Three-Way Comparison of Central DSA, %dd-cf DNA, and Molecular Biopsy Findings in the Trifecta Study

P. F. Halloran¹, L. G. Hidalgo², Z. Demko³, A. Prewett³, J. Reeve¹, C. Lawrence⁴, D. Lowe⁴, P. Billings³, .. and the Trifecta Investigators⁵

¹Alberta Transplant Applied Genomics Centre, Edmonton AB, AB, Canada, ²University of Wisconsin, Madison, WI, ³Natera Inc., San Carlos, CA, ⁴One Lambda Inc., West Hills, CA, ⁵., ., AB, Canada

Meeting: 2022 American Transplant Congress

Abstract number: 121

Keywords: Biopsy, HLA antibodies, Kidney transplantation

Topic: Clinical Science » Kidney » 45 - Kidney Chronic Antibody Mediated Rejection

Session Information

Session Name: Kidney Complications: Chronic Antibody Mediated Rejection & Immune Mediated Late Graft Failure

Session Type: Rapid Fire Oral Abstract

Date: Sunday, June 5, 2022

Session Time: 5:30pm-7:00pm

Presentation Time: 6:50pm-7:00pm

Location: Hynes Room 302

*Purpose: Trifecta (ClinicalTrials.gov #NCT04239703) is a prospective, IRB-approved, consented study of the relationships among three central tests in kidney transplant indication biopsies: molecular biopsy diagnoses (Molecular Microscope^® Diagnostic System; MMDx), %dd-cfDNA, and HLA antibody testing. This report analyzes all three results.

*Methods: MMDx was assessed at ATAGC; %dd-cfDNA by Natera Inc. (Prospera); central HLA antibody testing by One Lambda Inc. LGH interpreted HLA antibody as DSA using local donor-recipient genotyping. Local standard-of-care histology and DSA were recorded. Some DSA-negative HLA-antibody (“PRA”) positive biopsies were flagged as high risk (‘DSANHR’) due to incomplete donor class II genotyping.

*Results: Central DSA was associated with elevated %dd-cfDNA: geometric mean 0.45% in DSA-negative vs. 1.28% in DSA-positive (p=3.7×10^-7, using log %dd-cfDNA). Most samples called DSA-negative locally were confirmed DSA-negative centrally (113/118 (96%)). By MMDx diagnoses (Table 1; Figure 1A), 35/80 ABMR/Mixed biopsies (44%) were DSA-positive (including 6 DSANHR). Histology was similar: 29/59 ABMR/mixed DSA-positive (49%), Most DSA-negative ABMR/Mixed were sensitized: 30/45 (67%) were PRA+ve. In ABMR/mixed, 60/80 (75%) had %dd-cfDNA>1.0: 33/45 (73%) DSA-negative and 27/35 (77%) DSA-positive. Thus, high %dd-cfDNA was as frequent in DSA-negative as in DSA-positive ABMR/mixed (p=0.90). In Figure 1B, 11/22 DSA-negative ABMR with high %dd-cfDNA (67%) were PRA-positive. In logistic regression, continuous %dd-cfDNA measurements predicted ABMR/mixed better than DSA status (AIC 292.42 vs. 332.93 – smaller AICs are better). Log(%dd-cfDNA) added significantly to a model with DSA alone (p=4×10^-12). DSA added significantly to cfDNA alone (p=0.008). The best predictive model for biopsy ABMR/mixed used both %dd-cfDNA and DSA together.

*Conclusions: In the first 280 triple results (central DSA, %dd-cfDNA, and biopsy MMDx), 75% of molecular ABMR/mixed biopsies had %dd-cfDNA>1.0. Only 44% of ABMR/mixed were DSA-positive. However, most DSA-negative ABMR/mixed were sensitized (67% PRA+ve). Local and central DSA-negative results were similar. Thus %dd-cfDNA is a robust feature of active ABMR, regardless of DSA status. In regression, the best prediction of ABMR activity at the time of indication biopsy includes both %dd-cfDNA and DSA.

To cite this abstract in AMA style:

Halloran PF, Hidalgo LG, Demko Z, Prewett A, Reeve J, Lawrence C, Lowe D, Billings P. Three-Way Comparison of Central DSA, %dd-cf DNA, and Molecular Biopsy Findings in the Trifecta Study [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/three-way-comparison-of-central-dsa-%dd-cf-dna-and-molecular-biopsy-findings-in-the-trifecta-study/. Accessed May 9, 2025.

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