Higher PIRCHE-T2 and PIRCHE-B scores predict early allograft injury in kidney transplant recipients

Early allograft injury within the first year post-transplant is a critical determinant of long-term graft survival in kidney transplantation. Current standard-of-care relies on conventional HLA mismatch to assess alloimmune risk, which often falls short. Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) scores offer a more nuanced quantification of donor-derived HLA peptides presented to recipient CD4+ T cells via the indirect pathway, potentially capturing alloimmune risk beyond traditional metrics and improving patient stratification.

This single-center retrospective cohort study evaluated 683 adult kidney transplant recipients transplanted between 2021 and 2024. Researchers calculated five-locus PIRCHE-T2 (T-cell epitope load) and PIRCHE-B (surface-accessible amino acid mismatch) scores using high-resolution HLA typing. The primary endpoint was a composite of post-transplant allograft injury within one year, including donor-specific antibody (DSA) development, histologic or molecular rejection, or elevation of donor-derived cell-free DNA (dd-cfDNA). Predictive performance was assessed using receiver operating characteristic analysis and compared to an HLA A/B/DR antigen mismatch model.

Among 683 recipients, 250 (37%) experienced the primary composite endpoint of allograft injury within one year. Higher five-locus PIRCHE-T2 and PIRCHE-B scores were significantly associated with this composite outcome. For PIRCHE-T2, the adjusted hazard ratio (HR) per point increase was 1.009 (95% CI 1.004-1.014), and for PIRCHE-B, it was 1.043 (95% CI 1.027-1.060). Comparing low versus high-risk groups, the adjusted HR was 1.653 (95% CI 1.254-2.180) for PIRCHE-T2 and 2.280 (95% CI 1.664-3.123) for PIRCHE-B. Both scores demonstrated modest discriminatory performance, with an area under the curve (AUC) ranging from 0.575-0.621. Higher PIRCHE scores were also independently associated with an increased risk of de novo or recurrent DSA and dd-cfDNA elevation, and showed trends toward increased rejection risk. Sensitivity analyses including six-locus PIRCHE-T2 (incorporating DQA1) yielded consistent results.

Higher PIRCHE-B scores were particularly impactful, showing an adjusted HR of 2.280 (95% CI 1.664-3.123) for high-risk versus low-risk groups, indicating a more than two-fold increased risk of early allograft injury.