Faculty Bibliography

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.

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.

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.

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. We analyzed 26 highly sensitized (HS) patients from 2 desensitization trials using anti-CD38 monoclonal antibodies. Hierarchical clustering identified 3 serologic responder groups: high responders, low responders, and NR. Spectral flow cytometry and functional HLA-specific memory B cell (mBC) assessment were first conducted on peripheral blood mononuclear cells and bone marrow samples from 16 patients treated with isatuximab (NCT04294459). Isatuximab effectively depleted bone marrow plasma cells, peripheral CD38-expressing plasmablasts, plasma cells, transitional B cells, and class-switch mBCs, ultimately reducing frequencies of HLA-specific immunoglobulin G (IgG)-producing mBCs. Multidimensional spectral flow cytometry with partial least squares discriminant analysis revealed that pretreatment abundance of specific circulating mBC phenotypes, especially CD38neg class-switch mBCs, accurately distinguished between high serologic responders and low responders or NR (AUC 0.958, 0.860-1.000, P = .009), who also displayed significantly lower frequencies of HLA-specific IgG-producing mBCs (P < .0001). This phenotypical mBC signature predicting response to therapy was validated in an external HS patient cohort (n = 10) receiving daratumumab (NCT04204980). This study identifies critical circulating mBC subset phenotypes that distinguish HS patients with successful serologic responses to CD38-targeting desensitization therapies, potentially guiding treatment decision-making.

The degree of immunological compatibility between donors and recipients greatly impacts allograft survival. In the United States kidney allocation system, HLA antigen-level matching has been shown to cause ethnic disparities and thus, has been de-emphasised. However, priority points are still awarded for antigen-level zero-ABDR matching, zero-DR matching and one-DR matching. Recently, the degree of HLA molecular (eplet) mismatch has emerged as a more accurate measure of immunological risk, and eplet mismatch load has gained attention as a possible biomarker to improve HLA compatibility. However, little is known about the frequency of eplets in population groups, which is a necessary step to ensure that candidates from any ethnical background can have similar chances at a well-matched organ. Eplet frequencies were estimated using HLA alleles in the Common, Intermediate and Well-Documented (CIWD) 3.0.0 catalogue for six population groups: African-American (AFA), Asian-Pacific Islander (API), European/European descent (EURO), Middle East/North Coast of Africa (MENA), Hispanic/Latino (HIS) and Native-American (NAM). We determined that 98.6% (484 out of 491) of HLA eplets are expressed by the common HLA alleles in all population groups. Of the seven eplets that were expressed by less common HLA alleles, six were Class I eplets and one was expressed by HLA-DQB1 alleles and most were expressed by HLA alleles that were more commonly observed in European/European descent populations. Our observations indicate that HLA eplets will not cause any significant disparity if applied to HLA molecular compatibility, regardless of the ethnic origin of both recipients and donors.

BACKGROUND/UNASSIGNED:Prioritization of HLA antigen-level matching in the US kidney allocation system intends to improve post-transplant survival but causes racial disparities and thus has been substantially de-emphasized. Recently, molecular matching based on eplets has been found to improve risk stratification compared to antigen matching. METHODS/UNASSIGNED:To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high resolution allele-level HLA 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 for candidates by ethnicity. RESULTS/UNASSIGNED:The percentage of well-matched donors with zero-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates than percentage of donors with zero-ABDR antigen mismatches, and 2-fold less racially disparate for Latino candidates. For other HLA antigen and eplet mismatch thresholds, the percentage of well-matched donors was more similar across candidate ethnic groups. CONCLUSIONS/UNASSIGNED:Compared to the current zero-ABDR antigen mismatch, prioritizing a zero-DR/DQ eplet mismatch in allocation would decrease racial disparities and increase the percentage of well-matched donors. High resolution HLA deceased donor genotyping would enable unambiguous assignment of eplets to operationalize molecular mismatch metrics in allocation. KEY POINTS/UNASSIGNED:

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 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

Optimizing immunologic compatibility in organ transplantation extends beyond the conventional approach of Human Leukocyte Antigen (HLA) antigen matching, which exhibits significant limitations. A broader comprehension of the roles of classical and non-classical HLA genes in transplantation is imperative for enhancing long-term graft survival. High-resolution molecular HLA genotyping, despite its inherent challenges, has emerged as the cornerstone for precise patient-donor compatibility assessment. Leveraging understanding of eplet biology and indirect immune activation, eplet mismatch calculators and the PIRCHE-II algorithm surpass traditional methods in predicting allograft rejection. Understanding minor histocompatibility antigens may also present an opportunity to personalize the compatibility process. While the application of molecular matching in deceased donor organ allocation presents multiple technical, logistical, and conceptual barriers, rendering it premature for mainstream use, several other areas of donor-recipient matching and post-transplant management are ready to incorporate molecular matching. Provision of molecular mismatch scores to physicians during potential organ offer evaluations could potentially amplify long-term outcomes. The implementation of molecular matching in living organ donation and kidney paired exchange programs is similarly viable. This article will explore the current understanding of immunologic matching in transplantation and the potential applications of epitope and non-epitope molecular biology and genetics in clinical transplantation.