Down the Rabbit Hole of Xenotransplantation (Part One)

“Every adventure requires a first step.”- The Cheshire Cat

In recent years, exciting work has been making mainstream media headlines regarding animal-to-human (xeno) transplants. If you’d like to see some of the stories, I suggest reading:

• In a first, surgeons attached a pig kidney to a human, and it worked (October 2021)

• In medical first, kidneys from gene-edited pig implanted into brain-dead patient (October 2022)

• World's first genetically-edited pig kidney transplant into living recipient performed at Massachusetts General Hospital (March 2024)

• First-ever combined heart pump & gene-edited pig kidney transplant gives new hope to patient with terminal illness (April 2024)

• Woman is back on dialysis after doctors remove transplanted pig kidney (May 2024)

• The first man to receive a kidney transplant from a genetically modified pig has died (May 2024)

• A woman who received a pig kidney transplant plus a heart pump has died (July 2024)

• Their loved ones died after receiving pig organ transplants. The families have no regrets (August 2024)

• A transplanted pig kidney offers a grandmother hope for life without dialysis (December 2024)

We have appeared to be on the cusp of a stunning breakthrough for a while. Momentum seems to be increasing beyond the point where I usually pause a conversation to avoid accompanying hope with a side dish of false timeliness. Xenotransplantation is exciting, though, as while we have had some advancements, there haven’t been new treatment options for kidney failure in more than 50 years—and because it is becoming a bit of a household topic.

Intrigued, I wanted to learn more about what has been going on over on that side of nephrology and went down a bit of a rabbit hole reading about it over the holidays. I have enough notes for at least two more posts (oops!), and since xenotransplantation is an evolving concept, no doubt there are endless angles to consider. I remain cautiously curious and would like to know what your thoughts are. Here’s a little bit of what I’ve learned.

Combining Humans and Animals is Not New

Mixing parts across species is an ancient idea depicted in many mythological creatures. The ancient Egyptians had several, including Horus, a human body with a falcon head. The Greeks had a few as well: a Centaur’s upper half is human and lower half is horse. The Sumerians had a monster called Humbaba in the Epic of Gilgamesh and Enkidu that combines a bull, a vulture, a lion, and a snake. (Zhao, 2024). Obviously, I’ve been aware of mythology since childhood, but hadn’t thought about how the connection between human history and modern medicine can affect the way “new” ideas are framed. It’s not a new idea to have creatures with mixed parts is one takeaway…

Admittedly, I lack knowledge on the leap from mythology to human test subjects. However, it turns out that some 17^th century people were xenotransfused with sheep’s blood as an experimental treatment for psychiatric illness. The blood was believed by some to potentially induce calmer behaviors. (Sheep are placid...) This practice was, of course, deadly due to blood incompatibilities, but practitioners at the time had no way of knowing that (Zhao, 2024).

There was no effective treatment for kidney failure (aside from sweat lodges and blood-letting) for most of human history. In the very early 1900s, a few experiments of kidney xenotrans-plantation in living people were tried. There was possibly a pig kidney connected to a woman’s arm, portions of a rabbit kidney implanted into a child’s failing kidney, two cases of combination goat/pig kidneys grafted to human arms, and a monkey kidney placed into a human recipient’s groin. These attempts were desperate, heroic—and predictably unsuccessful. The idea was shelved for half a century, and the focus shifted to figuring out allotransplantation. (Toledo-Pereyra, 2003)

Progress in Treatments for ESKD

Peritoneal dialysis was first introduced in the 1920s after animal testing. Attempts to treat kidney failure with hemodialysis were mostly unsuccessful until the 1940s when Kolff developed the first artificial kidney. These options were inaccessible to most people, and could repeated only a few times before patients ran out of access sites. Also in the 1940s, several cadaver kidney allografts were attempted in living recipients. These were only briefly—if at all—successful. The first long-term successful human-to-human kidney transplant between identical twins occurred in 1954. (Toledo-Pereyra, 2003). Between 1959 and 1962, transplants between distant relatives were attempted with some success, using total body irradiation to suppress the immune system.

Sourcing human organs for transplant has historically been difficult, and the search for animal donors reemerged less than a decade later using knowledge gained from the successful human transplants. Dr. Keith Reemtsma transplanted 13 chimpanzee kidneys into humans between 1963 and 1964. All but one patient (and likely all of the chimpanzees) died within 10 weeks, as immunosuppressive therapy was in its infancy. The one outlier lived with her chimpanzee kidney for nine months, and even returned to work before suddenly and unexpectedly dying (Toledo-Pereyra, 2003). That is mindblowing, isn’t it?!

Chronic hemodialysis became possible in 1960 with the development of the Scribner shunt as the first reusable vascular access, but there were not enough machines and dialyzers to go around. Patients at the Seattle Artificial Kidney Center were individually selected for treatment by a “Life and Death Committee” of citizens and clergy starting in 1961. The United States began to pay for dialysis for Americans with the Medicare ESRD Program, which passed in 1972.

Kidney Transplant Breakthroughs

In 1963, the combination of prednisone with azathioprine made non-related allotransplantation more possible. Transplant programs opened nationwide. Cyclosporine, introduced in 1978, paved the way for deceased organ donations to rise continuing into the late 1980s, when shortages of cadaveric kidneys began to shift practice focus back towards living donors (Vella, 2024).

Numerous kidney transplants have been performed from pigs to non-human-primates (mostly baboons and rhesus monkeys) since the 1980s (Zhao 2024). The current estimated survival for non-human-primates is >1 year post pig kidney transplant. Graft survival has been up to 435 days, with fewer genetic modifications than what have been used in humans (Montgomery, 2022). Some studies hope to create a “bridge” transplant to sustain life until a human organ becomes available. Others hope to correct the allograft supply and demand issue by getting xenotransplants to last a lifetime.

Pig-to-human organ transplant interest is accelerating again due to the success in other primates. Pigs were chosen as the more appropriate animal for us to explore for sourcing xenotransplantation in part because more than 125 million pigs are already slaughtered for food in the USA annually, pigs have other medical uses (e.g., heparin, insulin, epinephrine, heart valves), and they produce large litters that quickly grow to full-size. Also, organs for human-use would need to be human-sized, and most primates are smaller than we are. Large primate species are endangered, reproduce in small numbers, take many years to grow to adult size, and are highly intelligent and sentient*—too much like us to consider sacrificing for organs (Zhao 2024).

*I would like to take this opportunity to argue that pigs are intelligent, emotional, and cognitively complex.

In 2021, two gene-edited pig-to-human kidney transplants were performed in brain-dead recipients, the first of their kind. The xenografts were connected to the femoral vasculature but were externally placed on the decedent’s thigh. In both cases, the kidneys re-perfused and functioned immediately. The eGFRs of both recipients which had been steady increased from 23 to 62 in one, and from 55 to 109 in the other after the xenotransplant. Hourly urine output more than doubled in both recipients, too (Montgomery 2022).

In 2023, a brain-dead man who had an AKI and was on dialysis prior to death was nephrectomized, transplanted with gene-edited pig kidneys, and maintained on life support. With no further dialysis, the xenograft increased creatinine clearance and decreased serum creatinine into normal range within 24 hours and maintained function for the duration of the study (Locke 2023).

Three living people have now received gene-edited pig kidney transplants. The attempts were made on patients who were out of dialysis access sites and had limited or no allotransplant options. The first recipient of a pig kidney survived for two months and his death is attributed to heart disease. The second recipient received an artificial heart pump at the time. The kidney failed due to low blood pressure and was removed after 47 days. The patient returned to dialysis and died a month later, after entering hospice. The most recent patient, transplanted in November, 2024 is reportedly doing well. One surgeon at the forefront of this movement, Dr. Robert Montgomery, is a heart transplant recipient himself.

There are no NIH clinical trials (as of January 2025) involving pig kidney xenotransplantation. The transplants that were performed were made possible through the FDA Expanded Access (compassionate use) pathway.

What Successful Xenotransplantation Could Mean

More than 100,000 Americans are actively awaiting a kidney transplant and this number increases each year. In 2024, around 27,000 people were transplanted (NYU Langone, 2024). Tens of thousands more (roughly 40% of patients on dialysis who are listed for transplant) die within 5 years while waiting (Locke 2023). Only about one third of patients now waiting for a kidney will receive one in time (Montgomery 2022). Kidney transplantation is and always has been a numbers problem.

NOTE: Pigs used for xenotransplantation must be genetically modified, as the human immunological response to a pig organ is stronger than it is to a human organ. Implantation of the donor pig’s thymus under its renal capsule months prior to kidney retrieval is done to promote human immunological tolerance of the xenograft. This practice has previously been done in allografts and even has a catchy name: the thymokidney (Montgomery 2022).

Until last month, it seemed that the patients selected for xenotransplantation were either (brain) dead or had such a short life expectancy that the experiment would likely not result in a loss of lifespan even if it did not work. Is that changing now? I wonder what the broader feelings are about xenotransplantation in industry and in society as a whole and am curious to see if the forward momentum will continue in 2025.