Faculty Bibliography

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Hepatitis C virus (HCV) positive-to-negative kidney transplants (KT) require direct acting antiviral therapy, but the optimal timing and duration remain unclear. We hypothesized that 14-day prophylactic course of glecaprevir/pibrentasvir 300/120 mg (GLE/PIB) would be safe and effective at treating donor-derived HCV viremia. METHODS:This was a prospective, single-center, single-arm, open-label pilot study. 20 adult HCV negative recipients of HCV nucleic acid amplification test positive deceased-donor kidneys (HCV positive-to-negative) received a 14-day course of GLE/PIB, with the first dose pre-transplant. HCV RNA viral loads (VL) were monitored on post-operative days (POD) 1, 3, 7, and 13. If VL was undetectable on POD 13, GLE/PIB was stopped, and if detectable, GLE/PIB was continued to complete an 8-week course. Surveillance monitoring continued after treatment to ensure sustained viral response (SVR). The primary outcome was efficacy of 14-day prophylactic GLE/PIB. Secondary outcomes included patient and allograft survival, the incidence, timing, and clearance of HCV viremia, and safety events. RESULTS:7/20 subjects (35%) never developed detectable HCV viremia. Only one subject had a detectable, but nonquantifiable, VL on POD 13 and completed an 8-week course. All subjects achieved SVR 12 weeks post-treatment with no relapses through 1-year follow-up. Mean time to undetectable HCV RNA VL was 10.5 (±4.7) days and mean peak VL was 371 (±715) copies/mL. 6-month and 1-year patient and allograft survival were 100% and 95%. CONCLUSION/CONCLUSIONS:A 14-day course of prophylactic GLE/PIB is safe and effective for HCV positive-to-negative KT and may prevent HCV transmission or significantly reduce the VL for those with detectable transmission allowing for rapid clearance within 2 weeks.

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.

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.

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.

BACKGROUND/UNASSIGNED:Imlifidase is an IgG-cleaving endopeptidase conditionally approved in Europe for desensitization of highly sensitized patients before kidney transplantation. We present 5-y outcomes and donor-specific antibody (DSA) levels for clinical trial participants from a single site who received imlifidase for desensitization before incompatible transplantation (NCT02790437). METHODS/UNASSIGNED:Imlifidase was administered up to 24 h before living or deceased donor kidney transplantation. DSAs were monitored before transplantation, at days 7 and 28, and at 5 y posttransplant. RESULTS/UNASSIGNED:At 5 y, 7 of 8 participants were alive. One of these 7 had suboptimal graft function secondary to donor-derived disease but remained dialysis independent. Three participants had antibody-mediated rejection (AMR), which occurred in the first 30 d in all cases and was successfully treated. No new episodes of suspected or biopsy-proven AMR occurred after 30 d posttransplant. Seven participants had DSA rebound. DSAs commonly persisted 5 y posttransplant, although they were generally lower strength compared with pre-imlifidase. Dilution studies of sensitized serum enabled the identification of lower AMR risk phenotypes for persisting DSAs. Severe and/or opportunistic infections were not observed at greater than expected frequency. CONCLUSIONS/UNASSIGNED:Five-year outcomes of imlifidase-enabled incompatible transplants are overall favorable. DSA rebound is common, but antibody strength lessens in the long term, and longitudinally persisting DSAs did not lead to premature graft failure.