What is the future of xenotransplantation? Pig liver and kidneys transplanted to humans for the first time

Would you like some pig liver?

The first-ever recipient of pig liver was a 50-year-old clinically dead man on March 10, 2024. The nine-hour procedure was performed at the Chinese military hospital Xijing. With the family's consent, the man was implanted with a 700-gram liver from a genetically modified miniature Bama pig. A total of 6 modifications replaced 3 carbohydrates on the surface of pig cells with 3 human surface proteins.

The liver remained connected to the recipient's bloodstream for 10 days, after which the experiment was planned to end. During this time, the recipient was given immunosuppressants, and his own functional liver was left in place. The color and texture of the pig liver appeared physiological, and it was able to excrete more than 30 ml of bile per day, indicating that it was functional. Researchers soon plan to conduct a full transplant on another clinically dead patient, removing his own liver.

Successful kidney xenotransplant

The first living recipient of a pig kidney was Richard Slayman, a 62-year-old American with end-stage kidney failure. Slayman received a kidney from a human donor in 2018, which gradually began to fail, making him reliant on dialysis again. Now, he received a kidney from a miniature pig with a record 69 genetic modifications. These modifications removed 3 genes for surface carbohydrates recognized by the human immune system as foreign, and added 7 genes for the production of proteins that help prevent graft rejection. The remaining 59 modifications inactivated viruses integrated into the pig genome.

The surgical procedure took 4 hours, and the pig kidney turned pink and began producing urine immediately after connecting to the patient's bloodstream, indicating a successful transplant. Four days after the procedure, the recipient's blood creatinine concentration dropped from nearly 900 to about 200 μmol/l. The patient is taking immunosuppressants, and no signs of graft rejection have been observed yet.

Heart replacement

The first successful heart xenotransplant occurred at the University of Maryland Medical Faculty's Surgical Clinic in January 2022. The new heart was given to 57-year-old David Bennett, a patient with terminal heart failure, who was connected to extracorporeal circulation at that time. The transplanted heart worked for 7 weeks post-surgery without signs of acute graft rejection. However, acute diastolic failure occurred afterward, and the patient died 2 months post-surgery. The failure of the transplant was due to a combination of factors, the main one likely being the poor physical condition of the severely immunocompromised patient, which limited the administration of effective graft rejection prophylaxis. The patient needed intravenous immunoglobulin administration twice when threatened by infection, which likely contributed to myocardial damage. The pig heart also had a latent cytomegalovirus, which might have reactivated and caused inflammatory processes after reducing antiviral prophylaxis, which the patient couldn't tolerate. Nevertheless, it seems the virus did not infect the patient nor spread to other body parts.

A long way to clinical use

All xenotransplantations so far have been performed either on clinically dead patients or as compassionate use, meaning on terminally ill patients who had exhausted all other therapeutic options. Scientists now hope to achieve regulatory authority approval for large-scale clinical trials of xenotransplantation. They plan to seek approval for trials involving pig kidney transplants, pediatric heart transplants, and the use of pig livers connected to the recipient's bloodstream extracorporeally.

What are the risks of xenotransplantation?

One of the main concerns of the U.S. Food and Drug Administration (FDA) is the risk of recipients being infected by pig pathogens. Therefore, genetically modified pigs intended for organ production are regularly tested for viral, bacterial, and fungal pathogens. There is also the possibility of reactivating latent viruses integrated into the pig genome. Although this has not been observed in monkeys or clinically dead humans who received pig organs with similar modifications, some lab experiments suggest that transmission of latent viruses to human cells or immunocompromised mice is possible. Richard Slayman and his surroundings remain under close observation.

Music of the future

The goal of biotechnologists developing pigs for organ production is to create a combination of genetic modifications so that the organ recipient does not need to take immunosuppressants at all. “It’s always been said that xenotransplantation is just around the corner, and it always will be. But now we have someone among us who is carrying a pig kidney in his body. It’s simply amazing,” concludes molecular biologist Wenning Qin from eGenesis, who provided the kidney transplanted to Richard Slayman.

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Sources:
1. Mallapaty S. First pig liver transplanted into a person lasts for 10 days. Nature 2024; 627 (8005): 710–711, doi: 10.1038/d41586-024-00853-8.
2. Mallapaty S., Kozlov M. First pig kidney transplant in a person: what it means for the future. Nature 2024; 628 (8006): 13–14, doi: 10.1038/d41586-024-00879-y.
3. Mohiuddin M. M., Singh A. K., Scobie L. et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report. Lancet 2023; 402 (10399): 397–410, doi: 10.1016/S0140-6736(23)00775-4.
4. Kotz D. Lessons learned: First pig-to-human heart transplant. University of Maryland, 2023 Jul 03. Available at: www.umaryland.edu/news/archived-news/july-2023/lessons-learned-first-pig-to-human-heart-transplant.php