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

Abstract

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.

An Integrated Approach Using HLAMatchmaker and Pirche II for Epitopic Matching in Pediatric Kidney Transplant—A Romanian Single-Center Study

“…This relies on two fundamental principles: (1) the immune system's capacity to recognize and make antibodies for non-self-antigens, particularly epitopes on those antigens, while disregarding self-antigens and epitopes; (2) a small number of polymorphic amino acids near the center of the epitope, which largely establish epitope binding affinity. The evidence and the rationale for these postulates have been reported previously [2,6,7,11]. By inspecting amino acid sequences in donor and recipient alleles, HLAMatchmaker is able to pinpoint and quantify the differences between them.…”

“…For solid grafts, the PIRCHE II describes the number of peptides of HLA proteins encoded in 2-5 exons of the donor's HLA but not in the recipient's. Similar to the naturally occurring thymic negative selection process, only candidate peptides proven absent in the patient's self-peptide background are considered allopeptides [2,13]. In a 2021 study, Unterrainer et al concluded that PIRCHE-II analysis could already be incorporated into kidney allocation algorithms providing an additional layer of compatibility assessment, particularly in cases where significant HLA incompatibilities exist between the donor and the recipient [14].…”

“…This arises due to the unique challenges and growth factors associated with pediatric transplant recipients, necessitating ongoing medical interventions to address evolving health needs and ensure optimal long-term outcomes. Considering the complications associated with the subsequent development of the de novo donor-specific HLA antibodies (dnDSA), a more detailed evaluation of immunological compatibility between donors and recipients must be obtained [1,2]. Numerous factors have been identified as potential contributors to the emergence of de novo HLA antibodies.…”

Strategies for choosing the best living donor: A review of the literature and a proposal of a decision‐making paradigm

“…[28][29][30] While a full discussion of the strengths and weaknesses of each analysis approach is beyond the scope of this review, there are recent publications that provide excellent discussion of these points. 31,32 A study of 596 kidney transplant recipients compared the various scoring systems and found that each was highly correlated with HLA DR-and DQ-de novo DSA formation and that neither system was superior to the other (R 2 = .85-.96). 33 The key consideration when using these new tools is to understand their limitations, namely that the enumeration of the mismatches does not address the immunogenicity of the epitopes.…”

“…There are various software packages available to assess EMM, including HLAMatchmaker, PIRCHE‐II, Amino Acid Sequence Comparison, and Three‐Dimensional Electrostatic Mismatch (EMS‐3D), Table 1 28–30 . While a full discussion of the strengths and weaknesses of each analysis approach is beyond the scope of this review, there are recent publications that provide excellent discussion of these points 31,32 . A study of 596 kidney transplant recipients compared the various scoring systems and found that each was highly correlated with HLA DR‐ and DQ‐de novo DSA formation and that neither system was superior to the other ( R 2 = .85–.96) 33 .…”