Blood testing detects early signs of liver transplant rejection

Blood testing detects early signs of liver transplant rejection

Liver transplantation is a life-saving operation, but a significant number of patients experience organ rejection or other complications. Now a new study by scientists at Georgetown University and Medstar Health describes how a single blood sample can be used to catch problems at their earliest stages to provide tailored treatment to prevent organ failure.

The research, funded in part by the National Institutes of Health, is a significant step toward developing a liquid biopsy that can not only detect post-transplant complications but also pinpoint the cause. The technology would largely eliminate the need for invasive testing.

The results were published June 17 in the journalNature communication“Circulating cell-free methylated DNA indicates cellular sources of allograft injury after liver transplantation.

There is a much better and more detailed understanding of what drives transplant failure. With this technology we can draw a blood sample and pretty much get an approximation of what's going on with the entire patient. “

Anton Wellstein, MD, PhD, professor of oncology and pharmacology at Georgetown Lombardi Comprehensive Cancer Center and senior author of the study

Liver transplants are only given to patients who are in urgent need. Unlike other organs such as the kidneys, which can be supported with dialysis, there are no machines or treatments that can save a patient if the liver fails. And with only a limited supply of livers available for transplant, preventing organ injury is paramount, said study co-author Alexander Kroemer, MD, PhD, a transplant surgeon at Medstar Georgetown University Hospital and director of the Center for Translational Transplantation at Georgetown University Medical Center.

There are several ways a transplanted organ can retain damage. The transplant process itself can injure the new liver, place stress on nearby organs, and trigger an immune response.

Currently, transplant doctors can use blood tests to detect possible damage and genetic testing to determine whether the damaged cells came from the donated liver or the patient's own body. However, identifying the exact cause often requires costly imaging studies or invasive follow-up tests such as a liver biopsy.

The new technology occurs by picking up DNA fragments found in the debris left behind in dying cells circulating in the blood. Wellstein's team found that chemical signatures left on these DNA fragments could be used in precise detail to identify the original cell type and where it came from.

“The new thing is that we can now find out the cellular origin of the damage,” explained Wellstein. “We can determine the cell types either in the transplanted organ or in other tissues in the host that are damaged or at risk of damage.”

The test's convenience means it can be repeated at frequent intervals, he said, making it easier for doctors to monitor patients and detect problems early.

“For example, if you know that the biliary compartment [of the liver] is injured but not the hepatocellular compartment, you can deliver a personalized treatment approach that leads to better care for the patient,” Kroemer said.

The blood test is not only faster and less invasive than a traditional tissue biopsy, but also potentially more accurate, he added. "With needle biopsies, there's always the potential for sampling because you're not sampling the entire liver," he said. “It’s just a small core that is being evaluated.”

When researchers began the project seven years ago, they had no idea whether it would even be possible to detect cell damage in blood samples.

“It was amazing how well it worked,” Wellstein said.

The research was supported by a $2.5 million grant from the NIH. It originally began as a research project by first author Megan McNamara, an MD/PhD student at Georgetown. McNamara was supported by an NIH-funded graduate student training grant.

Georgetown has filed patent applications for the technology with Wellstein, Kroemer and McNamara, referred to as co-inventors. Researchers are exploring additional uses, including in other organ transplants, in patients receiving radiation therapy for breast cancer, and in the treatment of melanoma.

The team is also seeking partners to commercialize the technology for clinical settings.

"We can make the discovery - that's where the academy comes in - but if you want to translate it for use in transplantation, it has to go to industry," he said.

In addition to Wellstein, Kroemer, and McNamara, other authors include Sidharth S. Jain, Amber J. Kiliti, Marcel O. Schmidt, A. Patrick McDeed, and Anna T. Riegel at Georgetown; Kesha Oza, Vinona Muralidaran, Digvijay Patil and Yuki Cui at Medstar Health. The additional authors report that they have no personal financial interests related to the study.

This work was supported by funding from National Institutes of Health Grants T32-CA009686, F30-CA250307, ​​R01-AI132389, R01-CA231291, and P30-CA51008.

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