Podcast - Can Xenotransplantation Solve the Kidney Transplant Shortage?

This episode of Kidney Health Connections highlights the potential of xenotransplantation to one day address the kidney shortage. Dr. Jay Fishman, a leader in transplant infectious disease at Massachusetts General Hospital and Harvard Medical School, discusses the scientific advances making pig-to-human kidney xenotransplants possible. He also explores the future of xenotransplantation and its potential to complement traditional organ donation, particularly for urgent or complex cases.

The conversation also covers other forms of innovation paving the way for safer and more effective transplant options, such as new technologies to preserve donated kidneys. These innovations could transform care delivery, offering scalable solutions to meet the growing demand for transplants.

Transcript

Introduction: Exploring xenotransplantation as a solution to the kidney shortage

Dr. George Hart: Welcome everyone to today's episode of Kidney Health Connections.

Despite recent advances which extend the hope to slow CKD progression, many Americans currently living with kidney disease will one day reach the point that their kidney function has declined to the point of organ failure.

Patients choosing the kidney transplant option frequently find access to a transplant limited, either because they don't have a living donor or because donor lists are too long—years too long. The traditional donor pools just can't keep up with the need. But fortunately, innovative transplant pioneers are making progress on a third transplant option, xenotransplantation, or transplant of an organ from another species into a human.

Here with us today we have Dr. Jay Fishman, director of the Transplant Infectious Diseases and Compromised Host Program at Mass General, also the associate director of the Mass General Transplant Center, and professor of medicine at Harvard Medical School. Dr. Fishman is a leading researcher on infectious diseases related to transplantation, and specifically xenotransplantation.

Dr. Fishman, welcome to the program today and thanks for joining us.

Dr. Jay Fishman: Thanks for having me.

Meet Dr. Jay Fishman: A pioneer in transplant infectious disease

Dr. George Hart: So you and I share something in common, which is kind of a clinical career devoted to transplant medicine. I was a practicing nephrologist for all of that time and now the chief medical officer here at interwell. While obviously you've still been focused on research and being a scientist in working with infectious diseases and ways to make transplants safer for patients. I'd love to hear a little bit more about your specific areas of research and how your career has unfolded.

Dr. Jay Fishman: Well, thank you. I've been at Mass General since medical school, and one of the exciting areas that, was still fairly new at that time, was the whole concept of infectious disease, let alone in transplantation. But the care of immunocompromised hosts who have many more infections, or are susceptible to many more infections, than normal individuals was exciting to me.

And so early on in my career, I started being interested in transplant infectious disease and started the first fellowship in the world, actually, in that field, and described a timeline—which becomes relevant in a second—but a timeline for likely infections after organ transplantation.

I also was trained in molecular biology and genetics, both at Mass General and at Harvard Medical School, and started studying both organisms and viruses affecting immuno-compromised hosts. And I became interested in xenotransplantation because the idea of putting pig organs into people, while attractive, seemed to me threatening in terms of the microbiologic issues.

And so I just tried to unravel some of that and I've been doing that for about 30 years. But it is this interface between basic research and clinical care that I find most interesting, and provides the most opportunities both for teaching and for advancing clinical care.

Why we need better options for patients with end-stage kidney disease

Dr. George Hart: So getting right into things, you know, in the United States—and I mentioned it in my intro—there are almost 90,000 people now waiting for a kidney transplant. Staggering numbers, and we don't seem to be making a huge dent in that gap, despite a lot of efforts on the living donor and the cadaveric donor side. How critical is it to improve options for patients with ESKD as it relates to getting access to a transplant?

Dr. Jay Fishman: We've got to get more people into and through transplantation because it was shown a very long time ago that transplantation, kidney transplantation, was a much better option in terms of survival and quality of life than is hemodialysis, or peritoneal dialysis for that matter. And it only takes a short period of time before the curves cross and shows you that, in fact, transplant outcomes are much better than dialysis outcomes.

And that's not even to talk about the accelerated progression of disease because of other comorbid conditions like diabetes and hypertension, diet, and poor nutrition. Those kinds of things all play a role in our patient populations.

Milestones in transplant medicine

Dr. George Hart: Yeah, absolutely. You know, you and I have seen a lot of change in transplant medicine over the past 30-some-odd years. I've spent a career trying to advocate for improved access. I, like you, had many conversations with patients about the risk of immunosuppression. And the truth is, things have come a long way since you and I first started.

Maybe you can walk this audience through what are some of the milestones and the things that have gotten better that really put us in a position now that we can even consider doing a transplant from one species into another.

Dr. Jay Fishman: Well, first of all, transplantation was still in its infancy. The first transplants were done in the 1950s. And so it's not a very old specialty. And so there was an educational piece that was missing. And so we weren't getting good referrals for transplant, and many nephrologists were leaving their patients on dialysis in preference to referring them for transplant.

But when I was young, we really didn't have very good immunosuppressive medicines to prevent graft rejection, kidney graft rejection, after transplantation. So immunologically we weren't very sophisticated. And as we have gotten more drugs that are useful in terms of immune suppression—and learn to manage some of those side effects, of course—but as we've had more drugs, the outcomes have been better.

Techniques have also improved, and also in terms of preserving kidneys. So we've done a variety of things that have moved the needle in terms of outcomes from transplant. The biggest, of course, I think, being the immunosuppressive regimen, and the options we now have in terms of drugs when people either have rejection or can't tolerate one or another drug. So that's been a big advance.

I think education of the public in general, the acceptance of transplantation as a therapeutic option has also been very important. And so that has put us in the precipice of where everybody now says, “Gee, I'd love to get a kidney because my kidneys are failing.” And we just don't have enough. We should have enough, but we don't have enough. And donation isn't perfect, and it varies a lot between organ procurement organizations and regions and the like. But in general, we just don't have enough good kidneys to put into our patients.

A groundbreaking moment: The first pig-to-human kidney transplant

Dr. George Hart: So your institution, Mass General, is one of the—is really, I guess, the first center that's really transplanted a modified and genetically engineered pig kidney into a living human recipient. It was done in 2024, I believe. And since then, several other individuals have been transplanted as well. What are we learning? And maybe, is this going to be a viable solution for this shortage that we are identifying?

Dr. Jay Fishman: Complicated question. So we were in this interesting situation where I had in my lab identified some of the potential viruses that would affect people who got transplanted from with pig organs, regardless of whether it was a kidney, or a liver, or a lung, or a heart. But we knew that the pigs carried certain organisms. We knew that there were immunologic barriers; there were sugars on the surface of pig blood vessels that provoked a very rapid rejection. Minutes, the organ would die.

And so one of the critical pieces was the availability of large animal models—non-human primates—to study these immunologic responses. But even after we defined the viruses and these immunologic responses and some of the immune barriers, we couldn't do anything about them.

But you may recall that there was a Nobel Prize given for CRISPR Cas9 for genetic modifications. And George Church, who's at Harvard Medical School, came to one of our lab meetings and he said, “How many edits would you like to make?” And we said, “Well, you know, if you put everything together, probably around 60 or 64 or something.” He said, “What would you like to do the following week?” And we used to do these manually, and most of the time it didn't work.

George and I and his co-workers got together and showed we could do it in cells, that we could knock out various genes. And those cells became the platform for developing pigs that had reduced immunologic barriers, had lost these carbohydrates, in fact, had knocked out a variety of copies of virus that I had discovered. And those edits made it at least conceptually feasible to do these transplants. Because anatomically, the pigs were of a good size, they were easy to breed, and we could breed them safely because we had an idea from human transplantation what it was we didn't want in the pigs to transmit to the recipients.

And so with those tools, we then said, “Can we make this work?” And there had been a lot of work done, as I said, in non-human primates that said the immune suppression that we need to use needs to be more intensive and a little different than what we use in standard allo, or human-to-human, transplantation.

And with that in mind, we did the first kidney transplant from a pig that was genetically engineered with 64 modifications into a human, who was a wonderful man named Richard Slayman, who understood that there were some risks associated with this, but was willing to go forward because he had no more access for hemodialysis. And so, this was our first individual, and we are very grateful to him and to the people who followed. But it was molecular biology, pig breeding, immune suppressive changes—so pharmaceutical development, all of these things had to come together to make this at all possible.

What’s next for xenotransplantation?

Dr. George Hart: Five years, ten years? What might be a horizon for where you might predict that we have the ability to work out, for lack of a better phrase, a lot of the bugs that we need to work out?

Dr. Jay Fishman: I would say five to 10 years. And I'll give you the reasons why. There may be some additional genetic modifications that are necessary. And we have studies going forward, under NIH supported research, to look at various genetic modifications that might improve outcomes overall, in the background. We are also studying variety of types of immunosuppression that we can do it so that it'll be less toxic and the risk of infections will be also less.

So we're saying five to 10 years. And why do I say that? Well, because the Food and Drug Administration, with whom we've worked very closely, has now approved a series of clinical trials that probably will enroll 50 to 100 patients over the next four or five years to try to do clinical xenotransplantation of kidneys, and of livers as well.

I think that's important because there are a lot of things we can't learn from non-human primates. Most of the infectious disease issues can't be resolved in primates, and much of the immunosuppression is different to some extent in primates than it is in humans. So we need this clinical experience.

In general, candidates are very willing, and they're great. These are great—we’ve got to remember, these are people who need kidneys. And they just illustrate the fact that we just don't have enough organs to take care of our patients. We’ve got to remember, these are our patients. So this isn't just experimentation. This is a commitment to try to make this safer and to roll this out for the greatest number of people we can. It's very exciting, though, at the same time.

Could xenotransplantation become a standard option for patients with kidney disease?

Dr. George Hart: Can you see this getting to a point where it becomes the standard and an offering for preemptive transplants? So instead of living donor transplants from family members, or other relatives, that this becomes commonplace?

Dr. Jay Fishman: I would say as a preface that we haven't done as well as we could on kidney transplantation in general, of referrals and getting people through the process. We haven't, in particular, done well in minority communities in educating physicians about referrals and, as I say, getting people through the evaluation process so they can get an organ.

We also aren't using enough live donors—living donors—which would take care of individuals who have family members or friends that are compatible. So we have some room to move in the system as it exists now.

The availability of xenotransplantation as a replacement for allotransplantation depends on how safe we can make it. And I think we can make it safe. We certainly have made a lot of progress in terms of, for example, the breeding of these swine who are not your usual swine. They are sized to the recipient. They have been screened microbiologically for over 400 organisms. We have new technologies to screen both the organ donor pig and the recipients to make sure they don't get infected. We've built in a lot of safety signals, but we're not there yet.

But I think that there may be a time when this becomes a reasonable option. I don't necessarily see this as replacing standard kidney transplantation, but it would be great if we had options, particularly for those people, highly sensitized people, who can't get kidneys, or people who urgently need kidneys, preemptive kidneys, because their dialysis access may have failed.

But on the other hand, can we get people organs before they enter dialysis? Yeah, that may be. That may be the option of the future.

Expanding xenotransplantation beyond kidneys

Dr. George Hart: The other question that comes to mind for me is the ability—and I think you hit on this a little bit—the ability to extend this offering beyond kidney transplantation because there is, you know, a backup offering of dialysis for many patients for many years. But if you need a liver transplant or a heart transplant, you don't have quite the same options as you do in the kidney world. Do you see this extending into these other organ systems?

Dr. Jay Fishman: Yeah, we have the same shortage of organs in the other organ systems that we do in kidneys. Not as severe, because there are more people with kidney failure. And we can talk about why that is. But in fact, there have been two—they didn't survive very long—two heart transplants at the University of Maryland.

But one of the concepts, for example, if people with liver failure—due to accidental drug overdoses or due to other reasons, and we're seeing a lot of that—could this provide a temporizing maneuver until they can get a liver transplant? So an external liver transplant to provide the functions of blood cleansing that the liver provides at the same time. We're not there yet, but those are going to enter clinical trials as well.

I think we don't know yet where this is all going to end up. I think we have competing technologies that I hope will develop. And, for example, we're doing studies on islet cells for diabetics that should be able to provide artificial pancreases that are implanted, that are cellular and won't be rejected. And that would be great because if we improve the care we give for diabetes, we'll have less kidney failure, less heart disease, et cetera. And those may be available off the shelf.

We're studying new technologies to preserve organs, not just kidneys, but starting with kidneys, so that we'll be able to freeze them and ship them around the world. And when you thaw them, they seem to work quite well. So can we do that, and will that improve our attempt at achieving equity for people who perhaps don't live in areas where they have enough kidneys? And you might be able to get a kidney off the shelf, either a human one or a pig one.

So there are new technologies that are converging, but they're all doing that because we know we don't have enough organs. Now there are a lot of things we should be doing better as a medical community, and our patients can participate in this as well. But simple things. I've mentioned diabetes, hypertension, smoking, alcohol, et cetera. All the things that we talk to our patients about are really important in terms of preserving kidney function, but also lung and heart and liver function. And if as a society we dedicated ourselves to that—to better nutrition, more exercise—those kinds of things, we could at least delay and push out the curve of people needing new organs.

That's pretty optimistic. I've been a doctor for a long time. You have also. But it's hard to take pills, it's hard to get exercise, it's hard to find time to do things when you're chasing your kids around the house. But it's important, and we have to convey that message through our schools and elsewhere.

The future of healthcare: Personalized medicine and multi-omics

Dr. George Hart: Well, I think, I mean, amen. You're preaching to the choir here. And I think you and I have probably had similar conversations.

And it's a lot of what we're trying to do in value-based care is to take a more holistic approach to how we deliver care by improving access, addressing social determinant of health limitations, and kind of embracing a total body view of how to improve one's health. So I really appreciate your comments and they certainly resonate, and I think will resonate with our audience today.

You've seen a lot of things. What excites you the most right now, as you get up and you look at where things are heading in the research that's coming out of your lab and the labs there at Harvard.

Dr. Jay Fishman: So I think there are a few things. I've mentioned that there are new immunosuppressive regimens. I think those are exciting. We're also starting to better understand how the immune response works so that we may be able to intervene earlier, both in terms of transplant, but also autoimmune diseases like lupus, rheumatoid arthritis, and others.

There's a new area which we call multi-omics. It's a fancy name for doing every test under the sun that can tell us if you've got infection, if you've got an immune response, if you're at danger for dying due to an infection, how can we intervene? And it's called multi-omics because it takes sequencing technologies, it looks at the proteins circulating in your blood, it looks at a variety of parameters and gives you a snapshot. So now we don't just have to look for 400 known organisms. I can look for unknown organisms; I can sequence anything that's circulating that has a DNA- or an RNA-basis—any organism that's replicating.

Well, if we could do that for the immune system, if we can use that for growth and for health and well-being—liver function, heart function, kidney function—we then get a picture of what the future holds for an individual and we can tell the difference between individuals and how to custom design healthcare for one versus another.

Closing thoughts: The exciting future of transplant medicine

Dr. George Hart: Dr. Fishman, this has been great. It's really fascinating to hear the work you do and all that you get to be a part of. I've enjoyed it and I'm sure our listeners have as well. This is a fascinating space to watch and we look forward to seeing how it evolves.

For our audience, please join us for more conversations on the future of kidney care by subscribing to Kidney Health Connections or visiting our website at interwellhealth.com.