Xenotransplantation or procedures is not a new concept. The history of animal-to-human transplant experiments has been evolving for centuries. Recently, one such encouraging finding was done by a medical team in the US, New York University Langone Health, who claim to successfully transplant a pigs kidney to a brain-dead human patient. The procedure was termed breakthrough as they used a kidney that had been grown in a genetically-altered-pig. It is considered to be the first successful case where an entire organ was transplanted from a pig to a human. As per healthcare experts, due to the obvious similarities between humans and other primates, particularly baboons or gorillas and the pigs, these are considered to be the most viable donor animals as they share similar DNA. Pigs organs in size, function are anatomically comparable to humans. However, experts cite that there are still significant scientific barriers to the successful implementation of such transplantation, though advances in technology can help to achieve this daunting challenge.Is it a Eureka moment yet?
The recent transplantation of a pig kidney into a human at the New York University Langone Health centre by Doctor Robert Montgomery is a moonshot moment, inform experts.
Terming it as an extraordinary experiment in xenotransplantation, Dr H Sudarshan Ballal, Chairman Manipal Hospitals, said, The experiment is done using the most modern technology in editing and genetically modifying the pig so that its organ does not elicit a strong immediate immune response in the host. This experiment could be a potential game changer in our future endeavor to overcome the extreme shortage of organs leading to the death of many people in the transplantation waiting list.
Highlighting the complications in such transplantation, Dr Sunil Shroff, noted Urologist, Managing Trustee, Mohan Foundation and president elect of the Indian Society Of Organ Transplantation informed that xenotransplantation has challenges.
One is there is a natural rejection when you put an animal organ to a human. As the animal tissue is different, so till now, pig heart has been used in a few instances. It is not very reactive so that procedure is done. But, other than that we have not used pigs for anything.
Affirming that this transplant is more unique, Dr Ballal stated that features of this transplant could pave the way for future successful xenotransplants.
First, the problem of hyper acute rejection which is seen with all xenotransplantations was avoided by genetically modifying the carbohydrate moiety of the pig gene so that the pig kidney would not mount a hyper acute response in the host. This turned out to be effective and successful since the kidney worked normally for a few days in the recipient with no evidence of hyperacute rejection clinically or on biopsies of the transplanted kidney. Secondly, the transplant was performed on a brain-dead recipient before switching off the support system so that even if there was an adverse effect on the recipient it would cause no harm since the person was brain dead anyway, he added.
Citing this as a first step or gradual evolution, Dr Shroff said, The experiment has been very innovative and the brain-dead patient is said to be observed for almost 52 hours and he did not seem to have any rejection or any problem. A genetically-modified pig was used to match the protein differences between pigs and humans. But there is a sugar called GAL in pigs which is not present in humans. So the reaction against that is very strong which can lead to hyperacute rejectiona violent immune response that can destroy a transplanted organ in minutes. They have addressed that issue to some extent with this experiment.
However, experts worry about the risks of zoonotic diseases, which will be transmitted into the human population. As both baboons and pig carry known myriad transmittable agents and perhaps many more, which cannot be detected. The bacteria, viruses and fungi may be fairly harmless in their natural host, a baboon or pig, yet extremely toxic--even deadly--in humans. COVID 19 which has changed our world came from an animal reservoir!
Is Zoonotic Disease a Speed Breaker?
Despite the more obvious similarities and pigs being the most viable donor animal for xenotransplantation, they share similar DNA and organs are similar in size and function. The zoonoses or transmission of infections from the host animal to the transplanted human being is a huge risk and challenge.
Explaining the risk, Dr Sunil Prakash, Senior Director, HOD, Nephrology and Renal Transplantation, Max Hospital, said, The two types of animal viruses that are especially troublesome are herpes viruses and retroviruses. Both types have already been proven to be rather harmless in monkeys, but fatal to humans. HIV also came from animal reservoirs. Some retroviruses may be latent and lead to disease years after infection. The animal tissues may wear out very soon in humans as the average life of pigs is much less than humans and their organs therefore have a shorter life span. The genes of these animals have to be modified and the human genetic code has to be inserted in their chromosomes successfully. These animals need selective breeding in sterile-controlled environments. The latest xenotransplant by Dr Montogomery has turned the medical world by storm as genetically-modified pig kidney is used in a brain-dead person. The kind of tolerance to a foreign tissue achieved is remarkable. This is leading to the holy grail of transplantation which is achieving graft tolerance without giving immunosuppressive medicines.
Nephrologists also inform that options for kidney ailments are plentiful as the technology like artificial kidney, haemodialysis, stem cell regenerating are looked upon. Still, xenotransplants can be a good alternative as it is costeffective, if it becomes practically viable.
Xenotransplants of pig kidneys to humans can be universally available because the other options will come at a high cost. What the scientific community will have to look at is, how long the pig's kidney lasts in the human being. The longevity of the graft, as the pig's kidney is smaller than the human kidney, that's one, second thing will be the cost of the procedure because we may need to give more kinds of medication to curb the rejection. So, these challenges will be there but the overall cost may likely be less compared to other technologies, Dr Shroff added.
Pig-to-Human Kidney Transplant What Awaits ESRD patients?
As we debate on the new kidney transplant solutions, over two lakh patients in India await organ donation with a mere 15,000 donors available. As per Union Health Ministry estimation, the annual requirement for kidneys could range between two-to-three lakhs with a mere 6,000 transplants occurring in reality. While other statistics indicate that approximately 7500 kidney transplants are performed at 250 kidney transplant centers in India. Of these, 90 percent come from living donors and 10 percent from deceased donors. The data are not as accurate due to the absence of a national transplant registry.
Experts inform that xenotransplantation could be very good news for patients with end-stage renal diseases (ESRD) as there would be no more anxious months of waiting for an organ donor. Disease-free pigs would provide most of the organs. Raised in sterile environments, they would be genetically-altered with human DNA so that the chance of rejection is greatly reduced.
I do believe the NYU experiment would certainly help us in the long-term treatment of end-stage organ failure of different kinds but not of any major benefit for acute critically -ill patients as other modalities of replacement therapy (extra corporeal therapies) are currently available to tide over the acute crisis. The major advances in modern technology in xenotransplantation would be the ability to genetically modify animals so that they do not elicit a very severe immune response in the host human being. Modern science has also brought in a host of different kinds of very powerful immunosuppressive agents which would either prevent or ameliorate different kinds of rejection in the field of transplantation. Advances in the field of organ support by extracorporeal therapy like CRRT for kidney, liver dialysis (MARS therapy) for liver , LVAD for heart and ECMO for lung and heart support can act as a bridge for people with severe organ failure till such time that they get a transplant, Dr Ballal added.
Citing that almost 10 to 12, 000 kidney transplants are done almost every year, Dr Shroff said, Last year was bad due to the pandemic. We did maybe only 5,000 transplants but we need more than 100,000 every year. Every 1 in 10 people in the world has a risk of kidney disease and many transcend to kidney failure due to lack of awareness and early diagnosis. So, we need to take a two-point strategy- one is early diagnosis and prevention and second is to make more organs available. So, in India, we dont even meet one in 10th of the demand or even less. So, thats the tragedy. Many of them die because they do not even get to the hospital, many are not affordable, kidney transplant happens only in corporate hospitals mostly. Only 10-20 percent happens in government hospitals. So, those who cant afford, dont even have a chance of getting a transplant.
Although clinical application of xenotransplantation in the kidney is probably still several years away, newer techniques like Next-Generation Sequencing and sequence- based typing is enabling the researchers to better understand the mysteries of xenotransplants to allow better acceptance of pigs genome in humans. Humanising non-human organs working in tandem with tolerance-inducing protocols, seem to be not far from the future.
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