Pam Harrison January 20, 2022
Hard on the heels of the so-far successful transplant of a genetically modified pig heart into a man 2 weeks ago, surgeons announced they have transplanted two similarly modified pig kidneys into a brain-dead human recipient.
After removing the patient's own kidneys, the doctors transplanted the two kidneys from the pig using conventional techniques.
The process demonstrates the long-term viability of the procedure and how such a transplant might work in the real world, the researchers say. The transplanted kidneys filtered blood, produced urine, and, importantly, were not immediately rejected. The kidneys remained viable until the study ended, 77 hours after transplant.
"We certainly think of this as a breakthrough," Jayme Locke, MD, professor of surgery and the Arnold G. Diethelm Endowed Chair in Transplantation Surgery, University of Alabama at Birmingham (UAB), told Medscape Medical News.
"But the other important thing we did here is that we mimicked exactly [the procedure for a] phase 1 clinical trial in living people so we could test our xenotransplant program — from our pathogen-free facility and pristine operating room...where one team performed the procurement and then simultaneously, a separate team prepared the recipient," she added.
The team did not expect the altered physiologic milieu of brain death to provide an optimal environment to support renal recovery. In fact, the recipient had been brain dead for 5 days prior to undergoing the transplant, so the fact that the recipient deteriorated physiologically was simply the result of this.
"We were able to test critical elements of our process from start to finish, and we demonstrated that this procedure is feasible, that it is safe, and it speaks to our ability to really ramp this up and do this for more people than just one individual," Locke affirmed.
The UAB researchers are not the first to report such a transplant. Surgeons a tNYU Langone Health in New York City reported a similarly successful procedure in October 2021, with the brain-dead recipient surviving for 3 days after the pig kidney was transplanted.
But crucially, the UAB work is is the first peer-reviewed study on such a procedure to be published; it appeared online January 20 in the American Journal of Transplantation.
Powerful Contribution From Registered Organ Donor
For the study, the transplant team at UAB set out to test the core principles of the pig-to-nonhuman primate (NHP) model without incurring any risk to a living patient.
To do this, they used a brain-dead human recipient who, prior to surgery, had undergone a "crossmatch compatibility test" to determine whether the genetically modified pig kidneys were a good tissue match.
As Locke explained, in the context of human-to-human transplantation, regulations require practitioners to do a crossmatch test before proceeding to transplantation to prove that the recipient's immune system will not immediately react to the donor organ and reject it immediately after transplantation.
"This was one of the critical endpoints of the study, and we were able to validate this flow crossmatch test, which is what we will need to be able to move this into living recipients, so this was a super important piece of the study," Locke emphasized.
This scientific and medical breakthrough would not have been possible without Jim Parsons, the recipient, or his family, Locke and her fellow researchers stress. Parsons, 57, was a registered organ donor through Legacy of Hope, Alabama's organ procurement organization, and he had longed to have his organs help others upon his death; but his organs were not suitable for donation. His family permitted UAB to maintain Parsons on a ventilator to keep his body functioning during the study.
"Mr Parsons and his family allowed us to replicate precisely how we would perform this transplant in a living human. Their powerful contribution will save thousands of lives, and that could begin in the very near future," Locke emphasized.
The pig kidneys were procured from genetically engineered pigs provided by Revivicor, Inc, which have a total of 10 modified genes, one of which is, critically, pig growth hormone.
"These animals can get to over 1000 lbs, and if you don't knock out the growth hormone, the pig kidney will continue to grow as if it were in an adult pig," Locke explained. "So one of the key gene edits that has to happen is to knock out the growth hormone so the kidney stays the appropriate size [required for transplant into a human] in the host, and this was another major milestone that occurred in this study," she affirmed.
Following the so-far successful transplant of a pig heart into a human in early January, Medscape Medical News spoke to experts about the implications of this, one of whom observed that "pig temperature is inherently higher than humans by several degrees," and therefore it will be important to see if pig organs can function properly in what for them will be "a relatively hypothermic environment."
A Paradigm Shift?
There were a number of very encouraging signs that the pig kidney may well have achieved full function had the recipient not developed multisystem organ failure 72 hours post transplant.
First and foremost is the fact that, when the clamp was removed during the transplantation phase, "the kidney immediately turned pink, which is a wonderful sign. There was a great thrill in the vessels, and you could hear Doppler signals throughout the kidney parenchyma," Locke related.
Within 23 minutes, the right kidney started making urine, which is also an excellent sign, she added.
No rejection was observed, and both kidneys maintained good color and turgor throughout the remainder of the operation.
However, "Neither kidney excreted significant creatinine into the urine," the authors note in their paper. But Locke said this wasn't especially surprising, because even "when you use kidneys from deceased donors, we often see delayed graft function, and it may take upwards of a week for the kidneys to even make urine, much less clear creatinine," she noted in a statement:
The researchers note that kidney disease kills more people each year than breast or prostate cancer. Although transplantation is the gold-standard treatment for end-stage kidney disease, fewer than 25,000 kidney transplants are performed each year in the United States, and 240 Americans on dialysis die every day.
Many of these deaths could be prevented if an unlimited supply of kidneys were available for transplant. The wait for a deceased donor kidney can be as long as 5 years, and in many states, it is closer to 10 years. Almost 5000 people per year die waiting on a kidney transplant.
Thus, "this game-changing moment in the history of medicine represents a paradigm shift and a major milestone in the field of xenotransplantation which is arguably the best solution to the organ shortage crisis," Locke says.
"We have obtained the safety and feasibility data necessary to begin a clinical trial in living humans with end-stage kidney failure," she concluded.
The study was funded by the United Therapeutics Corporation. Locke has received research grant from Hansa and received support from Sanofi to develop educational programs for dialysis and transplantation centers.Am J Transplant. Published online January 20, 2022. Abstract