Given the shortage of human donor organs, scientists are looking for ways to transplant organs from animals to humans. To gather data on feasibility and safety, scientists took an unconventional approach: they transplanted two recipient pig kidneys to a human brain-dead. Due to the genetic modification of the donor pig, the kidneys were not rejected. Moreover, they produced urine after a short time – even though their filtering capacity was still insufficient. The results pave the way for transplants into living humans.
All over the world, many seriously ill people wait in vain for an organ donor: the waiting lists are long and the number of organ donors is small. Therefore, scientists have long searched for ways to use animal organs for humans. Recent advances in genetic engineering meanwhile make it possible to modify donor animals – mainly pigs – so that the human body does not reject the animal organ. In January 2022, a pig heart was transplanted to a human who would have died without a donor organ. However, many unanswered questions remain about the feasibility and safety of such xenotransplantation.
Dead brain as a model organism
For ethical reasons, such questions cannot normally be answered to living people. Especially in cases where the patient can still live without a donor organ – for example by dialysis in the event of kidney damage – it would not be reasonable to take the risk of xenotransplantation without further safety testing. However, animal models are of very limited importance.
A team led by Paige Porrett of the University of Alabama in Birmingham is now reporting an unconventional solution to this problem: they used a human after brain death as a “model organism” to transplant a pig kidney into a human. ‘Although the dead brain is a hostile environment for a transplanted organ and therefore only a limited assessment of kidney function is possible, the model enables a better assessment of many of the risks,’ explain the researchers. “This makes it easier to develop Phase 1 clinical trials in live humans in the future.
Genetically modified pork kidneys
The recipient of the organs was a 57-year-old man who, before his death, declared his willingness to donate his organs for transplant and testing. With the consent of relatives, researchers selected it for their research. After his brain died in the fall of 2021, they mechanically supported his vital functions, removed both of the recipient’s kidneys in brain death, and transplanted him with the kidneys of a 13-month-old pig that was bred specifically for organ donation.
To prevent the rejection of the pig’s kidneys from the human body, the donor pig was genetically modified: scientists turned off four pig genes, including three that trigger an antibody response in the human immune system and one that would be responsible for excess tissue growth. They also introduced six human genes to prevent rejection. In order to be able to assess in advance whether the human immune system will accept new organs, they conducted a so-called crossmatch to ensure that the recipient’s blood serum does not contain antibodies to the donor tissue.
First success and open questions
In fact, scientists managed to transplant a human recipient pig kidney without acute rejection. “The kidney turned a nice pink color, and within 23 minutes, it began to produce urine,” says Porrett’s colleague Jayme Locke. The kidneys remained viable until the end of the experiment after 74 hours. As expected, the researchers found no evidence that the retroviruses were transmitted from pig to human in the recipient’s blood.
“Our study suggests that key obstacles to xenotransplantation in humans have been overcome,” say the researchers. At the same time, it is clear from the study that other questions remain unanswered. Scientists have found tiny blood clots in tissue samples from a transplanted kidney, the causes and significance of which have yet to be fully understood. Kidney function was also not as expected: although the transplanted organs were producing urine, they did not filter out creatinine from the blood, which is an important task for healthy kidneys. According to the researchers, one possible reason is that the kidneys in the body of a dead brain cannot function as well as in a living recipient.
“Trying to determine function in the face of brain death will always be a challenge,” said Locke. “Ultimately, we need to conduct a Phase I clinical trial in which we transplant the kidneys into a living human, in which conditions are more favorable to regeneration of the kidneys.”
Source: Paige Porrett (University of Alabama at Birmingham) et al., American Journal of Transplantation, doi: 10.1111 / ajt.16930