Characteristics of Early Antibody Mediated Rejection in Antibody Incompatible Living Donor Kidney Transplantation.

Antibody incompatible transplantation (AIT) may be an only option for highly sensitized patients. Severe form of early antibody mediated rejection (AMR) adversely affects graft survival after AIT. The aim of this study was to identify individuals at risk of AMR. We analyzed 213 living donor AITs performed at our center. Among 120 ABOi, 58 HLAi and 35 DSA + FCXM-negative cases, the rates of early AMR were 6%, 31%, and 9%, respectively (p < 0.001). On multivariate analysis for graft loss, early AMR had a HR of 3.28 (p < 0.001). The HLAi group had worse death-censored graft survival (p = 0.003). In the HLAi group, Patients with aggressive variant AMR (AAMR) had greater percentage of C3d complement fixing DSA, higher baseline class I and total DSA MFI levels and B-cell FCXM RMF. C1q and C3d complement fixing DSA and strong positivity of baseline B- or T-cell FXCM as predictors of AAMR had 100% sensitivity. Early AMR is of significant clinical concern in AIT as it results in poor graft survival and is not well described in literature. An aggressive variant is characterized by massive rise in DSA levels at rejection. Baseline DSA, C1q, and C3d and baseline FCXM values can be used to risk-stratify candidates for AIT.

European Consensus on the Management of Sensitized Kidney Transplant Recipients: A Delphi Study.

An increasing number of sensitized patients awaiting transplantation face limited options, leading to fatalities during dialysis and higher costs. The absence of established evidence highlights the need for collaborative consensus. Donor-specific antibodies (DSA)-triggered antibody-mediated rejection (AMR) significantly contributes to kidney graft failure, especially in sensitized patients. The European Society for Organ Transplantation (ESOT) launched the ENGAGE initiative, categorizing sensitized candidates by AMR risk to improve patient care. A systematic review assessed induction and maintenance regimens as well as antibody removal strategies, with statements subjected to the Delphi methodology. A Likert-scale survey was distributed to 53 European experts (Nephrologists, Transplant surgeons and Immunologists) with experience in kidney transplant recipient care. A rate ≥75% with the same answer was considered consensus. Consensus was achieved in 95.3% of statements. While most recommendations aligned, two statements related to complement inhibitors for AMR prophylaxis lacked consensus. The ENGAGE consensus presents contemporary recommendations for desensitization and immunomodulation strategies, grounded in predefined risk categories. The adoption of tailored, patient-specific measures is anticipated to streamline the care of sensitized recipients undergoing renal allografts. While this approach holds the promise of enhancing transplant accessibility and fostering long-term success in transplantation outcomes, its efficacy will need to be assessed through dedicated studies.

How Does Surgeons' Autonomic Physiology Vary Intraoperatively?: A Real-time Study of Cardiac Reactivity.

OBJECTIVE: To measure the physiological responses of surgical team members under varying levels of intraoperative risk. BACKGROUND: Measurement of intraoperative physiological responses provides insight into how operation complexity, phase of surgery, and surgeon seniority impact stress. METHODS: Autonomic nervous system responses (interbeat intervals, IBIs) were measured continuously during different surgical operations of various complexity. The study investigated whether professional role (eg attending surgeon), operative risk (high vs. low), and type of primary operator (attending surgeon vs. resident) impacted IBI reactivity. Physiological synchrony captured the degree of correspondence between individuals' physiological responses at any given time point. RESULTS: A total of 10,005 observations of IBI reactivity were recorded in 26 participants during 16 high-risk (renal transplant and laparoscopic donor nephrectomy) and low-risk (arteriovenous fistula formation) operations. Attending surgeons showed greater IBI reactivity (faster heart rate) than residents and nurses during high-risk operations and while actively operating (Ps<0.001). Residents showed lower reactivity during high-risk (relative to low-risk) operations (P<0.001) and similar reactivity regardless of whether they or the attending surgeon was operating (P=0.10). Nurses responded similarly during low-risk and high-risk operations (P=0.102) but were more reactive when the resident was operating compared to when the attending surgeon was the primary operator (P<0.001). In high-risk operations, attending surgeons had negative physiological covariation with residents and nurses (P<0.001). In low-risk operations, only attending surgeons and nurses were synchronized (P<0.001). CONCLUSION: Attending surgeons' physiological responses were well-calibrated to operative demands. Residents' and nurses' responses were not callibrated to the same extent. This suggests that risk sensitivity is an adaptive response to stress that surgeons acquire.

Surgical leadership in a culture of safety: An inter-professional study of metrics and tools for improving clinical practice.

BACKGROUND: Leadership in a safety culture environment is essential in avoiding patient harm. However, leadership in surgery is not routinely taught or assessed. This study aims to identify a framework, metrics and tools to improve surgical leadership and safety outcomes. METHODS: Qualitative interviews were performed with leadership experts from safety-critical professions. Non-probability-based sampling was undertaken in major international airlines. Data underwent thematic analysis and clinical adaptation by multiple surgeon-analysts using the framework method. RESULTS: 583 codes were synthesised into 10 themes. Leaders were identified as 'threat and error managers' who placed safety first. Their core attribute was humble confidence. This allowed them to set the tone for high standards of practice, whilst empowering individuals to speak up about safety issues. Safety-oriented leaders assumed complete responsibility and applied their authority discerningly to obtain optimal outcomes. Finally, effective leaders rallied support for their mission by instilling confidence, building collaborations and managing conflict. CONCLUSIONS: Surgical leadership requires the ability to manage risk, opportunity and people. The study provides an assessment matrix and deliverable tools for improving surgical safety.

Blood transfusions post kidney transplantation are associated with inferior allograft and patient survival-it is time for rigorous patient blood management.

Background: Patient Blood Management (PBM), endorsed by the World Health Organisation is an evidence-based, multi-disciplinary approach to minimise inappropriate blood product transfusions. Kidney transplantation presents a particular challenge to PBM, as comprehensive evidence of the risk of transfusion is lacking. The aim of this study is to investigate the prevalence of post-transplant blood transfusions across multiple centres, to analyse risk factors for transfusion and to compare transplant outcomes by transfusion status. Methods: This analysis was co-ordinated via the UK Transplant Registry within NHS Blood and Transplant (NHSBT), and was performed across 4 centres. Patients who had received a kidney transplant over a 1-year period, had their transfusion status identified and linked to data held within the national registry. Results: Of 720 patients, 221(30.7%) were transfused, with 214(29.7%) receiving a red blood cell (RBC) transfusion. The proportion of patients transfused at each centre ranged from 20% to 35%, with a median time to transfusion of 4 (IQR:0-12) days post-transplant. On multivariate analysis, age [OR: 1.02(1.01-1.03), p=0.001], gender [OR: 2.11(1.50-2.98), p<0.0001], ethnicity [OR: 1.28(1.28-2.60), p=0.0008], and dialysis dependence pre-transplant [OR: 1.67(1.08-2.68), p=0.02], were associated with transfusion. A risk-adjusted Cox proportional hazards model showed transfusion was associated with inferior 1-year patient survival [HR 7.94(2.08-30.27), p=0.002] and allograft survival [HR: 3.33(1.65-6.71), p=0.0008], and inferior allograft function. Conclusion: RBC transfusions are common and are independently associated with inferior transplant outcomes. We urge that further research is needed to understand the mechanisms behind the outcomes, to support the urgent development of transplant-specific anaemia guidelines.

Donating a Kidney to a Stranger: Are Healthcare Professionals Facilitating the Journey? Results From the BOUnD Study.

Unspecified kidney donors (UKDs) are approached cautiously by some transplant professionals. The aim of this study was to interrogate the views of UK transplant professionals towards UKDs and identify potential barriers. A purposely designed questionnaire was validated, piloted and distributed amongst transplant professionals at each of the 23 UK transplant centres. Data captured included personal experiences, attitudes towards organ donation, and specific concerns about UKD. 153 responses were obtained, with representation from all UK centres and professional groups. The majority reported a positive experience with UKDs (81.7%; p < 0.001) and were comfortable with UKDs undergoing major surgery (85.7%; p < 0.001). 43.8% reported UKDs to be more time consuming and 52% felt that a mental health assessment should take place before any medical tests. 77% indicated the need for a lower age limit. The suggested age range was broad (16-50 years). Adjusted mean acceptance scores did not differ by profession (p = 0.68) but higher volume centres were more accepting (46.2 vs. 52.9; p < 0.001). This is the first quantitative study of acceptance by transplant professionals to a large national UKD programme. Support is broad, however potential barriers to donation have been identified, including lack of training. Unified national guidance is needed to address these.

Exploring Staff Attitudes Towards Unspecified Kidney Donors in the United Kingdom: Results From the BOUnD Study.

Unspecified kidney donation (UKD) has made substantial contributions to the UK living donor programme. Nevertheless, some transplant professionals are uncomfortable with these individuals undergoing surgery. This study aimed to qualitatively explore the attitudes of UK healthcare professionals towards UKD. An opportunistic sample was recruited through the Barriers and Outcomes in Unspecified Donation (BOUnD) study covering six UK transplant centres: three high volume and three low volume centres. Interview transcripts were analysed using inductive thematic analysis. The study provided comprehensive coverage of the UK transplant community, involving 59 transplant professionals. We identified five themes: staff's conception of the ethics of UKD; presence of the known recipient in the donor-recipient dyad; need for better management of patient expectations; managing visceral reactions about the "typical" unspecified kidney donor; complex attitudes toward a promising new practice. This is the first in-depth qualitative study of attitudes of transplant professionals towards UKD. The data uncovered findings with strong clinical implications for the UKD programme, including the need for a uniform approach towards younger candidates that is adhered to by all transplant centres, the need to equally extend the rigorous assessment to both specified and unspecified donors, and a new approach to managing donor expectations.

Living Donor Kidney Transplantation in Older Individuals: An Ethical Legal and Psychological Aspects of Transplantation (ELPAT) View.

Living donor transplantation is the optimal treatment for suitable patients with end-stage kidney disease. There are particular advantages for older individuals in terms of elective surgery, timely transplantation, and early graft function. Yet, despite the superiority of living donor transplantation especially for this cohort, older patients are significantly less likely to access this treatment modality than younger age groups. However, given the changing population demographic in recent decades, there are increasing numbers of older but otherwise healthy individuals with kidney disease who could benefit from living donor transplantation. The complex reasons for this inequity of access are explored, including conscious and unconscious age-related bias by healthcare professionals, concerns relating to older living donors, ethical anxieties related to younger adults donating to aging patients, unwillingness of potential older recipients to consider living donation, and the relevant legislation. There is a legal and moral duty to consider the inequity of access to living donor transplantation, recognising both the potential disparity between chronological and physiological age in older patients, and benefits of this treatment for individuals as well as society.

Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.

BACKGROUND: Transplant rejection is a major cause of graft loss and morbidity. Currently, no human models of antibody-mediated rejection (AMR) exist, limiting mechanistic investigation and organ-specific targeted therapy. Here, using 12 human kidneys and ex-vivo normothermic machine perfusion, we demonstrate phenotypes of AMR after addition of antibodies against either human HLA class I or blood group antigens (A, B), thus modelling clinical AMR that can follow HLA incompatible (HLAi) or blood group incompatible (ABOi) transplantation. METHODS: Discarded human kidneys with wide ranging demographics and cold ischaemia times (11-54 h) were perfused with red blood cells and fresh frozen plasma (FFP) as a source of complement/coagulation factors. For the HLAi model, 600 µg of W6/32 anti-class 1 HLA antibody was added to the circuit (time '0'). For the ABOi model, high titre FFP of the relevant blood group antibody was added. Renal blood flow index (RBFi, mL/min/100 g), C3 desArg, prothrombin fragments 1 + 2 and histology were determined. Our endpoints included haemodynamic changes, thrombosis, and biopsy proven complement deposition. FINDINGS: Compared to control kidneys perfused without anti-donor antibodies, both models demonstrated haemodynamic collapse after antibody perfusion with only the HLAi model showing glomerular C4d deposition. INTERPRETATION: We show that a clinically relevant human kidney model of AMR is feasible, and anticipate that these models, with refinements, could provide a basis to test different strategies to prevent AMR. FUNDING: The Rosetrees and Stonygate Trust, The Royal College of Surgeons of England Fellowship Grant, NIHR Biomedical Research Centre/KCL Early Career Grant, Kidney Research U.K.

Crisis Preparedness: A Systems-Based Framework for Avoiding Harm in Surgery.

BACKGROUND: Highly performing healthcare organizations benefit from robust failure management systems. This involves the ability to respond and recover from critical events, as well avoiding harm in the first place (crisis preparedness). Currently, the surgical community may lack an integrated toolbox for crisis readiness. The study aims to create a practical framework for crisis preparedness in surgery. STUDY DESIGN: A multimethod qualitative study was designed to identify and translate crisis preparedness interventions from high-reliability industries to clinical practice. The tools and strategies identified were subsequently developed and clinically adapted for healthcare use. The study used (1) observational fieldwork in commercial aviation; (2) semi-structured interviews with senior airline pilots, and (3) mixed focus groups with healthcare and aviation safety experts. A crisis preparedness framework was derived by thematic analysis using the framework method. Clinical adaptation was achieved using expert consensus methodology. RESULTS: Twenty-two aviation and healthcare experts participated in 17 interviews and 3 focus groups. A framework for crisis preparedness was derived, consisting of 6 behavioral interventions: (1) anticipate threats and errors by building situational awareness using cognitive tools; (2) brief teams about goals, deviations, operational risks, and contingency plans; (3) implement standard operating procedures using checklists; (4) rehearse emergency drills before critical phases of work; (5) set the tone for a positive working environment by establishing cultural norms and empowering individuals to speak up about safety issues; and (6) debrief performance outcomes to derive learning lessons. CONCLUSIONS: Surgical crisis preparedness requires integrated systems rather than isolated safety interventions. This study provides a framework and the tools to achieve this.

European Guideline for the Management of Kidney Transplant Patients With HLA Antibodies: By the European Society for Organ Transplantation Working Group.

This guideline, from a European Society of Organ Transplantation (ESOT) working group, concerns the management of kidney transplant patients with HLA antibodies. Sensitization should be defined using a virtual parameter such as calculated Reaction Frequency (cRF), which assesses HLA antibodies derived from the actual organ donor population. Highly sensitized patients should be prioritized in kidney allocation schemes and linking allocation schemes may increase opportunities. The use of the ENGAGE 5 ((Bestard et al., Transpl Int, 2021, 34: 1005-1018) system and online calculators for assessing risk is recommended. The Eurotransplant Acceptable Mismatch program should be extended. If strategies for finding a compatible kidney are very unlikely to yield a transplant, desensitization may be considered and should be performed with plasma exchange or immunoadsorption, supplemented with IViG and/or anti-CD20 antibody. Newer therapies, such as imlifidase, may offer alternatives. Few studies compare HLA incompatible transplantation with remaining on the waiting list, and comparisons of morbidity or quality of life do not exist. Kidney paired exchange programs (KEP) should be more widely used and should include unspecified and deceased donors, as well as compatible living donor pairs. The use of a KEP is preferred to desensitization, but highly sensitized patients should not be left on a KEP list indefinitely if the option of a direct incompatible transplant exists.

Challenges and Opportunities in the Supply of Living Kidney Donation in the UK National Health Service: An Economic Perspective.

End-stage kidney disease is a significant burden on the healthcare systems of many countries, and this is likely to continue because of an increasingly aging and comorbid population. Multiple studies have demonstrated a significant clinical benefit in transplantation when compared with dialysis, however, there continues to be a shortage of donor kidneys available. This article provides an economic perspective on issues pertinent to living kidney donation and transplantation. Although ethics, equity, and cultural considerations often seem at odds with economic concepts around resource allocation, this article explains the situation around supply and demand for living kidneys and illustrates how this has been addressed in the economic literature. The article discusses different policy recommendations for resolving the imbalance between supply and demand in kidney donation, through policies under 3 main approaches: increasing supply, decreasing demand, and improving the allocation of kidney supply.

Alloimmune Risk Stratification for Kidney Transplant Rejection.

Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient's circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non-HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.

How crises work: A model of error cause and effect in surgical practice.

INTRODUCTION: Surgical crises have major consequences for patients, staff and healthcare institutions. Nevertheless, their aetiology and evolution are poorly understood outside the remit of root-cause analyses. AIMS: To develop a crisis model in surgery in order to aid the reporting and management of safety critical events. METHODS: A narrative review surveyed the safety literature on failure causes, mechanisms and effects in the context of surgical crises. Sources were identified using non-probability sampling, with selection and inclusion being determined by author panel consensus. The data underwent thematic analysis and reporting followed the recommendation of the SALSA framework. RESULTS: Data from 133 sources derived five principal themes. Analysis suggested that surgical care processes become destabilized in a step-wise manner. This crisis chain is initiated by four categories of threat or risk: (i) the systems in which surgeons operate; (ii) surgeons' technical, cognitive and behavioural skills; (iii) surgeons' physiological and psychological state (operational condition); and (iv) professional culture. Once triggered, the crisis chain is driven by only three types of errors: Type I. Performance errors consist of failures to diagnose, plan or execute tasks; Type II. Awareness errors are failures to recognise, comprehend or extrapolate the impact of performance failures; Type III. Rescue errors represent failures to correct faulty performance. The co-occurrence of all three error types gives rise to harm, which can lead to a crisis in the absence of mitigating actions. CONCLUSION: Surgical crises may be triggered by four categories of threat and driven by only three types of error. These may represent universal targets for safety interventions that create new opportunities for crisis management.

Crisis recovery in surgery: Error management and problem solving in safety-critical situations.

BACKGROUND: Surgical crises, both clinical and executive, carry risk of harm to patients, staff, and organizations. Once stabilized and contained, crisis recovery requires complex decision-making and problem-solving to address primary failures (errors) and their consequences. In contrast to other safety-critical professions, surgeons may lack access to crisis recovery strategies and tools that go beyond the technical aspects of clinical practice. This study aims to develop a framework for surgical crisis recovery based on problem-solving interventions used by pilots in commercial aviation. METHODS: This study undertook observational fieldwork, semistructured interviews, and focus groups with senior airline pilots and health care safety experts. Thematic analysis using the framework method identified key interventions applicable to surgical crisis recovery. Subsequently, expert group consensus adapted and content validated this model for clinical use. RESULTS: Qualitative data from 22 aviation and health care safety experts informed surgical crisis resolution. This consisted of 3 strategies: (1) building cognitive capacity by improving situational awareness and workload management; (2) using checklists in abnormal situations to implement emergency operating procedures; (3) undertaking structured decision-making using analysis-based problem-solving cycles (eg, T-DODAR framework). Twelve tools were validated and adapted to aid implementation of these strategies. CONCLUSION: Once stabilized, surgical crises may be resolved using 3 sequential strategies derived from commercial aviation.

The phenotype of HLA-binding B cells from sensitized kidney transplant recipients correlates with clinically prognostic patterns of interferon-γ production against purified HLA proteins.

B cells play crucial roles in cell-mediated alloimmune responses. In vitro, B cells can support or regulate indirect T-cell alloreactivity in response to donor antigens on ELISpot and these patterns associate with clinical outcome. Previous reports of associations between B-cell phenotype and function have examined global phenotypes and responses to polyclonal stimuli. We hypothesized that studying antigen-specific B cells, using samples from sensitized patients, would inform further study to identify novel targets for intervention. Using biotinylated HLA proteins, which bind HLA-specific B cells via the B-cell receptor in a dose-dependent fashion, we report the specific phenotype of HLA-binding B cells and define how they associated with patterns of anti-HLA response in interferon-γ ELISpot. HLA-binding class-switched and IgM+CD27+ memory cells associated strongly with B-dependent interferon-γ production and appeared not suppressible by endogenous Tregs. When the predominant HLA-binding phenotype was naïve B cells, the associated functional ELISpot phenotype was determined by other cells present. High numbers of non-HLA-binding transitional cells associated with B-suppressed interferon-γ production, especially if Tregs were present. However, high frequencies of HLA-binding marginal-zone precursors associated with B-dependent interferon-γ production that appeared suppressible by Tregs. Finally, non-HLA-binding marginal zone precursors may also suppress interferon-γ production, though this association only emerged when Tregs were absent from the ELISpot. Thus, our novel data provide a foundation on which to further define the complexities of interactions between HLA-specific T and B cells and identify new targets for intervention in new therapies for chronic rejection.

Critically important outcomes for infection in trials in kidney transplantation: An international survey of patients, caregivers, and health professionals.

BACKGROUND: Infections are a common complication following kidney transplantation, but are reported inconsistently in clinical trials. This study aimed to identify the infection outcomes of highest priority for patients/caregivers and health professionals to inform a core outcome set to be reported in all kidney transplant clinical trials. METHODS: In an international online survey, participants rated the absolute importance of 16 infections and eight severity dimensions on 9-point Likert Scales, with 7-9 being critically important. Relative importance was determined using a best-worst scale. Means and proportions of the Likert-scale ratings and best-worst preference scores were calculated. RESULTS: 353 healthcare professionals (19 who identified as both patients/caregiver and healthcare professionals) and 220 patients/caregivers (190 patients, 22 caregivers, eight who identified as both) from 55 countries completed the survey. Both healthcare professionals and patients/caregivers rated bloodstream (mean 8.4 and 8.5, respectively; aggregate 8.5), kidney/bladder (mean 7.9 and 8.4; aggregate 8.1), and BK virus (mean 8.1 and 8.6; aggregate 8.3) as the top three most critically important infection outcomes, whilst infectious death (mean 8.8 and 8.6; aggregate 8.7), impaired graft function (mean 8.4 and 8.7; aggregate 8.5) and admission to the intensive care unit (mean 8.2 and 8.3; aggregate 8.2) were the top three severity dimensions. Relative importance (best-worst) scores were consistent. CONCLUSIONS: Healthcare professionals and patients/caregivers consistently identified bloodstream infection, kidney/bladder infections, and BK virus as the three most important infection outcomes, and infectious death, admission to intensive care unit and infection impairing graft function as the three most important infection severity outcomes.