Is the level of HLA eplet mismatch a risk factor for graft loss among kidney transplant recipients who have already formed de novo donor specific antibody?

Wen, Jie; Basu, Arpita; Bentall, Andrew; Henderson, Nicole; Dukek, Brian A.; Gandhi, Manish J.; Schinstock, Carrie A.

doi:10.1016/j.humimm.2021.02.004

Cited by 4 publications

(3 citation statements)

References 21 publications

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“…Our knowledge of the clinical significance of different aspects of the HLA molecule is advancing rapidly [21]. Computer algorithms for determining eplet differences, including the HLA Matchmaker, Cambridge HLA Immunogenicity Algorithm, Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE-II) algorithm, and HLA epitope mismatch algorithm (HLA-EMMA), have been developed, and these algorithms are constantly evolving [22][23][24][25].…”

Section: Discussionmentioning

confidence: 99%

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Lee

Min

Kang

et al. 2022

IJMS

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We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels.

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Section: Discussionmentioning

confidence: 99%

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Lee

Min

Kang

et al. 2022

IJMS

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“…An interesting approach was taken by Wen et al 41 performing a retrospective evaluation of high-risk patients with 10 y follow-up posttransplantation and detailed maintenance immunosuppression and medication adherence information. Patients with preformed or early development (3 mo posttransplant) of DSAs were excluded.…”

Section: Assumptions Made In Data Interpretation To Support the Use O...mentioning

confidence: 99%

Can We Use Eplets (or Molecular) Mismatch Load Analysis to Improve Organ Allocation? The Hope and the Hype

Tambur¹,

Das²

2022

Transplantation

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In recent years, there have been calls for implementation of "epitope matching" in deceased-donor organ allocation policies (later changed to "eplet matching"). Emerging data indeed support the use of molecular mismatch load analysis in specific patient groups, with the objective of posttransplant stratification into different treatment arms. For this purpose, the expectation is to statistically categorize patients as low-or high-immune-risk. Importantly, these patients will continue to be monitored‚ and their risk category, as well as their management, can be adjusted according to on-going findings. However, when discussing deceased donor organ allocation and matching algorithms, where the decision is not modifiable and has lasting impact on outcomes, the situation is fundamentally different. The goal of changing allocation schemes is to achieve the best possible HLA compatibility between donor and recipient. Immunologically speaking, this is a very different objective. For this purpose, the specific interplay of immunogenicity between the donor and any potential recipient must be understood. In seeking compatibility, the aim is not to redefine matching but to identify those mismatches that are "permissible" or‚ in other words, less immunogenic. In our eagerness to improve transplant outcome, unfortunately, we have conflated the hype with the hope. Terminology is used improperly, and new terms are created in the process with no sufficient support. Here, we call for a cautious evaluation of baseline assumptions and a critical review of the evidence to minimize unintended consequences.

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“…Just as not all eplets are equally immunogenic, not all DSA are equally pathogenic and as such, eplet load is insufficient to inform risk stratification for DSA most likely to lead to adverse allograft outcomes (13,16,64,65). A novel approach to study the variable immunogenicity of HLA-DQ eplets was designed by Schawalder et al, utilizing pregnancy as the immunological trigger, allowing a study of variable immunogenicity without the need to account for medication non-adherence and other significant post-transplant complications (66).…”

Section: Load Vs Immunogenicitymentioning

confidence: 99%

Pediatric Kidney Transplantation—Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching

Charnaya

Erez²,

Amaral³

et al. 2022

Front. Pediatr.

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Kidney transplant is the optimal treatment for end-stage kidney disease as it offers significant survival and quality of life advantages over dialysis. While recent advances have significantly improved early graft outcomes, long-term overall graft survival has remained largely unchanged for the last 20 years. Due to the young age at which children receive their first transplant, most children will require multiple transplants during their lifetime. Each subsequent transplant becomes more difficult because of the development of de novo donor specific HLA antibodies (dnDSA), thereby limiting the donor pool and increasing mortality and morbidity due to longer time on dialysis awaiting re-transplantation. Secondary prevention of dnDSA through increased post-transplant immunosuppression in children is constrained by a significant risk for viral and oncologic complications. There are currently no FDA-approved therapies that can meaningfully reduce dnDSA burden or improve long-term allograft outcomes. Therefore, primary prevention strategies aimed at reducing the risk of dnDSA formation would allow for the best possible long-term allograft outcomes without the adverse complications associated with over-immunosuppression. Epitope matching, which provides a more nuanced assessment of immunological compatibility between donor and recipient, offers the potential for improved donor selection. Although epitope matching is promising, it has not yet been readily applied in the clinical setting. Our review will describe current strengths and limitations of epitope matching software, the evidence for and against improved outcomes with epitope matching, discussion of eplet load vs. variable immunogenicity, and conclude with a discussion of the delicate balance of improving matching without disadvantaging certain populations.

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Is the level of HLA eplet mismatch a risk factor for graft loss among kidney transplant recipients who have already formed de novo donor specific antibody?

Cited by 4 publications

References 21 publications

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients

Can We Use Eplets (or Molecular) Mismatch Load Analysis to Improve Organ Allocation? The Hope and the Hype

Pediatric Kidney Transplantation—Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching

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