For only the second time ever – and the first involving a clinical-grade organ – a genetically modified pig kidney has successfully been transplanted into a brain-dead human body, in a milestone example of xenotransplantation.
Hundreds of thousands of people around the world are trapped in an agonizing wait for a lifesaving organ donation. But there are never enough human organs to go around. Many people die or become too ill to receive a transplant while waiting.
Kidneys are the organs most in demand, with more than 800,000 people living with kidney failure in the US, and only around 25,000 transplants a year. Researchers around the world have long been working to find a solution to this shortfall, and they’ve turned to animal organs to see if they could be a solution.
Now, thanks to years of hard work, and thanks to the donation of the body of the kidney recipient, James Parsons of Alabama, and the assistance of his family, that hope is closer to reality.
“The concept of being able to have an organ waiting on the shelf, waiting for the person who needs it, is just remarkable to think about, and exciting for that person,” said lead surgeon Jayme Locke from the University of Alabama, Birmingham (UAB).
“I feel really privileged to be just a tiny part of a really big puzzle that people have been working on for many years.”
It has taken decades of gradual progress to reach this point. In the 1960s surgeons attempted xenotransplantations of chimpanzee kidneys in 13 end-stage kidney disease patients, but sadly, despite these animals being our closest living relatives, most of the desperate patients died within weeks.
In the 1980s, researchers proposed pig organs might be more suitable due to their closer size to human organs, and advances in genetics over the last few decades have increased this possibility, with last year a pig kidney being transplanted into a brain-dead human for 54 hours.
To this end, the UAB set up an extensive program in 2015 called Revivicor, which involved dedicated xenotransplantation facilities and highly trained multidisciplinary teams to advance this process clinically.
“In order to get the FDA’s approval, we have to be able to demonstrate to them that we can carry out xenotransplantation in the same safe and feasible manner that we do every day when we do an allotransplant,” explained Locke. “The only thing different is that the kidney came from a pig.”
While the physiology that arises from brain death limits the assessment of kidney function, this experiment, led by UAB surgeon Paige Porrett, allowed researchers to better understand many of the risks involved in this complicated operation to help them develop the first phase I clinical trials.
One of the main barriers to successful xenotransplantations is fooling our immune systems into accepting such alien tissues as our own.
Previous work in non-human primates identified carbohydrate molecules on the outer surface of the pig kidney that would signal ‘foreign invaders’ to our bodies. So the team genetically modified the pigs to lack these antigens.
They also modified genes to prevent blood clots and other known immune reactions, and the transplant proved these modifications were sufficient to prevent a human body from rejecting the pig’s organ in the short term.
The researchers also confirmed that the pig kidney could withstand the higher blood pressure humans have.
Viruses are another threat to a successful transplant, so Porrett and team took many measures to mitigate this. The donor pigs were kept as pathogen-free as possible, with checks every three months for 14 infections, and in the lead-up to the transplant the donor was tested every day.
No sign of pig cells or pig retroviruses were found in the recipient’s blood, and although the tests were limited to just 77 hours in the experiment, transplants of other pig tissues have shown similar results after a much greater duration.
While the procedure answered many questions, it also highlighted what areas need further investigation. For example, we do not yet know if one pig kidney alone is able to support a human adult, or if two would be required.
Porrett and colleagues also suspect the genetic modifications altered the structure and therefore function of the kidneys, which will require further testing to tease out how much functional differences were also due to the physiology of brain death.
“All of us at Revivicor are in awe of the historic achievements,” said UAB genetic engineer David Ayares. “We feel confident that this UKidney may turn out to be a life-saving solution for thousands of people on dialysis, subject to successful completion of our clinical trials and achievement of FDA approval in the next several years.”
While there is still a ways to go yet, this study has also established the safety and feasibility of using brain-dead patients as a model for preclinical research. To honor the recipient and his family, the researchers have proposed calling this “The Parsons Model”.
“Moving forward, the Parsons Model can be leveraged to study the safety and feasibility of all sorts of things designed to improve the human condition, whether it be a medication or a new surgical procedure,” explained Locke.
An adventure-loving father, James Parsons was an organ donor who succumbed to a dirt bike accident soon after his 57th birthday.
“Jim would have wanted to save as many people as he could with his death, and if he knew he could potentially save thousands and thousands of people by doing this, he would have had no hesitation,” said Julie O’Hara, Jim’s ex-wife.
“Our dream is that no other person dies waiting for a kidney, and we know that Jim is very proud that his death could potentially bring so much hope to others.”
This research was published in the American Journal of Transplantation.