Faculty Bibliography

The demand for transplant organs far exceeds the available supply. In the United States alone, more than 90,000 patients are currently on the kidney transplant waitlist, yet only about one third of them will ever receive a transplant. Xenotransplantation, organ transplants from gene edited pigs, offers a potential solution to this shortage. Successful investigational transplants of pig kidneys into brain-dead recipients and expanded access cases involving living human recipients have resulted in the green-lighting of the first human clinical trials. Using the benchmark of 2-year survival of non-human primates in pre-clinical studies, we developed a tool that can identify individual wait-listed patients predicted to have a shorter life expectancy than with a xenotransplant, utilizing Random Survival Forest, DeepSurv and Cox Proportional-Hazards models. We found that it is hard to identify patients that reach clinical equipoise unless the expected xenograft survival exceeds two years, with the Random Survival Forest model identifying less than 5% of such patients. Few patients would benefit based on survival alone and potential beneficiaries are spread across more than 200 transplant centers. Several incentives could allow more patients to reach equipoise. At the same benchmark of 2-year xenograft survival, keeping patients inactive on the waitlist while they have a functioning xeno-kidney increases the percentage achieving equipoise by up to 1.7% across cohorts. Granting patients with failed xenografts the same priority as prior living donors increases this by up to 17.9%, while assigning them the highest priority raises it by up to 28.5%. We are able, however, to identify phenotypes that have a high mortality and low transplant rates in the current allocation system that could serve as acceptable candidates; while not achieving equipoise, they would enjoy the benefits of being dialysis free.

BACKGROUND:Porcine genome editing has revolutionized xenotransplantation, recently enabling the first pig-to-human heart xenotransplants. However, the xeno-immune response in heart xenografts remains largely unexplored. This study aimed to precisely characterize the xeno-immune response and injury in two heart xenografts, transplanted from 10-gene-edited pigs into brain-dead human recipients. METHODS:We analyzed xenograft biopsies at 66-hour post-reperfusion using a multimodal phenotyping approach combining: morphological evaluation, immunophenotyping, ultrastructural assessment, automated quantification of multiplex immunofluorescence staining and gene expression profiling. Xenografts before implantation and wild-type pig hearts with and without ischemia reperfusion injury and brain death were used as controls. RESULTS:Both xenografts showed evidence of endothelial activation and mild microvascular inflammation without capillary C4d deposition. Immune infiltrates were mainly composed of CD15+ and CD68+ innate immune cells. Ultrastructural assessment showed endothelial swelling with occasional intravascular leucocytes. Deep-learning based automated multiplex immunofluorescence analysis confirmed that microvascular inflammation was primarily associated with CD15+ and CD68+ innate immune cells. Both xenografts showed increased expression of genes and pathways associated with monocyte/macrophage activation, neutrophil activation, interferon-gamma response, natural killer cell burden, endothelial activation, apoptosis and injury repair. This phenotype was absent in all control pig hearts, independently from ischemia reperfusion injury and brain death. CONCLUSIONS:Multimodal phenotyping of pig-to-human heart xenografts revealed early signs of xeno-immune response, characterized by mild innate microvascular inflammation, endothelial activation, and molecular signature characteristic of antibody-mediated rejection. Developing such precision diagnostic system could improve graft monitoring in future clinical settings.

INTRODUCTION:Xenotransplantation has emerged as a promising solution to organ shortage, generating numerous publications. However, no studies have analyzed the research dynamics of xenotransplantation research. We aimed to systematically assess xenotransplantation publication activity. METHODS:A systematic literature search was conducted up to November 22, 2024. Studies on xenotransplantation of solid organs and islets of Langerhans from animals to humans, or perfusion with human blood or its derivatives were included. Publication information, publishing journal, publication type, organ, donor species, and topics studied were extracted. RESULTS:Of 2944 publications, 706 met inclusion criteria: 41.2% original articles, 41.1% reviews, 14.2% publications without original data, 1.6% case reports, 1.3% research letters, 0.6% systematic reviews/meta-analyses. Publication activity displayed two peaks: in the 1990s, driven by the gene editing advancements, and in the early 2020s, following the first pig-to-human transplantation. The top five publishing countries were the USA with (48.2%), Germany (10.2%), UK (5.4%), Sweden (4.8%), and China (4.2%). Xenotransplantation journal accounted for 19.7% of publications, transplantation journals for 27.6%, and general medical journals for 5.4%. Islets of Langerhans were studied in 23.1% of studies, and the most studied organs were heart (21.2%), followed by kidney (17.1%), liver (12.2%), and lung (6.2%). The most represented thematic groups were rejection, immune mechanisms, overall challenges, gene editing, current research, and prospects. CONCLUSION:This first systematic assessment of xenotransplantation research highlights its growing global interest and evolving focus areas. The low proportion of publications with original data underscores the need for more original research. Limited representation in general medical journals highlights the importance of engaging a broader audience as clinical trials approach.

Swine-derived kidneys are a promising alternative organ source for transplantation, but compatibility in the major histocompatibility complex remains an immunological barrier. Furthermore, in repeat transplantations, CD4+ memory T cells can lead to a more rapid immune response against repeated exposure to the same antigens. Several studies have shown that HLA and SLA proteins share overlapping B cell epitopes due to structural or electrostatic similarities, but the role of overlapping T cell epitopes has not been fully explored. This study aims to computationally analyse the potential risk of memory T cell activation in subsequent human-after-swine and swine-after-human transplantation by evaluating shared T cell epitopes between the two graft sources. We show that while HLA and SLA demonstrate striking structural similarities, their linear protein sequences are very distinct, which translates to disparate HLA- and SLA-derived peptidomes and T cell epitopes. By applying the PIRCHE-II Tmem analysis to a simulated panel of recipients receiving repeat transplantations from a human kidney and from a swine xenograft, we observed a median of 1 shared T cell epitope in the cross-species context, compared to a median of 17 shared between two human-derived kidneys. This suggests that a swine xenograft exposes a low risk of T cell memory against a later human donor, and that xenotransplantation may provide an opportunity to receive a graft for highly HLA-sensitised recipients.

Documentation, coding, and billing (claims submission) are foundational to neurologic practice in the United States, enabling accurate reimbursement, effective communication, and data-driven advancements in patient care, research, and education. Neurologists navigate complex regulatory frameworks and evolving payer guidelines, requiring meticulous attention to diagnostic coding, evaluation and management (E/M) services, and procedure-specific requirements. This chapter examines critical aspects of neurologic billing and coding, including ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) for diagnostic accuracy, updated E/M guidelines emphasizing medical decision-making and time, and new telemedicine codes. It highlights the best practices for procedure coding and the use of digital health technologies. The challenges posed by prior authorization are explored, alongside potential solutions like artificial intelligence-driven tools and policy reform. By prioritizing precision, compliance, and technological adaptation, neurologists can enhance patient outcomes, support practice sustainability, and contribute to the broader goals of equitable, efficient, and innovative neurologic care.

The scarcity of transplantable organs represents a worldwide public health crisis, and as a result, thousands of people with end-stage kidney disease (ESKD) die waiting for a transplant each year. Xenotransplantation involves transplanting organs from an animal source into humans, offering a potential solution to this significant unmet need. Indeed, if there is a limitless supply of organs, many more patients who do not meet the current criteria for transplant eligibility could also be considered candidates. While there are examples of attempts to transplant animal tissues or organs into humans dating back over 300 years, none were successful due to cross-species immunologic incompatibility. Even so, significant advances in genetic engineering and the emergence of novel immunosuppressive agents have spurred impressive improvements in xenograft survival in preclinical studies involving nonhuman primates. Furthermore, recent reports of genetically modified pig kidney and heart xenotransplants in human decedents and living recipients on a compassionate use basis have provided impetus to advancing the field towards first-in-human trials. However, studies in nonhuman primates and humans thus far have described adaptive as well as innate immune-mediated xenograft injury. Understanding the mechanistic aspects of these responses at the cellular and molecular levels is critical to the development of targeted genetic modifications and innovative therapeutic strategies aimed at preventing rejection and inducing tolerance. Moreover, the physiological components of the bidirectional communication between the human host and pig xenograft must also be understood and manipulated. Here, we review the breakthroughs in renal xenotransplantation in the past few decades and highlight the immunologic hurdles that have yet to be overcome.

Human leukocyte antigen-level matching in US kidney allocation has been deemphasized due to its role in elevating racial disparities. Molecular matching based on eplets might improve risk stratification compared to antigen matching, but the magnitude of racial disparities in molecular matching is not known. To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high-resolution allele-level human leukocyte antigen genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased-donor pool, we profiled the percentage of well-matched donors available for candidates by ethnicity. The prevalence of well-matched donors with 0-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates and 2-fold less for Latino candidates compared to 0-ABDR antigen mismatches. Compared to 0-DR antigen mismatch, 0-DR eplet mismatch was 1.33-fold more racially disparate for Asian and 1.28-fold more for Latino, with similar disparity for Black candidates, whereas 0-DQ eplet mismatch reduced disparities, showing 1.26-fold less disparity for Black, 1.14-fold less for Latino, but 1.26-fold higher for Asian candidates. The prevalence of well-matched donors for candidates of different ethnicities varied according to which molecules were chosen to define a low-risk match.