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Emerging Investigator Awardee

Abstract Session

Systemic Lupus Erythematosus (SLE)

Session: Abstracts: Systemic Lupus Erythematosus – Diagnosis, Manifestations, & Outcomes I: Advances in Nephritis (0837–0842)

0839: Precision Liquid Biopsy for Lupus Nephritis: cfDNA Methylation and Fragmentomic Signatures Enable Non-Invasive Diagnosis and Dynamic Disease Tracking

Sunday, October 26, 2025

3:30 PM - 3:45 PM Central Time

Location: S102

Presenting Author(s)

IT

Iris Tang, MBBS, MRCP

Department of Medicine, LKS Faculty of Medicine, University of Hong Kong
Hong Kong, Hong Kong, China

Disclosure(s): No financial relationships with ineligible companies to disclose

Background/Purpose: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), lacks reliable non-invasive biomarkers for early detection and monitoring. This study investigates plasma cell-free DNA (cfDNA) methylation and fragmentation signatures as potential LN biomarkers.

Methods: We performed whole-genome methylation profiling of plasma cfDNA from distinct cohorts: SLE patients with biopsy-proven LN (active: n=10 and inremission: n=7), SLE patients without LN ( >10 years post-diagnosis, n=13), and healthy controls (n=10). Two novel methylation-based deconvolution methods were developed to quantify kidney-derived cfDNA and compared to classical non-negative least square (NNLS)algorithms. Fragmentation patterns were analyzed using cfDNA size profiles to differentiate active LN from remission.

Results: Our novel deconvolution methods outperformed NNLS in detecting low-abundance cell types. Active LN patients exhibited significantly elevated kidney-derived cfDNA levels compared to remission, never-LN SLE, and healthy cohorts (p< 0.05 for all) (Figure 1). The reads ratio-based method achieved high diagnostic accuracy for active LN (AUC=0.91) (Figure 2). All three methods strongly correlated kidney-derived cfDNA levels with LN disease activity. Active LN patients also exhibited increased short cfDNA fragments (30–157 bp) compared to remission (p< 0.001) (Figure 3). Combining NNLS-derived kidney cfDNA levels with short fragment proportions enabled exceptional discrimination between active and remission LN (AUC=1).

Conclusion: Kidney-derived cfDNA levels and short fragment proportions are robust biomarkers for distinguishing active LN from remission and never-LN SLE. These findings underscore the clinical potential of cfDNA methylation and fragmentation profiling as a non-invasive tool for LN diagnosis, monitoring, and personalized treatment strategies.