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HLA epitope matching in pediatric renal transplantation

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Abstract

Chronic graft loss due to antibody-mediated rejection (AMR) and the difficulty of re-transplanting highly sensitized patients are two of the major long-term challenges in pediatric renal transplantation. Treatments for AMR are often ineffective and desensitization protocols can be a high risk, making prevention a highly appealing strategy. Insights into the structural determinants of humoral alloantigenicity present an exciting opportunity to reassess our current paradigm of tissue matching and potentially preventing these complications. We review the theory behind human leukocyte antigen (HLA) B cell epitopes and the various systems that have been proposed to define them, including eplets. There is a growing body of clinical evidence suggesting that epitope-based tissue matching may be superior to traditional HLA antigen matching at predicting a range of clinical outcomes. However, additional studies are required to better understand the biological relevance of these systems of defining epitopes and their role in pediatric transplantation.

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Abbreviations

cPRA:

Calculated panel reactive antibody

DSA:

Donor-specific antibody

ESKD:

End-stage kidney disease

HLA:

Human leukocyte antigen

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Author information

Authors and Affiliations

  1. Department of Nephrology, Royal Children’s Hospital, Melbourne, Australia

    Matthew P. Sypek, Peter Hughes & Joshua Y. Kausman

  2. Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia

    Matthew P. Sypek, Peter Hughes & Joshua Y. Kausman

  3. University of Melbourne, Melbourne, Australia

    Matthew P. Sypek, Peter Hughes & Joshua Y. Kausman

  4. Murdoch Children’s Research Institute, Melbourne, Australia

    Joshua Y. Kausman

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  1. Matthew P. Sypek
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  2. Peter Hughes
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Correspondence to Matthew P. Sypek.

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Answers

1. c

2. b

3. e

4. c

Multiple-choice questions

Multiple-choice questions

  1. 1)

    Which of the following statements about HLA epitopes is incorrect:

    1. a)

      The same epitope present on two different HLA antigens can explain the cross-reactivity of an antibody that binds both antigens.

    2. b)

      Each HLA antigen contains multiple epitopes that can potentially bind anti-HLA antibody

    3. c)

      All members of an HLA serotype (e.g., HLA-A2) have the same amino acid sequence and therefore identical epitopes.

    4. d)

      HLA epitopes are defined as the region of the HLA antigen that binds to the paratope of an anti-HLA antibody

    5. e)

      The cluster of amino acid residues that plays a key role in determining antibody binding specificity is sometimes referred to as the ‘functional epitope’ region

  2. 2)

    Which of the following statements concerning HLA eplets is true?

    1. a)

      Eplets are defined as linear sequences of three amino acids on the surface of HLA molecules

    2. b)

      Eplets are clusters of amino acids that theoretically define the functional epitopes that determine HLA antibody binding specificity

    3. c)

      Eplets have been determined by antibody absorption/elution studies of serum containing anti-HLA antibodies

    4. d)

      Eplets are composed of 15–25 amino acid residues that bind to the paratope of an antibody

    5. e)

      Eplets typically cover an area of 650–900 Å2

  3. 3)

    Which one of the following has not been shown in clinical studies addressing the role of eplet mismatches in transplantation?

    1. a)

      The number of locus-specific class II eplet mismatches is predictive of HLA-DR and HLA-DQ de-novo DSA development post renal transplant

    2. b)

      HLA-DQ eplet mismatch of less than 17 is associated with low risk of locus-specific de novo DSA formation

    3. c)

      Class II eplet mismatch is associated with the development of transplant glomerulopathy

    4. d)

      Class I eplet mismatch > 10 in pediatric heart transplantation is associated with increased risk of graft failure compared with class I eplet mismatch < 10

    5. e)

      Class I eplet mismatch (highest vs. lowest quartile) in lung transplantation is associated with increased risk of chronic lung allograft dysfunction (CLAD).

  4. 4)

    Which of the following statements concerning pediatric renal transplantation is true?

    1. a)

      Eplet mismatch has been shown to be superior in predicting clinical outcomes compared to traditional HLA mismatch for pediatric patients receiving kidney transplants

    2. b)

      HLA matching in pediatric transplantation is not important as the developing immune system rapidly develops tolerance to foreign HLA

    3. c)

      Many children will require multiple transplants during their lives and therefore strategies to prevent HLA sensitization are important

    4. d)

      Deceased donor allocation policies that give priority to pediatric transplant recipients result in better histocompatibility matching for these patients

    5. e)

      Children with related potential donors should not enter paired kidney exchange programs, as this will result in poorer histocompatibility matching from unrelated paired donors

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Sypek, M.P., Hughes, P. & Kausman, J.Y. HLA epitope matching in pediatric renal transplantation. Pediatr Nephrol 32, 1861–1869 (2017). https://doi.org/10.1007/s00467-016-3557-4

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