SHORE: Donor-Derived Cell-Free DNA Validated as Biomarker for AMR, With Kiran Khush, MD

Donor-derived cell-free DNA (dd-cfDNA) has been validated as a reliable biomarker of biopsy-proven antibody-mediated rejection (AMR) in patients after heart transplantation, based on data from the recent SHORE study.1

AMR is famously difficult to diagnose. Its reported incidence varies widely between individual transplant centers, which has been attributed to different surveillance practices, interobserver variability in pathologic interpretation, and abnormalities in immunohistochemistry or histology. There is also no consensus on what findings should lead to AMR treatment, what therapies are most effective, and which endpoints are indicative of therapeutic response.2

The editorial team at HCPLive spoke with Kiran Khush, MD, professor of cardiovascular medicine in the department of medicine, Division of Cardiovascular Medicine at Stanford University School of Medicine, to discuss the implications of this study and its findings.

“Use of these non-invasive assays can be very helpful because they can indicate whether a patient is low risk or high risk,” Khush told HCPLive. “For the low-risk patients, by molecular testing, we can skip the biopsy, and many studies have shown that that’s very safe to do and that these patients have excellent clinical outcomes. And the non-invasive tests allow us to determine which patients are at high risk and really need a biopsy.”

The analysis included adult heart recipients transplanted between 2017 and 2022, excluding multiorgan reports. Additionally, patients who became pregnant were removed from the SHORE registry. Biopsy-proven AMR was graded locally; mixed rejection, such as ACR2R or 3R and pAMR1 or higher, was considered AMR. The incidence of AMR was assessed overall and in 4 clinical scenarios, including normal graft function/no known DSA, normal graft function/known DSA, graft dysfunction/no known DSA, and graft dysfunction/known DSA.2

Investigators considered dd-cfDNA to be paired with an EMB if drawn on the same day or ≤14 days before EMB. The biopsy-proven AMR incidence in each of the 4 clinical scenarios was then assessed for each of the following dd-cfDNA levels: <0.2%, 0.2-4.9%, and ≥0.5%.2

Ultimately, investigators included 2240 patients in the study, with a mean age of 54 years (standard deviation [SD], 12). Roughly 31.2% of patients received induction therapy, and 20.2% had a calculated panel reactive antibody ≥10% at the time of transplantation. The median number of dd-cfDNA results per patient was 14, and patients were followed for a median of roughly 48.8 months.2

Khush and colleagues recorded the presence of biopsy-proven ASMR in 656 (2.6%) of 24,768 biopsies; of these, pAMR1 (I+) was most common, occurring in 274 EMBs, followed by pAMR1 (H+) in 262 EMBs. Of the EMBs with AMR, 266 (40.5%) occurred in the first 2 months post-transplantation. After 55 days post-transplantation, 15,289 EMBs were performed, during which 409 exhibited AMR.2

The incidence of biopsy-proven AMR based on graft function and DSA status was 1.1% (95% CI, 0.9-1.2%) for normal function/no known DSA, 2.1% (95% CI, 1.2-3.7%) for abnormal graft function/no known DSA, 4.3% (95% CI, 3.6-5.2%) for normal graft function/known DSA, and 20.4% (95% CI, 15.3-26.8%) in abnormal graft function/known DSA.2

The percentage of dd-cfDNA tests with an associated EMB increased with higher dd-cfDNA levels, with dd-cfDNA levels ≥0.5% having the highest EMB rates for all clinical situations, ranging from 33% in patients with abnormal graft function and known DSAs to 55% in those with graft dysfunction and no known DSAs.2

Ultimately, investigators saw significant context-dependent variability of AMR incidence and the utility of dd-cfDNA in predicting biopsy yield. This is consistent with prior studies, which the team also noted should obviate the need for surveillance biopsies.2

Khush explained the intrinsic value of these results in a clinical setting, highlighting the reduced need for continued operations in light of this more effective method of scanning.

“This publication shows that, when you start treatment for AMR, you can check serial donor-derived cell-free DNA levels, and with successful treatment, the levels should decline over time,” Khush said. “This helps us avoid follow-up biopsies, which you’re doing while still determining whether or not our treatment is effective.”

References

1. CareDX. CareDX Announces Largest Landmark Study of Its Kind on Antibody-Mediated Rejection in Heart Transplantation Published in Journal of the American College of Cardiology: Heart Failure. October 23, 2025. Accessed November 6, 2025. https://investors.caredx.com/news/news-details/2025/CareDx-Announces-Largest-Landmark-Study-of-Its-Kind-on-Antibody-Mediated-Rejection-in-Heart-Transplantation-Published-in-Journal-of-the-American-College-of-Cardiology-Heart-Failure/default.aspx

2. Kim PJ, Alam AH, Teuteberg JJ, et al. Donor-derived cell-free DNA in antibody-mediated rejection. JACC: Heart Failure. Published online October 22, 2025:102716. doi:10.1016/j.jchf.2025.102716