Application of HLA molecular level mismatching in ethnically diverse kidney transplant recipients receiving a steroid-sparing immunosuppression protocol

Eva Santos; Katrina Spensley; Nicola Gunby; Judith Worthington; Candice Roufosse; Arthi Anand; Michelle Willicombe

doi:10.1016/j.ajt.2024.02.019

Application of HLA molecular level mismatching in ethnically diverse kidney transplant recipients receiving a steroid-sparing immunosuppression protocol

Am J Transplant. 2024 Feb 23:S1600-6135(24)00161-8. doi: 10.1016/j.ajt.2024.02.019. Online ahead of print.

Authors

Eva Santos¹, Katrina Spensley², Nicola Gunby¹, Judith Worthington³, Candice Roufosse⁴, Arthi Anand¹, Michelle Willicombe⁵

Affiliations

¹ Histocompatibility and Immunogenetics Laboratory, Northwest London Pathology NHS Trust, Hammersmith Hospital, London, UK.
² Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK; Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, London, UK.
³ Transplantation Laboratory, Manchester Royal Infirmary, Oxford Road, Manchester, UK.
⁴ Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, London, UK; Department of Histopathology, Northwest London Pathology NHS Trust, Charing Cross Hospital, London, UK.
⁵ Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK; Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Campus, London, UK. Electronic address: m.willicombe08@imperial.ac.uk.

PMID: 38403189
DOI: 10.1016/j.ajt.2024.02.019

Abstract

Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across different patient populations are lacking. Using HLA-Matchmaker, HLA-EMMA and PIRCHE-II, this study reports on the association between molecular mismatch (MolMM) and de novo donor-specific antibody (dnDSA) in an ethnically diverse kidney transplant population receiving a steroid-sparing immunosuppression protocol. Of the 419 patients, 51 (12.2%) patients had dnDSA. De novo DSA were seen more frequently with males, primary transplants, patients receiving tacrolimus monotherapy, and unfavorably HLA-matched transplants. There was a strong correlation between MolMM load and antigen mismatch, although significant variation of MolMM load existed at each antigen mismatch. MolMM loads differed significantly by recipient ethnicity, although ethnicity alone was not associated with dnDSA. On multivariate analysis, increasing MolMM loads associated with dnDSA, whereas antigen mismatch did not. De novo DSA against 8 specific epitopes occurred at high frequency; of the 51 patients, 47 (92.1%) patients with dnDSA underwent a pretreatment biopsy, with 21 (44.7%) having evidence of alloimmune injury. MolMM has higher specificity than antigen mismatching at identifying recipients who are at low risk of dnDSA while receiving minimalist immunosuppression. Immunogenicity consideration is important, with more work needed on identification, especially across different ethnic groups.

Keywords: de novo donor specific antibodies; epitopes; ethnicity; kidney transplant outcomes; molecular mismatch; steroid sparing.