Another success in pig organ transplantation! The world's first pig kidney was successfully transplanted into a human

Written by: Zhu Hengheng

Editor: Wang Xinkai

Layout: Li Xuewei

On October 20, 2021, New York University in the United States released a news that shocked the world. The world's first pig kidney transplant was completed at the Langone Medical Center of New York University School of Medicine.

It is reported that this is the first xenotransplantation study conducted in humans in nearly 30 years since the clinical use of xenotransplantation was urgently stopped in 1992. In that year, the University of Pittsburgh in the United States conducted two baboon liver transplants, and the patients lived for 70 days and 26 days respectively. In addition, a Los Angeles woman tried a pig liver transplant, but died 34 hours after the operation.

Although Professor Montgomery's team at the Department of Transplant Surgery at NYU Langone Medical Center announced that the operation was a success, with no rejection of the transplanted pig kidney and its normal functioning for 54 hours, the research data related to this significant operation has not been published in a peer-reviewed journal, and people have limited knowledge of it.

Recently, a research team led by Dr. Jayme Locke, professor of transplant surgery at the Heersink School of Medicine at the University of Alabama at Birmingham, also completed a pig kidney transplant, transplanting a gene-edited pig kidney into a 57-year-old brain-dead man. They also published the first peer-reviewed pig kidney transplant paper and disclosed more details of xenotransplantation.

The study, titled “First clinical-grade porcine kidney xenotransplant using a human decedent model,” was published in the American Journal of Transplantation.

Slowly progressing xenotransplantation

As we all know, for many end-stage diseases, such as kidney failure, heart failure, etc., organ transplantation is the most effective solution and can significantly prolong the patient's survival. Taking end-stage renal disease as an example, if the patient receives dialysis treatment, there is a 5%-15% risk of death each year, and the 8-year survival rate is about 35%. However, receiving a kidney transplant can effectively cure the disease, and the patient's 10-year survival rate is close to 70%.

However, in the United States alone, 800,000 people suffer from renal failure and more than 90,000 people are in urgent need of kidney transplants. However, only 25,000 patients receive suitable kidneys and complete the surgery each year, and most of the remaining patients eventually die due to worsening of their disease.

Since many animals and human organs have certain similarities and animal organs are very easy to obtain, many experts have long tried to solve the problem of organ shortage through xenotransplantation, but this process has not been smooth.

In 1963-1964, surgeons at Tulane University tried to transplant chimpanzee kidneys into 13 patients with end-stage renal disease. Because kidney dialysis was not yet available, the patients would have died. However, despite the close relationship between chimpanzees and humans, almost all of the recipients died within weeks.

But people have not given up the dream of xenotransplantation. After all, in 1954, kidney transplantation between identical twins extended the patient's life by 8 years. This "temptation" was something many surgeons could not refuse.

(Source: Pixabay)

By 1980, people found that pigs might be a better source of xenotransplantation because pigs have a lifespan of 30 years, their organs are closer to humans in size and easier to obtain. However, a series of immune rejection problems caused by xenotransplantation have not been solved.

In the 2000s, many researchers began working to reduce the occurrence of xenotransplantation rejection through gene editing technology.

Revivcor is a biotechnology company that specializes in providing transgenic pigs. Its pigs, called UKidney, are used as donors for xenotransplantation of kidneys. A total of 10 genes in the donor pigs have been changed, of which three genes, GGTA1, β4GalNT2 and CMAH, trigger acute rejection reactions in the pigs and are therefore knocked out. Similarly, the porcine hormone growth receptor gene is also knocked out to prevent the kidneys from growing in the recipients.

Figure | Genes that need to be knocked out and inserted (Source: UAB)

In addition, six genes including CD55, CD46, TBM, EPCR, HO1 and CD47 were knocked into the donor pigs. Among them, CD55 and CD46 can inhibit complement immunity and reduce the ability of antibodies to attack foreign organisms; TBM and EPCR can regulate coagulation function and prevent the formation of microvascular thrombosis in the graft; and HO1 and CD47 are immune regulatory genes that can reduce inflammation in xenografts.

Advances in gene editing technology have brought humans one step closer to xenotransplantation.

Details of first kidney xenotransplant surgery revealed

Although the emergence of gene-edited pigs has given people hope for xenotransplantation, rigorous clinical trials are still necessary to fill the risks and knowledge gaps of xenotransplantation.

For example, can pig kidneys tolerate the working environment in an adult's body? It should be noted that the arterial blood pressure of non-primates and pigs is significantly lower than that of adults, so transplantation into humans is equivalent to long-term work in a state of hypertension. Similarly, hemodynamic stability data during reperfusion after xenotransplantation of kidneys is also very important, which can reflect whether the clearance of inflammatory mediators in the xenograft will cause cardiovascular failure. In addition, whether there will be life-threatening complications during the operation also needs to be carefully explored.

To do this, the researchers first removed kidneys from clean donor pigs that were raised under sterile conditions, and then processed them for implantation in the same way that human kidney donors are stored, transported, and processed.

Subsequently, before surgery, the researchers performed a cross-matching compatibility test between the brain-dead recipient and the donor animal to determine if the transgenic pig kidney and the intended recipient were a good match. Although cross-matching between humans for kidney transplantation is well established, the pig-to-human tissue matching test was developed independently by the research team and validated in this trial.

Finally, the researchers placed the donor pig kidney in the anatomical position of a human recipient kidney, connected it to the renal artery, renal vein and other appendages, and gave the brain-dead patient standard immunosuppressive therapy.

After the transplant, the kidneys regained their bright pink color and began producing urine 23 minutes later. The experiment lasted for a total of 3 days, and the kidneys remained alive until the experiment ended 77 hours later.

However, during the experiment, the researchers found that only one kidney produced urine normally, while the other kidney did not produce urine. At the same time, the kidney that produced urine did not perform normal kidney functions to help clear creatinine from the blood. At present, the researchers are not clear about why there is a difference in urine volume between the two kidneys, nor why the kidney that produces urine normally cannot clear creatinine.

In addition, during the process of kidney biopsy monitoring, pathologists discovered that there were many unexplained tiny blood clots in the transplanted kidneys, and the research team is also investigating this.

The publication of these research details means that xenotransplantation is not ready for clinical application as the public expects. In fact, it is still full of unknowns. In the future, more clinical research is needed to solve a series of problems caused by xenotransplantation, so as to truly benefit mankind.

According to Dr. Jayme Locke, “There are still many limitations to using brain-dead models for clinical trials, such as the inability to measure basic kidney function. The next step is to conduct a Phase I clinical trial to transplant pig kidneys into living humans and examine the feasibility of xenotransplantation in an environment that is more conducive to kidney recovery.”

References:
https://onlinelibrary.wiley.com/doi/10.1111/ajt.16930
https://www.uab.edu/news/campus/item/12566-uab-announces-first-clinical-grade-transplant-of-gene-edited-pig-kidneys-into-brain-dead-human

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