Kidney transplant candidates' perspectives on the implementation of a Canadian Willingness to Cross program: A strategy to increase access to kidney transplantation for highly sensitized patients.

BACKGROUND: Kidney transplantation is the optimal treatment for end-stage renal disease. However, highly sensitized patients (HSPs) have reduced access to transplantation, leading to increased morbidity and mortality on the waiting list. The Canadian Willingness to Cross (WTC) program proposes allowing transplantation across preformed donor specific antibodies (DSA) determined to be at a low risk of rejection under the adaptive design framework. This study collected patients' perspectives on the development of this program. METHODS: Forty-one individual interviews were conducted with kidney transplant candidates from three Canadian transplant centers in 2022. The interviews were digitally recorded and transcribed for subsequent analyses. RESULTS: Despite limited familiarity with the adaptive design, participants demonstrated trust in the researchers. They perceived the WTC program as a pathway for HSPs to access transplantation while mitigating transplant-related risks. HSPs saw the WTC program as a source of hope and an opportunity to leave dialysis, despite acknowledging inherent uncertainties. Some non-HSPs expressed concerns about fairness, anticipating increased waiting times and potential compromise in kidney graft longevity due to higher rejection risks. Participants recommended essential strategies for implementing the WTC program, including organizing informational meetings and highlighting the necessity for psychosocial support. CONCLUSION: The WTC program emerges as a promising strategy to enhance HSPs' access to kidney transplantation. While HSPs perceived this program as a source of hope, non-HSPs voiced concerns about distributive justice issues. These results will help develop a WTC program that is ethically sound for transplant candidates.

Erythrocytosis and thrombotic events in kidney transplant recipients prescribed a sodium glucose cotransport-2 inhibitor.

INTRODUCTION: The safety and efficacy of sodium glucose cotransport-2 inhibitors (SGLT2i) in kidney transplant recipients remains uncertain. Transplant recipients may be at risk of thrombosis because of post-transplant erythrocytosis and SGLT2i are associated with an increase in hematocrit. METHODS: We determined SGLT2i use, the change in hematocrit and incidence of thrombotic events in kidney transplant recipients in 1700 prevalent patients in our center. RESULTS: Among the 42 patients treated with SGLT2i, the mean pre-transplant hematocrit was 31%, and none of the patients had a hematocrit ≥50%. The mean percent change in hematocrit measured at an average of 53 days after initiation of an SGLT2i was 11% and four patients (10%) had a hematocrit ≥ 50%. The mean hematocrit measured 3 months after treatment was 42% and two patients (5%) had a hematocrit ≥50%. One patient had a cerebellar stroke 14 months post-SGLT2i initiation when the hemoglobin was 173 grams/liter, and the hematocrit was 52%. CONCLUSIONS: All patients had a sustained increase in hematocrit 3 months after SGLT2i treatment. Hematocrit ≥50% occurred in 10%, and one patient had a thrombotic event that may or may not have been related to an increase in hematocrit. Clinicians may consider monitoring for erythrocytosis after starting and SGLT2i in kidney transplant recipients.

ABO-adjusted calculated panel reactive antibody (cPRA): A unified metric for immunologic compatibility in kidney transplantation.

Implementation of the kidney allocation system in 2014 greatly reduced access disparity due to human leukocyte antigen (HLA) sensitization. To address persistent disparity related to candidate ABO blood groups, herein we propose a novel metric termed "ABO-adjusted cPRA," which simultaneously considers the impact of candidate HLA and ABO sensitization on the same scale. An ethnic-weighted ABO-adjusted cPRA value was computed for 190 467 candidates on the kidney waitlist by combining candidate's conventional HLA cPRA with the remaining fraction of HLA-compatible donors that are ABO-incompatible. Consideration of ABO sensitization resulted in higher ABO-adjusted cPRA relative to conventional cPRA by HLA alone, except for AB candidates since they are not ABO-sensitized. Within cPRA Point Group = 99%, 43% of the candidates moved up to ABO-adjusted cPRA Point Group = 100%, though this proportion varied substantially by candidate blood group. Nearly all O and most B candidates would have elevated ABO-adjusted cPRA values above this policy threshold for allocation priority, but relatively few A candidates displayed this shift. Overall, ABO-adjusted cPRA more accurately measures the proportion of immune-compatible donors compared with conventional HLA cPRA, especially for highly sensitized candidates. Implementation of this novel metric could enable the development of allocation policies permitting more ABO-compatible transplants without compromising equity.

Transplantation of Patients With Long Dialysis Vintage in the Current Deceased Donor Kidney Allocation System (KAS).

RATIONALE & OBJECTIVE: In 2014 the wait-time calculation for deceased donor kidney transplantation in the United States was changed from the date of first waitlisting to the date of first maintenance dialysis treatment with the aim of minimizing disparities in access to transplantation. This study examined the impact of this policy on access to transplantation, patient survival, and transplant outcomes among patients treated with maintenance dialysis for a prolonged duration before waitlisting. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients identified in the US Renal Data System between 2008 and 2018 aged 18-70 years and in the 95th percentile of dialysis treatment duration (≥6.5 years) before waitlisting. EXPOSURE: Waitlisting for transplantation before versus after implementation of the policy. OUTCOME: Time from date of waitlisting to deceased donor transplantation and death, and from date of transplantation to all cause graft loss. ANALYTICAL APPROACH: Univariate and multivariable time to event analyses. RESULTS: Patients waitlisted after the policy change had a higher likelihood of deceased donor transplantation (HR, 3.12 [95% CI, 2.90-3.37]) and lower risk of death (HR, 0.74 [95% CI, 0.63-0.87]). The risk of graft loss was lower in the post-kidney allocation system (KAS) cohort (HR, 0.66 [95% CI, 0.55-0.80]). The proportion of adult patients treated with dialysis ≥6.5 years who were never waitlisted for transplantation remained high (73%) and did not decrease after the policy implementation. LIMITATIONS: Cannot determine causality in this observational study. CONCLUSIONS: The policy change was associated with an increase in deceased donor transplantation and marked improvement in patient survival for patients waitlisted after long periods of dialysis treatment without decreasing the utility of available deceased donor kidney supply. The policy was not associated with increased waitlisting of this disadvantaged population.

Clinical utility of complement-dependent C3d assay in kidney recipients presenting with late allograft dysfunction.

The objective of this study was to evaluate the utility of a complement-dependent C3d assay to risk stratify donor-specific antibodies (DSA) in a multicenter cohort of kidney recipients presenting with new-onset clinical dysfunction. A total of 106 subjects with evidence of DSA at a mean period of 5.3 ± 5.0 years posttransplant underwent testing using C3d reagents. C3d positivity was strongly associated with both the peak and sum IgG DSA MFI, with 98.3% (n = 57/58) of strongly reactive sera (peak MFI > 10 000) eliciting a positive signal. Patients with C3d+ DSA had a higher creatinine (P = .03), more significant graft fibrosis (P = .035), and a faster rate of graft loss posttest compared to those with C3d- DSA (P = .05). Subanalysis of patients with low-moderate level DSA confirmed the inferior outcome associated with C3d positivity. Despite the prognostic value of C3d as a stand-alone test, the assay did not provide independent risk prediction after incorporation of graft fibrosis in a multivariate model (P = .94). Overall, C3d offered limited discriminatory value for strong DSA with peak IgG MFI > 10 000 and in patients where histologic data is available, but its utilization may be considered in those with low-moderate level DSA and where an allograft biopsy is not accessible.

Clinical applications of next-generation sequencing in histocompatibility and transplantation.

PURPOSE OF REVIEW: Next-generation sequencing (NGS) can overcome traditional methodological barriers to facilitate detailed studies of large genomes. Here, we summarize recent NGS-based developments in histocompatibility and transplantation, and highlight the dynamic range of clinical applications achievable on this platform. RECENT FINDINGS: Multiple NGS-based protocols have been established to achieve unambiguous human leukocyte antigen genotyping. These methods are presently engaged to serve the high-throughput demand of large bone marrow registries; however, the scalable nature of NGS makes it an equally attractive technology for select applications within solid organ transplantation. Recently, the exquisite sensitivity of NGS has been leveraged to perform noninvasive allograft monitoring by tracking the dynamics of donor-derived cell-free DNA. Further, NGS-based T-cell receptor and immunoglobulin heavy chain repertoire profiling appear to be useful in clarifying disease-specific diagnoses in certain complex allograft pathology; detecting/quantifying minimal residual disease following allogeneic stem cell transplantation; and tracking donor-reactive T cells to understand the mechanism of tolerance in kidney transplant recipients. SUMMARY: NGS is superior to classical Sanger sequencing in its throughput, sensitivity, and the ability to provide phase-defined sequence data. These unique properties allow its broad application to diverse areas in clinical transplantation.

High-Functioning Deceased Donor Kidney Transplant System Characteristics: The British Columbia Experience With an Opt-In System.

Rationale & Objective: A high level of cooperation between organ procurement organizations and transplant programs may help maximize use of deceased donor kidneys. The practices that are essential for a high functioning organ donation and transplant system remain uncertain. We sought to report metrics of organ donation and transplant performance in British Columbia, Canada, and to assess the association of specific policies and practices that contribute to the system's performance. Study Design: A retrospective observational study. Setting & Participants: Referred deceased organ donors in British Columbia were used in the study from January 1, 2016, to December 31 2019. Exposures: Provincial, organ procurement organization, and center level policies were implemented to improve donor referral and organ utilization. Outcomes: Assessment of donor and kidney utilization along steps of the critical pathway for organ donation. Analytical Approach: Deceased donors were classified according to the critical pathway for organ donation and key donation and transplant metrics were identified. Results: There were 1,948 possible donors referred. Of 1,948, 754 (39%) were potential donors. Of 754 potential donors, 587 (78%) were consented donors. Of 587 consented donors, 480 (82%) were eligible kidney donors. Of 480 eligible kidney donors, 438 (91%) were actual kidney donors. And of 438 actual kidney donors, 432 (99%) were utilized kidney donors. One-year all-cause allograft survival was 95%. Practices implemented to improve the system's performance included hospital donor coordinators, early communication between the organ procurement organization and transplant nephrologists, dedicated organ recovery and implant surgeons, aged-based kidney allocation, and hospital admission of recipients before kidney recovery. Limitations: Assignment of causality between individual policies and practices and organ donation and utilization is limited in this observational study. Conclusions: In British Columbia, consent for donation, utilization of donated kidneys, and transplant survival are exceptionally high, suggesting the importance of an integrated deceased donor and kidney transplant service.

Optimization of all possible opportunities for deceased donor kidney donation and transplantation is essential to meet the need for transplantation. We examined the performance of organ procurement and transplant in a deceased organ donor system in British Columbia, Canada, and reviewed policies and practices that may contribute to the system's performance. We found a high level of donation, transplantation, and survival of donated kidneys and identified policies and practices that likely contribute to the system's performance.

Clinical relevance of HLA-DQ eplet mismatch and maintenance immunosuppression with risk of allosensitization after kidney transplant failure.

The optimal immunosuppression management in patients with a failed kidney transplant remains uncertain. This study analyzed the association of class II HLA eplet mismatches and maintenance immunosuppression with allosensitization after graft failure in a well characterized cohort of 21 patients who failed a first kidney transplant. A clinically meaningful increase in cPRA in this study was defined as the cPRA that resulted in 50% reduction in the compatible donor pool measured from the time of transplant failure until the time of repeat transplantation, death, or end of study. The median cPRA at the time of failure was 12.13% (interquartile ranges = 0.00%, 83.72%) which increased to 62.76% (IQR = 4.34%, 99.18%) during the median follow-up of 27 (IQR = 18, 39) months. High HLA-DQ eplet mismatches were significantly associated with an increased risk of developing a clinically meaningful increase in cPRA (p = 0.02) and de novo DQ donor-specific antibody against the failed allograft (p = 0.02). We did not observe these associations in patients with high HLA-DR eplet mismatches. Most of the patients (88%) with a clinically meaningful increase in cPRA had both a high DQ eplet mismatch and a reduction in their immunosuppression, suggesting the association is modified by immunosuppression. The findings suggest HLA-DQ eplet mismatch analysis may serve as a useful tool to guide future clinical studies and trials which assess the management of immunosuppression in transplant failure patients who are repeat transplant candidates.

Viral load kinetics and the clinical consequences of cytomegalovirus in kidney transplantation.

Background: Despite advances in clinical management, cytomegalovirus (CMV) infection remains a serious complication and an important cause of morbidity and mortality following kidney transplantation. Here, we explore the importance of viral load kinetics as predictors of risk and potential guides to therapy to reduce transplant failure in a large longitudinal Genome Canada Transplant Consortium (GCTC) kidney transplant cohort. Methods: We examined the relationship between CMV infection rates and clinical characteristics, CMV viral load kinetics, and graft and patient outcomes in 2510 sequential kidney transplant recipients in the British Columbia Transplant Program. Transplants were performed between January 1, 2008, and December 31, 2018, were managed according to a standard protocol, and were followed until December 31, 2019, representing over 3.4 million days of care. Results: Longitudinal CMV testing was performed in 2464 patients, of whom 434 (17.6%) developed a first episode of CMV viremia at a median of 120 (range: 9-3906) days post-transplant. Of these patients, 93 (21.4%) had CMV viremia only and 341 (78.6%) had CMV viremia with clinical complications, of whom 21 (4.8%) had resulting hospitalization. A total of 279 (11.3%) patients died and 177 (7.2%) patients lost their graft during the 12 years of follow-up. Patients with CMV infection were at significantly greater risk of graft loss (p=0.0041) and death (p=0.0056) than those without. Peak viral load ranged from 2.9 to 7.0 (median: 3.5) log10 IU/mL, the duration of viremia from 2 to 100 (15) days, and the viral load area under the curve from 9.4 to 579.8 (59.7) log10 IU/mL × days. All three parameters were closely inter-related and were significantly increased in patients with more severe clinical disease or with graft loss (p=0.001). Duration of the first CMV viremic episode greater than 15 days or a peak viral load ≥4.0 log10 IU/mL offered simple predictors of clinical risk with a 3-fold risk of transplant failure. Conclusion: Viral load kinetics are closely related to CMV severity and to graft loss following kidney transplantation and provide a simple index of risk which may be valuable in guiding trials and treatment to prevent transplant failure.

Clinical application of immune repertoire sequencing in solid organ transplant.

Background: Measurement of T cell receptor (TCR) or B cell receptor (BCR) gene utilization may be valuable in monitoring the dynamic changes in donor-reactive clonal populations following transplantation and enabling adjustment in therapy to avoid the consequences of excess immune suppression or to prevent rejection with contingent graft damage and to indicate the development of tolerance. Objective: We performed a review of current literature to examine research in immune repertoire sequencing in organ transplantation and to assess the feasibility of this technology for clinical application in immune monitoring. Methods: We searched MEDLINE and PubMed Central for English-language studies published between 2010 and 2021 that examined T cell/B cell repertoire dynamics upon immune activation. Manual filtering of the search results was performed based on relevancy and predefined inclusion criteria. Data were extracted based on study and methodology characteristics. Results: Our initial search yielded 1933 articles of which 37 met the inclusion criteria; 16 of these were kidney transplant studies (43%) and 21 were other or general transplantation studies (57%). The predominant method for repertoire characterization was sequencing the CDR3 region of the TCR ß chain. Repertoires of transplant recipients were found to have decreased diversity in both rejectors and non-rejectors when compared to healthy controls. Rejectors and those with opportunistic infections were more likely to have clonal expansion in T or B cell populations. Mixed lymphocyte culture followed by TCR sequencing was used in 6 studies to define an alloreactive repertoire and in specialized transplant settings to track tolerance. Conclusion: Methodological approaches to immune repertoire sequencing are becoming established and offer considerable potential as a novel clinical tool for pre- and post-transplant immune monitoring.

The Benefits of Preemptive Transplantation Using High-Kidney Donor Profile Index Kidneys.

BACKGROUND: The Kidney Donor Profile Index (KDPI) is a percentile score summarizing the likelihood of allograft failure: A KDPI ≥85% is associated with shorter allograft survival, and 50% of these donated kidneys are not currently used for transplantation. Preemptive transplantation (transplantation without prior maintenance dialysis) is associated with longer allograft survival than transplantation after dialysis; however, it is unknown whether this benefit extends to high-KDPI transplants. The objective of this analysis was to determine whether the benefit of preemptive transplantation extends to recipients of transplants with a KDPI ≥85%. METHODS: This retrospective cohort study compared the post-transplant outcomes of preemptive and nonpreemptive deceased donor kidney transplants using data from the Scientific Registry of Transplant Recipients. 120,091 patients who received their first, kidney-only transplant between January 1, 2005, and December 31, 2017, were studied, including 23,211 with KDPI ≥85%. Of this cohort, 12,331 patients received a transplant preemptively. Time-to-event models for the outcomes of allograft loss from any cause, death-censored graft loss, and death with a functioning transplant were performed. RESULTS: Compared with recipients of nonpreemptive transplants with a KDPI of 0%-20% as the reference group, the risk of allograft loss from any cause in recipients of a preemptive transplant with KDPI ≥85% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.39 to 1.64) was lower than that in recipients of nonpreemptive transplant with a KDPI ≥85% (HR, 2.39; 95% CI, 2.21 to 2.58) and similar to that of recipients of a nonpreemptive transplant with a KDPI of 51%-84% (HR, 1.61; 95% CI, 1.52 to 1.70). CONCLUSIONS: Preemptive transplantation is associated with a lower risk of allograft failure, irrespective of KDPI, and preemptive transplants with KDPI ≥85% have comparable outcomes with nonpreemptive transplants with KDPI 51%-84%.

Novel alleles in the era of next-generation sequencing-based HLA typing calls for standardization and policy.

Next-Generation Sequencing (NGS) has transformed clinical histocompatibility laboratories through its capacity to provide accurate, high-throughput, high-resolution typing of Human Leukocyte Antigen (HLA) genes, which is critical for transplant safety and success. As this technology becomes widely used for clinical genotyping, histocompatibility laboratories now have an increased capability to identify novel HLA alleles that previously would not be detected using traditional genotyping methods. Standard guidelines for the clinical verification and reporting of novelties in the era of NGS are greatly needed. Here, we describe the experience of a clinical histocompatibility laboratory's use of NGS for HLA genotyping and its management of novel alleles detected in an ethnically-diverse population of British Columbia, Canada. Over a period of 18 months, 3,450 clinical samples collected for the purpose of solid organ or hematopoietic stem cell transplantation were sequenced using NGS. Overall, 29 unique novel alleles were identified at a rate of ∼1.6 per month. The majority of novelties (52%) were detected in the alpha chains of class II (HLA-DQA1 and -DPA1). Novelties were found in all 11 HLA classical genes except for HLA-DRB3, -DRB4, and -DQB1. All novelties were single nucleotide polymorphisms, where more than half led to an amino acid change, and one resulted in a premature stop codon. Missense mutations were evaluated for changes in their amino acid properties to assess the potential effect on the novel HLA protein. All novelties identified were confirmed independently at another accredited HLA laboratory using a different NGS assay and platform to ensure validity in the reporting of novelties. The novel alleles were submitted to the Immuno Polymorphism Database-Immunogenetics/HLA (IPD-IMGT/HLA) for official allele name designation and inclusion in future database releases. A nationwide survey involving all Canadian HLA laboratories confirmed the common occurrence of novel allele detection but identified a wide variability in the assessment and reporting of novelties. In summary, a considerable proportion of novel alleles were identified in routine clinical testing. We propose a framework for the standardization of policies on the clinical management of novel alleles and inclusion in proficiency testing programs in the era of NGS-based HLA genotyping.

Validation of next-generation sequencing-based chimerism testing for accurate detection and monitoring of engraftment in hematopoietic stem cell transplantation.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving treatment for various hematological disorders. The success of allo-HSCT depends on the engraftment of donor cells and the elimination of recipient cells monitored through chimerism testing. We aimed to validate a next-generation sequencing (NGS)-based chimerism assay for engraftment monitoring and to emphasize the importance of including the most prevalent cell subsets in proficiency testing (PT) programs. We evaluated the analytical performance of NGS-based chimerism testing (AlloSeq-HCT and CareDx) with a panel of targeted 202 informative single-nucleotide polymorphisms (SNPs) (i.e., linearity and precision, analytical sensitivity and specificity, system accuracy, and reproducibility). We further compared the performance of our NGS panel with conventional short tandem repeat (STR) analysis in unfractionated whole blood and cell-subset-enriched CD3 and CD66. Our NGS-based chimerism monitoring assay has an impressive detection limit (0.3% host DNA) for minor alleles and analytical specificity (99.9%). Pearson's correlation between NGS- and STR-based chimerism monitoring showed a linear relationship with a slope of 0.8 and r = 0.973. The concordance of allo-HSCT patients using unfractionated whole blood, CD3, and CD66 was 0.95, 0.96, and 0.54, respectively. Utilization of CD3+ cell subsets for mixed chimerism detection yielded an average of 7.3 ± 7-fold higher donor percentage detection compared to their corresponding unfractionated whole blood samples. The accuracy of the NGS assay achieved a concordance of 98.6% on blinded external quality control STR samples. The reproducibility series showed near 100% concordance with respect to inter-assay, inter-tech, inter-instrument, cell flow kits, and AlloSeq-HCT software versions. Our study provided robust validation of NGS-based chimerism testing for accurate detection and monitoring of engraftment in allo-HSCT patients. By incorporating the cell subsets (CD3 and CD66), the sensitivity and accuracy of engraftment monitoring are significantly improved, making them an essential component of any PT program. Furthermore, the implementation of NGS-based chimerism testing shows potential to streamline high-volume transplant services and improve clinical outcomes by enabling early relapse detection and guiding timely interventions.

Comprehensive immune profiling of SARS-CoV-2 infected kidney transplant patients.

Introduction: The immune responses of kidney transplant recipients against SARS-CoV-2 remains under studied. Methods: In this prospective pilot study, we performed comprehensive immune profiling using cellular, proteomic, and serologic assays on a cohort of 9 kidney transplant recipients and 12 non-transplant individuals diagnosed with COVID-19. Results: Our data show that in addition to having reduced SARS-CoV-2 specific antibody levels, kidney transplant recipients exhibited significant cellular differences including a decrease in naïve-but increase in effector T cells, a high number of CD28+ CD4 effector memory T cells, and increased CD8 T memory stem cells compared with non-transplant patients. Furthermore, transplant patients had lower concentrations of serum cytokine MIP-1ß as well as a less diverse T cell receptor repertoire. Conclusion: Overall, our results show that compared to non-transplant patients, kidney transplant recipients with SARS-CoV-2 infection exhibit an immunophenotype that is reminiscent of the immune signature observed in patients with severe COVID-19.

Cutting through the weeds: Evaluation of a novel adsorption with crossmatch cells and elution protocol to sharpen HLA antibody identification by the single antigen bead assay.

The single antigen bead (SAB) assay is the most used test for the identification of HLA specific antibodies pre- and post-transplant. Nevertheless, detection of spurious reactivities remains a recognized assay limitation. In addition, the presence of weak reactivity patterns can complicate unacceptable antigen assignment. This work presents the evaluation of the adsorption with crossmatch cells and elution (AXE) technique, which was designed to help differentiate weak HLA specific antibodies targeting native antigens from spurious and background SAB assay reactivity. The AXE protocol uses selected donor cells to adsorb HLA specific antibodies from sera of interest. Bound antibodies are then eluted off washed cells and identified using the SAB assay. Only antibodies targeting native HLA are adsorbed. Assay evaluation was performed using five cell donors and pooled positive control serum. AXE efficiency was determined by comparing SAB reactivity of adsorbed/eluted antibody to that of the antibodies in unadsorbed sera. A robust efficiency was seen across a wide range of original MFI for donor specific antibodies (DSA). A higher absorption/elution recovery was observed for HLA class I antigens vs. class II. Locus-specific variation was also observed, with high-expression HLA loci (HLA-A/B/DR) providing the best recovery. Importantly, negligible reactivity was detected in the last wash control, confirming that AXE eluates were not contaminated with HLA antibody carry-over. Donor cells incubated with autologous and DSA-containing allogeneic sera showed that AXE selectively adsorbed HLA antibodies in a donor antigen-specific manner. Importantly, antibodies targeting denatured epitopes or other non-HLA antigens were not detected by AXE. AXE was particularly effective at distinguishing weak HLA antibodies from background reactivity. When combined with epitope analysis, AXE enhanced precise identification of antibody-targeted eplets and even facilitated the characterization of a potential novel eplet. Comparison of AXE to flow cytometric crossmatching further revealed that AXE was a more sensitive technique in the detection of weak DSA. Spurious reactivities on the current SAB assay have a deleterious impact on the assignment of clinically relevant HLA specificities. The AXE protocol is a novel test that enables users to interrogate reactive patterns of interest and discriminate HLA specific antibodies from spurious reactivity.

Use and Outcomes of Induction Therapy in Well-Matched Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: The optimal induction treatment in low-immune risk kidney transplant recipients is uncertain. We therefore investigated the use and outcomes of induction immunosuppression in a low-risk cohort of patients who were well matched with their donor at HLA-A, -B, -DR, -DQB1 on the basis of serologic typing. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our study was an observational study of first adult kidney-only transplant recipients in the United States recorded by the Organ Procurement and Transplant Network. RESULTS: Among 2976 recipients, 57% were treated with T cell-depleting antibodies, 28% were treated with an IL-2 receptor antagonist, and 15% were treated without induction. There was no difference in allograft survival, death-censored graft survival, or death with function between patients treated with an IL-2 receptor antagonist and no induction therapy. In multivariable models, patients treated with T cell-depleting therapy had a similar risk of graft loss from any cause, including death (hazard ratio, 1.19; 95% confidence interval, 0.98 to 1.45), compared with patients treated with an IL-2 receptor antagonist or no induction. The findings were consistent in subgroup analyses of Black recipients, patients grouped by calculated panel reactive antibody, and donor source. The incidence of acute rejection at 1 year was low (≤5%) and did not vary between treatment groups. CONCLUSIONS: Use of induction therapy with T cell-depleting therapy or IL-2 receptor antagonists in first kidney transplant recipients who are well matched with their donor at the HLA-A, -B, -DR, -DQB1 gene loci is not associated with improved post-transplant outcomes.

Isolated Hepatic Chronic Ductopenic Rejection Requiring Liver Retransplant in the Absence of Kidney Graft Rejection After Combined Liver-Kidney Transplant: A Case Report.

The liver is considered the most immunotolerant organ among all solid-organ transplants. Liver transplant recipients have a lower incidence of rejection and better outcomes after episodes of rejection, with spontaneous operational tolerance developing in up to 20%. In multiorgan transplants, a protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been demonstrated. We describe an unusual case of isolated liver allograft rejection in a patient with polycystic liver and kidney disease who received a combined liver-kidney transplant from the same donor. After initial discharge from the hospital, our patient had 2 episodes of biopsy-proven late acute cellular rejections, despite higher levels of immunosuppression required for her kidney allograft, which were addressed with pulsed steroid therapy. She had no evidence of ischemic cholangiopathy on imaging. Later, a subsequent liver biopsy demonstrated features consistent with chronic ductopenic rejection. She was eventually listed for liver retransplant and has recently received a second liver transplant while continuing to have no concerns with her kidney allograft function. Examination of the explanted liver confirmed graft loss from chronic ductopenic rejection. The exact reasons why our patient developed acute graft rejection progressing to chronic end-stage rejection of the liver allograft despite not developing graft rejection in the kidney allograft from the same donor remains elusive. Our experience demonstrates that graft tolerance in multiorgan transplant recipients can be organ specific and despite the belief of "immunologic privilege," isolated liver allograft rejection can occur in multiorgan transplant, resulting in graft loss.

Pretransplant Calculated Panel Reactive Antibody in the Absence of Donor-Specific Antibody and Kidney Allograft Survival.

BACKGROUND AND OBJECTIVES: Panel reactive antibody informs the likelihood of finding an HLA-compatible donor for transplant candidates, but has historically been associated with acute rejection and allograft survival because testing methods could not exclude the presence of concomitant donor-specific antibodies. Despite new methods to exclude donor-specific antibodies, panel reactive antibody continues to be used to determine the choice of induction and maintenance immunosuppression. The study objective was to determine the clinical relevance of panel reactive antibody in the absence of donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective observational study of kidney allograft survival among 4058 zero HLA-A-, B-, DR-, and DQB1-mismatched transplant recipients without antibodies to donor kidney antigens encoded by these HLA gene loci. RESULTS: Among 4058 first and repeat transplant recipients, patients with calculated panel reactive antibody (cPRA) 1%-97% were not at higher risk of transplant failure, compared with patients with cPRA of 0% (death censored graft loss: hazard ratio, 1.07; 95% confidence interval, 0.82 to 1.41). Patients with cPRA ≥98% had a higher risk of graft loss from any cause including death (hazard ratio, 1.39; 95% confidence interval, 1.08 to 1.79) and death censored allograft failure (hazard ratio, 1.78; 95% confidence interval, 1.27 to 2.49). In stratified analyses, the higher risk of graft loss among patients with cPRA ≥98% was only observed among repeat, but not first, transplant recipients. In subgroup analysis, there was no association between cPRA and graft loss among living related transplant recipients. CONCLUSIONS: Calculated panel reactive antibody is poorly associated with post-transplant immune reactivity to the allograft in the absence of donor-specific antibody. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_01_25_CJN13640820_final.mp3.

High-throughput sequencing defines donor and recipient HLA B-cell epitope frequencies for prospective matching in transplantation.

Compatibility for human leukocyte antigen (HLA) genes between transplant donors and recipients improves graft survival but prospective matching is rarely performed due to the vast heterogeneity of this gene complex. To reduce complexity, we have combined next-generation sequencing and in silico mapping to determine transplant population frequencies and matching probabilities of 150 antibody-binding eplets across all 11 classical HLA genes in 2000 ethnically heterogeneous renal patients and donors. We show that eplets are more common and uniformly distributed between donors and recipients than the respective HLA isoforms. Simulations of targeted eplet matching shows that a high degree of overall compatibility, and perfect identity at the clinically important HLA class II loci, can be obtained within a patient waiting list of approximately 250 subjects. Internal epitope-based allocation is thus feasible for most major renal transplant programs, while regional or national sharing may be required for other solid organs.