Molecular Diagnostics Pinpoint Heart Transplant Trouble

Ingrid Hein

April 12, 2018

NICE, France — The molecular diagnosis of heart transplant biopsies is more precise than histologic analysis, and could become a new standard, results from the INTERHEART study (NCT02670408) show.

"Agreement in histology is significant, but there are a lot of discrepancies," said Philip Halloran, PhD, MD, from the Alberta Transplant Applied Genomics Centre at the University of Alberta in Edmonton.

Molecular diagnosis is more objective and reproducible than histology, and provides new understanding of an organ's reduced function in response to injury, he explained here at International Society for Heart and Lung Transplantation 2018 Scientific Sessions.

Because increased diagnostic accuracy can eliminate confusion between transplant rejection and organ injury, treatment can be more precise and the administration of unnecessary immunosuppression drugs can be prevented, he said.

Halloran and his colleagues assessed endomyocardial biopsy samples from 462 patients who had undergone heart transplantation at one of eight centers. Biopsies were performed a mean of 810 days after transplantation.

Archetypal analysis, which assigns idealized extreme examples to compare all points analyzed, was conducted with Affymetrix microarrays. To compare molecular with histologic diagnoses, biopsies were assigned to one of three groups: no rejection, antibody-mediated rejection, or T-cell-mediated rejection.

For molecular diagnosis, the researchers used a molecular diagnostic system developed for kidney transplant biopsies (Nat Rev Nephrol. 2016;12:534-548), which they found they could use for hearts (J Heart Lung Transplant. 2017;36:1192), as reported by Medscape Medical News.

Molecular Results Different From Histologic Finding

For the biopsies assigned to the no rejection group, the rate of agreement between molecular and histologic approaches was 82%. For those assigned to antibody-mediated rejection, the rate of agreement was 33%, and for those assigned to T-cell-mediated rejection, it was 36%. For biopsies with mixed results, the rate of agreement was 13%.

The low rate of agreement between the two approaches is not a surprise. For 160 years, "we have looked down a microscope at a piece of tissue that's been cut and stained with ancient dyes. We know that between two pathologists reading rejection, there's only 28% agreement above random," Halloran said.

A previous study looked into histologic kappa values for concordance among pathologists (Transplantation. 2012;94:1172-1177). "There's truth there, but there's also a lot of noise, meaning errors," he explained.

In their investigation, Halloran and his colleagues found that molecular readings correlated with heart function, improved accuracy, and improved prediction of future failure.

"Knowing what we know, we should be making diagnoses by looking at the messages from genes," he asserted, adding that it's time to embrace precision medicine.

Molecular Adds "Fourth Dimension" to Diagnosis

During the course of their investigation, the team found another dimension to molecular analysis, which they identified as "injury". When they examined the histologic results, they found a high rate of error, particularly for biopsies assigned to T-cell-mediated rejection.

These were, in fact, serious injuries that were not rejection but were confused with rejection, Halloran explained during his presentation of this second analysis of the data. "These were false-positives caused by injury, not rejection," he reported.

The histologic approach is not reliable and can lead to misdiagnosis, which could mean that patients are subjected to unnecessary treatment.

"Antirejection drugs are heavy stuff. You don't want those if you don't need them," said Halloran. "We need to include the dimension of injury in our diagnosis. This is something we can't read with histology."

Antirejection drugs are heavy stuff. You don't want those if you don't need them.

"This is significant progress," said Andrew Fisher, PhD, from the Institute of Transplantation at Freeman Hospital in Newcastle Upon Tyne, United Kingdom.

"Using an objective scientific approach instead of by eye, we can look at the molecular signature of a biopsy to make a more accurate diagnosis," he told Medscape Medical News.

In fact, a similar study looking at the molecular diagnosis of lung biopsy — conducted by a team led by Halloran's son, Kieran Halloran, MD, also from the University of Alberta — will be presented at the meeting later this week.

Halloran reports holding stock in Transcriptome Sciences. Fisher has disclosed no relevant financial relationships.

International Society for Heart and Lung Transplantation (ISHLT) 2018 Scientific Sessions: Abstract 43, presented April 11, 2018; Abstract 178, presented April 12, 2018.

Follow Medscape on Twitter @Medscape and Ingrid Hein @ingridhein


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