Search

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. [ABSTRACT FROM AUTHOR]

Donor-derived cell-free DNA (dd-cfDNA) has shown a good ability to rule out acute cellular rejection (ACR) in heart transplant (HT) recipients, and is thus a promising biomarker for this entity. NTproBNP is a widely available biomarker, but there is scarce information on its relation with ACR, and its possible correlation with dd-cfDNA in this setting. We prospectively obtained levels of both biomarkers in all patients included in the FreeDNA-CAR study (NCT 04973943). According to protocol, all HT recipients underwent surveillance endomyocardial biopsies (EMB) at 15 days, 1, 2, 3, 4, 6 and 12 months post-HT, between April 2019 and April 2022. Biomarker levels were extracted prior to EMB. Primary end-point of this subanalysis was the correlation between dd-cfDNA and NTproBNP levels. The cohort included 206 HT patients from 12 different centers (mean age 54 ± 11 years, 73% male). We report the analysis of the first 848 visits. ACR, defined as grade ≥2R, was present in 35 EMB (4.1%), and AMR≥1 in 14 EMB (1.7%). Median (IQR) NTproBNP values for each ACR group were: 0R 1100 pg/ml (450-2580), 1R 1367 pg/ml (588-3298), 2R 2401 pg/ml (1115-6680) and 3R 4740 pg/ml (Figure 1A); and median dd-cfDNA values: 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%. Using a GEE (generalized estimating equation) approach (Figure 1B), a statistically significant correlation between both biomarkers was found, with a coefficient of 0.002 ± 0.0006, meaning that for every increase of 100 units of NTproBNP, %dd-cfDNA increased in 0.002 (p < 0.001). In a cohort of HT patients in their first post-transplant year, dd-cfDNA and NT-proBNP showed a good correlation. Further studies are needed in order to determine if the combination of both biomarkers could improve individual performance and increase the number of EMB that could be safely eliminated. [ABSTRACT FROM AUTHOR]