Robert Montgomery

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including non-human primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently …

Introduction Thoracoabdominal normothermic regional perfusion (TA‐NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA‐NRP‐procured organs are limited by potential misclassification since TA‐NRP is not differentiated from donation after cardiac death (DCD) in registry data. Methods We studied 22 donors whose designees consented to TA‐NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022. We identified these donors in SRTR to describe organ utilization and recipient outcomes and compared them to recipients of traditional DCD (tDCD) and donation after brain death (DBD) organs during the same timeframe. Results All 22 donors progressed to cardiac arrest and underwent TA‐NRP followed by heart, lung, kidney, and/or liver procurement. Median donor age was …

Obesity is a chronic, relapsing disease that increases the risks of living kidney donation; at the same time, transplant centers have liberalized body mass index constraints for donors. With the increasing number of antiobesity medications available, the treatment of obesity with antiobesity medications may increase the pool of potential donors and enhance donor safety. Antiobesity medications are intended for long-term use given the chronic nature of obesity. Cessation of treatment can be expected to lead to weight regain and increase the risk of comorbidity rebound/development. In addition, antiobesity medications are meant to be used in conjunction with—rather than in replacement of—diet and physical activity optimization. Antiobesity medication management includes selecting medications that may ameliorate any coexisting medical conditions, avoiding those that are contraindicated in such conditions, and …

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell–mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting …

Purpose: The 10-gene-edited xenografts have revolutionized xenotransplantation by recently allowing pig-to-human heart transplantation. There is an unmet need for a precise characterization of the immune response of heart xenografts transplanted to humans.Methods: We performed a complete phenotyping of the two successful heart xenografts transplanted into two brain-dead human recipients. For each xenograft, serial biopsies were performed from right and left ventricles, as well as from coronaries. We used a multimodal strategy combining i) morphological evaluation, ii) multiplex immunophenotyping, iii) ultrastructural assessment, iv) gene expression profiling, and v) whole-slide AI-based automated quantification of cell infiltrates. Xenografts before implantation and wild-type pig hearts with ischemia-reperfusion injury were used as controls.Results: At 66 h post-reperfusion both xenografts showed evidence …

The first two living recipients of pig hearts died unexpectedly within two months, despite both recipients receiving what over 30 years of nonhuman primate (NHP) research would suggest were the optimal gene edits and immunosuppression to ensure success. These results prompt us to question how faithfully data from the NHP model translates into human outcomes. Before attempting any further heart xenotransplants in living humans, it is highly advisable to gain a more comprehensive understanding of why the promising pre-clinical NHP data did not accurately predict outcomes in humans. It is also unlikely that additional NHP data will provide more information that would de-risk a xeno-heart clinical trial since these cases were based on the best practices from the most successful NHP results to date. While imperfect, the decedent model offers a complementary avenue to determine appropriate treatment …

Purpose: Recent advances in living and decedent human xenotransplantation using pig organs show promise for first-in-human trials. In 2022, two heart xenografts from 10-gene edited pigs were transplanted into 2 human decedents, primarily to evaluate hyper-acute antibody mediated rejection and function of the xenograft over 3 days.Methods: We performed multi-omics profiling to assess the dynamic interactions between these two pig heart-xenografts and the two human decedents. We generated bulk transcriptomic, lipidomic, proteomic & metabolomics, and single-cell transcriptomics datasets, across blood samples every 6 hrs, as well as histological and transcriptomic tissue profiling to assess global and specific biological changes that correlate with immune related outcomes and xenograft function.Results: In decedent 1 we observed significant early immune-activation changes in PBMCs (using scRNAseq …

Background Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach.Methods We did a complete phenotyping of two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling and cell deconvolution. Xenografts before implantation, wild-type pig kidney autografts, as well as wild-type, non-transplanted pig kidneys with and without ischaemia-reperfusion were used as controls.