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Clinical application of PIRCHE scores: reclassifying immunologic risk in patients with medium eplet mismatch
Miklos Z Molnar1,2,3, Kendon J Holdaway4, Divya Raghavan4
1Transplant Institute, University of Rochester Medical Center, Rochester, NY, United States.
Background:
Molecular histocompatibility assessment using eplet mismatch and Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) scores has improved immunologic risk stratification in kidney transplantation, but its clinical implementation remains limited, particularly for donor-recipient pairs with medium eplet mismatch.
Methods:
We conducted a single-center retrospective cohort study of 493 adult kidney transplant recipients (2021-2024). Eplet mismatch was categorized based on Wiebe/Nickerson criteria, and medium mismatch pairs were further stratified using PIRCHE-T2 and PIRCHE-B scores. The primary outcome was early allograft injury within one year, defined as a composite of donor-specific antibody (DSA) development, histologic or molecular rejection, or elevation of donor-derived cell-free DNA (dd-cfDNA). Associations were assessed using Cox regression and Kaplan-Meier analyses.
Results:
Zero and low eplet mismatch groups had similar outcomes and were combined as the low-risk reference group. Compared with this group, medium eplet mismatch was associated with increased risk of early allograft injury (adjusted hazard ratio [aHR] 2.44, 95% confidence interval [CI] 1.41-4.23), biopsy-conditioned rejection (aHR 7.47, 95% CI 2.07-26.91), and elevated dd-cfDNA (aHR 4.83, 95% CI 1.70-13.75), while high mismatch conferred greater risk (aHR 5.17, 95% CI 2.86-9.33). Among medium mismatch recipients, ~20% were reclassified as medium-low risk based on PIRCHE scores; this subgroup showed no statistically significant increase in risk relative to the low-risk group for early allograft injury (aHR 1.87, 95% CI 0.92-3.81), DSA, rejection, or dd-cfDNA, although confidence intervals were wide and a clinically meaningful increase in risk cannot be excluded.
Conclusions:
Medium eplet mismatch recipients with low PIRCHE scores had no statistically significant increase in risk compared with the zero/low mismatch group, although confidence intervals were wide. Molecular matching may help refine risk stratification and expand donor options, but the PIRCHE-T2/-B thresholds-derived from an overlapping cohort-require external validation before clinical use.