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Pig Kidneys to Humans: Next Steps for the UAB Xenotransplantation program

On September 30, 2021, a University of Alabama at Birmingham medical team transplanted two pig kidneys into a brain-dead human recipient, a major step toward future pig-kidney transplants to people with kidney failure.

UAB physicians are already working on the next steps to begin a clinical trial of the pig kidneys in living humans. Two major approvals will be required.

The U.S. Food and Drug Administration protects public health by ensuring the safety and efficacy of drugs and biological products. UAB will need an Investigational New Drug Application, or IND, to administer the biological product — genetically modified pig kidneys — to humans.

Secondly, the UAB Institutional Review Board for Human Use, or IRB, established by federal regulations to protect human subjects in research, must review and approve the proposed clinical trial before the start of a Phase I trial to test that transplants are safe in living humans.

“We already have ongoing conversations with our IRB and have begun to develop our Phase I protocol,” said transplant surgeon Jayme Locke, M.D., director of the Comprehensive Transplant Institute in UAB’s Department of Surgery and lead surgeon for last fall’s transplant. “To have IRB approval for a Phase I trial, we are going to need FDA to accept an IND. We are in the process of gathering all of the information and putting that application together. The FDA can give approval for the biological product, in this case the pig kidney, but our institution’s IRB ultimately has the say for approval of the actual clinical trial.”

Members of the federally regulated IRB at UAB include faculty and staff with expertise in research, as well as people from the community. These can span physicians, scientists, nurses, bioethicists, lawyers and members of the clergy. The IRB’s guiding ethical principles are respect for persons, beneficence and justice.

In last September’s experiment, the pig kidneys came from a 10-gene-edited pig housed at a pathogen-free, surgically clean facility at UAB. In anticipation of a clinical trial, UAB is continuing to develop the herd to have sufficient numbers of 10-gene-edited pigs at the appropriate size for human use.

Development of the facility was a five-year collaborative effort with United Therapeutics and its subsidiary, Revivicor, who developed and provided the pigs. “There are already plans to size-up the facility as necessary,” Locke said.

UAB researchers purposefully did not announce last year’s September experiment — done under the umbrella of a UAB IRB study protocol — until this year’s Jan. 20 publication of their peer-reviewed study in the American Journal of Transplantation.

“Peer review is rigorous,” Locke said. “It ensures that critical questions have been answered and any limitations have been acknowledged. It’s the kind of rigor necessary for regulators to have comfort in issuing something like an IND, which we will need.”

“Our goal is not to have a one-off. Our ultimate goal is to get this into a Phase I clinical trial, to be able to move this towards FDA approval to make xenotransplantation broadly available to patients with kidney failure.”

Last fall’s transplant was designed and conducted to meet standards directly comparable to those that would apply to a Phase I clinical trial and mirrored — as much as possible — every step of a conventional transplant between humans. It included IRB and Institutional Animal Care and Use Committee approval, a tissue compatibility confirmation before starting the operations, using the standard procedures of human-to-human transplants to remove, preserve, transport and transplant the kidneys into a human, and giving the standard immunosuppression therapy to the recipient.

Looking further ahead

It is unknown whether the pig kidneys would just supply a bridge therapy until a later human organ is available, or would serve as a long-term destination therapy.

“We will only know the answer when we put the kidneys into a living person,” Locke said. “The brain-dead recipient model only takes it so far because ultimately the brain death catches up to the rest of the body.”

Whether bridge or a solution, Locke thinks pig kidneys will be better than being on dialysis. Forty percent of people on the human kidney transplant waiting list die within five years despite dialysis.

The wait to possibly be able to offer pig kidneys for the tens-of-thousands of people with end-stage renal failure who need kidney transplants will be longer than any first steps to transplant a pig kidney into a living human, even in the best of circumstances.

More than 800,000 Americans are living with kidney failure. Most never make it to the waiting list, and far too few human organs are available to put a dent in that number.

At UAB, Locke holds the Arnold G. Diethelm Endowed Chair in Transplantation Surgery in the Marnix E. Heersink School of Medicine.