Kidney transplant from pig to human, here are drugs to avoid rejection

A mix of drugs commonly used by transplant doctors and already approved by the FDA can prevent pig kidneys implanted in a human being from being rejected. This was discovered by a team of pioneering xenotransplant researchers who add this new step forward to a path started several years ago by scientists at the University of Alabama in Birmingham (Uab). This is the third discovery made by the same research group that at the beginning of 2022 announced in the 'American Journal of Transplantation' that it had successfully transplanted genetically modified pig kidneys into a brain-dead man.

That report recognized the so-called Parsons model, developed by Uab with the non-profit organization Legacy of Hope, as valid for evaluating the safety and feasibility of such transplants. A model named after Jim Parsons, organ donor, first man to join the Uab's first xenotransplant study in the world. Parsons was declared brain dead after a dirt bike accident in late September 2021, and although his organs were not suitable for donation he was able to leave a useful legacy for the thousands of people on the waiting list for a donation. In fact, on September 30, 2021, his family accepted that Parsons would become the first person to have 2 genetically modified pig kidneys transplanted into his abdomen after the removal of his native kidneys.

These kidneys, obtained from a pig in a clinical-grade pathogen-free facility and transported to UAB, were engineered with 10 key genetic modifications that made them suitable for therapeutic use in humans. And when transplanted they filtered blood and produced urine, without being immediately rejected. They remained viable until the end of the study, 77 hours after transplantation. The trial demonstrated that such a transplant can work, while providing crucial data. The new step forward described by the authors in the Journal of Clinical Investigation has now been the definition of the right mix of immunosuppressive drugs which, with the addition of a complement inhibitor – the scientists explain – represent the optimal immunosuppressive regimen for pig kidney xenografts to man.

It is, highlights the study's lead author, Jayme Locke, professor of surgery at the Marnix E. Heersink School of Medicine at UAB, “a treatment regimen that transplant doctors work with every day. It is an already approved regimen by the FDA and which we routinely use for human-to-human allotransplantation.” The findings bring the promise of xenotransplantation as a therapy to potentially cure end-stage renal disease – just as human-to-human allotransplantation can do – and address the global kidney organ shortage crisis a little closer to home. In the USA alone, to give an idea, more than 800 thousand people live with kidney failure and 90 thousand are waiting for a kidney transplant.

The authors of the study examined a series of 3 cases of xenotransplantations performed by Locke's team on 3 deceased people. In the first model they used standard immunosuppression and although biopsies of the pigs' kidneys were histologically normal on the first day after transplantation, they began to show some signs of rejection the following day. With the second and third models, the researchers then used standard immunosuppression with the addition of a complement inhibitor, which is already a common regimen for patients with a rare kidney disease known as atypical hemolytic uremic syndrome, or Ahus.

This addition prevented the immune system from forming a phenomenon known as the 'membrane attack complex', which works like a microscopic battering ram that breaks through a cell's defenses, ultimately causing the organ to collapse. Result: When the complement inhibitor was used, the transplanted pig kidneys were not rejected and were able to provide life-sustaining functions. “It's like creating a force shield around the kidney,” Locke says. “This finding is great news. We know that the patient can tolerate the immunosuppressive regimen used. This is another key element that I hope will soon lead to FDA approval for a Phase I clinical trial in living humans.”