Presenter identifies next steps in kidney xenotransplantation
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Several knowledge gaps remain in xenotransplantation despite the successful procedure of a porcine kidney into a brain-dead recipient, according to a presentation at the 2022 Innovations in Dialysis: Expediting Advances Symposium.
“We would argue that xenotransplantation could be viewed as sort of an artificial transplantation, and perhaps it is an impossible solution that we can make possible,” Jayme E. Locke, MD, MPH, FACS, FAST, a transplant surgeon and the director of the division of transplantation surgery at the University of Alabama at Birmingham and the director of the Comprehensive Transplant Institute at the university, said in the presentation.
Because pig kidney function is similar to that of a human, pigs are considered the ideal animal for kidney xenotransplantation. Additional reasons include the animal’s ability to reproduce large litters quickly, rapid growth and a long-life span.
As Healio has previously reported, the University of Alabama at Birmingham Comprehensive Transplant Institute received $19.5 million grant in 2016 to launch a xenotransplantation program. At the time, Locke and colleagues identified challenges of xenotransplantation as immunological incompatibility and viral transmission.
To combat viral transmission from donor pigs and recipients, a pathogen-free facility was designed and built for the program. All pigs in this study were genetically modified to be blood type O, and researchers bred the pigs in the facility.
“We realized that we needed a human model to be able to test our genetic edits,” Locke said. “But we needed a human model that wouldn't risk a living person, so this is where we began to think about the concept of human brain death as a novel preclinical human model.”
Considering patients who were declared brain dead allowed the team to test the engineering and immunosuppression without harming a living person. However, enrolling a brain-dead patient restricted research approval.
Locke’s team at UAB enrolled a patient who was brain dead for 5 days and conducted the study for 77 hours. The team performed a successful xenotransplant on Sept. 30, 2021. Within 20 minutes of reperfusion, the kidney began to produce urine.
With this study, Locke and colleagues set the model for kidney xenotransplantation. Additionally, they established the first flow crossmatch for human use in this setting.
In 2022, the University of Maryland School of Medicine and the University of Maryland Medical Center made headway in xenotransplantation after using a genetically modified pig’s heart in a transplant with a living recipient. Locke noted that the pig used in the heart xenotransplantation differed from the pig in Locke’s study because it was bred in a bio-secure facility, not a pathogen-free one. Locke suggested that is how the pig used in the heart xenotransplantation may have been exposed to porcine cytomegalovirus.
Locke said, “The knowledge gaps that we have filled by moving this into a preclinical human model are that we know that we can avoid hyperacute rejection in humans and we know that the alpha galactose knockout is, in fact, a critical gene deletion.”
Although the xenotransplant was successful, Locke said future studies need to address long-term function of the transplanted kidney in a living human, the durability of the transplant, predictive capabilities of difference crossmatch techniques, optimal immunosuppression regimen, gene edits, molecular mechanisms of graft damage in human recipients, porcine endogenous retroviruses infection in living humans and cross-sensitization in living humans.
Therefore, this model will eventually need to be moved to a living human recipient to receive further approval.
“We still don’t know if there’s creatinine clearance after pig-to-human kidney transplant. We also don’t understand the histologic changes seen in the study,” Lock said. “I think this should be done in the setting of a phase 1 clinical trial as opposed to emergency authorization uses.”
Reference:
Locke JE, et al. Am J Transplant. 2022;doi:10.1111/ajt.16930.
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Locke J. Making the impossible possible: The road to clinical trials of porcine kidney xenotransplantation. Presented at: IDEAS; Aug. 15-16, 2022; Seattle (hybrid meeting).
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