The Banff 2022 Kidney Meeting Report: Re-Appraisal of Microvascular Inflammation and the Role of Biopsy-Based Transcript Diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from 19th-23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30 anniversary of the first Banff Classification, pre-meeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis.

The Impact of HLA-DQαβ Heterodimer Mismatch on Living Donor Kidney Allograft Outcomes.

Background: HLA-DQ mismatch has been identified as a predictor of de novo donor-specific HLA antibody formation and antibody-mediated rejection. There are insufficient data to guide the incorporation of DQ mismatch into organ allocation decisions.

Methods: We used a retrospective longitudinal cohort of adult living donor kidney transplant recipients from 11 centers across the United States for whom high-resolution class II typing was available.

Anti-HLA serologic response to CD38-targeting desensitization therapy is challenged by peripheral memory B cells in highly sensitized kidney transplant candidates.

High human leukocyte antigen (HLA) sensitization limits access to compatible transplantation. New CD38-targeting agents have been shown to reduce anti-HLA antibodies, although with important interpatient variability. Thus, pretreatment identification of responder and nonresponder (NR) patients is needed for treatment decision-making.

Sensitive HLA antibody testing and the risk of antibody-mediated rejection and graft failure.

Solid phase detection and identification of HLA antibodies in kidney transplantation currently relies on single antigen bead (Luminex®) assays, which is more sensitive than the previously used enzyme-linked immunosorbent assays (ELISA). To evaluate the impact of more sensitive HLA testing on antibody-mediated rejection (AMR) occurrence and allograft survival, we analysed 1818 renal allograft recipients transplanted between March 2004 and May 2021. In 2008, solid phase testing switched from ELISA to Luminex.

HLA molecular mismatches and induced donor-specific tolerance in combined living donor kidney and hematopoietic stem cell transplantation.

Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT).

Methods: All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions.

Qualitative, rather than quantitative, differences between HLA-DQ alleles affect HLA-DQ immunogenicity in organ transplantation.

Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies.

Calibration of Priority Points for Sensitization Status of Kidney Transplant Candidates in the United States.

Key Points: There are multiple factors associated with high sensitization levels among kidney transplant candidates, which differ by candidate sex. Since the initiation of the kidney allocation system, candidates with higher sensitization have higher rates of deceased donor transplantation. Priority points assigned to candidates associated with sensitization have led to inequities in access to deceased donor transplantation.

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant.

Significance Statement: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant.

The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis.

HLA (emphasis on DQ) compatibility for longer allograft survival in pediatric transplantation: Modern evidence and challenges.

Kidney transplantation is the treatment of choice for children with end-stage kidney failure, yet suboptimal outcomes, the need for long-term immunosuppression, and the dependency on consecutive transplants pose significant barriers to success. Providing better HLA-matched organs to pediatric patients seems to be the most logical approach to improve graft and patient outcomes and to reduce risk of anti-HLA sensitization after graft failure. We here review recent literature on HLA matching in pediatric kidney transplantation.

HLA-DQ antibodies in alloimmunity, what makes them different?

Purpose Of Review: De novo HLA-DQ antibodies are the most frequently observed after solid-organ allotransplantation; and are associated with the worse adverse graft outcomes compared with all other HLA antibodies. However, the biological explanation for this observation is not yet known. Herein, we examine unique characteristics of alloimmunity directed specifically against HLA-DQ molecules.

Improving equity in kidney transplant allocation policies through a novel genetic metric: The Matched Donor Potential.

The demand for donors' kidneys continues to increase amid a shortage of available donors. Managing policies to thoughtfully allocate this scarce resource is a complex process. Although human leukocyte antigen (HLA) matching has been shown to prolong graft survival, its relative contribution to allocation schemes is empirically compromised owing to competing priorities.

Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report.

The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.

Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document.

Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification.

HLA-DQ Mismatches Lead to More Unacceptable Antigens, Greater Sensitization, and Increased Disparities in Repeat Transplant Candidates.

Background: In single-center studies, HLA-DQ mismatches stimulate the most pathogenic donor-specific antibodies. However, because of limitations of transplant registries, this cannot be directly confirmed with registry-based analyses.

Methods: We evaluated patients in the Scientific Registry of Transplant Recipients who were relisted after renal graft failure with new, unacceptable antigens corresponding to the HLA typing of their previous donor (UA-PD) as a proxy for donor-specific antibodies.

Development of de novo donor-specific antibodies in renal transplant recipients with BK viremia managed with immunosuppression reduction.

Background: Reduction of immunosuppression (IS) upon detection of Polyomavirus (BK) viremia is widely used to prevent BK virus nephropathy. This retrospective case-control study assesses the frequency of de novo donor-specific antibodies (dnDSA) in renal transplant recipients with IS modulation due to BK viremia and the associated risk of antibody mediated rejection.

Methods: Our cohort included recipients of kidney transplantation between 2007 and 2017 with clinical, HLA antibody, and biopsy data.

Can We Use Eplets (or Molecular) Mismatch Load Analysis to Improve Organ Allocation? The Hope and the Hype.

In recent years, there have been calls for implementation of "epitope matching" in deceased-donor organ allocation policies (later changed to "eplet matching"). Emerging data indeed support the use of molecular mismatch load analysis in specific patient groups, with the objective of posttransplant stratification into different treatment arms. For this purpose, the expectation is to statistically categorize patients as low- or high-immune-risk.

Clinical utility of serial serum dilutions for HLA antibody interpretation.

Luminex single antigen bead (SAB) testing has increased the sensitivity and specificity of accurately identifying HLA antibodies, in support of all organ transplantation. However, as described in manufacturers' recommendation, the output of the assay, using mean fluorescence intensity (MFI) units, is only semi-quantitative. Therefore, the ability to use MFI values to compare between different assays, to accurately guide clinical practice, or be used as an endpoint measure in clinical trials, is limited.

Assessment of Virological Contributions to COVID-19 Outcomes in a Longitudinal Cohort of Hospitalized Adults.

Background: While several demographic and clinical correlates of coronavirus disease 2019 (COVID-19) outcome have been identified, their relationship to virological and immunological parameters remains poorly defined.

Methods: To address this, we performed longitudinal collection of nasopharyngeal swabs and blood samples from a cohort of 58 hospitalized adults with COVID-19. Samples were assessed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load, viral genotype, viral diversity, and antibody titer.

Molecular histocompatibility beyond Tears: The next generation version.

Human Leukocyte Antigens (HLA) matching at the serological level used to serve as the measure of histocompatibility between organ donors and recipients. With advancements in HLA typing methods more precise HLA mismatch assessment tools were developed to measure dissimilarities at the molecular level, collectively referred to as Molecular Mismatch load analysis tools. Currently, several software are aimed at deciphering the dissimilarities using somewhat different immunologic rationales.

Innate-like self-reactive B cells infiltrate human renal allografts during transplant rejection.

Intrarenal B cells in human renal allografts indicate transplant recipients with a poor prognosis, but how these cells contribute to rejection is unclear. Here we show using single-cell RNA sequencing that intrarenal class-switched B cells have an innate cell transcriptional state resembling mouse peritoneal B1 or B-innate (Bin) cells. Antibodies generated by Bin cells do not bind donor-specific antigens nor are they enriched for reactivity to ubiquitously expressed self-antigens.

Significance of HLA-DQ in kidney transplantation: time to reevaluate human leukocyte antigen-matching priorities to improve transplant outcomes? An expert review and recommendations.

The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the observed ethnic/racial disparity, as data emerged associating HLA matching with decreased access to transplantation for African American patients. In recent years, it has been increasingly recognized that a leading cause of graft loss is chronic antibody-mediated rejection, attributed to the development of de novo antibodies against mismatched donor HLA expressed on the graft.