Urine Test Detecting Organ Rejection Could Replace Invasive Biopsies

Georgia Tech researchers have recently developed a nanoparticle that allows physicians to detect transplanted organ rejection with a simple urine test. The nanoparticles build up in these transplanted organs and release fluorescent molecules that alter the host’s urine appearance if rejection occurs. This process of detecting organ rejection with a urine test could potentially replace the need for invasive biopsy samples.

One issue with current means of detecting organ rejection is that the transplanted organ often has suffered serious damage by the time a biopsy reveals the rejection. Additionally, organ biopsies are invasive, prone to risk, and in some cases incapable of detecting early-stage immune rejection.

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“The biopsy is not predictive. It’s a static snapshot. It’s like looking at a photo of people in mid-jump,” said Gabe Kwong, co-principal investigator in the study and an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “You don’t know if they’re on their way up or on their way down. With a biopsy, you don’t know whether rejection is progressing or regressing.”

In early stages of rejection when a patient may feel fine, a biopsy could provide no indication of organ rejection when T cells have already started to attack the organ. The nanoparticle tested by these researchers, however, detects an enzyme called granzyme B. This enzyme drives the transplanted tissue cells into a programmed cell death known as apoptosis.

The researchers note that by detecting this enzyme linked to organ degradation early on, their nanoparticle technique sets itself apart from traditional biopsy methods. “Before any organ damage can happen, T cells have to produce granzyme B, which is why this is an early detection method,” said Kwong.

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The researcher’s findings come from a study conducted in a mouse model, recently published in Nature Biomedical Engineering this past week. Their research was funded by the National Institutes of Health, the National Science Foundation, and the Burroughs Wellcome Fund.

“This is sensitive enough to possibly detect budding rejection before you see significant injury to the transplanted organ and that could help clinicians treat early to prevent damage,” explained Dr. Andrew Adams, co-principal investigator and an associate professor of surgery at Emory University School of Medicine. “Right now, most tests are aimed at organ dysfunction, and sometimes they don’t signal there is a problem until organ function is below 50 percent.”

These nanoparticles are created with iron oxide at the center and a double-coating of dextran and polyethylene glycol on the outside to keep the body from degrading it too quickly. Amino acid bristles stick out from the iron ball with fluorescent molecules attached to their tips.

These particles are injected intravenously and are too large to accumulate in native tissues or be excreted through the kidneys. The nanoparticles have been engineered to still be small enough to accumulate in the tissue of transplanted organs, where they are sent to detect rejection.

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Once the T cells begin to secrete the granzyme B, amino acid degradation occurs in the transplanted organ’s cells, ultimately leading to cell death. The amino acids engineered in the nanoparticle mimic these target amino acids in the tissue, and are cut by the enzyme at the same time it attacks the foreign organ. Once these amino acids are cleaved, they release the tiny reporter molecules that go on to make the urine fluoresce.

In their experiment, the researchers noted that the animals’ urine glowed and was visible in the bladder via near-infrared images.

The team plans to alter their technique to detect attacks by antibodies, rather than T cells, in transplant rejection. “Antibodies kill their target cells through similar types of enzymes. In the future, we envision a single sensor to detect both types of rejection,” Kwong said.

“This method could be adapted to tease out multiple problems like rejection, infection or injury to the transplanted organ,” said Adams. “The treatments for all of those are different, so we could select the proper treatment or combination of treatments and also use the test to measure how effective treatment is.”

Sources: Medgadget, Georgia Tech,