Observed elevated donor‐derived cell free DNA in orthotopic heart transplant recipients without clinical evidence of rejection

Abstract

Donor-derived cell free DNA (dd-cfDNA) has rapidly become part of rejection surveillance following orthotopic heart transplantation. However, some patients show elevated dd-cfDNA without clinical evidence of rejection. With the aim to provide a clinical description of this subpopulation, we retrospectively analyzed 35 cardiac transplant recipients at our center who experienced elevated (≥.20%) dd-cfDNA in the absence of clinical rejection, out of a total 106 recipients who had dd-cfDNA results available during the first year. The median time to first elevated dd-cfDNA level was 46 days, and the highest dd-cfDNA recorded within 1 year was .31% [inter-quartile range, .23-.45]. Twenty-two (63%) patients experienced infections (cytomegalovirus (CMV) or other), and 16 (46%) presented with de novo donor-specific antibodies. Cluster analysis revealed four distinct groups characterized by (a) subclinical rejection with 50% CMV (n = 16), (b) non-CMV infections and the longest time to first elevated dd-cfDNA (187 days) (n = 8), (c) right ventricular dysfunction (n = 6), and (d) women who showed the youngest median age (45 years) and highest median dd-cfDNA (.50%) (n = 5). Continued prospective analysis is needed to determine if these observations warrant changes in patient management to optimize the utilization of this vital noninvasive graft surveillance tool.

Evolving the surveillance and workup of heart transplant rejection: A real-world analysis of the Molecular Microscope Diagnostic System

“…Thus, discordance of dd‐cfDNA to suggest graft injury at an earlier time course should raise the suspicion of a pathological process, particularly rejection even if other diagnostic modalities such as EMBx are not suggestive, and this may at least partially explain our findings. Discordant specimens for a longer timeframe should raise the suspicion of de novo DSA development, microvascular disease, cardiac allograft vasculopathy, and cytomegalovirus or other infections 2,6 . Many of these same etiologies within the differential diagnosis of an elevated dd‐cfDNA may also yield an MMDx specimen without evidence of rejection accounting for possible discordance between these modalities, or alternatively, the MMDx specimen may be insufficient if rejection in fact is present 7 …”

“…2,6 Many of these same etiologies within the differential diagnosis of an elevated dd-cfDNA may also yield an MMDx specimen without evidence of rejection accounting for possible discordance between these modalities, or alternatively, the MMDx specimen may be insufficient if rejection in fact is present 7. Although our understanding of the performance of MMDx among OHT patients is limited, published literature on this modality among kidney transplant recipients is more informative.…”

Early elevated donor‐derived cell‐free DNA levels in heart transplant recipients following precision‐controlled cardiac transport system or ice‐cooled organ transport

“…This study has the usual limitations associated with a relatively small single‐center retrospective study and may not be generalizable. There are multiple confounders that exist with elevations of dd‐cfDNA not associated with rejection which is previously well described 16 . Additionally, limited data exists on the clinical implications of early elevations in dd‐cfDNA in the month following heart transplant.…”

Anything But a Biopsy: The Quest for Noninvasive Alternatives in Heart Transplantation

“…17,18 It remains difficult to know what to do with discrepant information where cell damage/injury is seen in the absence of clear rejection or allograft dysfunction. [18][19][20] Given the cost, complexity, and uncertainties that exist coupled with the push to optimize noninvasive surveillance pathways, there remains keen interest in novel biomarker approaches.…”

“…17,18 It remains difficult to know what to do with discrepant information where cell damage/injury is seen in the absence of clear rejection or allograft dysfunction. 18-20…”