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De novo donor‐specific antibody (dnDSA) develops in 15–25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA‐DR/DQ/DP conformational epitopes for 286 donor–recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus‐specific epitope mismatches were more numerous in patients who developed HLA‐DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA‐DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA‐DR, 17 for HLA‐DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA‐DR and HLA‐DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA‐DR and 3 HLA‐DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA‐DR and DQ epitope matching outperforms traditional low‐resolution antigen‐based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long‐term graft outcome.

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II donor-specific antibody (DSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before DSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor ofDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of DSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before DSA development were significantly lower than the levels>6 months before DSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developingDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of DSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels<5 ng/ml unless essential, and monitoring for DSA may be advisable in this setting.

First-person consent for organ donation after medical assistance in dying (MAiD) or withdrawal of life-sustaining measures (WLSM) should be an option in jurisdictions that allow MAiD or WLSM and donation after circulatory determination of death. • The most important ethical concern-that the decision for MAiD or WLSM is being driven by a desire to donate organsshould be managed by ensuring that any discussion about organ donation takes place only after the decision for MAiD or WLSM is made. • If indications for MAiD change, this guidance for policies and the practice of organ donation after MAiD should be reviewed to ensure that the changes have not created new ethical or practical concerns.

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA ‐ DR / DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA ‐ DR / DQ whole antigen mismatch, HLA ‐ DR / DQ single molecule eplet mismatch improved the correlation with de novo donor‐specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell–mediated rejection ( P = .0006), HLA ‐ DR / DQ de novo donor‐specific antibody development ( P < .0001), antibody‐mediated rejection ( P < .0001), as well as all‐cause graft loss ( P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA ‐ DR / DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Objectives:Create trustworthy, rigorous, national clinical practice guidelines for the practice of pediatric donation after circulatory determination of death in Canada.Methods:We followed a process of clinical practice guideline development based on World Health Organization and Canadian Medical Association methods. This included application of Grading of Recommendations Assessment, Development, and Evaluation methodology. Questions requiring recommendations were generated based on 1) 2006 Canadian donation after circulatory determination of death guidelines (not pediatric specific), 2) a multidisciplinary symposium of national and international pediatric donation after circulatory determination of death leaders, and 3) a scoping review of the pediatric donation after circulatory determination of death literature. Input from these sources drove drafting of actionable questions and Good Practice Statements, as defined by the Grading of Recommendations Assessment, Development, and Evaluation group. We performed additional literature reviews for all actionable questions. Evidence was assessed for quality using Grading of Recommendations Assessment, Development, and Evaluation and then formulated into evidence profiles that informed recommendations through the evidence-to-decision framework. Recommendations were revised through consensus among members of seven topic-specific working groups and finalized during meetings of working group leads and the planning committee. External review was provided by pediatric, critical care, and critical care nursing professional societies and patient partners.Results:We generated 63 Good Practice Statements and seven Grading of Recommendations Assessment, Development, and Evaluation recommendations covering 1) ethics, consent, and withdrawal of life-sustaining therapy, 2) eligibility, 3) withdrawal of life-sustaining therapy practices, 4) ante and postmortem interventions, 5) death determination, 6) neonatal pediatric donation after circulatory determination of death, 7) cardiac and innovative pediatric donation after circulatory determination of death, and 8) implementation. For brevity, 48 Good Practice Statement and truncated justification are included in this summary report. The remaining recommendations, detailed methodology, full Grading of Recommendations Assessment, Development, and Evaluation tables, and expanded justifications are available in the full text report.Conclusions:This process showed that rigorous, transparent clinical practice guideline development is possible in the domain of pediatric deceased donation. Application of these recommendations will increase access to pediatric donation after circulatory determination of death across Canada and may serve as a model for future clinical practice guideline development in deceased donation.

T cell-mediated rejection (TCMR) in kidney transplantation, standardized by the Banff working classification, is a histologic diagnosis based on T lymphocytic infiltration of the tubules, interstitial space, and/or arterial intima and media. 1 The alloimmune basis of TCMR (including Banff Borderline) is supported by its strong correlation with degree of donor-recipient HLA-DR/DQ eplet molecular mismatch (mMM). 2 Despite modern era maintenance immunosuppression with tacrolimus (Tac) and mycophenolic acid (MPA), clinical TCMR in the first year remains between 5 and 15% documented by for-cause biopsies, while subclinical TCMR (≥Banff Borderline) occurs in up to 30% of early surveillance biopsies. [3][4][5][6]