麻豆传媒

Two gene-edited pig kidneys were successfully transplanted into a brain-dead human, researchers announced.

The unique surgery, which the transplant team suggested could serve as a "radical solution" to the ever-growing organ shortage, was performed in preparation for an upcoming phase I pig renal xenotransplantation clinical trial.

Transplant of the right and left pig kidneys with 10 genetic modifications into a human decedent using conventional heterotopic allotransplantation techniques was reported by a group from the University of Alabama at Birmingham in the .

"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," said lead surgeon Jayme Locke, MD, director of the university's Comprehensive Transplant Institute, in a statement. "We have bridged critical knowledge gaps and obtained the safety and feasibility data necessary to begin a clinical trial in living humans with end-stage kidney failure disease."

The procedure was performed days after a separate team transplanted a single kidney from a genetically engineered pig into a brain dead patient. This groundbreaking 2-hour procedure at NYU Langone's Transplant Institute in New York City on Sept. 25, 2021, was likewise deemed a success and 2 months later in another decedent.

This novel idea to solve the organ shortage doesn't just stop at kidneys either. Another team at the University of Maryland Medical Center recently transplanted a into a living patient during a 9-hour surgery.

The results are a "remarkable achievement for humanity and advance xenotransplant into the clinical realm," Selwyn Vickers, MD, dean of the UAB Heersink School of Medicine, added in a statement on Locke's paper. "With this study, our research teams have also demonstrated that the decedent model has significant potential to propel the xenotransplantation field forward."

During the 4-hour transplant procedure, the team induced immunosuppression and successfully placed both kidneys after crossmatch testing. After a visual assessment of xenograft perfusion and hyperacute rejection, the team performed post-implantation xenograft biopsies.

During a nail-biting 74-hour post-transplant period where the decedent was maintained in the operating room, Locke's team continued to closely monitor the newly placed pig kidneys for function. During these few days, the decedent developed progressive multisystem organ failure that had evidence of shock liver, pancytopenia, as well as disseminated intravascular coagulation. But some good news -- hyperacute rejection wasn't observed.

"This human preclinical model is a way to evaluate the safety and feasibility of the pig-to-non-human primate model, without risk to a living human," Locke added. "Our study demonstrates that major barriers to human xenotransplantation have been surmounted, identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans, and lays the foundation for the establishment of a novel preclinical human model for further study."

Getting the go-ahead from FDA will hinge on being "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," Locke said. "The only thing different is that the kidney came from a pig."

While this preclinical study wasn't specifically designed to "optimize renal performance or immunologic outcomes," the team saw the right kidney made 700 cc of urine within the first 24 hours. In fact, the pink-looking kidney started making urine after just 23 minutes. But as for the other kidney, only scant urine production was seen.

"While the etiology of this mismatch in renal performance is unknown, the accrual of additional warm ischemic time on the left kidney during clamping in the donor may have played a role," the researchers suggested.

On the first post-operative day, a urinalysis from the right kidney showed normal specific gravity and the presence of red blood cells (>25), mild proteinuria (2+), and mild glucosuria (1+). The color was red and the urine was slightly cloudy. Although normal serum electrolytes were maintained during these few days post-op, creatinine clearance didn't recover.

While the exact reason behind this remains unclear, Locke's group said there are a few likely contenders. One of these possible reasons could be due to the "patient" being brain-dead plus hemodynamic decompensation requiring vasoactive agents. They did, however, point out that serum creatinine and blood urea nitrogen were originally in the normal range while in the donor pig.

"Trying to ascertain function in the face of brain-death is always going to be challenging," Locke said. "Ultimately, we will need to move into a phase I clinical trial in which we transplant these kidneys into a living human being where the environment is more favorable for kidney recovery."

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