(1006) Donor-Derived Cell-Free DNA as a Potential Biomarker for Acute Cellular Rejection Surveillance (FreeDNA-CAR Study)

• Published in: The Journal of heart and lung transplantation Vol. 42; no. 4; pp. S433 - S434
• Main Authors: Jimenez-Blanco Bravo, M., Crespo-Leiro, M., Garcia-Cosio, M., Perez-Gomez, L., Lopez-Vilella, R., Ortiz Bautista, C., Farrero Torres, M., Maestro Benedicto, A., Diaz Molina, B., Diez-Lopez, C., Rangel Sousa, D., Salterain, N., Garrido Bravo, I., Segovia-Cubero, J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-04-2023
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2023.02.1217

There is a clear need for a non-invasive biomarker that could allow surveillance of acute cellular rejection (ACR) without the need of repeated endomyocardial biopsies (EMB) in heart transplant (HT) recipients. Donor-derived cell-free DNA (dd-cfDNA) is currently under study for this purpose.
This was a multicenter, observational, prospective study. According to protocol, all patients included underwent surveillance EMB at 15 days, 1, 2, 3, 4, 6 and 12 months post-HT. Dd-cfDNA levels were determined prior to each EMB, using Next Generation Sequencing technology (Allonext® assay, Eurofins Genome). Primary end-point was the association between dd-cfDNA levels and the presence of ACR, as determined by ISHLT 2004 classification.
We herein report the results of the first 848 pairs of EMB-dd-cfDNA determinations. The cohort included 206 recipients from 12 different centers (mean age 54 ± 11 years, 73% male). ACR, defined as grade ≥2R, was present in 35 EMB (4.1%), and AMR ≥1 in 14 EMB (1.7%). Median dd-cfDNA values for each ACR group were: 0R 0.088% (0.038-0.22), 1R 0.15% (0.056-0.4), 2R 0.23% (0.06-0.6) and 3R 0.6%. AMR0 median (IQR) values were 0.1% (0.04-0.24), and AMR≥1, 0.2% (0.075-0.7), respectively. In order to reduce the skewness, %ddcfDNA was logtransformed as log2(x+0.01) (Figure 1A). Using a GEE (generalized estimating equation) model, we found a statistically significant association between %dd-cfDNA and ACR ≥2R (OR 1.23, IQR 1.04-1.45), p <0.01 (Figure 1B). A 0.15% ddcf-DNA threshold revealed a negative predictive value of 97%, and could allow to save 57% of surveillance EMB.
Dd-cfDNA appears to be an excellent biomarker for acute cellular rejection. Its high negative predictive value could allow to eliminate the need to perform a significant percentage of surveillance EMB currently performed in HT recipients.