Short Study Hints at Viability of Genetically Modified Pig-to-Human Kidney Xenografts

In a brief, 54-hour study, researchers from New York University Langone Transplant Institute demonstrated that genetically modified kidney xenografts from pigs were viable and functioning in human recipients for a little over 2 days.

Their results are published in The New England Journal of Medicine.

Successful outcomes with xenotransplantation have been difficult to achieve, with failures primarily due to transplant rejection. Earlier this year, the surgical team at the University of Maryland Medical Center, Baltimore, performed a first-of-its-kind xenotransplant in a 57-year-old Maryland man with terminal heart disease. This was the first successful transplant of a genetically modified pig heart and was given emergency use authorization by the FDA under its expanded access provision.

Unfortunately, the patient, David Bennett, died 2 months later.

In this most recent study of the viability of xenografts, NYU Langone researchers led by Robert A. Montgomery, MD, transplanted kidneys from two genetically modified pigs into two brain-dead human recipients on ventilators in whom circulatory and respiratory functions were maintained throughout this 54-hour study. Kidneys were obtained from genetically modified alpha-1,3-galactosyl-transferase–knockout pigs. The transplant team performed biopsies and monitored urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection.

A few moments after reperfusion, both xenografts began to produce urine, and over the study period, kinetic eGFR increased in both transplant recipients from pre-transplantation levels. In the first patient, the increase was from 23 to 62 mL/min/1.73 m²; in the second, it was from 55 to 109 mL/min/1.73 m². The transplanted kidneys stayed pink and were well-perfused, and they continued to make urine throughout the study.

Hourly urine output with the xenograft was more than twice the amount achieved with the patients’ original kidneys, researchers noted.

"The mean hourly xenograft urine output in Recipient 1 was 406 ml during the first 24-hour period and 255 ml during the second 24-hour period; in Recipient 2, the mean hourly output was 744 ml and 571 ml in the first and second 24-hour periods, respectively," they wrote.

Biopsies taken at 6, 24, 48, and 54 hours showed no signs of hyperacute or antibody-mediated rejection or inflammation.

Alpha-gal epitopes exist in animal tissues and are the primary cause of xenorejection.

"The use of genetically modified pigs that lack the alpha-gal epitope is a straightforward type of genetic modification to test in clinical trials involving humans, and our results suggest that the elimination of alpha-gal alone can prevent hyperacute rejection in pig-to-human transplantation," concluded Montgomery and colleagues.

In his accompanying editorial perspective, Richard N. Pierson III, MD, of the Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, commented on the dearth of studies on xenotransplantation.

"The limited clinical experience to date may make it hard to obtain informed consent for initial xenotransplantation trials. But I believe ethical equipoise can be achieved for carefully selected patients whose particular situations make participation in a xenograft trial a reasonable alternative, despite the uncertain prospects," he wrote.

Pierson also stressed the value of these results from Montgomery et al, as well as previous studies of xenotransplantation.

"Supported by these encouraging results, multiple groups are preparing to request regulatory approval for clinical trials. The Food and Drug Administration (FDA) says it’s receptive to considering a clinical xenotransplantation trial that uses both an experimental drug regimen and a multiply modified, genetically engineered pig organ, as long as the investigators provide scientific justification for both," he wrote.

Ultimately, concluded Pierson, studies like the one from Montgomery et al help pave the way for future trials, towards the ultimate goal of unearthing the promise of organ xenotransplantation.

"…xenotransplantation carries the promise of an unlimited supply of readily available, safe, optimally functioning organs," he wrote. "The recent cases provide an opportunity to educate health care professionals and the public about xenotransplantation’s potential, as well as its public health risks and financial implications. Increased public awareness and full transparency during clinical trial planning and execution will be needed to generate support for organ xenotransplantation trials. But with iterative improvements now further informed by recent clinical experimentation, general dissemination of organ xenotransplantation has begun to seem like a feasible near-term goal."

The primary limitation of this study from Montgomery et al was its short follow-up.

"Our study of two successful renal xenotransplantations is reassuring in that, with the use of organs from alpha-1,3-galactosyltransferase–knockout pigs with a negative or low positive cytotoxic xeno-crossmatch, the risk of hyperacute rejection was low and immediate catastrophic failure was unlikely. An assessment of the durability of positive outcomes in this model, as well as adaptive immune responses, will require longer-term studies involving recently deceased humans or clinical trials involving humans," the study authors concluded.

This study was supported by Lung Biotechnology, a wholly owned subsidiary of United Therapeutics.

Montgomery reported receiving grants/contracts from United Therapeutics Corporation, and serving as a consultant on the advisory board of eGenesis, Inc.

Pierson had no disclosures.

Montgomery RA, et al "Results of two cases of pig-to-human kidney xenotransplantation" N Engl J Med 2022; DOI: 10.1056/NEJMoa2120238.

Pierson RN "Progress toward pig-to-human xenotransplantation" N Engl J Med 2022; DOI: 10.1056/NEJMp2118019.