Population Frequencies Determined by Next-generation Sequencing Provide Strategies for Prospective HLA Epitope Matching for 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 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 more uniformly distributed between donors and recipients than the respective HLA isoforms. Simulation 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

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

Survival in Southern European patients waitlisted for kidney transplant after graft failure: A competing risk analysis

Background Whether patients waitlisted for a second transplant after failure of a previous kidney graft have higher mortality than transplant-näive waitlisted patients is uncertain. Methods We assessed the relationship between a failed transplant and mortality in 3851 adult KT candidates, listed between 1984–2012, using a competing risk analysis in the total population and in a propensity score-matched cohort. Mortality was also modeled by inverse probability weighting (IPTW) competing risk regression. Results At waitlist entry 225 (5.8%) patients had experienced transplant failure. All-cause mortality was higher in the post-graft failure group (16% vs. 11%; P = 0.033). Most deaths occurred within three years after listing. Cardiovascular disease was the leading cause of death (25.3%), followed by infections (19.3%). Multivariate competing risk regression showed that prior transplant failure was associated with a 1.5-fold increased risk of mortality (95% confidence interval [CI], 1.01–2.2). After propensity score matching (1:5), the competing risk regression model revealed a subhazard ratio (SHR) of 1.6 (95% CI, 1.01–2.5). A similar mortality risk was observed after the IPTW analysis (SHR, 1.7; 95% CI, 1.1–2.6). Conclusions Previous transplant failure is associated with increased mortality among KT candidates after relisting. This information is important in daily clinical practice when assessing relisted patients for a retransplant.This study was supported in part by the Spanish Ministry of Economy and Competitiveness (MINECO) (grant ICI14/00016) from the Instituto de Salud Carlos III co-funded by the Fondo Europeo de Desarrollo Regional±FEDER, RETICS (REDINREN RD16/0009/0006, RD16/0009/0031

The banff 2019 kidney meeting report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

P3(2): a sex- and gender-sensitive model for evidence-based precision medicine: from knowledge generation to implementation in the field of kidney transplantation.

Precision medicine emerged as a promising approach to identify suitable interventions for individual patients with a particular health concern and at various time points. Technology can enable the acquisition of increasing volumes of clinical and "omics" data at the individual and population levels and support advanced clinical decision making. However, to keep pace with evolving societal realities and developments, it is important to systematically include sex- and gender-specific considerations in the research process, from the acquisition of knowledge to implementation. Building on the foundations of evidence-based medicine and existing precision medicine frameworks, we propose a novel evidence-based precision medicine framework in the form of the P3(2)model, which considers individual sex-related (predictive [P1], preventive [P2], and personalized [P3] medicine) and gender-related (participatory [P4], psychosocial [P5], and percipient [P6] medicine) domains and their intersection with ethnicity, geography, and other demographic and social variables, in addition to population, community, and public dimensions (population-informed [P7], partnered with community [P8], and public-engaging [P9] medicine, respectively). Through its ability to contextualize and reflect on societal realities and developments, our model is expected to promote consideration of diversity, equity, and inclusion principles and, thus, enrich science, increase reproducibility of research, and ensure its social impact

Sex matters: COVID-19 in kidney transplantation

Contains fulltext : 232513.pdf (Publisher’s version ) (Open Access

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. Tran et al. combine high throughput sequencing, structural biology and computational simulation to determine the HLA allele and antibody-defined epitope frequencies in renal transplant patients and donors. These results demonstrate the feasibility of HLA epitope matching using data from a national transplantation program.Personalised Therapeutic