Abstract: TH-PO1000
Quantifying Donor-Recipient Mismatches Using Recipient-Derived Sources of Donor DNA
Session Information
- Transplantation: Basic - Immune Biology, Tissue Injury, and Emerging Technologies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2001 Transplantation: Basic
Authors
- Caldato Barsotti, Gabriel, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Rajeevan, Nallakkandi, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Kumar, Ashwani, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Reghuvaran, Anand, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Tanvir, E M, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Formica, Richard Nicholas, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Rao, Arundati, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Sareen, Niketa, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Sun, Zeguo, Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- Bow, Laurine M., Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
- De Kumar, Bony, Versiti Blood Research Institute, Milwaukee, Wisconsin, United States
- Menon, Madhav C., Yale School of Medicine Department of Internal Medicine, New Haven, Connecticut, United States
Background
Non-HLA donor–recipient (D-R) genetic mismatches contribute to unfavorable kidney allograft outcomes, but donor DNA is frequently unavailable post-transplantation, with retrieval rates ranging from 31 to 68%. We tested whether recipient-derived samples could serve as a surrogate source of donor genotype to infer clinically relevant D-R mismatches
Methods
In this proof-of-concept study, 11 unselected kidney transplant recipients underwent whole-exome sequencing (WES;100×) of genomic DNA (g-DNA) from buffy coat and plasma cell-free DNA (cfDNA). In parallel, urine cell-pellet was collected at the time of allograft biopsy and U-DNA was isolated. Donor g-DNA was obtained from the transplant HLA bank. Custom hybrid-capture probes were added for intronic coverage (300×) of 55 targeted non-HLA genes. D-R mismatches were defined at genome-wide (non-HLA), secreted/transmembrane protein, exonic non-synonymous, and targeted gene scales, benchmarked against actual donor g-DNA. Wilcoxon or Paired t-tests were applied based on data distribution
Results
U-DNA captured 75.8±35.1% of D-R mismatches, compared to 1.9±0.3% cfDNA (P<0.001). Superior mismatch inference with U-DNA vs cfDNA was consistent across secreted/transmembrane (76.8%vs1.7%), exonic non-synonymous (77.9%vs1.2%), and targeted gene categories (76.5%vs2.8%;all P<0.001). U-DNA non-detection of recipient SNPs (3.6±1.8%) was significantly lower than cfDNA (10.1±8.8%). U-DNA successfully inferred gene-level mismatches at LIMS1 and correctly identified donor-risk alleles at SHROOM3 and APOL1. Two outliers showed reduced U-DNA performance due to leukocyturia and native kidney contribution to U-DNA.
Conclusion
U-DNA combined with recipient g-DNA provides proof of concept for non-invasive inference of non-HLA donor genotype and D-R mismatches, enabling bedside assessment of immunogenically relevant non-HLA mismatches when donor DNA is not available.
Acknowledgment
MCM acknowledges funding from the National Institutes of Health (R01DK132274, R21AI178705) and the U.S. Department of Defense (HT94252310454, HT94252310441).
Funding
- Other U.S. Government Support