Three recent cases of pig-to-human kidney xenotransplantation demonstrate feasibility with no hyperacute rejection.
In the New England Journal of Medicine, a team from the New York University (NYU) Langone Transplant Institute published results from 2 cases of transplanted kidneys from genetically modified pigs into brain-dead human recipients.
The xenografts produced urine immediately after reperfusion, Robert A. Montgomery, MD, DPhil, and colleagues reported. Over 54 hours, estimated glomerular filtration rate (in mL/min/1.73 m2) increased from 23 to 62 in recipient 1 and from 55 to 109 in recipient 2. Serum creatinine level decreased from 1.97 to 0.82 mg/dL in recipient 1 and from 1.10 to 0.57 mg/dL in recipient 2.
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The transplanted kidneys were well-perfused. The investigators found no signs of hyperacute or antibody-mediated rejection in samples from biopsies performed at 6, 24, 48, and 54 hours. They did, however, observe early, focal C4d deposition.
The new report follows publication earlier this year of a paper in the American Journal of Transplantation in which a team from the University of Alabama at Birmingham (UAB) described their experience with transplanting 2 kidneys from a genetically modified pig into a brain-dead recipient. The kidneys remained viable until they were removed at 74 hours. One kidney produced relatively little urine, Jayme E. Locke, MD, MPH, and colleagues reported. Serum creatinine did not decrease and neither kidney excreted significant creatinine into the urine, according to the team.
The UAB investigators observed no hyperacute rejection, but biopsies revealed thrombotic microangiopathy without cellular rejection or deposition of antibody or complement proteins. Vascular integrity of the graft was maintained, despite the higher mean arterial pressure of humans compared with pigs.
In all cases, recipients were treated with immunosuppression.
Pigs Genetically Modified to Lower Rejection Risk
In the NYU cases, pigs were bred with deletion of the alpha-1,3-galactosyltransferase gene (GGTA1) and with subcapsular autologous thymic tissue.
In the UAB case, the pig was genetically modified with deletion of 3 pig carbohydrate antigens (GGTA1, β4GALNT2, CMAH) and the pig growth hormone receptor gene. Human genes were inserted, including 2 human complement inhibitor genes, 2 human anticoagulant genes, and 2 immunomodulatory genes. The 10-gene edited pig did not express red blood cell antigens and was considered a universal blood donor.
Risk for Porcine Infections
All genetically modified pigs were bred and housed specifically for transplantation and monitored to be free of infectious agents, such as porcine cytomegalovirus and porcine endogenous retrovirus C. Using a risk mitigation strategy, no chimerism or transmission of porcine retroviruses was detected in the 3 cases.
In an accompanying editorial, Richard N. Pierson III, MD, of Massachusetts General Heart Center in Boston, reviewed the progress made in the field. “Given the field’s enormous potential benefits to human health and current estimates of the likely risks to recipients and society at large, initial clinical kidney and heart xenotransplantation trials could begin within a few years.”
Disclosure: The NYU study was supported by Lung Biotechnology, a wholly owned subsidiary of United Therapeutics. The UAB study was supported by United Therapeutics. Please see the original references for a full list of disclosures.
References
Montgomery RA, Stern JM, Lonze BE, et al. Results of two cases of pig-to-human kidney xenotransplantation. N Engl J Med. Published online May 18, 2022. 386:1889-98. doi:10.1056/NEJMoa2120238
Porrett PM, Orandi BJ, Kumar V, et al. First clinical-grade porcine kidney xenotransplant using a human decedent model. Am J Transplant. 22(4):1037-1053. doi:10.1111/ajt.16930
Pierson III RN. Progress toward pig-to-human xenotransplantation. N Engl J Med. Published online May 18, 2022. 386:1871-1873. doi:10.1056/NEJMp2118019
