An easier, more accurate way to predict transplant rejection

For patients who’ve had a heart transplant, the first post-operative year is filled with as many as a dozen biopsies to check for rejection of the donor organ. It’s expensive, stressful, painful — and biopsy of a single sample of tissue doesn’t always catch rejection underway in other parts of the heart.

But a new approach developed by a research team led by cardiothoracic surgeon Michael Mitchell, MD, and Aoy Tomita-Mitchell, PhD, at Children’s Hospital of Wisconsin Research Institute could dramatically change the way that doctors predict transplant rejection, and it’s as easy as a blood test. That’s big news because early detection is key to improving outcomes for the 10 to 20 percent of all heart transplants that fail due to rejection.

“It felt like a charge to create this test, not only for the sake of science, but to bring it into the clinics,” Dr. Mitchell says. “We can now detect very minor injury to the heart noninvasively.”

Using a sample of a patient’s plasma, the extremely sensitive test targets areas in the genome, measuring something called cell-free DNA.

“We have fragments of DNA that circulate in our blood,” Dr. Mitchell explains. “These fragments come from normal cell turnover, injury to the cells and inflammation. If you’ve had a transplant, a fraction of the circulating DNA comes from the donor organ, and this fraction increases with injury to the donor organ.”

Dr. Mitchell and Dr. Tomita-Mitchell, who are married and share a lab, use a unique, targeted approach to sequencing. “It’s a more efficient way,” Dr. Tomita-Mitchell explains. “We’re just trying to measure the difference between two people so we only need to find where those differences exist; we don’t need to sequence the entire genome.”

The test exceeded expectations during a pilot study at Children’s Hospital of Wisconsin in 2012. Now a new five-year, $3.27 million grant from the National Institutes of Health is funding a longitudinal study to test the method with 480 adult and pediatric heart transplant patients at five hospitals around the country. Mats Hidestrand, PhD, co-principal investigator on the grant and a researcher in Cardiothoracic Surgery at the Medical College of Wisconsin, and Steven Zangwill, MD, director of Pediatric Heart Failure and Heart Transplantation at Children’s Hospital of Wisconsin, are key partners.

While a blood test probably won’t replace heart biopsies entirely, it could reduce the number of biopsies required, improving transplant patients’ outcomes and comfort while reducing healthcare costs.

The transplant rejection study is just the latest example of Dr. Mitchell’s and Dr. Tomita-Mitchell’s commitment to translational research. They have developed a test for the noninvasive prenatal dectection of fetal chromosomal abnormalities, and have also developed a population-based screen for 22q deletion syndrome, also known as DiGeorge Syndrome, which is associated with heart defects and other complications. Their goal is to bring basic science research back to patients in order to improve the lives of patients with congenital heart disease.

Children’s Research Institute is the perfect place to pursue those sorts of translational innovations, according to the couple.

“There are a lot of great ideas coming out of the researchers at Children's Research Institute and there are a lot of great, creative clinicians at Children’s Hospital of Wisconsin, and when those two groups come together, it’s a very powerful collaboration,” Dr. Mitchell says.

If the clinical multi-center study performs as well as they hope, it could help more than just heart transplant patients.

“We’re very excited to expand this to other solid organs,” Dr. Mitchell says. “This is a long-term team effort.”