1334 - Association of Donor-Derived Cell-Free DNA with Microvascular Inflammation Phenotypes in Kidney Allografts

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Author Block: M. Sablik¹, R. Brousse¹, R. Ponsirenas¹, E. Huang², M. Z. Molnar³, J. Hogan⁴, T. Alhamad⁵, P. Jain⁶, M. Naesens⁷, D. Mandelbrot⁸, G. Gupta⁹, O. Aubert¹⁰, D. Anglicheau¹⁰, c. lefaucheur¹¹, A. Loupy¹, ¹Paris Institute for Transplantation and Organ Regeneration, Paris, France, ²Cedars Sinai Medical Center, LA, CA, ³University of Utah Hospital, Salt Lake City, UT, ⁴Hospital Robert Debré, Paris, France, ⁵WashU Medicine, Saint Louis, MO, ⁶TGH FKP, Tampa, FL, ⁷UZ Leuven, Leuven, Belgium, ⁸UW Health, Madison, WI, ⁹VCU, Richmond, VA, ¹⁰Necker Hospital, Paris, France, ¹¹Saint-Louis Hospital, Paris, France
*Purpose: Donor-derived cell-free DNA (dd-cfDNA) has shown to improve the detection of kidney allograft rejection. However, its ability to identify the recently defined microvascular inflammation (MVI) phenotypes in the Banff 2022 Classification remains unclear.
*Methods: We included 4,071 pediatric and adult kidney recipients from 28 centers, who underwent allograft biopsy with concurrent assessment of dd-cfDNA, anti-HLA DSA, and functional parameters between September 2011 and April 2025. Clinical and histology data were integrated to classify biopsies according to the Banff 2022 Classification. We performed uni- and multivariable logistic regressions to determine the association between dd-cfDNA and MVI phenotypes.
*Results: Among the 5,225 biopsies, MVI phenotypes were identified in 915 (17,5%) cases, including 191 MVI, DSA-negative C4d-negative (MVI, DSA- C4d-), 92 probable AMR (mild MVI with DSA positivity), 503 AMR and 129 mixed cases. We observed increasing dd-cfDNA levels from probable AMR (0.34% [IQR 0.22-0.62]) to MVI, DSA- C4d- (0.75% [0.35-1.70]), AMR (1.10% [0.45-2.20]) and mixed rejection (2.00% [0.90-4.56]) (Figure). Among six parameters integrated in the idd-cfDNA model (eGFR, proteinuria, graft instability, rejection history, DSA, dd-cfDNA), dd-cfDNA (OR 2.20, 95% CI 1.93-2.51, p<0.001), proteinuria (OR 1.19, 95% CI 1.05-1.34, p=0.005), and rejection history (OR 4.85, 95% CI 3.38-6.86, p<0.001) were associated with MVI, DSA- C4d- in univariate analysis. In multivariable analysis, dd-cfDNA remained independently associated with MVI, DSA- C4d- (adjusted OR 1.77, 95% CI 1.49-2.11, p<0.001). Dd-cfDNA was significantly associated with probable AMR in univariate analysis (OR 1.37, 95% CI 1.13-1.66, p=0.001), but this association did not persist in multivariable analysis (p=0.133).
*Conclusions: In this large multicenter kidney transplant cohort, we demonstrated that dd-cfDNA was independently associated with MVI, DSA-negative, C4d-negative, highlighting its promising role in diagnosing and guiding treatment for this phenotype.