The Peter Attia Drive - #155 - Chris Sonnenday, M.D.: The history, challenges, and gift of organ transplantation

Episode Date: March 29, 2021

Chris Sonnenday is the Transplant Center Director for Michigan Medicine. As Peter’s senior resident while at Johns Hopkins, Chris made a lasting impression on him with his remarkable leadership and ability to maintain his humanity through the stressors of that challenging environment. In this episode, Chris tells the incredible backstory of the history of transplant medicine, focusing on the kidney and the liver. He discusses the surgical and immunologic developments that launched the field forward, but also lays out the challenges ahead for the field, such as the rising prevalence of chronic kidney and liver failure. Chris also tells many stories of tragedy and triumph that comes with working in organ transplantation, but ultimately explains the rewarding nature of being a witness to the gift of organ donation.   We discuss: What attracted Chris to medicine, and his leadership in residency (3:30); How Chris maintained his empathy and humanity through the stresses of med school and residency (8:30); Why Chris chose a complicated field like transplant medicine (23:15); Explaining kidney transplantation to showcase the challenge of organ transplantation surgery (28:00); Overcoming the immune-based challenges of transplant surgery (37:00); How the discovery of cyclosporine transformed the field of organ transplantation (49:00); Rising chronic kidney failure due to the prevalence of pre-diabetes and metabolic syndrome (53:45); Why living kidney donations are superior, and the possibility of a market for kidney donation (59:30); Designing a fair system of organ distribution (1:17:30); The debate on what constitutes “death” when deciding when to take organs from a registered organ donor (1:21:45); Reflections on the gift of organ donation (1:33:15); The history of liver transplantation and why it’s so complex (1:39:15); Addressing acute liver failure and the amazing baboon experiment (1:46:15); The potential for the rising prevalence of NAFLD and NASH to overwhelm the liver transplant infrastructure in the US (1:54:45); The importance of teamwork in successful organ transplantations, and the most tragic event Chris has ever witnessed (2:05:45); and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: http://peterattiamd.com/ChrisSonnenday Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. I guess this week is Chris Saananday. Chris is the transplant director for Michigan medicine. He received his medical degree at Vanderbilt and went on to complete his residency in general surgery at Johns Hopkins, which is where we met. He went on to complete multiple fellowships, the training, trauma surgery, a pedabiliary oncology, and of course, transplant surgery. More than any of Chris' academic accolades, the thing that makes him most special to me is just the kind of human being he is.

And some of you may have heard me talk about Chris in the past. I've spoken about him on multiple podcasts, both this podcast and other podcasts where I've been interviewed. And I've always really referred to him as probably the most special resident I ever had the privilege of working alongside. And he's frankly unlike anyone I've ever met. And I've long wanted to talk with him. And this podcast really served as an opportunity to do two things. One was sort of showcase the type of leadership that Chris has developed and carried with him from Baltimore to Michigan, and also to really tell the story of transplant medicine, which is something that I think most people don't fully appreciate and understand.

And yet it touches so many lives. We, in this episode, go into great detail about it. Frankly, we talk about the entire history of two organs in particular, kidney, which is illustrative of so much and liver, which is really Chris' specialty. And we talk about them from the lens of the surgical developments and of course the immunologic developments, which are probably the cornerstone developments. We talk about some of the tragedies, of course, and the miracles that have been witnessed by this field.

So I think this is an episode you won't want to miss, even if you think at the outset that transplant surgery is something that's a bit too far removed from your day-to-day life. So without further delay, please enjoy my conversation with Chris Saunand. I'm really happy to finally sit down with you though. We had always thought we'd be doing it in person, but decided just didn't want to wait any longer.

No, I miss you dearly. And I think during our discussion today, people are going to get to understand why you've played such an important role in my development. I'll just state for everyone that you were one of my senior residents, what we call chief residents, when I was going through my training at Hopkins. And I think on other podcasts, people have probably heard me mention you. I've certainly talked about you. I talked about you on Jaco's podcast several years ago. I've talked about you on this podcast. And usually in the context of what I consider to be the most

remarkable leadership, residency was not, not without its stresses and stressors. And I think we have lots of great memories from it, but also some not-so-great ones. And therefore, anything that could have been done by those around us to make the process better was always appreciated. And I think we'll get to that later, but let's just start by telling folks like how you even got interested in medicine, let alone surgery.

Well, first of all, thank you so much for the invitation. It's awesome, even virtually, to get to hang out with you and reminisce a little bit, but also talk about our work. And I'm really proud of the work you've done with this podcast. It's been so impactful to patients, providers. It's just a cool way to see your leadership and impact extend. Yeah, medicine for me was something I stumbled to, so I grew up in the DC area. My dad is a retired breast-retiring minister.

My mom was a medical social worker. The only other physician in my family is my grandfather, who was an internist and researcher in St. Louis. And I went to college without a clear plan other than wanting to play college soccer, which is what I was fortunate enough to do. And I had imparted to me by my parents that, you know, they would support whatever I chose to do, but wanted it to be something that served other people. And I, you know, through the course of my studies did come to medicine for some of the somewhat cliché reasons, you know, it was a really exciting,

challenging field that appealed to kind of the problem solver, the scientist in me, but first and foremost was a way to serve people. And came to surgery very late too. In medical school, I was one of those people that kind of liked everything and was fascinated by kind of all fields, but really became attracted to what fortunately I think still sustains me today. And that is that being a surgeon provides this really unique opportunity to enter people's lives in their

provides this really unique opportunity to enter people's lives in their scariest kind of darkest moments and to have the privilege to be able to walk that with them and try to help them navigate that time and to have skill in some cases to solve the problem. And I think that was remarkable to me. I was struck by the challenge of it and was fortunate to make the decision to train in surgery and end up at Hopkins, where as I totally agree with how you described it, it was like the one hand kind of forged us into the people we are today, but also was difficult and challenging, and that's partially also what made it the experience it was. Yeah, how did you pick Hopkins? I mean, I guess you could say Hopkins sort of picks people and not the other way around, but how did you at least have the desire to go to such a rigorous program?

Was it something that said, hey, once I've committed to doing this, I might as well go to the best place? Yeah, it was a combination of things, you know, as I mentioned, I decided a little late medical school that I wanted to train in general surgery. And I went and consulted with the program director at my medical school who was John Tarplay, kind of a legendary general surgeon at Vanderbilt, who had spent a lot of his career in Africa, actually doing mission work and surgery.

And I went to meet with him. And to be honest with you, the goal of that meeting was to have him tell me that I even had a shot at staying at Vanderbilt. You know, that was that was my kind of what I thought would be the the best I could do. And we talked for a long time. He's a wonderful person wanted to hear about my goals. And he said, I think partially a guess, but he said, you know what, I think we need to send you back to the mother ship, because he had trained at Hopkins

and he still carried with very passionate memories about the training there and the standard of clinical excellence that the training programs they're represented. And so, I was fortunate enough to get an interview and was obviously impressed with the history and the emphasis on clinical excellence. But like you, I think I was also really attracted to the idea of mentorship and one individual

in particular, Keith Lillamo, who was the program director at the time now, the chair of surgery at Massachusetts General Hospital. I really got the feeling that he was invested in the development and training of his residents, not only as surgeons, but also as individuals and as leaders. And exactly like you said, kind of once I got that sense, I wanted to swim in that pool, so to speak, figuring that I would gain as much from obviously the terrific history and mentors and training environment, but also the individuals who we were lucky to train next to. I mean, I think when you feel like you're just running with superstars every day,

that does push you to be the best possible physician surgeon person you could be. I can think of so many individuals just like you that inspired me to push myself beyond kind of expectations that I probably even had for myself at that period of time. There's no doubt during this discussion, Chris, I'm going to have to embarrass the hell out of you because the reality of it is you were definitely, and you're just going to be too modest to accept it, but you were certainly in a league of your own, even amongst that caliber of individual. So it's one thing to say you played for the Yankees. It's another thing to say you were Mickey Mantle or Joe DiMaggio.

And I think one of the things I want to dig into today is for many of us, certainly myself, I'd put in that category. You show up with all of these ideas about what you can be and what this process is like. And some are all in the way a tiny piece of you gets a little broken. You lose a little bit of your humanity, your tolerance for distress goes down, the empathy goes down a little bit, your tolerance for others around you, even on the same team goes down a little bit, whether it's your tolerance for an error that a nurse makes, your tolerance for an error that the lab makes. I mean, I just watched in myself over five years a degradation of humanity, but in my

case, led to a very extreme outcome, which was departing. I can safely say you're the only person in whom I didn't witness that. And simultaneously, you were the best of the best. So to me, that's just an unusual combination that I definitely want to understand that a bit more. Well, I mean, that's very kind of you. I didn't feel that way at the time, which is, I guess, true of all of us. The battle you're waging within is different than what everybody sees on the outside. I mean, I think one way of asking that question is kind of what sustained me during that time period, what kept all of us going, but me in particular. I definitely had an overwhelming sense from day one of arriving in Baltimore, and this

speaks to kind of my medical training in general, but certainly specifically our residency that I felt like I was very lucky to be there, you know, that there were hundreds of qualified individuals who could have taken that spot, and probably thousands of other individuals who didn't get the opportunities I did to get to that spot. So I felt obligated if that's the right word to kind of maximize that entire experience. I also felt the burden, if you will, of the expectations of those around me. You know, I mean, the expectations of those that were training us, our colleagues, et cetera. You know, I always, one of the things I said to Dr. Lillon, Dr. Cameron, when I left was,

you know, thank you for your high expectations. Like, that's really what drove me to achieve things that I didn't necessarily think were within me. I will say, though, that the last thing, and this is true to this day, so it's not specific to residency, is that I have always found fortunately that what recenters me when medicine gets hard, because it does get difficult,

whether you practice in a busy primary care practice where you're cram in through 40 patients a day or you're doing operations where a wrong move leads, can lead to somebody's death. There are good days and bad days and there are pressures that can do all the things to you that you alluded to. But what has always resented me as the patients, I mean, to be honest, that privilege that I was speaking of earlier

of being invited into people's lives in these crazy moments and actually having the opportunity and or being. And somehow, even in the thick of residency, when you're like, why is it that this lab I ordered 14 hours ago has still hasn't been done? Or why can't I find the X-rays that were just on this desk like two hours ago?

Are all the other crazy things that we had to deal with or why is there no food to eat at 11 o beds petted a lot worse off than I did. And I think that the privilege of being involved in their carers kind of what resentered me and still does today, you know, when I have days like that, that is always what is able to kind of pull me back to the right frame of mind. Another thing that I think made you very special that wasn't, that I think was actually distinct from everything you're describing.

Everything you're describing was an incredible visible display. But you could have, I think, had all of those characteristics and you wouldn't have created the magnet that someone like me felt. Now I can't speak for the other residents. It would be hard for me to imagine I'm the only one that felt this way. But I just remember any time my rotation card showed I was going to be your junior resident. It didn't matter what the rotation was. I couldn't wait for that month to arrive. So that speaks to something a little different.

And let's go back to, you went to Northwestern if I recall, right, for college. And so you were Division 1 athlete, you're playing soccer. Were you the team leader? I was a captain. I was not the best player on the team, at least on my college teams for sure, but I do feel very lucky that I was elected to represent the team and to serve. And a leadership role, at least as it is within the context of an athletic team. One of the things that has always been true for me, you know, and this dates back to sports as a kid. And to be honest, as part of the reason why I chose to be a transplant surgeon, is that I always

migrated to team collaborative activities. I was never an individual sport athlete, you know, I swam a bit, I played tennis a bit, but I never kind of like was captivated by those sports in the same way that I was of just being on a team. And in fact, there were multiple times in my development as a young kid playing soccer in the DC area, which is a very competitive kind of soccer environment, you know, where I was lucky to kind of be on the some of the teams that I was on playing with elite players. But being on that team, being in that environment seemed to pull the best out of me. And I think that was true in residency too, you know,

what I relished the most was like, yeah, it was five in the morning, but you showed up and there was Peter and there was Megan and there, you know, it was your team. And I was like in the morning, but you showed up and there was Peter and there was Megan and there was your team. And I was like, you felt like you were unstoppable to some degree even though you were doing what at times seemed like a possible task. And I feel the same way about transplant. I feel like part of the reason I chose it was clear that no one can accomplish what it takes to take a liver transplant from their diagnosis to listing to operation, to recovery, to transforming them to a new life afterwards without a really highly functioning

team. And that is what always inspired me to give my best because I feel like I'm not a team where other people are doing the same thing. I mean, there's a story I'll tell that I would imagine you don't recall because it was so commonplace, but it really stood out to me as an example of what a great leader would do. So you'll have to forgive me for explaining a process that you understand, oh, too well, but most people don't.

Actually, I'm going to have you explain it. Tell folks what the M&M conference was every Tuesday morning. Yeah. So, so you're referring to what what at Hopkins was called morbidity and mortality conference, which is, you know, I think there are versions of that throughout medicine, but in surgery, it is a unique part of the culture. So, one of the things that makes surgery and surgery unique as a discipline is the sense of ownership, accountability, responsibility for the outcomes of the patients that you're privileged to care for. And so morbidity and mortality conferences, a weekly conference where we reviewed

essentially patients' stories, patients' cases, particularly patients that had suboptimal outcomes, whether it was a complication as hopefully routine as a wound complication or something that they would extend their recovery, but they would recover from fully to a death related to a surgical procedure, or at least to a diagnosis that we tried to address with a surgical procedure. My former chair here at Michigan, Mike Mahon, used to say that you could look into a department

soul by attending their morbidity and mortality conference. It becomes the kind of cultural event of the department because you get a sense for what that level of accountability is. Is the conference spent kind of blaming the anesthesiologist or the nurse or the patient's comorbid conditions or is the discussion about what we could do better next time to make the patient's outcome better? And I think there are lots of examples that, I'm sure you and I could regale for for hours of kind of how lessons learned in that room in the morning, you know, shape the way we think about medicine, the way we think about responsibility, all kinds

of other things. One thing I always admired is that the chair who was there for most of the time, we were there, John Cameron, he would often be the moderator of morbidity and mortality conference. And he always led, as you recall, with his own cases, which is a remarkable example of the level of accountability that I think he was trying to encourage among the faculty and residents there. Yeah, that's one of the things that stood out to me because I went to medical school at Stanford. And it was just a different culture. It wasn't nearly as rigorous. And so even in medical school, you would still attend that during your surgical rotations,

but it was not the conference that I saw at Hopkins, which was, I mean, this was the most intense hour of the week. and it was taking place outside of the operating room. So this was kind of the story that I'll tell that it just remains to this day etched in my mind. So by this point, you're now the trauma fellow. So you have now finished residency. You are now staying at Hopkins for another year to do what can only be described as the craziest fellowship ever. It's a hepatobiliary oncology fellowship combined with trauma every third time as if that weren't enough. And it's either July or August. So it's very early in the academic year. I'm the third year resident. So I'm kind of your most senior resident on that service, and

you're the ACS. So you're functioning like the attending. And we had just come on that morning to receive sign-off from the team that was leaving. And we both recalled just how chaotic that could be, right? You've got people that are just getting shot two hours earlier, you've got to run to the OR with them, and you're being told about this patient, this patient, this patient, and I mean, almost as a matter of fact,

one of those patients was being discharged that day. And it was sort of like this person on this floor is gonna go home in a couple of hours. Nobody needs to go and even see that person. You not only went and saw that person, but realized something was wrong and it it pains me that I don't remember what was wrong. But either you sensed that this person had a compartment syndrome that got missed. I think they'd been hit by a car that that day before or something like that. You sensed something that was missed for you to be the one to go and catch it was out of this world, right? Never would the attending go and be the one to go and

check on the patient whose discharge paperwork is already signed to go home. But you did that. You caught the misdiagnosis, took the patient to the operating room, operated, you know, probably saved his leg. You then presented that case at M&M several weeks later. But the part that blew my mind was you never mentioned the circumstances around which this patient came into our care. In other words, there was no blaming. There was no, well, you know, Mr. Smith was about to be discharged, but I decided to go and make sure he was okay and realized he actually had a compartment syndrome

and needed surgery to save his leg. Instead it was, you presented it as though it was your fault, as though you had missed it. And honestly, it sounds crazy. That was one of the moments when I realized I'm not good enough to be in this profession. You know, maybe none of us are, but I don't know if you remember that case. Yeah, I do actually now that you recall it. And the circumstances were as you described, it was one of those crazy days where 35 things are happening and we were all over 34 of them.

Unfortunately, the 35th was this poor guy who was getting ready to be wheeled out of the hospital. You know, I don't remember the circumstances of the M&M discussion, but I do certainly carry the philosophy in my work currently, and certainly that there is not value in kind of assigning blamed individuals. There's only value in recognizing opportunity for us as a system as a team to get better.

And partially it's because I think, you know, if I were to throw stones in that case, I could walk out of that conference in an hour later, be the one responsible for kind of generating a similar or worse complications. So I think there's some humility that has to enter into understanding that no one has all the answers nor should be expected to kind of catch everything. In fact, one of the things that I think has, as you know, one of the criticisms of the

M&M morbidity and mortality culture is that at least historically it had been a little bit too much about assigning individual blame and not about recognizing opportunity for change. But I do think that over time I've seen that change and certainly the way morbidity and mortality conferences are run now, for example, at my institution and others that I've visited are much more focused on what's right for the patient than rather, you know, who do we have to kind of string up for, you know, this particular mistake, which is number one better for patients.

Number two sets a better example for the trainees and learners in the room that are trying to do this and just as an important piece of creating the right culture where everybody's kind of ores are moving in the same direction. At what point during residency did you decide that it was going to be transplant medicine that it was going to be transplant medicine versus the other things that you had clearly shown a fantastic predilection for such as pancreatic surgery, liver surgery, and all facets of surgical oncology in the GI tract. Yeah, honestly I was greedy. I kind of wanted to do it all. You know, when I entered Hopkins, I had developed an interest in diseases of the

hepatic ability system and upper GI tracks. So that was another thing that clearly drove my interest in that residency where they had such expertise and concentration of experts in those diseases. I did my intern year rotation in transplant and then again a third year rotation in transplant. year rotation in transplant and then again a third year rotation in transplant. My fellow as an intern and then my junior attending as a third year was one of the people who's been, you know, one of the most important influences on my professional career, who's Bob Montgomery now the head of transplantation at NYU and a transformative figure in our field over the last couple of decades. And partially it was his example of what I thought I could aspire to be as a transplant

surgeon. Partially it was realizing that the distance from kind of bench to bedside and transplantation is really short. You know, it was unlike anything that I had seen even in a very innovative, progressive, you know, surgical department. And finally, you know, specifically speaking to my previous interest, I did see liver transplantation specifically as being completely complementary to being a comprehensive, a badabillary surgeon and physician for patients with, you know, have hadabillary disease.

You know, it's interesting. Another part of the world, it's pretty commonplace for a badabillary surgeons and liver transplant surgeons to be the same individuals. You know, in the US, just with training, tracks changing over time and such, there are, there tend to be surgical oncologists who do a badabillary surgery and transplant surgeons

who may do some of thatabillary surgery, but I clearly thought it would make me a more complete surgeon and physician to train in both. And I've been very lucky. I mean, this isn't something that can happen necessarily at every institution, but I've straddled that line in my career too. I about half my clinical practices is a padded billary surgery surgery of the liver, bile duct, and pancreas for mostly for cancer but other benign diseases, and then liver transplantation. So I feel like I won the lottery, I'm kind of walking that line to be able to combine

those disciplines. Tell folks a little bit about what you mean by bench to bedside and that distance being short. It's a term we throw around a lot in medicine, but it's significance is huge. I want to make sure people understand it. I mean part of it is just understanding the history, right? So transplantation as a field is very young. So the first kidney transplants were done in the 1950s. The first liver, heart, and lung transplants attempted in the 1960s, none of which were particular successful until the 1980s related to all sorts of important changes,

but particularly the development of effective immunosuppression. And then once it became a feasible and successful medical intervention, then developing all of the systems around making that a reality for more people and extending that to people with organ failure of various causes. So here we are surgical residents in the 1990s and a field that really is about 10 years old in terms of kind of being operationally expanding enough to really be a reality

at most major medical centers. And so you would see things being discussed kind of in morning reporter rounds or like, nah, this is a really tricky case of acute rejection. We haven't tried X yet and then you'd see, we try X and it would work or not work and we just, or there were surgical techniques living donor liver transplantation basically a major part of my practice now was created in the

1990s and early 2000s. So I think the ability to see innovation become reality in very rapid form was number one inspiring. I mean, you felt like you were doing something that was new and innovative and just really incredible, but also to be honest, it made you feel like you could potentially have some impact in the development of a field that was an ascent and I would put myself in maybe the second or third generation of transp planners in terms of its history

Which is you know, I feel very fortunate to be kind of a witness to that history and participate in some of it moving forward Let's use kidney as an example to explain to people the challenges today We take kidney transplants almost for granted because the success rate is so high. In fact, even when I was a resident, if you demonstrated that you had enough of this skill and the interest, even the transplant fellow would let you, as the, you know, mid-level resident or the senior resident general surgery, do kidney transplants. You mentioned Bob Montgomery. There was a stretch on transplant where Bob and I did 13 consecutive kidney transplants together in a period of like four days. So the fact that kind of a knuckle dragger like me could have been

doing this speaks to how well it works today. But as you said, this is a procedure that even in the 1960s carried with it a mortality of more than 50%. So let's break down for people the evolution of this from sort of the technical evolution. It was only what maybe a little over a hundred years ago that the anastomosis was even understood. To then the complications of acute rejection, chronic rejection, and even understanding what the immune system is doing. So, and then we're going to get to liver after, because of course liver takes it to a whole new level in all regards. Kidney transplantation is kind of the best example of all the challenges that you just alluded

to. It was also the first solid organ, at least, that appealed to the earliest pioneers in the field as something that, you know, it seemed feasible to give someone an extra kidney. Like that, you could kind of imagine a way technically to make that work. As opposed to doing what we now do for say, hard or liver transplantation, where you're doing an orthotopic transplant, you're literally taking out the prior organ and putting in the new one. That's a little different than a hetero-topic kidney transplant where you're giving them an extra organ and hoping that replaces the function of their failed kidneys.

People probably don't understand that, but when we do kidney transplants, we don't go in to the RetroParent Neum take out the old kidneys. We're putting the new kidney basically in their pelvis, attaching it to the blood vessels in the pelvis and taking the little tube that drains urine and just putting that into the bladder, the uritor. And obviously that's much easier than if you were gonna remove the old kidneys and put the new kidney in their place

given the location of the kidneys. To make kidney transplantation feasible was a collision of lots of hard work by multiple individuals, some of whom thinking about what you just said, literally, what are the technical details of taking an organ out of a either living or deceased donor, mitigating the injury that goes from cutting off its blood supply until you're able to restore it into the recipients' bodies. So there's this whole concept of the technique, the preservation, and then the implantation.

And then parallel to that was this whole question of, well, how do we handle the immunologic consequences of that? And so the series of events that occurred and allowed kidney transplantation to be a reality were really that the technical and preservation elements came to fruition before we figured out the immunologic elements. And in fact, the first kidney transplant, as you know, performed in 1954 at Brigham and Women's Hospital by Joseph Murray, who eventually won the Nobel Prize, was in identical twins. Right?

So, he had two brothers, one brother who had kidney failure, another brother who was healthy, took one of the healthy brothers' kidneys and transplanted it into the sick brother. And that proof of principle was what created even kind of the possibility, the vision that transplantation could work because we understood the technical and preservation challenges of actually taking an organ out of one person's body

and putting it into someone else. Murray was a plastic surgeon, wasn't he? Yeah, just Murray was a plastic surgeon and interestingly, although he and his colleagues figured out this technical piece, what attracted him to transplant was the concept of tissue transfer and the immunology of that.

So a lot of the early work in immunology was done with skin grafts, and kind of understanding why you could take a skin graft from your own body and put it somewhere and it would live. But if you took a skin graft from someone else's body and put it on a site, it would not, it would generally not live. And so there was this whole kind of cadre of clinician scientists who were interested in that question, including interestingly plastic surgeons like Joseph Murray. So he became involved in that with a group of other surgeons, including some folks

who had vascular expertise and others and kind of conceived and developed in preclinical models and animals, this idea of putting a kidney in the pelvis and attaching it to the blood vessels and bladder and then pulled it off in a human. And a lot of, if you look at the history of kidney transplantation through the 1950s and into the 1960s, most of the kidney transplants were performed between twins, which there's a limited supply of the failed warkins there. So you can see right there that that was going to be a capacity problem. But you know, for example, the first kidney transplant at the University of Michigan was

performed in 1963 between two twin sisters who a few years ago we were celebrating our 5,000th transplanted organ at the University of Michigan and those two sisters came back to celebrate that event. So I mean, it was a remarkable achievement, but it was a little bit of a false pretense because none of the immunologic barriers were being confronted. And really what happened over the next four decades were the development of effective immunosuppression to make that a reality. And as you alluded to, it's pretty remarkable to think that, you know, in the 1960s and 70s and into the early 80s, kidney transplants were being done. And there were success stories. The field worked out how to understand who had preformed antibodies to particular donors,

so you could avoid those and pick pairs that might be more successful. There were increasingly sophisticated immunosuppression strategies that did work, you know, and drugs that were available like steroids and esothiopron were making transplantation a possibility, but it's pretty remarkable to think in comparison to what we expect now that in the 1960s and 70s, if you look at some of the published series, there were mortality rates, mortality rates, meaning the patient died after kidney transplantation of 50, 60, even 70%. So it's not only that they lost their graft, but the consequences of the operation, the immunosuppression, subsequent, usually infections, was making these procedures highly morbid and

unsuccessful, at least at rates that we would think of as acceptable now. And what was the life expectancy if you opted for dialysis in the 1960s? How long could you be expected to survive? It's a great question, and the first and most important kind of answer to that question is the assumption that you could get dialysis. So dialysis was not available everywhere. It was largely centered around hospitals that had the ability to provide that service. Dialysis care was not routinely covered by insurers.

In fact, it wasn't until kind of a quirky rider to the law that created Medicare in the 1960s that patients with dialysis even had the option, the ability to get health insurance. It was hard to get dialysis, and then the survival on dialysis due to the challenges of infection from repeated access, the hemodynamic consequences and cardiovascular consequences, we know of what were then more crude, primitive dialysis machines was such that the life expectancy was probably measured in months to years. So two to four years might be a very successful outcome for someone on dialysis. The average life expectancy if you take all commerce for an individual on dialysis

now is about 10 years or so. But again, that is partially affected by the fact that dialysis is more freely available. People elderly individuals and people with other comorbid disease have access to dialysis they wouldn't have had. So there were no good solutions, you know, for patients with organ failure in those times. I want to make sure people really get a sense of what these immune-based challenges were. We take it all for granted today because we can rattle off all MHC2, MHC1 complexes, and

that stuff's been worked out in the most elegant manner. But in the 1960s, that was not the case. Maybe start by explaining ABO in compatibility, because I think that's something people understand. If you came in the hospital and you'd lost blood, and we wanted to give you a blood transfusion, we couldn't just wily nilly give you anybody's blood. We'd have to make sure that the blood type matched. That's not entirely true if you had, we could give you, sure that the blood type matched. That's not entirely true if

you had, you know, we could give you, oh, negative blood no matter what, but walk people through kind of A, B, O, which would be this, in my mind, at least the simplest form of antibody mediated rejection. And then let's use that as a way to explain what was actually happening to all those non-twin transplants. Yeah. So that's a great model to start with. So, if you think about it in really basic forms, our immune system has evolved to recognize self-recognize our own tissues and has been primed to recognize things that do not look like us,

mostly to be able to fight off viruses and other environmental challenges, but that unfortunately makes it difficult for something like transplantation. So in the case of a blood compatibility, we carry a blood of us of a particular type, it has to do with the protein signature on the coding of those red blood cells. And we know that if you give someone who carries blood of a certain type, a blood type that is incompatible, so let's make it the simplest. Someone who has blood type A, someone who has blood type B,

and you give the individual blood type A blood from an individual blood type B, they will have antibodies that attack those blood cells and essentially destroy the blood cells because they think they are recognized as foreign. It's more complex than that because there's also these things called the RH antigens, which are kind of what make blood positive and negative.

And you're correct that blood type O, individuals who do not have blood type O do not have preformed antibodies to that donor pool. So that is kind of the universal donor pool. But it was figuring out that incompatibility understanding that was kind of the first step in understanding how you would potentially take an organ out of one individual and place it into another. Because, and this is still true to this day, that kind of step one in matching a donor and recipient is knowing their blood type, because that's kind of the first step. It gets more complicated than that for all the reasons you alluded to, because it turns out those are not the only proteins on the surfaces of those cells that are recognized by our immune system. And this in particular, this group of protein called

human leukocyte antigens, which is what you were alluding to, or HLA types, is what on a very crude way determines one individual from another, that profile. And so the history of this is pretty interesting, going back to my skin graft analogy. So what investigators around the turn of the century were figuring out is again, so you could take a skin graft from elsewhere in your body and it was it would tend to work. You took a skin graft from somewhere somewhere else from another individual. It did not work. Then even more interestingly, if you took a second skin graft from that same individual and put it on, it died faster.

It's as if the body was primed to destroy that new skin graft. Kind of sounds like a vaccine, huh? Exactly. It's the same principle. So it was this kind of the second-hit hypothesis that the body, the immune system, learned to recognize this foreign tissue, and the immune system was even more effective in eliminating it. And it was that whole series of experiments that led to these concepts right in the middle of the last century, where the question was, and this was debated by individuals much smarter than us, many of

whom now have Nobel prizes after their name. So was there something circulating in the recipients serum that found this tissue, antibodies, was the theory, attacked this tissue, set off the immune cascade, destroyed the tissue. Or was it more complicated than that? Was there kind of like we've learned about in embryology from thymic development? Was there some sort of priming event

that had to take place where the body presented this foreign tissue to the immune system, and then the immune system learned how to recognize it as self-reform and destroy it. And that debate went on for decades. Right, so just to separate that, in the case of blood incompatibility, it was pretty easy to figure out that it was just these soluble circulating antibodies.

They weren't, quote, unquote, smart. They were just floating around. You could do it in a test tube, you know, literally. That's right. So you have a blood type A with its little A antigen. And if the recipient has an anti-A, it grabs onto it. And these things precipitate out of solution of this reaction. And of course, now the question that you're posing is, is that how it works on organs, or is there something more complicated where there's

another actor? Correct. And the reason that that was such a fundamental question, because if you believed it was like the blood analogy, and that, okay, so if we could identify the patients that had preformed antibodies, preformed proteins in their serum that we're going to ruin this opportunity. Then, well, that's great. Then we can select out the patients that have that reaction and use the organ to transplant others. So that's the concept of what is now called in transplant across match.

So the idea of taking donor cells, recipient serum, mixing them in an assay, and determining whether or not that serum lices those cells. And that is more or less the technique that is used to cross-match individuals to match, you know, as you'll hear, people talk about, oh, I want to donate a kidney to my uncle or something, I wonder if I'm a match. That's to some degree what they're talking about is whether or not that assay says that their uncle in this case doesn't have preformed antibodies that are going to destroy their cells. So that would explain kind of that initial screening step.

And the other thing that that helped explain is why sometimes when you would do a transplant, either in animals or eventually in humans, there was this phenomenon, which came to be known as hyperacute rejection, where you would put the organ in, you would take the clamps off, the organ would fill with blood, looks like you've won the game,

and then it would immediately start to thrombose and die, essentially. That process called hyperacute rejection, it was figured out was because of the circulating antibodies to those HLA engines of the donor. So that made some sense. We can try to figure that out. What didn't make sense is you would do the transplant, you would get past that hyperacute stage, the organ's working, and then a day later,

three days later, six months later, the organ would fail from acute rejection. So basically the same process, but with a different kind of lead time. And it was after much debate in the field, the nuances of which are more sophisticated than I can explain, but it was figured out that what was actually happening was not this circulating what we came to call antibody mediated or humoral rejection, but actually was happening on a cellular level, so-called cellular rejection. And as we learned eventually over time, that had to do with what we now learn in basic immunology, antigen presenting cell, with carrying an antigen from the foreign tissue,

in this case, the donor tissue, immuninator cells, and we discovered and learned eventually they were T cells. That recognition, priming the immune system to form injury, either by various means, cytokines, eventual antibody formation, et cetera. And that was what was destroying organs in that kind of subacute phase. And as we figured out over the course of decades, the drugs that we had to blunt that initial immune response, high-dose steroids, I refer days at Thiaprin, they tried total body irradiation at some of the early stages. That was franny moor that was doing that.

Up at the Brigham as well, right? And the Brigham. Exactly. Those weren't effective in preventing that cellular level rejection. And it was only later, really, the 1980s that we developed immunosuppressive agents that were selective enough to interfere with that cellular reaction.

And it was then that transmit really became a reality. Because now you had the ability to sustain an organ beyond just weeks to months, and you're looking at more long-term survival. Really, the turning points are twofold, right? One, it's the knowledge of what's happening, because certainly by the 80s, it was not a technical challenge to be able to remove a kidney, transport a kidney, transport a kidney and put it in. By the way, was Wisconsin solution already around by the 80s or did that come later? Yeah. So, or at least the predecessor is a Wisconsin solution and...

Till folks what that is and why that matters so much as well. The theory is you take an organ out of the donor body, whether deceased or living. You flush the blood cells in such out of it so that it doesn't clot, you then store it on ice and transport it to the recipient and put it in. And there were all kinds of initial thoughts about, well, do you just put it in saline essentially and transport it to the other room?

And what they found was that, and this was experimentation that happened over decades, was that there were cellular processes occurring both as kind of at the time from when a Schemia begins, when the vessels are clamped and the organ is coming out. And before blood flow and oxygen is restored to the organ. There were cellular processes occurring that could be mitigated by creating preservation solutions, essentially saline, that was fortified with particular molecules. And the history of all this is beyond me, but literally they tried, it's like making data, they tried, you know, different electrolyte solutions and additives It's like making gatorade. They tried different electrolyte solutions and additives and other nutrients until they figured out which mitigated that is schemic time the best. And the crazy thing to think about, and this gets to

alludes to something maybe we could talk about later in terms of where is preservation going in the future. But the crazy thing is we're pretty much more or less doing that now. So some of the fluid solutions and some of the minor details of what additives are in the fluid has changed. But that's essentially the way we've been preserving organs since the 1960s, 70s, which is pretty remarkable that that was one, as you said, one of the early barriers figured out in the field. Once this notion of the HLA system is understood and we understand these different types of compatibilities, a drug is discovered and it's my favorite drug on the planet happens to come from basically a fungus.

And this is another drug that came from a fungus, but a different one. The drug is called cyclosporin. And I think you could make the case, but I'd one. The drug is called cyclosporin. And I think you could make the case, but I'd like to hear your take on it because you know this field so much better than I do. But if I were telling the story, I would say that was the turning point, was the advent of cyclosporin. Do you agree with that or do you think that I'm overstating that? No, 100%. As you said, and similar to the stories of drug development that happened in other circumstances,

you know, this was a recognized compound that had been experimented in a number of different lines of investigation, and an investigator who's really one of the central figures in the history of transplant, name, sir, or I call him in Cambridge, performed a series of preclinical experiments that showed that using this medication prevented rejection in transplant models. What eventually was discovered is that it was interfering with the cascade that occurred when that foreign antigen was presented to the recipient T cell. In other words, it was a more selective immunosuppressant, so directly interfering with the cascade of events that happens downstream of the T cell receptor. And it's specifically inhibited IL-2 secretion. It affects IL-2's secretion,

but there's actually some interesting debate about how the calcinarin inhibitors, so cyclosporin, and then its eventual cousin, tachylimus, works. They both function at the level of what are called immunofilons, these, you know, sizable intracellular components. And although they affect both kind of the activation of cytokines after that T cell recognition, including IL-2, they also seem to have other effects on the affinity of the binding of T cell receptor. They have systemic effects that are kind of interesting,

like for example, Tachrolymos, the other medication I mentioned, has a potent vasoconstrictor effect in certain organs. We probably don't fully understand its impact, but certainly the central component of its mechanism was interfering with the cascade that occurs after T cell receptor binding. You're absolutely right. It literally was a game changer overnight. So if you look at papers written in the 1980s about kidney transplant outcomes,

there's literally an inflection point. You went from recipients having one year graphed survival rates, even with kind of the best immunosuppressive regimens that had been figured out at that point, one year graph survival rate is probably in the 70-60% range. Boom, you know, 90% overnight just with the addition of cyclosporin and then, you know, eventually refining some of the multi-drug regimens. So it was a complete game changer. It not only revolutionized the impact of kidney transplantation, which from a public health

standpoint is clearly the most impactful organ we transplant. You know, the number of patients with end stage real disease and the number of patients of chronic kidney disease, you know, from a public health standpoint, kidney transplantation is just a fundamental important medical therapy. So not only did it make that a reality and make it a preferred alternative to dialysis, it also reinvigorated the other solid organ transplants as being a reality. So liver transplantation, which essentially had been on a more or less enforced hiatus through the 60s and 70s, heart transplantation similarly, long transplantation as well, the confidence that now that we understood some of the

technical and kind of patient-related factors that dictated the success of the operation, to now also have the promise that those organs would last more than 90 days reinvigorated those fields completely. And, you know, again, almost over a night, over the course of years, you started to see liver transplant programs, heart transplant programs, lung transplant programs, pop up at major chomemetic centers all throughout the country in the 1980s and into the early 1990s. So that was really the revolution that occurred because of that drug development.

When we look at the demand for kidney transplantation today, what percentage of it is chronic versus acute kidney failure? The vast majority is chronic. So there are occasions where patients can get acute renal injury from traumatic events, other medical catastrophes where they get acute kidney injury in the chronic, in this case of sepsis or something that they otherwise recover from. And we still see occasionally patients who get, for example, post-striptococcal glomerular arthritis or other diseases that are more linked to kind of an acute event.

The vast majority of kidney transplants on the United States, the primary indication is diabetes or hypertension. So this is chronic kidney disease as a consequence of those comorbid conditions, which is one of the reasons, again, from a public health standpoint, the impact of kidney transplantation is massive. So you have 100,000 people roughly waiting for a kidney transplant in the United States. You probably have four full-that are there about on dialysis, and then probably ten full-that number with chronic kidney disease. So the potential impact of having an effective and durable therapy for chronic kidney disease is remarkable. I think it's really important to consider as a public health bro.

I can't agree with you, Morkris. About three years ago, I sort of had this obvious epiphany. I say obvious because I'm thinking, why did it take me so long to do the math? I realized if my interest clinically is trying to figure out how to help people live longer and live better, you've got to start thinking about what are the things that you have to plan for. So if you're flying a glider where you know you want to cross a 200 foot chasm, but now all of a sudden you say, well, I want that chasm to be 300 feet, you have to start thinking about how much higher does that glider need to fly. But now all of a sudden you say, well, I want that chasm to be 300 feet.

You have to start thinking about how much higher it is that glider need to fly. And one of the things that really occurred to me was kidney function. We sort of have in the back of our minds, eh, you know, look, if a person reaches the finish line of life and their glimereular filtration rate is 40, great. You know, they don't need dialysis, they're doing just fine. And if we think that an average life expectancy should be 71 or something, and we think that, hey, we're gonna tolerate a person's

GFR being in the low 40s when they're in their early 70s, that's great. But if we're trying to figure out a way to help people live and live well into their 90s or beyond, that becomes a very unacceptable GFR. You're going to run into trouble. So looking at Sustaten Sea beyond just creatinine and other biomarkers and looking at micro-obduement in the year and twice a year, I mean, we do all these things, but even though they seem

kind of crazy, because it's how you sort of start to catch that early, early, oh, look, you know what, your blood pressure of 130 over 85 is not really acceptable. That's going to take you from a GFR of 95 to 85 in the next decade, and we consider that to be too precipitous of decline. So unfortunately, my view is that I think the demand for kidneys is only going to go up as we see the ramp and explosion of pre-diabetes in metabolic syndrome. I totally agree with you. I think, and there's so many kind of wrinkles to that question to think about.

The first is that is the obvious statement that as you preach better than anybody, we don't do preventative care, you know, in this country very well. And we particularly don't do it for things where we don't have reliable measures. So to your point, we use serum creatinine as kind of our best guess at kidney function. There's lots of reasons why that's a poor indicator. It's very dependent on muscle mass and other variables that prevent you from using some sort of kind of normalized number as an acceptable range. There are more sensitive markers as you alluded to.

There's now, I think, fortunately, finally being recognized the whole question of how creatinine and GFR and race interacts and how that needs to be accommodated for. So you're right. So number one, we don't measure it well, so therefore we don't appreciate the size of the problem. Number two is we, again, this is kind of a situation where transplant is a victim of its own success. As transplantation has gotten more successful, transplant centers around the country, transplant providers, and just the medical community in general has started to say, well, why don't we provide kidney transplants for 70-year-olds if there are otherwise healthy individuals?

Because their life expectancy might be 20 years from that point. The collision of that and then what you alluded to, this pre-diabetes, metabolic syndrome, progressive kidney dysfunction in an aging population is gonna create an enormous demand for kidney transplantation. We transplanted an 81 year old a few weeks ago, and I remember as I was looking at the census, I don't do kidney transplant very commonly as part of my clinical practice. I was looking at the census, I was like, wait a minute, is that?

Is this gentleman 10 years out from a transplant back in the hospital for some other reason or did we actually transplant this 80-winter? But the point is there are individuals who are healthy, functional people otherwise. We have a whose life part of what we're talking about is survival benefit, right? You compare their survival on dialysis

to their survival with the transplant. Transplant is gonna win almost every time, as long as they can tolerate the operation in the immunosuppression. It isn't kind of remarkable to think of the scope of that problem, and particularly to take a longevity lens on it. It's really kind of an interesting challenge to think about for the next 20, 30 years of transplantation.

Before we get on to liver, which is such an amazing story as well, I want to wrap a few things up on kidney. So, let's talk about the evolution from cyclosporin to program for tackle imus, as you discussed, and where we are today on some of the most common immunosuppressive regimens. And then I also want to touch on this idea of not just living donors, but the live donor swaps and stuff, because I'll tell you one of the things that I'll never forget from my intern rotation on transplant, which like you captivated me beyond words. I mean, I transplant was never even something on my radar before residency.

And for the entire time I was in residency it was always one of those things was like I could see myself doing this. This is so cool. And it was actually, I think it was Bob Montgomery as well that shared this with me, which was a live donor zero out of six HLA match is always going to beat six out of six Cateverec match. And I remember thinking, how is that possible? Now, tell folks what I just said, what explain what I just said to people, and more importantly explain why it's true. Yeah, so it's pretty remarkable to consider the impact of living donation. And to your earlier question, kind of figuring out the appropriate place for living donation

as transplantation moves forward. So in kidney transplantation, encounter distinction, deliver transplantation, but in kidney transplantation, living donation has been part of kidney transplantation from its origins, you know. So as I alluded to already, the first transplant done between identical twins, living donation remained a part of the development of kidney transplantation, and then really took off in the 1990s, we witnessed it happening with the development of the laparoscopic donor nephrectomy operation, a procedure pioneered by two individuals at Hopkins, Luke, Ebusy, and Lloyd Ratner, and that having a procedure that

was of such tremendous benefit to the recipient that then was safe and a smoother recovery for the donor really allowed that to explode. And if you look at kidney transplantation in the United States now, let's say 18 to 20,000 patients a year undergo kidney transplant in the United States, and it's actually about half and half living donors and deceased donors. And that's probably with under realizing the potential of living donation for all the reasons you said. So part of what you're leading to is if you kind of compare head to head, let's say you have a patient on dialysis, a patient who receives a deceased donor kidney transplant, and a patient

who receives a living donor kidney transplant and a patient who receives a living donor kidney transplant. Let's say the starting line is the same for all three of those. And let's say that their similar age, similar comorbid conditions, similar amyosuppressive regimen for the transplant recipients. The benefits are pretty clear. The dialysis curve is going to drop off pretty quickly. In fact, the studies that have shown that where the dialysis and transplant curves cross, even with the risks of undergoing a surgical procedure and starting immunosuppression,

occurs in less than a year. It's probably in somewhere between 90 and 250 days depending on patient characteristics. So that's clear, dialysis loses. What's interesting then is that there's a difference between the deceased and living donor curves, and that's what you were kind of so fascinated about. And the reasons for that are many,

but it probably speaks to the fact that even with all of the best technique in advances, there is really no way to mitigate the fact that a deceased donor that goes through the process and the trauma of brain death or donation after cardiac death gets removed from that individual's body preserved, put on ice, transported to another center, and then sewn into the recipient. And that interval of time can be six to 48, 72 hours in some circumstances.

As opposed to a living donor, elective operation side by side or sequential operating rooms, that kidney is in a healthy environment with a healthy normal person, normal vital signs. We dissect out the kidney, clamp the blood vessels, take it out of the body, flush it, walk it over to the recipients room, and and sometimes it's sewn in under an hour.

So the time, the ischemic time from coming out of the donor's body to into the recipient. It turns out that ischemic period is critical and is really almost linearly related to the graft survival. Part of that is probably due to the consequences just of the ischemia-reprofusion injury and literally knocking off some nephrons just from that process. Part of it also is we've learned is that

that ischemia-reprofusion injury cascade that starts is a priming event for the immune system. So not only do deceased donor kidneys kind of pound for pound compared to living donor kidneys, take that initial hit from the Schemery Profusion Injury. They're also more prone to rejection. You see more immunologic injury, depends on the circumstances.

They often require more immunosuppression, greater frequency of rejection. So it really is almost like two different products from a recipients point of view. And so, you know, I think if you had your druthers, you know, as a person in need of a kidney transplant, you would want to have the access and the opportunity to get a living donor any day of the week if that is possible to you. And this other point, though, is to narrow that gap between the two. It's that with the deceased donor, you at least try to maximize the immunocompatibility. And with the living donor, you have much more flexibility.

Correct. That's exactly right. So what you were describing is kind of the story you alluded to with Bob is you're comparing a living donor kidney, so optimal conditions of the transplant, but not a perfect immunologic situation, at least from looking an HLA alone, versus a deceased donor kidney that immunologically is a home run. That's about as good a situation as you can get, but still takes homologically is a home run. It's about as good a situation as you can get, but still takes that ischemic hit and we can't make up for that. So even the best homologic situation can't mitigate that, which I think is a realization that doesn't always kind of come to fruition,

but it is again one of the reasons why we feel comfortable really pushing every kidney transplant candidate to think very seriously about exploring options for living donation. It's also what's led to some of the things you alluded to. Pair kidney exchanges and other things to try and expand the compatibility of donors and recipients. Let's use an example to explain that to people because it's really quite fascinating and we trained very close to some of the people who really did a lot of the work behind optimizing the mathematical algorithms around that. So let's pretend that you called me

tomorrow and said, Peter, you're not going to believe this, but I'm kind of at the end of my rope with my kidneys. I'm going to need to have a transplant and I, you know, I was sad. I thought about it and I decided, you know what? There's no greater way that I wanna be able to thank Chris for all he's done for me than to give him a kidney. And I've got two and I'm perfectly healthy and I'm willing to part with one of them. So I call you up and I say, Chris, I wanna give you one of my kidneys,

I wanna be a living donor to you. So we would go and meet with the transplant team and they would do some tests. And what if they discovered that I was a lousy match for you? We didn't even have the same blood type, never mind HLA compatibility. What would be some of the options we would explore? So the circumstance you're talking about is this really kind of frustrating scenario where a kidney transplant candidate has done the right things. They've taken care of themselves.

They've gotten to a transplant center, they're listed, you know, for transplant, we think they're a good candidate. They've even gone to the effort that you just described of identifying living donors. And the living donor or donors that they identify are not compatible with them or at least safely. So as you said, they might be of a different blood type. Let's say I'm an A and you're a B. That's just not a barrier that we're used to crossing, at least with any kind of reasonable likelihood of the success rates we were discussing earlier. It may also be that I have preformed antibodies

to HLA antigens that you have. And it turns out there's certain populations that are more prone to that challenge. So it's a really frustrating challenge because here it is, it's like you have this diamond and the rough, but you can't apply it. And so what some really smart people figured out, well, if I've got two pairs and they're incompatible with each other, but happen to be compatible with the opposite. So let's say that we're an A and a B, and there's another pair over here that's a B and

an A, and by all other measures are compatible. Is it reasonable to swap those kidneys? And those sorts of swap kidney swaps or paired exchange began in the 1990s and really took off in the 2000s because it allowed people to avail themselves of broader opportunities for transplant. Now, what you're alluding to in terms of the kind of the mathematics of it is you can imagine there's some ethical quandaries there. So let's say, so you come forward to donate me a kidney, you're extremely healthy person you've taken, take care of yourself.

I assume Jill has approved this at some point in the discussion. I haven't asked her, but you know, she can't wait to say hi to you after this podcast. So I think she would let me donate to you happily. That's an important part of the discussion. But then let's say the pair that we were talking about, exchanging with, is someone about our age who needs a kidney and they're 75-year-old father. So, I swapped to them this perfectly healthy kidney from someone who's in good health

and younger, and I get an exchange for that a 75-year-old kidney. Now, for some of the reasons we just talked about, it might still be in my best interest to take that living donor kidney. But you can imagine that there are differences in quality and then to add even more complexity to it. What if let's say the individual that you would be donating to across the swap, you just by coincidence are a perfect match for HLA match across the board. But that individual that I'm swapping for, you know, we're missing out six. Exactly. Or there's very sophisticated assays that actually can look for low levels of what we call donor specific antibody to that. Let's say that I've got some

low level antibodies to that individual. Is it worth the swap, is it worth the extraneous oppression I would need to make that a reality to make that pair exchange work? And so some smart people, including colleagues of ours that we both know, Dory Segev and his wife, some Regentury, who's a mathematician, started thinking about that. Like, so could we start putting some value on those exchanges and create networks of individuals, it's kind of like the dating game for kidneys where you come forward with your donor

and the algorithm looks at all the other possible pairs and tries to match individuals in a way that maximizes predicted outcome. And there are now national networks that facilitate those sorts of exchanges and have really expanded kidney transplantation in ways that I don't think even we would have predicted watching it back in the 1990s. You know, for example, there was a day maybe three weeks ago where I did a laparoscopic donor and a frecktony operation. So we removed a kidney from an individual.

That morning, one of my colleagues was doing a similar operation in another room. Both those kidneys shipped out to other institutions. Two kidneys came back later and our colleagues put them in later in the day into two of our recipients. So it was like, we've completely dissociated the donor operation from the recipient operation, which from a patient's perspective is great. And so the donors don't have to travel. The recipients have more access to organs. And I think thinking about how that is applied and expanded has really been a game changer

for kidney transplantation access. Chris, is there any serious discussion about opening up a market for kidney donation? So everything we just described is it's happening through altruism. I would give you my kidney because I love you. But is there a serious discussion that says, look, what if I've just decided, you know what? I'm willing to gamble, but I don't need a kidney. I don't know a given individual, but for a big enough sum of money, I'm willing to part with my kidney.

Are those discussions even entertained? Great question, and this is a frequently debated and never resolved kind of debate and transplantation. So to put some framework behind that question, so when transplantation. So to put some framework behind that question. So when transplantation started to become a successful Medical intervention. So we're talking now 70s into the 1980s development of cyclosporin

We then started to think about so okay, this is a successful venture. We now have So, okay, this is a successful venture. We now have organ donation laws that exist around the country. We need to create networks to make sure that a liver that becomes available in Utah is accessible to the patient in Michigan, as it to California or other circumstances. So there was a whole infrastructure put around that challenge. The legality of it was, and the decision that was made at the time these laws were passed, that it was illegal to sell an organ. And the reasons that that principle was upheld is kind of central to transportation, particularly in the United States, but in most countries around the world, is that

in the United States, but in most countries around the world is that the belief was that organ donation was a gift. The ethical principle was that the donor has autonomy over that decision and makes it freely. The concern about allowing people to pay for organs, like on an open market, was that can potentially be coercive and can create markets where individuals who have lower standing in society or are economically disadvantaged, then are put in this to position where they can be selling their organs to achieve some game. And actually, just literally this last weekend, there was an article in the New York Times about the growth of kidney

transplantation in Afghanistan, and that is exactly what happened. They have turned away from understanding relationships between donors and recipients, and that's what's happened. That wealthy people who have the resources are paying poor people for their kidneys, and then not certainly caring for them afterwards. So as a general principle, the trans-my community has decided

against paying for organs as the principle being that it's coercive. Now, there's lots of people that disagree with that on general principle and say, well, why don't we just create a better system, allow some exchange of compensation to donors. And I think we are slowly migrating towards some version of that, so to give you a few examples. The legality of this has been so tight that it's been impossible even for donors to be reimbursed for like transportation to the Transplant Center or time off work or other sacrifices that they had to personally make that had nothing to do with the actual donation, but just to facilitate that occurring. And there are now laws being passed in states and other

initiatives either through advocacy groups. There's a national group that does advocacy for living donors and provides resources and support for travel to transplant centers and reimbursement for time away from work and such. But what if we created a principle where, say for example, a living donor is compensated with some agreed upon amount of money that compensates for the time of their recovery? I think there may come a time that some version of that becomes reality. There's also principles of should living donation provide special kind of healthcare benefits to individuals over time.

Maybe it qualifies you for discounted public insurance or something so that you can never lose health insurance if you were to God forbid have a problem yourself down the road. So I think there are some versions of this that will come to fruition gradually, but I think at least in the United States, our medical legal environment and the principles behind transplantation will not permit an open market for buying and selling of organs. I like that idea though about providing ongoing medical coverage. You know, it's funny, whenever the debate comes up about whether we should be paying NC2A athletes, especially the football players, right?

They generate so much revenue for the university and then they get spanked if they accept like a $50 gift from a booster. I've always thought one solution to that is fine. If you don't want to pay athletes for playing sports at a university, you should at least cover their medical bills for the rest of their lives. Like if an athlete suffers some consequences as a result of playing sports, which many of them do, we should at least make sure that we take care of them if we're going to profit off them to the course of that. Tell folks a little bit about, if it's still the case, I assume it's still the case, there are some states in which you're better off and more likely to get

an organ, like a liver, for example, than other states. How does that work? And what would be the best states to live in if you're vying for an organ versus the worst? Right. So fortunately, that is changing rapidly and it's changing rapidly because it's been a focus of intentional policy change in the way organs are allocated. So it's not like when we were in residency where it was almost comical? Correct. So part of the issue is simply a supply and demand issue. So if you look, for example, a California state with a huge population. There is such a demand for transplant that if you restricted, if you kind of imagine California

as just its own unit, it's almost like the organ donation supply in California would never meet the demand. That's true in other major, particularly urban population centers like New York and parts of the East Coast. There are other parts of the country, and they tend to be in the Midwest, but there's some other locations in the South as well, where just based on population size, the amount

of individuals in need of an organ transplant is modest compared to the supply of organ donors. And I think that has created this disparity where depending on where you live, you may have better access to organs in various places. The solution to that obviously is to change the system. So in other words, the way that organ donation is coordinated nationally is through these organizations called organ procurement organizations or OPO's.

There's 58 of them in the country. Some of them are pretty easily understandable, like Michigan has, for example, one OPO that covers the whole state. There's like six in Texas. So it's a little bit of a confusing network, but the point is those are the organizations that nonprofit organizations that are responsible for identifying organ donors and facilitating the gift from procurement to transplant.

And then the waiting list, you hear people say that they're on the waiting list for an organ. The way that an organ is actually placed is every time an organ donor becomes available, the list is run, according to a predetermined algorithm of how that particular organ is prioritized. And the problem at least historically is that that list has been run largely locally or regionally first, and only then kind of offered out or broadly. And so what has changed in heart, lung,

and liver transplantation, and is about to change in kidney transplantation, is those kind of relatively artificial state or regional boundaries have just gotten destroyed. And so now the way organs are allocated are literally by concentric circles. So they offer it based on distance from the donor hospital.

And that has created some interesting phenomena. I mean, the good news is, to your point, is that the geographic variation that exists across the country has decreased. So it's not as important now to go to a certain place if you know you need a liver transplant, for example. It also has created a system where if you're really sick, you know, at the top of the list for liver transplantation, for example, you're going to get transplanted quickly because you've got access to this broad swath of organ toners. The challenge is kind of the people that are medium sick, some of whom are still quite ill from their disease, who have all these sicker people kind of ahead of them on the list getting

transplanted. And that speaks to the kind of need for expanding the donor pool alternative donor sources, more living donation than a case of kidney and liver transplantation to kind of meet that need. So the system has gotten more fair, but it's only exposed the need even more, I guess, is the best way to set. That's good to hear because it definitely struck me as a pretty unjust system 20 years ago, especially with liver, reminded me of some great injustice. You alluded to brain death earlier. We've been remiss in not, I think, explaining to people a little bit what that means. And especially now as we sort of talk a little bit about liver

where a much greater number of the transplantations are from non-living donors, the donors are non-living. So what does it mean to be brain dead? And how does that factor into, from a legal standpoint, what does it mean? And then from a physiologic and biologic standpoint, what does it mean? It's interesting.

You would think that this would be like something you could flip to page one in medical textbook and there would be, you know, but it's actually been a relatively kind of complex set of definitions to come to. And the importance of establishing brain death was in many ways driven by the development of transplantation because if we were going to use deceased organ donors for transplant, we needed to establish clearly defined ways that these were individuals that could not recover, you know, we're not going to be salvageable such that they could then go on to be organ donors. And to be even more specific about that, the whole question of what defines death, you

know, so is death when the heart stops or do we consider death when the brain has lost function and control? So just to clarify that for people, right, the first thing you said is when the heart stops is what we call cardiopulmonary death. So a person has a heart attack, the heart stops, cardiopulmonary death. A person has cancer. Eventually leads to cardiopulmonary death.

This brain death thing, how does it show up? Give people examples of the physical way, the physiologic ways people get there. It's a kind of confusing concept. How can the body be alive but the brain be dead? And there are a whole number of circumstances where that can occur. But essentially, the central component of the definition is that the brain sustains an injury. That could be from anoxia, from an anoxic event. It can be literally from a traumatic event, penetrating injury, a devastating head trauma.

It can be from an intercranial event, a bleed, or such, such that the pressure in the brain and the injury that evolves in the brain increases to a point that blood flow and oxygen delivery to the brain stops. And so all the cellular processes that are occurring kind of from literally the skull base up have stopped. And there are clinical ways to define that diagnosis.

So there are characteristic neurologic manifestations of brain death, the classic ones that you see on TV are the blown pupils as someone's brain is swollen to no longer allow blood flow into the skull. There are core bodily functions that the brain drives, such as respiratory drive, that are part of that definition as well as as well as a bunch of additional primitive reflexes. And really what evolved over time is a clinical definition of brain death that includes multiple elements, including that the individual has to be chemodynamically stable. They can't be hypothermic. They can't be in some metabolic condition that could confuse the issue. But then the central focus of it is this thing called

an apnea test where they literally stop the mechanical breathing support and see whether or not the individual generates the drive to breathe on their own. And so there are clinical brain death exams that physicians are used to doing to document that. And then there are ancillary studies that can actually show that blood flow has stopped into the brain.

And I think coming to a consensus on that definition was really critical to allow the establishment of what equates with death, so the loss of the function of that individual, even if there are other physiologic, like their heart beating, are maintained. And establishing that diagnosis then allowed the step to go from, well, if they are brain dead, but there still have present circulation, can we then move to organ procurement? Because in the absence of that, you could kind of ethically equate organ procurement as as prompting death, right? So in other words, if these individuals are not yet dead, organ procurement is expediting your death, which with their death, with violates all the principles of kind of autonomy and the principle of organ donation that transplantation is built on. So there's a couple things there.

I just want to highlight before you go on, Chris, just so people understand, brain death still requires cardiopulmonary support. That's the very important thing people need to understand. A brain dead individual is not going to be laying in a bed. Their brain not functioning yet somehow they're alive. By definition, if your brain is dead and you are not on full cardiorespiratory support, you will be dead within moments.

So that's why this apnic test is done while they're hooked up to a respirator that is just turned off but not disconnected. They will fail to breathe as you point out. They will fail the apnic test and then they'll be resumed on cardiopulmonary support because of course the goal is to continue to oxygenate their body perfectly to maintain the appropriate levels of tissue health. The other thing that's worth mentioning, it's like, if you watch TV, you might be lulled into thinking that the same set of doctors that are trying to understand if you're brain dead and trying to take care of you after whatever

accident you had that led to the situation you're in, have anything to do with the doctors that are coming along to take the kid in your liver. And because that would seem a little grotesque, right? So explain that sort of line between those two teams of physicians, because you and I have been multiple times on both sides of that. We've been taking care of those patients in the ICU that are going to become donors. And then we've been on, you know, on the other side where you're now part of the team that's harvesting organs. Correct. So it's a clear ethical principle that is central to not only the kind of effective operationalizing of transplant, but also to the

establishment of the public trust that is critical to allowing transplantation to exist. And you know, the way I explain that to transplant families and organ donor families is that the systems are completely separate with an opportunity for integration in between that only occurs when certain events has happened in the individual's care. So number one, the concept of brain death has to be thought about to begin with. You know, that that's part of the diagnostic evaluation of that individual, the brain death exam needs to be confirmed, the family and or patient through previous documentation has identified that individual as an organ donor,

and only then after those steps is the transplant machinery or specifically the organ procurement organization involved. So some people have the concern, well, gosh, are the people that want more organs for trans might gonna somehow interfere in the decisions that are made about this individual who's undergoing some tragedy that's leading to the end of their life. And the reality of that is fortunately that we have no impact on that decision.

I think the other principle that is fortunately that we have no impact on that decision. I think the other principle that occurs is that then the care of that individual body, because if there have been declared brain death, we consider the individual, then passes from the caregivers, the healthcare team that's been caring for them, to the organ procurement organization and their team for them, to the organ procurement organization and their team, and then eventually to the transplant teams into the procurement. So there's a clear transition from when they go from an individual under the care of ICU team or the teams that are caring for them to the individual's food responsibility.

It is to facilitate the gift of transplant and I think in situations that fortunately occur more and more often where either the individual themselves have already identified on their driver's license or through conversations with their family that they in the event of a tragedy they want to be an organ donor or families come forward and I always think this is incredibly generous. I mean, this usually occurs out of the worst day of their life and they come forward to say that they would want their loved one to be an organ donor. Nothing happens on the transplant side until all those steps have occurred. And so I think it's really kind of critical to understand that. It is worth alluding to the concept of donation after cardiac death, which is where that gets a little more confusing. So there are individuals

who have suffered a life threatening event, a devastating head trauma, but that has not caused brain death, other medical conditions where the care team and the caregivers have decided that their life is not salvageable, but they're not technically brain death. And that's always been a conundrum because what if those individuals want to donate their organs, but they don't meet this very strict criteria that we've established as an important principle to allow organ donation. established as an important principle to allow organ donation. What has evolved in the United States and around the world over time is this concept of donation after cardiac death. Importantly, there still needs to be the establishment of death before we can procure organs to again separate the process of declaring death from

the process of procuring organs. And so what happens in a donation after cardiac death situation is the family chooses to withdraw care, care is withdrawn, the individual then expires over some period of time, and then depending on the circumstances of that individual's death, how quickly it happens, etc., if we then believe it's appropriate to still utilize those organs, organ for care, it can occur. And those decisions are all made before withdrawal of care. So in other words, the family has decided to proceed with pursuing organ donation. The arrangements have been made to have the teams and individuals available

there to procure the organs and preserve the organs appropriately. But nothing happens until that individual is declared dead by a provider that has nothing to do with the transplant team. So I think even in the case of donation after cardiac death, we've kept that very clear delineation between individuals caring for the patient and individuals processing the gift of the donor for transplant. You alluded to something earlier,

which reminds me of one of the sadder stories when I was in residency actually when this happened. So one of my mom's closest, closest friends, her son who was five years younger than me. So I grew up together, was driving home one morning after a night shift and fell asleep, crashed, and died, you know, an immediate brain death. His mom, single mom, no relationship to his father had to make this what can only be described as, as you said, the worst, the worst day of your life.

And now you have to make a decision. And, you know, on her forget she, she made this decision to have every, every single aspect of her son donated, you know, cornea's skin, his liver was split into two. So two people benefited from his liver as both kidneys, heart lungs. It's always stuck with me. And if that wasn't enough, a couple of years later, I would go on to meet a friend that I ended up working with actually who lost his son to his, he was in a jeep accident, rollover jeep. And same thing, you know, he and his wife had to make this awful decision about their 21-year-old son

who had just died. Without hesitation, they did the same thing, which was every piece of our son, Aaron, who was his name, is going to be donated to help someone else. What was especially amazing in the case of this couple, I think I can say their names. I think they're actually quite vocal about this Jeff and Tina Webster is that they got to know every one of the recipients and as I got to know them and got to know the stories I was just blown away by it and again I'm someone who's been around this stuff, right? Like it's not like I haven't seen these things before but The man who got his liver has a tattoo of their son on his arm. You know, it's that kind of stuff.

It is hard to believe. I mean, do people ever ask you, Chris, hey, you know, should I check that box on my driver's license when I'm at the DMV about, do I want to be an organ donor? I mean, how do you talk to people about something like that? Yeah, it's a great question. And it is one that I get asked. And actually, my oldest daughter tells me she occasionally gets asked now. I guess, because people know her dad's a trans-want surgeon.

So, what are the reasons that people hesitate to do that? And I think some of it is what we already alluded to is kind of the concern or the mythology that somehow would affect their own healthcare. And sometimes I'll answer questions about that. But I always try to focus on the profound impact that transplantation can have. And try to share with them what I've learned from donor families over the year. And one of the privileges of the position I am in now is that I do get to occasionally do advocacy work and other opportunities to meet donor families. So families like you just told of the websters that have a history of a family member who

was an organ donor and many of them can point out tell of the process they walk through with that decision making and the memories of their loved one. But one of the things that donor families really universally share is that their experience of organ donation, whether or not they were able to meet the eventual recipients of their loved ones organs, but that the experience of organ donation and knowing that their loved ones organs

live on in another individual and save their life is the only good thing about what was otherwise the worst day of their lives. And I've heard that actual phrasing repeated by multiple families, by multiple individuals who had to say goodbye to their son, daughter, sister, brother, husband, wife, but took some solace in the fact that you were honoring their life by passing on the gift of their organs to another individual. So I think it's important for people to hear that it can be a transformative gift.

I think the other thing I share with people and let them make their own decisions is that there is an incredible need for organ donation. There are currently more than 100,000 people waiting on the waiting list for the various organs and each year there are less than 40% or so of that number done. And the need only grows each year. The gap between donation and supply grows each year. Furthermore, the outcomes of the individuals who get transplanted improves each year. So not only do we have this tremendous need for individuals dying of organ failure, but the life that they can look forward to is in most cases incredibly

good, restoring them back to life expectancies that approximate normal and qualities of life that in many cases are totally normal. So that's the vision I try to share with people when they're considering organ donation, but acknowledge that it's a very personal decision and people have to be comfortable with that. I do encourage people if they feel passionately about it to make the decision themselves. Because I can tell you, like you said, you know, we've been on both sides of this, that walking through that decision-making with someone's loved one who is in the middle of the night

in a foreign hospital trying to make the decision about the wishes of their loved one is an impossible task. So the more that you can register yourself and communicate that to your family, the actually easier you make it on, your loved one's God forbid they end up in that situation having to facilitate that gift. Yeah, I think that's the point. You can think of this as an advanced directive, which actually is the biggest service you can give to people around you

so that they don't have to, there's no ambiguity about what your wishes are. We've talked a lot about kidney, but I think I'd be remiss if we didn't spend some time talking about the liver, which is really the bread and butter of your clinical practice. And it's certainly one of the most technically demanding operations in the field. It's no surprise then that the most amazing surgical resident I ever got the train alongside is doing the pinnacle of what surgery offers.

Let's go back to the 1960s. There's a young guy, it's 1963. There's this guy nobody's ever heard of, Thomas Starrzel. He's plugging away at this operation. He actually, I think, if I'm not mistaken, was the first guy to figure out that you could add prednisone to Immurin and actually increase survival to levels that were still abysmal by today's standards, but reasonable. I think he was getting 70% survival at one year, But four years later, a three-year-old boy dies on the operating table bleeds to death. And at that point, people sort of had enough, and there was kind of as you alluded to earlier, this moratorium on liver transplants until we figure

this out more. Let's start with the technical aspect of it. What is it about the liver that is so difficult to surgically implant? I mean, the liver is the largest difficult to surgically implant. I mean, the liver is the largest solid organ in the body. It has some interesting anatomical nuances. It has a dual blood supply, so it's supplied by the hepatic artery, which is a major branch essentially off the aorta, as well as the portal vein, which is the blood drainage of all of the intestinal blood flow. And the reason that returns through the liver

is the liver is the filter, essentially the metabolic filter for the metabolites absorbed in the GI tract. It then lives on top of the vena cava, the major vein returning blood from the lower part of the body back to the heart, and actually sits right below the diaphragm, right below the right atrium, where it has this complex venous network that drains into the Vena Cava. So it's anatomically made not to be messed with in some ways.

This is the way you'll hear people talk about it. I mean, in addition to that, you then have have all the intra-hepatic anatomy, which can be profoundly complex as well. But the thing that makes liver transplantation really the challenge that it is surgically is not so much the anatomy, which fortunately with experience you learn how to navigate. It's the fact that liver failure, at least the diseases for which we most commonly transplant. So the development of cirrhosis or the end stages of chronic liver injury and fibrosis, leads not only to synthetic failure of the liver, so the liver loses the

ability to process some of those metabolites. It loses its ability to make new proteins, including some of the proteins that help your blood clots and other important functions. But because the liver is become this scarred, fibiotic organ, all of that blood flow that's returning from the intestines has to make its way through what used to be this soft, compliant sponge, and is now literally the consistency of a rock. And so what happens is you develop this condition called portal hypertension, where the pressure in the portal-venous system increases such that it tries to find other ways back to the heart. And so it forms collateral channels.

Those collateral channels are what form the varicies or varicocities that are developed in the GI tract that can lead to life threatening hemorrhage and liver patients. It's what leads to the formation of a cytees or the fluid retention that you see in patients with liver disease, with these huge protuberant, distended abdomens. And it also makes the surgical field this kind of rats' nest of collateral venous vessels.

So you've got the challenge of a large organ with challenging anatomy. You have the challenge of this condition that makes the dissection and the predeliction towards bleeding even higher. And then you have the synthetic function which is occurs in the setting of, you're doing this operation, the setting of an individual who's not making normal clotting factors. So it's really both the circumstance of the technical challenge, but more often the

circumstances in which you're doing it. And as you know, liver failure leads to cackexia and muscle loss. So these are debilitated sick patients that you're then doing a big operation on in suboptimal conditions. And so the fact that Tom Starsel and his contemporaries took that operation on in the 1960s when electrocatery wasn't really a thing. Most hospitals didn't really have blood banks. We didn't even have critical care in Asesia, at least with any resemblance to what it is now. I mean, it's pretty remarkable that that was even conceptualized, much less achieved technically. And as you alluded to, it was really their realization that not only was the procedure

so technically demanding that the risk of early mortality was quite high, but you were doing it in an immunologic setting that just was not successful. And so, you know, even the patients that survived the operation and the early recovery, there were really no survivors past 90 days and the first dozens of transplants done, which is what led to the moratorium on liver transplantation that occurred in the late 60s. And I would add one other thing to punctuate everything you said, Gris, which is not only are these the sickest patients I've ever seen. I mean, these patients are staggeringly sick, but they lack something that every other sick patient has prior to a transplantation. So whether we're talking about cardiac transplantation,

pulmonary transplantation, pancreatic transplantation, renal transplantation, all of those organs have some form of extra-caporial support that is offered to them, to at least bridge the gap or tune them up a little bit prior to surgery. The liver remains the only major organ with no form of extra-caporial support. Now I could spend an hour giving you my theories as to why that's the case. I think it speaks, I'll give you the punchline, I think it speaks to one particular function of the liver, although I think there are many, but I think the one that just can't be done by a machine is the regulation of blood glucose. It is so complicated to manage gluconeogenesis glycogen storage.

I mean, you have to be able to regulate something to the milligram level with seconds to spare. There are probably a dozen other reasons, but every attempt at extra-caporial liver support has failed, including some crazy stories that, you know, I heard from God, one of our, one of the Transpens surgeons I remember, it might have been Montgomery, even told a story about the Baboon. Yeah, that's a Mel Williams story, classic.

Oh, that's right, that's right. Mel Williams, why don't you tell folks that story actually, it's just the scariest thing. So what you're alluding to is exactly correct. So there have been all kinds of both mechanical and even anatomic models trying to address liver dysfunction or to bridge that gap from liver failure to transplant. And nothing has worked real well. I mean, essentially, we've tried what's

been called liver dialysis. In other words, trying to remove some of the toxins from the blood stream that the liver is responsible for filtering. We've tried things that do address the portal hypertension. So at least you kind of alleviate that problem. But nothing has replaced the synthetic function that you describe. So one of the obvious conjectures, well, then we need a physiologic solution to this.

Could we support patients, particularly patients with acute liver failure, where the injury is acute, and the liver is this incredible organ in that it does have this regenerative capacity. Hepatocytes will replenish over time. So the thinking was, well, if someone comes in with a Tylenol overdose or an acute viral toxicity to their liver,

could we just bridge them long enough until those new hepatocytes start to come into play? And so it was under that principle that the concept of, well, can we do some sort of extracorporeal model to support these patients? And so Mel Williams, who was the, he was a contemporary and a student of David Hume, who was one of the godfathers of transplant and transplant immunology specifically, Christian Barnard, who did the first heart transplant, actually

trained in his lab, and Dr. Williams worked there as well, and then eventually came to Hopkins and started the transplant program at Johns Hopkins. He was a kidney transplant recipient eventually himself, received a living donor kidney from his wife, and unfortunately died recently later in age, not related to his transplant, a remarkable kind of luminary figure, and one of the best storytellers, you know, you've ever heard.

But he tells the story of that they decided, well, why don't we address acute liver failure by hooking up the patient to a extra-caporial, essentially, you know, bypass circuit and put a baboon on the other side of the circulation. So the baboons liver would essentially filter the toxins out. They'd be the blood would be returned to the individual and that would address their acute liver failure. So they worked on this prep and they did all kinds of preclinical studies and eventually

they had somebody come in with a acute liver failure and I don't know the specifics of IRB regulations at that time but sure, they got approval to do this. And one of the things they quickly realized is, and I don't know any of the veterinary medicine behind this, but you can't sedate a baboon very easily, you know, it takes herculean doses of sedatives. And you can't have a baboon running around the medical ICU at Johns Hopkins Hospital. So they decided, and maybe what wasn't the most ingenious method, to put the baboon in a body cast. So they would, at least the baboon would be frozen to the bed.

So they do the preparation, and unbelievably, it starts to work. So the patients and cephalopathy clears. The patient starts to wake up. So this poor individual wakes up in the ICU at John Tappian, so he doesn't know what's happened to him, looks over and there's a baboon lying next to him in the bed next to him. So what does he do? He tries to get up and start pulling it lines. So the solution they decided to that is they actually put him in a body cast, so there was a baboon in this poor individual in a body cast in the ICU next to each other

in Johns Hopkins, and that was a short-lived series of experiments, but it did prove the principle that that would work, that if you had an actual functional liver in cross-circulation with an individual, and actually he went on to do some preparations between, for example, family members. If a family member came in with a cute liver failure, you could put them in cross circulation with sibling or something. And some of those did work and maintain those patients. It also led to the principle that is part of an investigational product now that created this essential dialysis column populated with hepatocytes, with hepatocytes stem cell

line that populates the hepatocytes. And that has been shown at least in some studies to at least provide some limited short-term support as well. But the principle behind what you said is absolutely right, that we have not figured out how to provide extra-caporial support for liver patients. So they really are the patients that face death if they are not able to be transmitted in a timely fashion. One of the most stark memories I have from residency on the side of patients

that would ultimately need a transplant was probably my second year in the old SICU. The young woman came in, she was 21 years old, she'd overdosed on Tylenol. And it's funny when you realize how dangerous Tylenol is and yet how willy-nilly it's available. You know this, of course, but just for folks listening, the LD50, the lethal dose at which 50% of the population would be dead from a drug, that's a, you know that one would know that for every drug out there, What's the LD50 of fentanyl? What's the LD50? Well, the LD50 of Tylenol might only be 10 to 20 times beyond what you would normally

take for your headache. And so the ease with which a person can end their life with Tylenol is staggeringly high. And as was the case in with this girl, you know, I think she broke up with her boyfriend and took a bottle of Tylenol and by the time she sort of realized that this was a bad idea, it was too late. And there was the saddest memory I have, Chris, as the following. Before she really went into acute liver failure and then suffered sort of the encephalopathy that would then rob her of her cognition while we waited for a transplant. There was a lucid period of time when her PT, you know, INR, PTT were through the roof, LFTs were through the roof and it was very clear she was going to die without a liver transplant

and yet she was cognizant enough to know that. And I don't remember how big that window was, but it existed. Now, we could have been wrong. Maybe she was going to recover, but it turned out she ended up getting transplanted and it was just amazing to see her wake up from that and realize like she had another lease on life. And you could say, I mean, look, someone could say, well, she made a dumb mistake,

and maybe she didn't deserve another chance. But of course, I would say who among us hasn't done really dumb things? It's so true. It's, you know, fortunately, a cute liver failure only accounts for about 5% of the liver transplants done in the United States. So it's a relatively uncommon situation in In part, because the liver is pretty resilient, so sometimes even a catastrophic overdose

with good critical care and other measures, many of those patients will recover. But we are often faced with the situation where just exactly like you described, a person comes in with a Tylenol overdose. It's an intentional overdose, or at least as suicidal type gesture. And we have to make the decision with limited information about whether or not we think they're an appropriate transplant candidate.

And occasionally there are reasons why they're not, you know, uncontrolled comorbid disease or maybe, you or maybe other factors. But usually it's exactly the circumstance you described. It's a young distressed person who reacted badly to a particular event. And makes a very impulsive decision. Impulsive decision.

With a freely available drug like out of their medicine kept. And I think the approach of our center, which I think is true of most transplant centers, is to give those patients the benefit of the doubt and try and get them to transplant rapidly, and then use all the appropriate resources afterwards to help support them and make sure that any mental health issues and such are addressed.

So they are tragic and dramatic circumstances that can be incredibly rewarding, you know, transplants, as you would imagine, though, to see them literally get transformed from the transplant. Chris, when you and I were in medical school and residency for that matter, it seemed abundantly clear that hepatitis C was going to overwhelm the liver transplant infrastructure within the United States. Today, there's good news and there's bad news. The good news is that hepatitis C is not going

to overwhelm the liver transplant infrastructure of the United States. The bad news is that something else is going to do that, and that's naffled the a Nash. Can you tell us the twin stories of these two things? And how is it that something that we believed could never be cured, got cured? And then how is it that this thing that we didn't know existed 20 years ago is going to be, if it not already is, the leading indication for liver transplant in the developed world? It's such a kind of at once compelling but also humbling story and I'll and telling it all add even a third actor that you know is part of this as well. So, hepatitis C as you alluded to, you know, a viral illness, bloodborne illness that has

kind of an interesting history. Some people that are exposed to, so hepatitis C rarely causes an acute illness fortunately. Some people that are exposed to, so Hepatitis C rarely causes an acute illness, fortunately. Some people that are exposed to it can clear the virus, so spontaneously clear the virus, but the majority are left with chronic vibremia and subsequent inflammation, which is silent for years and in some cases decades. So the kind of history of this in the United States is that people were exposed to this in the 70s and 80s either due to a time when the blood

supply was not really tested as stringently and they acquired it through blood transfusion or they acquired it from use of IV drugs or other exposures, but then it went on out there life. And then here they are 20, 30 years later with cirrhosis and eventual complications of cirrhosis and indication for transplant. And for about 20 years, that was the predominant indication for transplant in the United States, which was a challenge because the medications we had to treat hepatitis C were not particularly effective, you know, response rates of 15 to 30% or so. So every one of those patients got recurrent hepatitis C after their transplant and many went on to develop graph failure, you know, and cirrhosis, essentially,

of their transplanted graph. So it was a particularly frustrating clinical problem because there was this enormous need, but also we were only kind of partially solving the problem. And what has happened and what you're alluding to is in the last 10 years essentially was the development of these direct antiviral agents that have transformed the field of epitidescy. And it's, you know, you can make some arguments about what's the greatest medical advance we've witnessed in our, you know, medical career,

but that's up in the top two or three. Yeah, I don't think I could think of something more impressive in my adult life. Maybe you could argue the retroviral regimens that made HIV a chronic disease instead of a could rival it, but I mean this is transformative. So you take patients who were on a certain path towards liver failure and death, cure their viremia, and what we actually anticipated would happen was that all the patients who already

had cirrhosis would eventually go on to need transplant anyway. But what we've seen is a precipitous drop in the number of patients needing transplant for hepatitis C because once they clear the virus, their liver does recompensate and repair somewhat. And the patients that are not serotic or with advanced fibrosis yet are never going to get there. So it is it is truly a curative situation. So that drop has happened precipitously over the last three to five years. It has been replaced nearly completely by actually two diseases. The first and the one that has this incredible broad public health impact is non-alcoholic

fatty liver disease, or the concept of fatty deposition in the liver that leads to chronic inflammation and kind of just like a chronic virus, ongoing inflammation, fibrosis, eventually cirrhosis. And with the obesity epidemic and other associated diseases, the prediction is that by 2030 or so, it will become the leading indication for liver transplantation. And we've already seen that curve start to inflect up pretty highly. The only thing that makes the story a little more interesting or frustrating is there's another curve that over the last several years has inflected even at a steeper slope. And that is the incidence of alcohol-related

liver disease, which has always been an important cause of liver disease in the United States, but unfortunately, and whether you blame it on the economic downturn in the late 2000s or other factors, really have seen an explosion of alcohol-related liver disease, made worse, by the way, by the pandemic. And I think that has occurred at a time when transplant centers have adapted their approach to patients with alcohol-related liver disease to make it a little less of kind of this terrible, Spanish-inquisition kind of approach to, you approach to either you're in or out, if we think you're committed to sobriety, to a system where we have developed resources, mental health professionals, counselors, and such to support people in their sobriety to allow them to get

transmitted successfully. I hope that that curve plateaus, we unfortunately don't have an intervention for fatty liver disease that I see breaking that, the slope of that curve quickly. And it has changed our field because the population of patients with fatty liver disease is much different than the population with chronic liver disease of other causes, whether it's alcohol, hepatitis C. Most of those patients have liver disease and the consequences of liver disease,

but usually, fortunately, not much in the way of other morbidity. Whereas you take the fatty liver disease population, they are, first of all, off an obese, which poses surgical risk and other challenges. But on top of that, they have all the other manifestations of their metabolic syndrome. They have cardiovascular disease, hypolipidemia, etc. which poses medical management challenges both for making sure we select patients that are likely to be successful with transplant

but also with caring for them afterwards. I mean, you'll hear the comments said that we've kind of converted our liver transmy population to look a lot more like our kidney transmypopulation because they're dealing with these cardiovascular comorbidities and other things that are just that are threatening their long-term survival as much as their liver disease and anemia suppression is. I sort of think that the uptick in alcohol associated liver disease or affl-dece, is kind of the parallel but gets less attention than what we're seeing with the opiate crisis.

So the opiate crisis is, I think it's easy and understandable that you would throw the manufacturers under the bus and in truth they deserve to be thrown under the bus. And you can throw the physicians under the bus who in truth they deserve to be thrown under the bus. And you can throw the physicians under the bus who prescribe them to freely, and that's fair as well. But the elephant in the room is the why, right? Like, why is it that people are self-medicating with opiates that are made too freely available, et cetera? And I think with opiates, because the outcomes can be quite binary and stark in the nature of the overdose, the nature of the death, it becomes very easy to focus on that. But acute alcohol toxicity is virtually unheard of. Very few people will

drink themselves to death in a moment. Much more common, of course, is the chronic toxicity of alcohol. And I think that you're one of the few specialists within medicine as a transplant doc or a hepatologist who actually gets to see what that looks like, but I think it doesn't really register for most people that they're basically two sides of the same coin. Yeah, I totally agree with you. I think we, unfortunately, that perception that they're different, or the fact that we kind of both medically and society-wise treat them differently, has prevented us from addressing the problem with the appropriate attention it needs.

One of our hepatologists here at the University of Michigan, Jessica Melendure, who's really dedicated her career to understanding alcohol, really delivered disease, as she has refined kind of her approach to the evaluation and management of this disease, is she really makes the sense that the emphasize of the point that this is a behavioral disease. You can argue Nash can be a behavioral disease in some cases as well,

but therefore the resources have to be put forth to address the behavioral disease. And I think, you know, we have largely turned a blind eye at the impact of alcohol-related liver disease and alcohol use disorder in our society because of just the fact as you said, it's a freely available substance, the machinations and just kind of destruction that people have to go through their life to get opiates. It's not the case for alcohol. You can go to the 7-11 and get the kind of equivalently damaging dose, you know, there. And I

think it's made the problem much harder to address and I am glad to see the transplant community and the medical community kind of repivoting in our focus towards trying to help people address the reasons why they're involved in this cycle. Because it is tragic and one of the classic 65-year-old guy who's been drinking all his life and gets to the end of his life and has cirrhosis and complications. That's right. Most of us think of the Mickey Mantle story where it's exactly what you described, but it is the same disease and yet one population numbs within acute numbing agent, opiates, that have an acute toxicity and the other numbs with a chronic numbing agent that has a chronic toxicity. To somehow put those into different silos, when I think the underlying conditions are

similar is probably slowing our progress. Yeah, I totally agree. I totally agree. Chris, the last thing I want to talk about from a transplant perspective, there's so much I want to talk about, but I want to be respectful of your time, and I know you've got a head off to a meeting shortly. You talked about the team. One of the things about transplant that attracted you to it was the team, And I think it's probably not obvious to people how big that is.

It's obvious to me because I got to see it during residency, but I don't think there's a field of medicine that has a bigger team when you income. But I mean, the only one that I could maybe think of would be like that would arrive. It might be pediatric cardiac surgery where you just have such, you know, the overlap is huge. But even that might not be as big as what we're talking about here in terms of the perfusionists and the surgeons and the anesthesiologists and the nursing and the ICU.

And then the logistics associated with organ procurement. It's an enormous team. And you lost a number of team members a while ago, shortly after you got to Michigan. I think that story is obviously tragic, but also highlights the incredible risk that goes into this. Do you mind telling that story a little bit? Yeah, sure. So what you're referring to was a in June of 2007, we had a team that had flown from Michigan to Wisconsin to retrieve lungs for one of our recipients. They had actually procured the lungs. They had just taken off from Milwaukee and had a tragic set of circumstances that happened

to the plane and tried to turn it around and get back to Milwaukee and essentially crashed into Lake Michigan shortly thereafter and all six individuals on board died. There's a story in there about how important teamwork is in transplantation, you know, so six people lost their life as one small part of trying to get this set of lungs to a recipient. There were two pilots on board who passed away. Two of our perfusion staff, so individuals who are responsible for the coordination of kind of the procurement operation, the handling of the organ, its preservation, transport

back to the recipient team, and then two surgeons. There was a cardiac surgeon, and actually a fellow who died in that accident as well. And I can tell you that first and foremost, it's hard to speak about it now without getting emotional. It was the most devastating event that I've ever witnessed professionally, you know, directly. You know, there was a patient on the table, chest open on the table as the lungs were flying back. That operation had to be stopped.

One of our coordinators who was the person responsible for, you know, sorting all these logistics was the person who figured out that the plane had gone down and that had to tell our team what had occurred, it was devastating to put it mildly not to mention most importantly the loss that those families sustained. I think it shook us all in a way that I think is still relevant. We still celebrate the lives of those individuals here at Michigan every June. You know, if there is any good news about that event,

it did two things, one of which I think was kind of more immediate and personal and that is it really made apparent to all of us here and I think in the broader transplant community, how precious each member of our team is and how important their contributions are and how much they put at stake to make these incredible events of organ transplants happen.

The second thing is it made our field pause and figure out, do we need to be doing things differently? Do we need to be shipping teams all over the country to procure organs when there are qualified surgeons right next to where that organ may have come from? Do we need to reconsider how we travel in terms of the expertise of the flight teams and such and the actual planes themselves? And it has motivated differences. For example, in the liver community, now we used to fly out every time there was an organ to, you know, we would go to wherever that donor hospital is. Now more than 50% of the time, you know, one of our colleagues at another center procures that organ

for us and ships it to us, which is the way that it should be. I mean, I think if you were a layperson looking at the system, you're like, wait a minute, why are you shipping teams all over the stuff when you have qualified people right there? So it has motivated change in our community that I think needs to continue to evolve, but you're absolutely right that it was a terrible event to remind us of the kind of sanctity

and importance of our teams for sure. Chris, I want to thank you for sharing that story. It's hard to believe it was 13 and a half years ago. I mean, I remember it like it was yesterday, so I can't imagine how proximate it feels to you as well. This has been wonderful to sit down with you and talk about this. I always enjoy our times together and I have the fondest memories of sitting in that empty cafeteria two in the morning between traumas. And again, as long as I was sitting there with you, it was always enjoyable. It was never like, I can't wait to get back to the call room

and try to get 10 minutes of sleep. It was like, I'd rather be sitting here with Chris absorbing his wisdom, even if it means getting no sleep tonight. So that wisdom continues. And I know that you're surrounded by patients that are, I hope they realize how lucky they are to have you as their doc. I'm sure they do.

Now, you're very generous, Peter. And I just want to say how grateful I am for you inviting me. I also really am grateful for you using your platform to highlight the importance of organ donation and the miracle really that it is that transplantation works. And so I'm grateful for the opportunity and most of all just to see you in the next little bit.

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