Objective:

To investigate the association between HLA molecular mismatch and recipient T follicular helper (Tfh) cell-related genetic variations with the development of de novo donor-specific antibodies (dnDSAs) after kidney transplantation.

Approach:

• Study Design: Retrospective single-center cohort study analyzing 210 kidney transplant recipients from 2011 to 2024.
• HLA Mismatch Analysis: Quantified donor–recipient HLA molecular mismatch using eplet mismatch analysis, PIRCHE-T2, and HLA-EMMA.
• Genotyping: Recipient single-nucleotide polymorphisms in Tfh-related genes (CXCR5 rs3922 and CTLA4 rs231775) were genotyped.
• Primary Endpoint: Class II dnDSA development defined as newly detected donor-specific antibodies with a normalized mean fluorescence intensity >1,000 and persistence confirmed at least six months later.
• Statistical Analysis: Associations between candidate variables and class II dnDSA development were assessed using Firth penalized logistic regression.

Key Findings:

• 20 recipients (9.5%) developed class II dnDSAs during follow-up.
• Higher class II molecular mismatch loads were significantly associated with dnDSA development, with HLA-EMMA showing the strongest association.
• High HLA-EMMA class II load and Tfh cell-related immunogenetic variation were independently associated with class II dnDSA development.
• Recipients with both high HLA-EMMA class II load and Tfh-related polymorphisms showed the highest cumulative incidence of dnDSA development.

Interpretation:

Both donor-derived structural antigenicity and recipient Tfh-related immunogenetic variation are associated with the development of class II dnDSAs after kidney transplantation.

Limitations:

• The study is retrospective and conducted at a single center.
• The identified thresholds and integrated risk stratification approach require validation in independent cohorts.

Conclusion:

The integration of HLA molecular mismatch and Tfh-related genetic variations may enhance understanding of dnDSA development.