According to Nature, the early success of the world's first living human pig kidney transplant surgery has sparked hopes among researchers for larger-scale clinical trials involving pig organs. Such trials could pave the way for clinical xenotransplantation, where animal organs are used in human recipients.
The recipient of the pig kidney transplant is a 62-year-old end-stage renal failure patient named Richard Slayman. According to his transplant surgeon, the patient recovered well after the surgery on March 16. The transplanted kidney was taken from a genetically engineered miniature pig with a record-breaking 69 genome edits aimed at preventing rejection of the donor organ and reducing the risk of viral infections lurking within the organ for the recipient.
Yang Luhan, CEO of Hangzhou Qihan Biotechnology Co., Ltd., stated that this case demonstrates, at least in the short term, the safety and kidney-like functionality of these organs. Yang is also one of the founders of eGenesis, the US biotechnology company that produces these pigs. It is reported that the company is in discussions with the US Food and Drug Administration (FDA) regarding the clinical trial of its pig kidney and liver transplantation projects.
All animal organ transplants into living humans in the United States, including Slayman's transplant, have received FDA "compassionate use" approval, allowing their use in cases where patients are critically ill and have no other treatment options. However, Yang hopes that the new results will prompt the FDA to approve comprehensive clinical trials, as xenotransplantation can "bring hope and life to patients and their families."
This surgery also makes it more likely for clinicians to alleviate the shortage of life-saving human organs by using animal organs. In the United States alone, nearly 90,000 people are waiting for kidney transplants, and over 3,000 die annually while on the waiting list. Wayne Hawthorne, a transplant surgeon at the University of Sydney, stated, "Despite significant increases in organ donation rates, we still need millions of organs to transplant into patients."
"This is good news for the field," said Muhammad Mohiuddin, a surgeon and researcher at the University of Maryland School of Medicine, and chairman of the International Xenotransplantation Association, regarding the clinical trials that will generate much-needed rigorous data on the safety and efficacy of xenotransplantation.
One of the transplant surgeons involved in the surgery, Tatsuo Kawai, stated that the surgery to transplant a pig kidney into Slayman took four hours. Slayman's right kidney was a donated human kidney, transplanted in 2018, but it had failed. Consequently, Slayman resumed regular dialysis, but he developed complications, necessitating frequent hospital visits, making him a candidate for xenotransplantation.
Slayman's latest kidney comes from a pig that has undergone CRISPR-Cas9 genome editing by scientists at eGenesis, modifying 69 animal genes. An animal called the crab-eating macaque survived for several months to years after receiving organs from pigs edited with the same genetic modifications.
These edits include removing three genes that contribute to the production of three types of sugars on the surface of pig cells. The human immune system attacks cells that carry these sugars, considering them markers of foreign invaders. Additionally, seven genes producing human proteins that help prevent organ rejection were added during editing.
Another 59 gene changes were made to deactivate viruses embedded in the pig genome. These changes address the issue of viruses becoming active once they enter the human body. Yang stated that researchers have not yet observed this in vivo, clinically dead humans, or non-human primates undergoing transplants. However, some laboratory experiments suggest that these viruses can spread from pig tissues to human cells and immunocompromised mice.
The first successfully transplanted transgenic pig heart into a living body was found to be infected with a potential virus, which may have led to the eventual failure of the organ. Kawai stated that prior to approving the surgery, the FDA's main concern was the risk of pig pathogens infecting the recipient. It is understood that eGenesis regularly tests its pigs for pathogens, including porcine cytomegalovirus.
Before the surgery, researchers collected and froze blood samples from Slayman, his family, and his surgeons. Kawai stated that if Slayman were to become infected with a virus, researchers could test these blood samples to determine if they were the source of the pathogen.
Slayman will continue to undergo regular pathogen testing, and if he exhibits symptoms, his family and caregivers will also be tested.
Yang emphasized the importance of these precautions because a healthy pig is vastly different from an immunocompromised human. She stated that despite no detection of viruses, bacteria, or fungi in the pig's body prior to transplantation, they could still exist and grow in the immunocompromised human body.
The kidneys filter toxins from the body, produce urine, and help control blood pressure. Kawai stated that when surgeons restored blood flow to the transplanted pig organs, they immediately turned pink and began producing urine, a sign of successful transplantation.
Another indicator of kidney health is the level of a chemical compound called creatinine in the blood—high levels indicate that the kidneys are not effectively filtering waste. Kawai said that before the transplant, Slayman's creatinine level was 10 milligrams per deciliter, but by the fourth day, it had dropped to 2.4 milligrams per deciliter. He hopes this indicator will drop to 1.5 milligrams, which is approximately within the normal range. Mohiudin stated, "So far, the kidney function appears to be normal."
Slayman is undergoing treatment with immunosuppressive drugs, and there have been no signs of organ rejection so far. Researchers at eGenesis, the company, expressed their goal of identifying the correct gene-editing combination in pigs to eliminate the need for immunosuppressive drugs in organ recipients, as these drugs weaken the body's ability to fight pathogens.
