Marlene Busko

April 10, 2017

SAN DIEGO — Levels of donor-derived cell-free DNA in the blood of people who have undergone lung transplantation can predict risk for organ rejection and death, according to a small, exploratory case–control analysis of patients from the Genome Transplant Dynamics study (NCT02423070).

This is valuable information because "more than two-thirds of donor-derived cell-free DNA elevations in the first 6 months of transplant were clinically silent," which is "really startling," said Sean Agbor-Enoh, MD, from the Laboratory of Transplant Genomics at the National Heart, Lung and Blood Institute in Bethesda, Maryland.

"Think about that," he told the audience here at the International Society of Heart and Lung Transplantation 2017 Scientific Sessions. "We do surveillance biopsy on these patients and the biopsy is normal, but these patients have ongoing allograft injury."

About half of all lung transplant recipients die 5 to 6 years after transplantation, mostly because of graft failure. Until now, there has been no quantitative test to predict which patients are likely to experience rejection, Dr Agbor-Enoh pointed out.

However, recent research has shown that during organ rejection, high amounts of graft-derived cell-free DNA are shed into the bloodstream. Dr Agbor-Enoh and his colleagues therefore hypothesized that donor-derived cell-free DNA — which can accumulate and lead to graft failure and death — is a marker for early graft injury after transplantation.

In their study, the researchers used the AlloSure test — developed by CareDx and previously used in the study of heart and kidney transplantation — to quantify the amount of donor-derived cell-free DNA in the blood of 62 lung transplant recipients.

With this test, cell-free DNA is extracted from the plasma of transplant recipients. Donor DNA is identified using amplified analysis of single-nucleotide polymorphisms (SNPs), and the percentage of donor-specific DNA is then calculated.

The team determined levels of donor-derived cell-free DNA in patients at baseline and at 3, 6, 12, 18, and 24 months after transplantation. The 20 patients who experienced early graft failure comprised the case group and in 42 patients who did not comprised the control group.

Levels of donor-derived cell-free DNA were higher in the case group than in the control group from 0 to 6 months, and levels were even higher from 12 to 24 months.

In the control group, the initial level of donor-derived cell-free DNA was high, but it subsequently decayed logarithmically and stabilized.

Predicting Failure

A level of donor-derived cell-free DNA of at least 1.25%, indicating early graft injury, predicted a composite outcome of early graft failure, repeat lung transplantation, and severe chronic lung allograft dysfunction.

The risk for graft failure was 7.7 times higher in the case group than in the control group (P < .0001), and the risk for all-cause mortality within 2 years was 4.0 times higher (P < .0001).

Of the patients who had elevated levels of donor-derived cell-free DNA in the first 6 months after transplantation, 20.0% developed an infection, 7.6% experienced acute lung rejection, and 72.0% showed no clinical signs of injury.

The findings show that "lung transplant patients can have ongoing allograft injury that nadirs around 6 to 12 months after transplantation," Dr Agbor-Enoh explained.

After the presentation, discussant Erik Verschuuren, MD, from the University Medical Centre in Groningen, the Netherlands, asked whether risk factors for organ rejection such as lungs from older or marginal donors had been adjusted for.

They had, Dr Agbor-Enoh reported, and the main predictors of poor outcome were graft dysfunction, a female donor, and a donor with a history of heavy alcohol use.

These are early days, but this is a noninvasive way "to diagnose rejection or damage to the graft before it becomes evident clinically or on a biopsy," said session cochair David Taylor, MD, from the Cleveland Clinic Foundation.

 
I think it's going to have a powerful role in managing all transplant recipients.
 

"I think it's going to have a powerful role in managing all transplant recipients," he told Medscape Medical News. However, "we need more information, and we need to see better delineation of the risks."

Although this technique is not ready for use in clinical practice just yet, cochair Hermann Reichenspurner, MD, from University Heart Center in Hamburg, Germany, said he will follow the research closely.

He predicted that this could be ready for clinical practice in 2 years. "It's a good way of getting away from invasive tests," he pointed out.

Dr Agbor-Enoh, Dr Taylor, and Dr Reichenspurner have disclosed no relevant financial relationships.

International Society of Heart and Lung Transplantation (ISHLT) 2017 Scientific Sessions: Abstract 0148. Presented April 6, 2017.

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