Pig kidneys in humans? Xenotransplantation explained.
00;00;04;28 - 00;00;30;19
Intro
Welcome to Hot Topics in Kidney Health, brought to you by the National Kidney Foundation. Each episode we highlight the latest in kidney research bring you up to date news in kidney care. Dispel myths and answer your kidney health questions from the invention of the dialysis machine to the first successful kidney transplant. Science has come a long way in extending life for kidney patients is transplantation between humans and animals the next step?
00;00;31;13 - 00;00;57;00
Intro
In this episode, you will hear from the doctors behind the first successful transplant of a human receiving a pig kidney. And where the science can take us from here, we dedicate this episode to the person family who made the selfless decision to delay their grieving process and permit the doctors at the University of Alabama to maintain Jim Parsons body functioning on a ventilator so the scientific and medical breakthrough could be possible.
00;00;57;20 - 00;01;21;01
Jessica Washington
Hi, my name is Jessica Washington. And I'm an and care patient advocate, and I'm also living with stage two kidney disease. Today, I'm here with Dr. Jamie Lott, director of the Comprehensive Transplant Institute at the University of Alabama at Birmingham Department of Surgery and lead surgeon on a study targeting xenotransplantation. Hi, Dr.. Can you tell the audience more about yourself and what brings you here today?
00;01;21;13 - 00;01;48;25
Jayme Locke, MD
Yeah. Thank you so much, Jessica. My name is Dr. Jamie Lau. I'm a transplant surgeon at the University of Alabama at Birmingham, and I direct our transplant institute. And I am here because I am super passionate about helping patients who have kidney disease and specifically helping patients who have kidney failure overcome that by helping them achieve transplant. And what I know as well as most probably listening to this is that we have an organ shortage, not just in the U.S., but in the world.
00;01;48;25 - 00;02;08;01
Jayme Locke, MD
And quite frankly, it's sort of an unmitigated crisis. And it's really challenging for me as a transplant surgeon who evaluates patients five days a week for weightlifting to know that even those individuals were able to waitlist are going to really struggle to find an organ. And many of them are going to die before we ever have a kidney come available.
00;02;08;14 - 00;02;16;12
Jayme Locke, MD
And so I am here today to talk about the potential radical solution to that problem, which is the concept called xenotransplantation.
00;02;16;23 - 00;02;28;10
Jessica Washington
Great. I know I can speak as a kidney patient and say we're happy to have someone like you doing this kind of work because there definitely is a serious shortage. So xenotransplantation, can you tell us exactly what that is?
00;02;28;19 - 00;02;55;26
Jayme Locke, MD
Absolutely. So when you think about transplantation, we usually refer to it as something called ALO transplantation, and that implies that you're taking an organ from an up from one human and you're giving it to another human. Xenotransplantation is really the concept of using organs that go across species So in this case, we're taking a kidney from a pig and we're talking about transplanting that into a human being.
00;02;56;08 - 00;02;58;19
Jessica Washington
Wow. Why pig kidneys of all things.
00;02;59;03 - 00;03;21;19
Jayme Locke, MD
That's a really great question. So there are a couple of different reasons why. So the first is, as I put on my transplant surgeon hat for a moment, you know, one of the questions I have is, well, I've got to make sure that I have an animal kidney that is going to function similarly to a human kidney. So can it filter like a human kidney?
00;03;21;19 - 00;03;43;21
Jayme Locke, MD
Does it have the same kidney blood flow that a human kidney does? Can it help patients balance electoral rights and their fluid balance? Can it do some of the other functions that a kidney has to do, like make a risk for eating and do other things that kidneys are needed for? And the answer is in a pig kidney is that it actually looks and functions very similar to a human kidney.
00;03;43;22 - 00;04;05;12
Jayme Locke, MD
So if you were to look at something like the glomerular filtration rate, so many people are familiar with their GFR. It helps them determine what stage of kidney disease they're. And so when you look at the GFR between a pig kidney and a human kidney, they are very similar. So that's really encouraging that from a functional standpoint, a pig kidney could support a human being.
00;04;06;05 - 00;04;25;04
Jayme Locke, MD
The other thing is is that humans, we live a really long time. Right. So we have a pretty long average life expectancy not and all animals have similar ones. We know that a pig has a life expectancy of 30 years. So that also gives us confidence that that kidney could potentially last a human 30 years, which is great.
00;04;25;04 - 00;04;46;27
Jayme Locke, MD
I mean, if we had a human to human kidney transplant that did that, people would be ecstatic. And then the final thing, if I take off my transplant surgery hat and I think about this from an industry side and being able to generate enough of these, you also have to pick an animal that can reproduce rather quickly and have relatively large litters so that you can actually keep up with the need.
00;04;47;07 - 00;05;06;07
Jayme Locke, MD
Because what we know is there are 37 million Americans with chronic kidney disease and of those there are about 700,000 or so who already meet the definition for kidney failure. And so that's a lot of people who actually potentially need a kidney transplant to solve their end stage disease problem. And so that's a lot of pig kidneys that we need.
00;05;06;07 - 00;05;15;27
Jayme Locke, MD
So having an animal source that you can breed rapidly and be able to generate enough organs to meet that overwhelming demand is really crucial.
00;05;16;05 - 00;05;33;09
Jessica Washington
Well, that's interesting because I thought about just the fact that you're talking about how they're similar and, you know, how they they filter their urine and blood and all that kind of stuff. But I never thought about the part of having the numbers that you might need to get there as well. And I think that's a really interesting piece to add to it.
00;05;33;10 - 00;05;39;03
Jessica Washington
So were there changes that had to be made to the human body to accept the pig kidney or vice versa?
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Jayme Locke, MD
So really, all the changes that have been done are to the pig kidney itself. So the changes that were made were not to change the function of the kidney. So the kidney still functions like a kidney functions. In fact, if you were to look at the pig kidney, it looks almost exact same as a human kidney looks. The genetic changes that were made were really to sort of modify the pig tissue, if you will, to make it more acceptable in the setting of a human's immune system.
00;06;07;17 - 00;06;31;27
Jayme Locke, MD
So we all have our immune systems. They're very important to us. They are part of what helps us fight off infections and other things. So, for example, when we're exposed to a bacteria or a virus, our immune system sees that as far and those cells attack it and they curious of that virus or of that bacteria. In the context of transplantation, that can be really problematic.
00;06;31;27 - 00;06;55;04
Jayme Locke, MD
And so that is why patients are on immunosuppression in order to keep our immune system from being overly reactive. But we also know that even in human to human transplantation, you have to have enough compatible t that the immunosuppression drugs that we have are sufficient, right? So if we try to go across too much of it, incompatibility, the drugs don't work well and the organ rejects.
00;06;55;04 - 00;07;11;06
Jayme Locke, MD
So in the setting of the pig kidney, we had to alter the genetics enough so that it could be acceptable enough that would standard immunosuppression like we use in human to human kidney transplantation, that the pig kidney would be accepted and not be immediately rejected.
00;07;11;15 - 00;07;18;04
Jessica Washington
Wow. Okay. So was there a specific set of modifications that had to be done to the genetics of the pig?
00;07;18;09 - 00;07;45;17
Jayme Locke, MD
Yes, there were. That's a great question. So there were three genes that we knocked out and these genes that we knocked out, you can think of them almost as little nametags that sort of said, Hey, I'm a pig. And so we kind of knocked those out so that it doesn't look so pig like anymore. And then there were another six genes that were human transgene that were actually knocked in.
00;07;45;17 - 00;08;06;29
Jayme Locke, MD
And these were designed to help better regulate the human immune system as well as the human clotting system. And then there was a fourth gene that was knocked out, and that gene is called the pig growth hormone receptor. And the reason we knocked that out is because you probably know or had seen on TV, pigs get pretty big.
00;08;06;29 - 00;08;24;17
Jayme Locke, MD
They can be upwards of £4,000. Most people are not that big. And so one of the things we wanted to make sure of is that this pig kidney and its new host would not outgrow it. So that was the reason that we knocked out the growth hormone receptor to keep that pig kidney appropriately sized for a human being.
00;08;24;23 - 00;08;36;26
Jessica Washington
Wow. That's interesting. And did it take time to kind of figure out which genes you needed to modify or did you guys kind of were you able to kind of look at the makeup of a human in a pig and know what does it fit for us? Or was it you.
00;08;36;26 - 00;09;03;27
Jayme Locke, MD
Know, this is really the result of probably 30 years worth of work and certainly not all my work I'm standing on the shoulders of the Giants. You know, I'm not the person who's modified the pig kidney. I'm the person who's trying to figure out how to make it work in a living person. But it's really a testament to our scientists who have been at this for a very long time and sort of, I hope, also gives people a hope and a knowledge that that folks are not forgotten.
00;09;04;13 - 00;09;18;19
Jayme Locke, MD
There's teams and teams of people out there who work tirelessly every day trying to solve this problem and who have dedicated their entire lives and careers to being able to get us to this point in the context of xenotransplantation.
00;09;18;21 - 00;09;35;08
Jessica Washington
Yeah, I think I think for me, it's great to hear that it's been ongoing for that many years. To know that, you know, kidney patients aren't forgotten about. And it's just something that's taking time to figure out, but it's being worked on. So the patient that was chosen for this trial why were they best suited based on everything?
00;09;36;07 - 00;10;05;12
Jayme Locke, MD
So in our case, we did what we call a pre-clinical human model. So this involved an individual who had been declared brain dead. So they were in fact deceased. That is the typical type of donor that is used in the context of deceased donation. So Brain-Dead donors, that's where we get kidneys and livers and other things. In this particular setting, this individual was not able to have their organs placed for the purposes of transplantation.
00;10;05;12 - 00;10;20;28
Jayme Locke, MD
And that does happen sometimes with our deceased donors. So in this context, we approach this individual's family about participating in this study. And so they were enrolled in this study and they underwent xenotransplantation.
00;10;20;29 - 00;10;25;07
Jessica Washington
Wow. How confident are you that this is actually going to work when you guys showed this?
00;10;25;23 - 00;10;49;20
Jayme Locke, MD
It's a great question. So this was just a really a pivotal study for so many reasons. So let me just back up for a second and come to your question. But, you know, we've learned so much. We've we've done a lot of these transplants of pig kidneys into non-human primates. So typically baboons. And they are very close to humans, but they are not a perfect replica of a human being.
00;10;50;03 - 00;11;08;21
Jayme Locke, MD
And one of the things that had never been developed before was a cross match that was specific to a pig, to a human. So in the context of human to human transplantation, before we do the transplant, in addition to making sure that blood types match, we also have to make sure that tissue types match and we do across much.
00;11;09;08 - 00;11;37;19
Jayme Locke, MD
If that cross match is positive, we don't do that transplant unless we enroll them in a special desensitization protocol. And the reason for that is because if we were to go across that positive cross match as soon as we restored blood flow to that kidney, it would do something that we call hyper acute reject, where within 2 minutes of turning beautiful and pink like it's supposed to, it would turn completely black because it would have clotted from the inside out and it would be immediately rejected.
00;11;38;03 - 00;12;16;22
Jayme Locke, MD
And that's why in the setting of human to human transplantation, it's actually a requirement to have a cross match prior to going to the operating room and being able to demonstrate that that cross match is in fact negative even programs who have what we call incompatible programs where they go across these positive cross match, those patients undergo all sorts of therapies and they still have to have a negative cross-match before they go to transplant, meaning those therapies have to have eliminated that incompatibility for it to work Well, the problem is we didn't have a cross match for pig to human, so we had to develop that.
00;12;17;08 - 00;12;38;09
Jayme Locke, MD
But the only way to test that would be to actually do the transplant into a person and prove that in fact, that kidney was not immediately or hyper acutely rejected. So you can imagine you know, as a transplant surgeon, I was a bit uncomfortable thinking about having to do that to a living person because it's a never event for us.
00;12;38;09 - 00;13;05;29
Jayme Locke, MD
I mean, that's futile. I mean, why would you do that? So that's really where this preclinical human model of brain death came about. And that's what's so significant and important about Mr. Parsons. Contribution and his family's willingness to allow him to participate. So we developed a cross-match. We tested that with Mr. Parsons but using his blood and the pig cells, and we showed that the cross-match was negative.
00;13;05;29 - 00;13;39;29
Jayme Locke, MD
So we predicted that this kidney would not immediately reject. And then we did the transplant. And I will tell you, I think you could have heard a pin drop in the room. I think it was a remarkable moment. I will say that in that moment, I think we all felt sort of that the magnitude and the pressure of what it meant and this overwhelming desire to have it work, because you just sat there and all you could think about was all the patients.
00;13;40;15 - 00;14;06;12
Jayme Locke, MD
And we just we didn't want it to not work. And when we took the clamps off and restored blood flow and that kidney turned pink and it stayed pink. And then 20 minutes later, it made urine I don't even know how to characterize it, but it was just it was remarkable. And I think for me, as a transplant surgeon, it was the last piece of preclinical data.
00;14;06;12 - 00;14;18;11
Jayme Locke, MD
I felt like I needed to really feel like I could offer this experimental therapy in the context of a clinical trial. To a living person. So it was it was amazing.
00;14;19;00 - 00;14;36;28
Jessica Washington
Wow. Thank you for that. I mean, I got chills really just hearing you even describe what what it was like in the room as much as you could, cause I can only imagine what that was like with all the hard work you guys have done. So, okay, so this transplant was done on someone who was brain dead. What do you think is next for this?
00;14;37;27 - 00;14;55;23
Jayme Locke, MD
Well, I think there's still more we can learn with that preclinical model. I think we will continue that work but honestly, I think for us to take this to the next step, we're going to have to move this into living persons in the context of a limited phase one trial where we can look at early timepoints of safety and efficacy.
00;14;55;25 - 00;15;17;13
Jayme Locke, MD
You know, the non-human primate model, the baboon model is amazing and has taught us so much. It has helped us understand kidney function and demonstrate all of those things. But the pig was genetically edited to make it perfect for a human. And so when we try to do this in non-human primate model, it's like a model of incompatible transplantation.
00;15;17;13 - 00;15;37;26
Jayme Locke, MD
So it's just not perfect enough, I think, for us to be able to examine some of the longer term outcomes the preclinical human models. Amazing. For all the reasons I just told you, it helped us really validate this assay. That's going to be critical. But for us to get longer term safety and efficacy data, we're going to have to actually do this in living persons.
00;15;37;26 - 00;16;13;26
Jayme Locke, MD
And I think we have enough data between the non-human primates as well as the preclinical human model that I feel comfortable moving this forward. So I think our next steps are going to be to work collaboratively with regulators so that FDA actually will regulate the pig kidney as a biologic product and they will help us figure out how to do that and whether that means we need to do additional non-human primate or more studies in the preclinical human model, as well as help us develop and think through inclusion criteria for these phased clinical trials.
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Jayme Locke, MD
But that's really where I think the next frontier is, is moving this into living people.
00;16;19;11 - 00;16;25;21
Jessica Washington
That's great. And that's put you on the spot. How far off do you think we are from, from putting this into a living person?
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Jayme Locke, MD
I really genuinely believe will. I honestly believe we'll be there within the next year to two years and again. And that would be in the context of a limited phase one trial. So you have to kind of march through all those steps. And that's really important because we want to make sure we have all the key safety and efficacy questions answered.
00;16;43;26 - 00;17;25;26
Jayme Locke, MD
And so that will be the next frontier in the next journey to do that and do that in collaboration with regulators and hopefully in the next five to ten years as we march through all those steps, it will ultimately achieve full approval and be available for all the people in need. I think, encouragingly, we've had the opportunity to look at testing multiple blood samples of different human sera with these pig cells, and it looks like about two thirds of humans will have a negative cross-match with this pig, which is wonderful because, you know, if you you think we do about 20 to 25,000 kidney transplants a year if we could do another 50 to 60,000 with
00;17;25;26 - 00;17;39;15
Jayme Locke, MD
xeno transplants, we can almost eliminate the list between the two. And then we can start thinking about what about all those patients that never make it to the waiting list. Know, are we able to help them as well. And so it's exciting. It's exciting to me.
00;17;40;17 - 00;18;07;02
Jessica Washington
That's extremely exciting to hear. Wow, that has made definitely excited for the future of this. So we talk about, you know, one or two years trying to get there with a living person. But going back a little bit to the experiment being done on it during a 77 hour scan and the kidneys were viable during that time with the Plan B kind of in between that to keep increasing the time to see how long it can last before we get to trying it on a human alive.
00;18;07;18 - 00;18;36;14
Jayme Locke, MD
That's a really great question and totally spot on. Brain death is is a very complex process and there are lot of sort of derangement it so a lot of instability. So what do I mean by that? Huge swings in blood pressure. So these patients are these dissidents excuse me, are often on multiple IV blood pressure medicines to maintain their blood pressure.
00;18;37;16 - 00;18;58;11
Jayme Locke, MD
And so this is a very hostile environment in which to do a kidney transplant. We would not normally do that in a human to human transplant. You have to be healthier than that to be able to have a transplant. And so our ability to keep a Brain-Dead individual going for a prolonged period of time is not very good because brain death is death.
00;18;58;11 - 00;19;22;22
Jayme Locke, MD
So you essentially are fighting that. And that is just a battle that you cannot win. And then importantly, before we embarked on this, you can imagine, even though this individual is brain dead and their death date has already been declared, we are, for all intents and purposes, keeping their body functioning despite that and we have to take them.
00;19;22;22 - 00;19;47;25
Jayme Locke, MD
And so that really delays a family's ability to grieve, to go through that normal process of funeral arrangement. And other things. And so before we even started this pre-clinical study, we actually engaged in ethicist and had them take a look at this and we also talk to our local community and and really we settled on not keeping this going more than seven days.
00;19;47;25 - 00;20;14;24
Jayme Locke, MD
That that was probably the extent of what we were going to be able to learn from this model, balancing sort of that brain death environment, but also balancing that with the needs of a grieving family and making sure that we honor that as well. So that's been really important to us. So yes, it'd be great if we could get out for seven days, but this model is not going to give us the kind of long term data that I think we all want to be able to see.
00;20;15;03 - 00;20;19;14
Jayme Locke, MD
And it's really going to take us moving this into living persons to achieve that.
00;20;19;18 - 00;20;29;10
Jessica Washington
Right. And that makes sense. Thank you for explaining that. Well, I think that's all the questions that I have for you. Is there anything that you want to add about the study or anything going forward?
00;20;29;21 - 00;20;48;27
Jayme Locke, MD
Well, one, I do want to make sure I think the Parsons family, we have named this the Parsons model in his honor. And I think their gift is truly extraordinary. And has really helped us advance the field in a meaningful way, and I think is going to help us make a difference in hundreds of thousands of people's lives to the patients out there.
00;20;49;04 - 00;21;06;12
Jayme Locke, MD
Please know that that you are not forgotten. We are working tirelessly to help be able to find an unlimited source of work. And we know what the cure is. I once you have kidney failure, it's getting a kidney transplant. And we need to figure out how to make sure that there's one available so that no one goes without.
00;21;07;05 - 00;21;26;22
Jayme Locke, MD
So just know that there are many of us out there fighting for you. We are hopeful that this is our solution and we are hopeful that we can bring this to the clinic in the near future. So just stay hopeful. You're important to us. And if you want to learn more, you can go to UAB Medicine dot org and just want to thank you all for having me.
00;21;26;22 - 00;21;30;11
Jayme Locke, MD
And Jessica, it's super fun. Doing this with you. So thank you very much.
00;21;30;12 - 00;21;36;24
Jessica Washington
Thank you. Dr. Mark, it was great chatting with you today and thank you for all that you're doing for the kidney community. We appreciate it. Our pleasure.
00;21;37;07 - 00;22;03;04
Intro
Thank you for listening. We love highlighting the milestones of our kidney patients. Today, we're shining a light on Kelly Williams, who was on dialysis for eight years before finally receiving the gift of life from a stranger. This year, she is celebrating three years with her kidney transplant. Congrats on being three years kidney strong, Kelly. Make sure to rate and review us on Apple Podcasts, Stitcher, Spotify, or wherever you listen to podcasts.
00;22;03;19 - 00;22;14;22
Intro
You can also email us directly with your comments and suggestions and calf podcast at Kidney Fork. We hope you'll join us next time. And from all of us and chaos. We wish you good health.