Published online 28 March 2011 | Nature | doi:10.1038/news.2011.189

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DNA mismatch reveals organ rejection

A test that spots donor DNA in a transplant recipient's bloodstream could replace invasive biopsies.

An organ transplant is also a DNA transplant.A. Tsiaras/SPL

A test of genetic material carried in a patient's blood could reveal whether organ transplants have been successful, without the need for invasive biopsies.

At present, to detect whether an organ recipient's immune system is attacking the new tissue, doctors take many small samples from the organ during the first year or more after a transplant. But such biopsies are painful, costly and slow, and can cause medical complications.

Researchers studying heart transplants have now discovered a non-invasive blood test that, they say, "holds promise" for replacing biopsies and might be applicable to all transplants.

The test exploits the fact that an organ transplant adds the donor's DNA to the recipient's body. When a donated organ is rejected and its cells begin dying, pieces of this donor DNA enter the recipient's bloodstream.

"There is always a baseline level of DNA from the donor floating around in the blood of the recipient," says Stephen Quake, a bioengineer at Stanford University in California, who led the work. "But when the pieces reach a certain level it gives us a very powerful predictor that a rejection event is going on."

"We have established the proof of principle," he adds. "It looks like it is going to be good enough that we could miss out the biopsy." The findings are published this week in the Proceedings of the National Academy of Sciences1.

Early warning

The team based the test on earlier work, in which Quake had detected fetal DNA in the bloodstreams of pregnant women as a non-invasive pre-natal test for Down's syndrome2. An earlier, similar approach to rejection testing involved looking for male Y chromosomes in the blood of women who received male hearts — but Quake wanted a method applicable to both sexes.

In the latest study, the researchers looked at 44 blood samples from 7 recipients of heart transplants. The samples provided snapshots of different stages of transplant success and failure: 23 were taken when a transplant was healthy and at least three months before any failure; 15 were taken three months or fewer before rejection; and 6 samples were taken after rejection had been confirmed.

The researchers sequenced the DNA in the samples, checking it against the genetic codes of the donor and the recipient, and found significant changes in the proportion of donor-derived DNA in the recipient's blood at different stages of rejection.

On average, less than 1% of the DNA in healthy samples was from the donor, rising to 3–4% for those who were 'at rejection'. The method correctly identified rejection in 83% of the near-rejection samples.

Despite the misses, when the test falsely suggested that a successful transplant was failing, Quake believes the test holds potential and could detect rejection more than a month earlier than a biopsy would. He now wants to license the technique to a company to pursue clinical trials, and do further work himself to test the approach in organs other than the heart.

Note of caution

Other transplant researchers acknowledge the test's potential, but say that more evidence — including some from clinical trials — is needed before it can enter routine diagnostic use.

The study was performed on a small sample group, and the amount of donor DNA detected varied widely between patients, notes Bruce McManus, who studies transplant rejection at the University of British Columbia in Vancouver, Canada.

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"False positives and false negatives could pose a problem for possible practical clinical utility," he says. "There will need to be more patients evaluated." Animal studies are also needed to conclusively show that the presence of donor DNA is linked to donor organ cell death, he adds.

McManus heads a team that is working to build upon an existing non-invasive rejection test, called AlloMap. This test monitors the activity of genes in the recipient's immune system, but it isn't always reliable, and so biopsies are still required.

Elaine Reed, an immunologist researching transplant rejection at the University of California, Los Angeles, points out that, like existing tests, Quake's technique only spots rejection once it has begun. "Ultimately, we want to know before it happens because we want to spare the graft from being damaged," she says. 

  • References

    1. Snyder, T., Khush, K. K., Valantine, H. A. & Quake, S. R. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.1013924108 (2011).
    2. Fan, H. C., Blumenfeld, Y. J., Chitkara, U., Hudgins, L. & Quake, S. R. Proc. Natl Acad. Sci. USA 105, 16266-16271 (2008). | Article |
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