Xenotransplantologists do not lose hope
The human body does not reject a pig kidney with one gene turned off for more than two days
Elena Kleshchenko, PCR.news
The New England Journal of Medicine published the results of pig kidney transplantation to people with brain death (Montgomery et al., Results of Two Cases of Pig-to-Human Kidney Xenotransplantation). Both experimental operations were performed in the fall of 2021 at the University of New York. The kidneys were taken from GalSafe pigs with the alpha-1,3-galactosyltransferase gene knocked out. No signs of rejection were observed for more than 50 hours.
Xenotransplantation of organs of genetically modified pigs from Revivicor has been carried out by three teams in the USA over the past year. In January 2022, researchers from the University of Maryland transplanted a genetically modified pig heart to a patient with heart failure. A patient named David Bennett lived for about two months after the transplant.
In October, scientists from the University of Alabama at Birmingham conducted an experiment on the transplantation of genetically modified pig kidneys to a brain-dead person. In an animal of the same lineage from which the heart was taken for transplantation, 10 genes were changed. The experiment lasted three days, then the transplanted kidneys and the human body were comprehensively examined. There were doubts whether a pig's kidney would be able to work fully in the human body, in particular, because pigs have lower average blood pressure than adults. However, the kidneys remained viable for 54 hours, producing urine (one is better, the other is worse). There were no signs of rejection, there were no serious episodes of bleeding, although a biopsy revealed thrombotic microangiopathy.
Similar experiments on pig kidney transplantation from Revivicor to two brain-dead recipients took place in September and November 2021 at the Langone Health Medical Center of New York University. However, the kidneys in these two cases were taken from a GalSafe pig — only one alpha-1,3-galactosyltransferase gene was knocked out in this line of animals. GalSafe pigs were approved by the US FDA for food consumption at the end of 2020; such pork can be eaten by people with a meat allergy caused by a tick bite, in addition, biomedical products derived from this line of animals are safer.
In both cases, the kidney vessels were sutured with the femoral artery and vein, leaving the kidney itself outside the body for easy observation. A cannula was inserted into the ureter of the transplant to measure the volume of urine. For additional protection from the immune response, the pig's thymus was transplanted under the renal capus (a shell of connective tissue) — such a system is called "thymopochka". Positive and negative selection of immature T cells takes place in the thymus, thus the immune response is modulated. Previously, it was shown that thymopochki promote immune tolerance and reduce the risk of late rejection caused by T-cell-mediated immune activation. Methylprednisolone was administered intravenously to the recipients as an immunosuppressant. Blood circulation and respiratory activity were maintained artificially. Kidney function was assessed by the volume of diuresis and glomerular filtration rate.
Xenografts began to secrete urine within a few seconds after reperfusion. The study lasted 54 hours — the limit set by the Ethics Council of New York University (this time is usually enough to pick up organs for transplantation). During the observation, glomerular filtration rates in both recipients increased, and creatinine levels decreased by more than half, which confirms the activity of xenografts. The transplanted kidneys remained pink and excreted urine throughout the study. A biopsy performed after 6, 24, 48 and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. The hourly diuresis of the xenograft was more than twice as high as the diuresis of the native kidneys.
It is known that vascular rejection during xenotransplantation of organs occurs within a few minutes after reperfusion, so 54 hours can be considered a good result. Nevertheless, the first author of the study, Robert Montgomery, admits that a late immune reaction could occur if patients were on life support for months.
Some commentators were skeptical about these results. Only one gene was modified, whereas it is known that the best results can be achieved by modifying three or more genes. In addition, it is difficult to say what was the contribution of the recipients' own kidneys that were not removed. "You can't interpret the results," says Paige Porrett, a transplant surgeon at the University of Alabama, the first author of a paper on pig kidney transplantation with ten gene modifications. (In their experiment, they removed both human kidneys.) Porret said that her group has transplanted pig kidneys to several more people with brain death and plans to publish the results soon.
Technically, the experiment can be made longer, up to several months (as is done, for example, in the case of the death of a pregnant woman, so that the fetus can complete development). But such manipulations performed for research purposes create ethical problems,
The issue of infectious safety remains unresolved. At a webinar on April 20, 2022, organized by the American Society of Transplantologists, researchers from the University of Maryland reported that the cause of David Bennett's death could be pig cytomegalovirus — it is harmless to humans, but can contribute to organ rejection. As stated in the article by researchers from Alabama, Revivicor monthly checks its animals for infections, including cytomegalovirus, but a latent infection may have gone unnoticed.
Another problem is the possibility of "jumps" of mobile elements from pig to donor, in particular, endogenous pig retrovirus (PERV). The pigs used in the New York study tested positive for PERV-A and PERV-B, but not for PERV-C, which, according to the authors, reduces the risk of transmission. Pigs with a genome cleared of retroviruses for the needs of transplantation receive George Church from Harvard University with co-authors.
The groups of Porrett and David Cooper from Massachusetts General Hospital in Boston, as reported by the journal Nature, are asking the FDA to start small clinical trials on kidney transplantation from transgenic pigs to humans. As Cooper says, the kidney is an ideal organ to start with, because, unlike the heart, it can be removed if problems arise and the patient can be transferred to dialysis.
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