First Living Patient Received Pig Kidney Transplant

Rapid advancements

Slayman's transplant was the latest in a string of recent developments in the field of xenotransplantation. Building on decades of research studying the transplantation of genetically modified pig kidneys into nonhuman primates, scientists from eGenesis (a company that maintains it is committed to ending the global transplant shortage and transforming the treatment of organ failure), Massachusetts General, and several other US academic centers recently published results showing that genetically altered pig kidneys could last years in nonhuman primates despite some of the challenges of working in this animal model (2).

“We take for granted small things that we do to manage our patients, but in nonhuman primates, the availability of tools, technology, and treatment is much more limited,” Riella explained. “So just seeing these kidneys, working in nonhuman primates for 2 to 3 years, has given us the confidence that it was scientifically justifiable to move the needle and move to patients.”

The eGenesis team used organs from a miniature breed of pigs to avoid having organs that might outgrow their human or nonhuman primate recipients. The investigators used CRISPR [clustered regularly interspaced short palindromic repeats]-Cas9 [CRISPR-associated protein 9] gene editing to make 69 changes in the pig's genome. Three genes encoding pig proteins that can trigger an immune reaction in humans were removed to prevent rejection, Riella explained. Scientists added seven human genes to the pig's DNA to make the organs more compatible with the human immune system or to reduce the risk of clotting. The other 59 alterations inactivated porcine endogenous viruses hiding in the pig genome. Concern about pig viruses spreading to humans has been one barrier to xenotransplants in humans.

In parallel to successful studies in nonhuman primates, transplant teams across the country have developed a human preclinical model for pig kidney xenotransplants in human recipients, declared dead based on neurologic function, who were maintained on mechanical support for up to 2 months (3–6).

The genetically modified pig organs used in these decedent studies had fewer genetic modifications. Montgomery and his colleagues used a single gene edit to remove the gene encoding the alpha-gal protein that can trigger hyperacute rejection and standard immunosuppression. Locke and her colleagues (4) used pig kidneys with 10 genetic modifications—three to knock out three pig antigens that triggered hyper-rejection in nonhuman primate studies, a fourth modification removed a gene encoding a pig growth hormone to prevent the organ from outgrowing its human recipient, and the six human genes were inserted into the pig's genome to modulate the human immune response to the kidney. Locke also deployed immunosuppressive drugs routinely used for human kidney allograft recipients.

“It's thrilling to see the progress unfolding,” Montgomery said in the statement. “While each transplant center studying this takes different approaches with the number of gene edits and medications, another big step will be when the FDA authorizes clinical trials so we may better understand what will work best for patients on our waiting lists.”

Paient selection

While both decedent and nonhuman primate models have proved valuable, Riella noted that both have limitations. He explained that studies in human recipients declared dead based on neurologic function can only be conducted for a short time, limiting researchers’ ability to assess longer-term outcomes like rejection or the risk of the pig organ transmitting infections to human recipients. The only option to determine those outcomes would be studies in human patients. A team at the University of Maryland School of Medicine transplanted two pig heart allografts into living human recipients under compassionate use exemptions (7). The first patient lived for 2 months posttransplant and the second for 6 weeks (8).

About 2 years ago, Riella and his colleagues began searching for a potential human recipient who was an appropriate candidate for a pig allograft. They selected Slayman, who has type 2 diabetes and hypertension and previously had a successful human kidney allograft that lasted for 5 years, but he had to return to dialysis after the allograft failed. He was struggling on dialysis and required two procedures each month to keep his vascular access open and was running out of options for vascular access locations, Riella said. Slayman faced a long wait time ahead on the deceased donor transplant list.

“He was very uncomfortable, and it was affecting his quality of life,” Riella noted. After several discussions about the known and unknown risks of a pig kidney xenotransplant with his clinicians, Slayman opted to take the risk to become the first living human to receive a pig kidney transplant.

Riella and his colleagues used a combination of thymoglobulin, rituximab, steroids, and an experimental complement inhibitor ravulizumab for induction immunotherapy. For maintenance therapy, Slayman was started on tacrolimus, mycophenolate, and prednisone, which are commonly used after transplant of a human allograft. He also received an infusion of the experimental immunosuppressant tegoprubart, an anti-CD154 antibody costimulation blockade therapy that is currently in human clinical trials, Riella said. He noted that the drug was part of the “secret sauce” that improved survival in nonhuman primate pig kidney xenotransplantation studies.

So far, the gamble has paid off for Slayman. Riella noted that Slayman reported enjoying small things that many people may take for granted, like being pain-free and being able to shower after having his vascular access removed. “For patients like him, a transplant can be life-changing,” Riella remarked. “His energy is very good.”

Riella shared that he and his colleagues are carefully monitoring Slayman's health. He will have blood draws three times each week and clinic visits twice each week. Eventually, they hope to space out visits and follow the same monitoring regimens used for human allograft recipients.

In his statement, Slayman, who has been a patient at Massachusetts General for 11 years, said he had the utmost trust in his clinicians, felt well-informed about the potential risks, and wanted to help others. “I saw it not only as a way to help me but also as a way to provide hope for the thousands of people who need a transplant to survive,” he reflected.

If the transplant is successful and leads to a successful clinical trial, it could change the paradigm for kidney care away from dialysis toward transplant for most patients, Riella said. He noted that human kidney allografts would remain the gold standard, but individuals who do not have the luxury of waiting for a deceased donor organ would have an alternative. Some patients, he noted, may still require dialysis because they may not be good candidates for transplant.

Already, Riella and his colleagues have received an overwhelming response from patients with kidney failure. “The number of messages that we’ve received after doing the xenotransplant from patients sharing their hopes and also their struggles and how they were seeing a light at the end of the tunnel was even more impactful than we could ever imagine,” he said.