained DSA response. The modulation group had excellent five-year outcomes despite higher rates of early rejection episodes. This work further develops an understanding of post-transplant DSA dynamics and their influence on graft survival following HLA-incompatible kidney transplantation.

Fresh versus frozen PMBC using the SARS CoV-2 T-SPOT.COVID test. Which works best?

With the onset of the SARS-CoV-2 pandemic and subsequent vaccination programme, a need has arisen to check for the development of T lymphocyte immunity against the virus. The SARS CoV-2 T-SPOT.COVID test measures the level of T cell immunity and has been used extensively in our laboratory over the last 6 months. Whilst this kit has been designed to be used on freshly isolated human peripheral blood mononuclear cells (PBMC), the use of frozen cells would improve clinical utility. To this end we have directly compared the use of fresh and frozen PBMC in this assay. Using healthy control blood along with renal and liver transplant patient samples we have shown that results with frozen cells are generally comparable to those from fresh cells in many, but not all samples tested, and that it is important to assess PBMC cell number and viability in thawed samples before proceeding in order to be able to interpret these results correctly.

Decisions around Deceased Organ Donation in Young South Asian Individuals in the United Kingdom.

There is a large disparity between the demand and availability of organs for transplantation from within the UK's ethnic minority groups. Our aims were to identify the perceptions, knowledge of and level of engagement with organ donation since the law changed in England in 2020. A questionnaire survey using Google Forms was designed based on prior literature and information on NHSBT website. It was distributed through media outlets and cultural/professional organizations. Status on Organ Donation Registry and Quiz scores were analyzed against multiple variables. Three hundred and sixty-five people between 18 and 24 years old completed the questionnaire. 72.3% were female, 57% were health-care students, 86.3% were of South Asian ethnicity, and 11% were immigrant respondents. Overall, 43.6% were registered to donate. South Asian groups, particularly those of Pakistani ethnicity and migrant students, were less likely to register to donate. Being more knowledgeable about the organ donation process, females, nonreligious groups, and health-care students are more likely to be registered to donate. This study identified barriers around deceased organ donation decisions and demonstrates the need for further targeted and continual education to the young South Asians individuals, to produce positive associations that will percolate to older and future generations.

HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation.

BACKGROUND: HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized and difficult to match but not much is known about its long-term graft and patient survival. METHODS: One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes. RESULTS: The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P = 0.001; and microbead assay/flow cytometry crossmatch, P = 0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P < 0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode. CONCLUSIONS: One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.

Immunoglobulin isotype compositions of ABO specific antibodies are dependent on the individual patient blood group and blood group specificity: Results from a healthy donor cohort.

Antibodies specific for the blood group ABO system antigens are of clinical significance and immunological interest. Routine clinical methods typically employ direct or indirect haemagglutination methods to measure IgM and IgG, respectively. We have developed a simple, single tube method to quantify IgM, IgG, and IgA specific for A and B antigens in order to improve accuracy and reproducibility, and to investigate the relationships between ABO group antibody type, and antibody level. Plasma samples from 300 healthy blood donors were studied. Levels of IgM and IgG binding to reagent group A and B red cells were measure by agglutination (HA) and multi-colour flow cytometry (MC-FC). IgA was also measured by MC-FC. Our FC method was found to be significantly more reproducible than HA for the measurement of blood group A and B specific antibodies. We found statistically significant correlations between antibodies measured by GC-HA and MC-FC, but sufficient differences to indicate that these methods are not equivalent. By MC-FC, IgM, IgG and IgA levels and isotope profiles were found to be dependent on both the donor ABO type and the specificity of the antibody. This study demonstrated heterogeneity in the immunoglobulin class profiles of ABO-blood group specific antibodies within the healthy population. Differences in isotype profiles of ABO-blood group specific antibodies may indicate fundamental differences in the immune mechanisms that generate these antibodies. This is likely to be relevant to the clinical situations where management or diagnosis depend on ABO-specific antibody detection and measurement.

An Update on Evaluation and Management in Cystinuria.

Cystinuria is the most common cause of inherited stone disease and is caused by the failure of absorption of filtered dibasic amino acids including cystine in the proximal tubules. It is associated with a very high recurrence rate in affected patients, with the potential for significant morbidity in such patients due to the need for repeated surgical interventions. A multimodal and multispecialty approach in a dedicated centre is the key to improving treatment outcomes and patient adherence to the treatment. This article reviews the latest knowledge on the clinical and diagnostic features and summarises key developments to aid clinicians in diagnosis and management options, together with future directions for the care of these patients.

C3d-positive donor-specific antibodies have a role in pretransplant risk stratification of cross-match-positive HLA-incompatible renal transplantation: United Kingdom multicentre study.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

Direct quantitative measurement of the kinetics of HLA-specific antibody interactions with isolated HLA proteins.

HLA specific antibodies vary in their pathogenicity and this is likely to be the net effect of constant chain usage, quantity, specificity, and affinity. Here we have measured the affinity of human monoclonal antibodies for a range of HLA proteins. Purified antibodies and ligands allowed dynamic interactions to be measured directly by surface plasmon resonance. Physiochemical differences between pairs of ligands were quantified using electrostatic mismatch and hydrophobic mismatch scores. All antibodies were characterized by fast on-rates and slow off rates but with a wide range of association rates (kon, 3.63-24.25 × 105 per mol per second) and dissociation rates (koff, 0.99-10.93 × 10-3 per second). Dissociation constants (KD) ranged from 5.9 × 10-10 M to 3.0 × 10-8 M. SN320G6 has approximately a twenty-fold greater affinity for HLA A2 compared with SN607D8, but has a similar affinity for HLA-A2 and B57. In contrast, SN607D8 has greater than a twofold greater affinity for HLA-A2 compared with A68. Similarly, WK1D12 has about a threefold greater affinity for HLA-B27 compared with B7. The higher affinity interactions correlate with the specificity of stimulating antigen. This is the first study to directly measure the binding kinetics and affinity constants for human alloantibodies against HLA.

A new data-driven model for post-transplant antibody dynamics in high risk kidney transplantation.

The dynamics of donor specific human leukocyte antigen antibodies during early stage after kidney transplantation are of great clinical interest as these antibodies are considered to be associated with short and long term clinical outcomes. The limited number of antibody time series and their diverse patterns have made the task of modelling difficult. Focusing on one typical post-transplant dynamic pattern with rapid falls and stable settling levels, a novel data-driven model has been developed for the first time. A variational Bayesian inference method has been applied to select the best model and learn its parameters for 39 time series from two groups of graft recipients, i.e. patients with and without acute antibody-mediated rejection (AMR) episodes. Linear and nonlinear dynamic models of different order were attempted to fit the time series, and the third order linear model provided the best description of the common features in both groups. Both deterministic and stochastic parameters are found to be significantly different in the AMR and no-AMR groups showing that the time series in the AMR group have significantly higher frequency of oscillations and faster dissipation rates. This research may potentially lead to better understanding of the immunological mechanisms involved in kidney transplantation.

Clinical Relevance of Donor-Specific IgM Antibodies in HLA Incompatible Renal Transplantation: A Retrospective Single-Center Study.

Immunoglobulin G (IgG) antibodies against donor human leukocyte antigens (HLA) are monitored in the pre-and post-transplant period due to their established role in predicting rejection and renal allograft survival. However, the role of immunoglobulin M (IgM) anti-HLA donor-specific antibodies (DSA) is not fully understood, especially in highly-sensitized patients undergoing direct transplantation. We designed this study to determine whether IgM DSA predicts rejection episodes and/or graft failure. Samples from 92 patients who had undergone HLA-antibody incompatible transplants were tested at 5 time points: days -8 (pre-plasmapheresis), 0, 7, 14, and 30 using Luminex microbead assay with ethylenediaminetetraacetic acid containing wash buffer (LABScreen®, One Lambda, Canoga Park, CA). IgM was defined positive if the mean fluorescence values were greater than 2000. Presence of pre- and post-transplant IgM was correlated with early antibody mediated rejection episodes (within 30 days post-transplantation) and graft failure. Statistical analyses were performed using SPSS IBM software. Graft survival estimates were death-censored. The presence of pre-transplant IgM DSA did not predict rejection (p=0.83) or graft failure (p=0.424). The post-transplant IgM DSA levels peaked at day 14 (similar to IgG DSA levels). Presence of IgM DSA post-transplant (de novo and resynthesis) was not associated with rejection (p=0.83). However, post-transplant IgM was associated with graft failure (p=0.037). This study shows additional testing of post-transplant IgM DSA over and above IgG is important as post-transplant IgM DSA is associated with graft failure.