Insight Molecular Diagnostics discussed the potential use of donor-derived cell-free DNA testing in heart transplant surveillance during a virtual session featuring transplant cardiologist Dr. Max Liebo of Loyola University.
Chief Executive Officer Josh Riggs said the company’s GraftAssureDx test is moving through the U.S. Food and Drug Administration process for kidney-transplant monitoring. Following work in kidney transplantation, Insight Molecular Diagnostics plans to prepare for an expansion of its claims into heart transplantation, he said.
Biopsy burden in heart-transplant care
Nick Loannou, vice president of medical affairs at Insight Molecular Diagnostics, said heart transplantation has advanced substantially since the first procedure in 1967 and the 1983 FDA approval of cyclosporine, an immunosuppressive drug. However, transplant recipients have historically required frequent biopsies to monitor for rejection.
Loannou said patients typically undergo 14 to 18 biopsies in the first year after a heart transplant. Dr. Liebo said Loyola’s prior protocol called for 17 surveillance biopsies in the first year and 26 invasive procedures during the first five years following a transplant, excluding additional biopsies performed when symptoms or clinical changes raised concerns.
“The actual number of biopsies that come back positive for rejection is not very high compared to the number of biopsies we do,” Liebo said. He described rejection treatment as aggressive, potentially including hospitalization, intravenous steroids, plasmapheresis and, in cases involving antibodies, treatments intended to reduce antibody production.
According to Loannou, prospective multicenter trials conducted between 2019 and 2023 validated donor-derived cell-free DNA as a biomarker for acute rejection. He also cited a 2022 American College of Cardiology expert review that identified the testing as a promising non-invasive alternative to endomyocardial biopsies. The Scientific Registry of Transplant Recipients recorded 4,636 U.S. heart transplants in 2024, Loannou said.
Using cell-free DNA as a rule-out test
Liebo said Loyola has used molecular testing for years, initially relying on gene-expression profiling. The center began using the AlloSure donor-derived cell-free DNA test around 2017 or 2018, he said, and now uses cell-free DNA surveillance after the first month or two following transplant.
He described dd-cfDNA primarily as a “rule-out” tool. A normal result can provide reassurance that rejection is unlikely and may help clinicians avoid a biopsy. An abnormal result, however, does not specifically establish acute rejection because elevated donor-derived DNA may also reflect other forms of injury to the transplanted heart.
“I don’t necessarily treat patients with steroids or plasmapheresis,” Liebo said, “based off of an abnormal cell-free DNA.” Rather, an elevated result identifies patients who need additional assessment, including biopsies and potentially antibody tests, angiography or other diagnostic procedures.
At Loyola, patients generally still receive biopsies during the earliest post-transplant period because cell-free DNA testing has not been thoroughly evaluated during the first month after transplant, Liebo said. After approximately two months, the center uses cell-free DNA testing for routine surveillance and reserves biopsies for the minority of patients with abnormal results.
Potential role for in-house testing
Insight Molecular Diagnostics said its droplet digital PCR-based assay could be performed in a hospital laboratory rather than exclusively through a centralized testing facility, with results available within 12 hours. Liebo said faster in-house access could be particularly useful for patients admitted to the hospital with symptoms that could indicate rejection.
Current send-out assays can take roughly three to five days to return results, according to Liebo. In a patient presenting with clinical concern for rejection, clinicians may already have begun empiric treatment or obtained a biopsy before the test result arrives, he said.
A faster test could help clinicians assess whether the heart is likely the source of a patient’s symptoms, Liebo said. If cell-free DNA were normal, clinicians could potentially focus on other causes and avoid unnecessary hospitalization or treatment. He compared the potential use of rapid cell-free DNA testing to the use of troponin or BNP as markers that inform evaluation of cardiac conditions.
For routine surveillance, Liebo said same-day testing could also improve convenience and adherence. Existing send-out testing may require separate laboratory visits or coordination of home blood draws, while an in-house test could be collected alongside other routine clinic labs.
- Liebo said Loyola currently uses donor-derived cell-free DNA testing in all of his heart-transplant patients.
- He said the center uses both CareDx and Natera products and is not committed to either vendor.
- He said he would expect in-house testing to be adopted if it demonstrated comparable performance and improved convenience and turnaround time.
Adoption and planned comparison study
During the question-and-answer session, Liebo said broader adoption of cell-free DNA testing may depend on physician experience, evolving evidence and the gradual replacement of long-standing biopsy protocols. He said recent transplant guidelines and scientific presentations increasingly point toward molecular testing as the future of rejection screening.
Liebo also noted that cell-free DNA may become useful not only as a substitute for biopsies but potentially as an earlier signal of rejection in some patients. He described a case in which a patient’s cell-free DNA level rose before a biopsy appeared normal, with more severe rejection later becoming evident.
Riggs said Insight Molecular Diagnostics is excited to work with Loyola on a head-to-head study intended to show whether GraftAssure technology can produce equivalent results to currently used assays. Liebo said a test adopted in-house would need data supporting its performance, but he did not believe every transplant center would necessarily need to conduct its own single-institution validation study if comparable results were established.
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