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

1. 0:00 – 1:15

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. [upbeat music] Well, Chris, we've been talking about doing this for probably two years now, um, so I'm really happy to finally sit down with you, though we had always thought we'd be doing it in person, but-

   2. CSDr. Chris Sonnenday0:21

      Yes

   3. PAPeter Attia0:21

      ... decided, just didn't wanna wait any longer. Um [laughs]

   4. CSDr. Chris Sonnenday0:25

      [laughs] Agreed.

   5. PAPeter Attia0:26

      But, uh, no, I, I miss you dearly, and, uh, I think, uh, during our discussion today, people are gonna get to understand why, uh, you know, why you've played such an important role in my development. Um, I guess let's just... You know, I'll, I'll just state for everyone that you were, you were one of my senior residents, what we call chief residents-

   6. CSDr. Chris Sonnenday0:44

      Mm-hmm

   7. PAPeter Attia0:44

      ... when I was going through my training at Hopkins, and, um, I think on other podcasts, people have probably heard me mention you. I've certainly talked about you. Uh, I talked about you on Jocko's podcast several years ago. I've talked about you on this podcast, and, uh, usually in the context of, you know, what I consider to be the most remarkable leadership. Uh, residency was not, um, not without its stresses and stressors.

   8. CSDr. Chris Sonnenday1:08

      Yeah.

   9. PAPeter Attia1:09

      Um, and I think we have lots of great memories from it, but, but also some not so great ones, and, and-

   10. CSDr. Chris Sonnenday1:13

       [laughs]

   11. PAPeter Attia1:14

       ... therefore anything that,

2. 1:15 – 7:30

   What attracted Chris to medicine, and his leadership in residency

   1. PAPeter Attia1:15

      [laughs] anything that could've been done by those around us to make the process better was always appreciated. And, uh, uh, I think we'll get to that later, but l- let's just start by telling folks, like, how you even got interested in, in medicine, let alone surgery.

   2. CSDr. Chris Sonnenday1:28

      Yeah. Uh, well, first of all, thank you so much for the invitation. It's, uh, it's awesome even virtually to, 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, um, so impactful to patients, providers. It's just a cool way to see your, your leadership and impact extend. Um, yeah, medicine for me was something I stumbled to. So, um, I grew up in the DC area. Um, I was, um... My dad is a retired Presbyterian minister. My mom was a medical social worker. Um, the only other physician in my family is my grandfather, um, who was a- an internist and researcher, uh, in St. Louis. And, you know, I went to college without a clear plan other than wanting to, to play college soccer, which is what, uh, I was fortunate enough to do. And, um, and I, uh, had imparted to me by my parents that, you know, they would support whatever I chose to do, but, uh, wanted it to be, uh, something that served other people. And, um, and I, you know, through the course of my studies, you know, did, uh, come to medicine for some of the somewhat cliche reasons, you know. It was a way-- It was a really exciting, challenging, uh, field that appealed to kind of the, the, the problem solver or the scientist in me. But first and foremost, was a way to serve people. Um, and, uh, you know, was-- came to surgery very late, too. In medical school, I was one of those people that kinda liked everything and, uh, was fascinated by kind of, you know, all fields. Um, but really became attracted to what fortunately I think still sustains me today, and that is that, um, being a surgeon provides this really unique opportunity to enter people's lives in their, um, scariest, kinda darkest moments. And to have the privilege to be able to walk that with them and try to help them, you know, uh, navigate that time and, and to have skill in, in some cases to solve the problem, and I think that was remarkable to me. I was, you know, struck by the, the challenge of it and, um, you know, was fortunate to, to make the decision, uh, to train in surgery and end up at Hopkins, where as I totally agree with how you described it, it was like at the one hand kind of forged us into the people we are today but, you know, also, uh, was difficult and challenging and, and that's partially also what made it, you know, the experience it was.

   3. PAPeter Attia4:29

      Yeah. How did, how did you pick Hopkins? Um, I know everybody who... Uh, I mean, I guess you could say Hopkins sort of picks people and not the other way around.

   4. CSDr. Chris Sonnenday4:36

      Mm-hmm.

   5. PAPeter Attia4:36

      But how did you at least have the desire to go to, to such a rigorous program? Um, was it something that said, "Hey, once I've committed to doing this, I might as well go to the best place"?

   6. CSDr. Chris Sonnenday4:47

      Yeah. It was a, it was a combination of things. You know, as, as I mentioned, I decided a little late in medical school that I wanted to train in general surgery, and I, and I went and consulted with the, uh, program director at my medical school, who was John Tarpley, kind of a legendary general surgeon at Vanderbilt, and, uh, who had spent a lot of his career in Africa actually doing, doing, uh, you know, mission, uh, work and surgery. And, um, you know, I, I went to meet with him, and to be honest with you, the goal of that meeting was to h- 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, the best I could do. And, and, uh, we talked for a long time. He's a wonderful person, wanted to hear about my goals. And, um, and he said, uh, he said, I think partially in jest, but he said, "You know what? I think we need to send you back to the mothership." 'Cause he had trained at Hopkins, and he, you know, he, uh, still carried with, you know, very passionate memories about the training there and the, the kind of, um, standard of clinical excellence that, that, the training programs there represented. Um, and so, you know, I was fortunate enough to get an interview and, and, and, uh- Was obviously impressed with the history and the, the emphasis on clinical excellence. But like you, uh, I think I was also really attracted to the idea of mentorship, and one individual in particular, Keith Lillemoe, who was the program director at the time, now the chair of surgery at Massachusetts General Hospital. Um, you know, I really got the feeling that he was invested in the development and, um, uh, training of his residents, not only as surgeons, but also as individuals and as leaders. And, um, and exactly like you said, kinda once I got that sense, I, I wanted to swim in that, in that pool, so to speak. You know, figuring that, um, I would gain as much from obviously the terrific history and mentors and training environment, but also, uh, you know, the individuals who we were lucky to train next to. You know, I mean, I think you, uh, when you feel like you're just running with superstars every day, that does push you to be the best possible, uh, physician, surgeon, person you can be. And, you know, I can think of so many individuals just like you that, you know, inspired me to, to, uh, push myself to beyond kind of expectations that I probably even had for myself at that period of time.

3. 7:30 – 25:15

   How Chris maintained his empathy and humanity through the stresses of med school and residency

   1. PAPeter Attia7:30

      Yeah, I mean, uh, it's-- uh, there's, there's no doubt during this discussion, Chris, I'm gonna have to embarrass the hell out of you because, you know, the reality of it is y- you were definitely, um, uh, and, and you're just gonna be too modest to accept it, but you were certainly in a league of your own, even amongst that caliber of individuals. So, you know, um, w- d- you know, it's one thing to say you played for the Yankees. It's another thing to say you were Mickey Mantle or Joe DiMaggio. Um, and I think, y- you know, to me, one of the things I wanna dig into today is for many of us, certainly myself, um, I'd put in that category, you know, you show up with all of these ideas about what you can be and, um, what this process is, is like, and somewhere along the way, a tiny piece of you gets a little broken. Um, you lose a little bit of your humanity. You, you just-- your, 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, uh, that in my case led to a very extreme outcome, which was departing. Um, 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 it do- it's, it's-- to me, that's just an unusual combination that I, I definitely wanna understand that a bit more.

   2. CSDr. Chris Sonnenday9:12

      Well, I mean, that's very kind of you. I didn't feel that way [laughs] at the time, which is, I guess, true of all of us. You don't, uh-- the, the, the battle you're waging within is, you know, different than what everybody sees on the outside. Um, you know, I mean, I think, um, you know, one way of asking that question is kinda what sustained me during that time period, what, you know, um, kept all of us going, but, but me in particular. You know, I, I definitely had a, um, you know, 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, um, you know, I was very lucky to be there. You know, that there were, there were hundreds of qualified individuals who could have taken that spot, um, and, and other-- and probably thousands of other individuals who, who didn't get the opportunities I did to get to that spot. Um, and so I felt, uh, you know, obligated, if that's the right word, to kind of maximize that entire experience. Um, you know, I also, um, felt the, the burden, if you will, of, of the expectations of those around me. You know, I mean, it-- the, the, um, uh, the expectations of those that were training us, our colleagues, et cetera. You know, I always-- I-- one of the things I said to, to Dr. Lillemoe and Dr. Cameron when I left was, you know, "Thank you for your high expectations." Like, that's really what drove, um, me to achieve, uh, things that I didn't necessarily think were within me. I will say, though, that the last thing, and this, this is true to this day, so it's not specific to residency, is that I have always found, fortunately, that, um, what re-centers me when medicine gets hard, 'cause it does get difficult, whether you practice in a, you know, busy primary care practice where you're cramming through 40 patients a day or you're doing operations where a wrong move leads-- can lead to somebody's death, you know, there are, 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 re-centered me is the patients, I mean, to be honest. I've, I've-- that, um, that privilege that I was speaking of earlier of being invited into people's lives in these crazy moments and actually having the opportunity to intervene. And somehow, even in the thick of residency when you're like How can, you know, why is it that this lab I ordered f- 14 hours ago has still hasn't been done? Or, you know, why can't I find the X-rays that were just on this desk like [laughs] two hours ago?

   3. PAPeter Attia12:23

      Right.

   4. CSDr. Chris Sonnenday12:23

      Uh, you know, or what are all the other crazy things that we had to deal with, or why, why is there no food to eat at 11:00 at a 24/7 operation? Um, you know, the thing that always kinda recentered me is reminding me that, you know, the people upstairs, uh, in those beds had it a lot worse off than I did. And, you know, I think that, that the privilege of being involved in their care is kind of what recentered me, and still does today. You know, when I have days like that, I, that is always what is able to kind of pull me back to the right frame of mind.

   5. PAPeter Attia12:58

      A- another thing that I think made you very special, um, that wasn't-- that I think was actually distinct from everything you're describing, everything you're describing was on 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, but I, I just, I n- I, it would be, um, hard for me to imagine I'm the only one that felt this way. But I just remember anytime my rotation card showed I was gonna be your junior resident, it didn't matter what the rotation was, I couldn't wait for that month to arrive. And, um, so that speaks to something a little different. And I, I mean, like, let's go back to you went to Northwestern, if I recall, right, for college?

   6. CSDr. Chris Sonnenday13:42

      Mm-hmm.

   7. PAPeter Attia13:43

      And, and so-

   8. CSDr. Chris Sonnenday13:43

      Yes

   9. PAPeter Attia13:43

      ... you're a Division I athlete, you're playing soccer. Were you the team leader?

   10. CSDr. Chris Sonnenday13:49

       Um, I was a captain. Um, you know, I think, uh, um, I was not the best player on the team, at least on my college teams, for sure. But, um, I do feel very lucky that I was, um, you know, elected to represent the team and to serve in, you know, a leadership role, at least as it, as it is within the context of an athletic, uh, team. You know, I do think that, um, one of the things that has always been true for me, you know, and this dates back to, you know, sports as a kid and, you know, uh, and to be honest, is part of the reason why I chose to be a transplant surgeon, is that I always migrated to team, you know, collaborative, uh, activities. Um, you know, I was, I was never an individual sport athlete. You know, I, I swam a bit, I played tennis a bit, but I never kind of like was captivated by those sports, uh, in the same way that I was of just being on a team. And in fact, you know, both it, it, 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, um, you know, where I was lucky to kind of be on the, some of the teams that I was on playing with, you know, elite players. Um, but being on that team, being in that environment, you know, seemed to pull the best out of me. And, um, and I think that was true in residency, too. You know, what, what I relished the most was like, you know, yeah, it was 5:00 in the morning, but you showed up, and there was Peter, and there was Megan, and there, you know, it was your team. And it was like, you know, this like you felt like you were [laughs] you know, unstoppable to some degree, even though you were, you know, doing what at times seemed impossible task. And, and I feel the same way about transplant. You know, I feel like y- the part of the reason I chose it, it was clear that no one can accomplish what it takes to take a liver transplant patient from, you know, from their diagnosis, to listing, to, to operation, to recovery, to, you know, transforming, transforming them to a new life afterwards without, you know, a really highly functioning team. And that, that is what always has kind of inspired me to, um, you know, give my best because I feel like I'm on a team where other peoples are doing the same thing.

   11. PAPeter Attia16:22

       I mean, there's a story I'll, I'll tell that I would imagine you don't recall because it was so commonplace. Um, but it, it really stood out to me as an example of what, like, a, a great leader would do. So you'll have to, you'll have to forgive me for explaining a process that you understand oh too well, but most people don't, which is, um-- Actually, I'm gonna have you explain it. Tell folks what the M&M conference was every Tuesday morning.

   12. CSDr. Chris Sonnenday16:50

       Yeah. So, so you're referring to what, what at Hopkins was called Morbidity and Mortality Conference, which is a, um, you know, I think there are versions of that throughout medicine, but in, in surgery, it is a unique part of the culture. So, um, I think one of the things that makes surgeons and surgery unique as a discipline is the sense of, uh, ownership, accountability, responsibility for, uh, the, the outcomes of the patients that you're privileged to care for. And so, uh, Morbidity and Mortality Conference was a weekly conference where we reviewed, um, uh, essentially patients', uh, stories, patients' cases, particularly patients that had, uh, suboptimal outcomes, whether it was a, a complication as, as hopefully routine as a wound complication or something that they would, would extend their recovery, but they would recover from fully, to a, um, to a death related to a surgical procedure or, or at least to a diagnosis that we tried to, uh, address with a surgical procedure. And I think, you know, every-- My former chair here at Michigan, Mike Mahan, used to say that, um, you know, you could look into the s- into a department's soul by attending their, you know, Morbidity and Mortality Conference. It, it, it is, it becomes the kind of cultural event of the department because you get a sense for what that level is, of, of accountability is. Is, is the conference spent kind of blaming the anesthesiologist or the nurse or, you know, uh, or the patient's comorbid conditions, or is the, is the discussion about what we could do better next time, um, to, uh, make the patient's outcome better? And I think, you know, there are, um, uh, lots of examples that, you know, I'm sure you and I could regale for for hours of kinda h- how lessons learned in that room, you know, in the morning, um, you know, shape the way we think about medicine, the way we think about responsibility, you know, all kinds of other things. Uh, one thing I always admired is that the chair who was there for most of the time we were there, John Cameron, um, he would often be the, the, uh, moderator of Morbidity and Mortality Conference, and he always led, as you recall, with his own cases. Um, which is, you know, a remarkable example of, um, the level of accountability that I think he was trying to, to encourage among the, the faculty and residents there.

   13. PAPeter Attia19:42

       Yeah, that's one of the things that stood out to me because I went to medical school at Stanford, and-

   14. CSDr. Chris Sonnenday19:48

       Yeah

   15. PAPeter Attia19:48

       ... it was just a different culture. It wasn't nearly-

   16. CSDr. Chris Sonnenday19:51

       Yeah

   17. PAPeter Attia19:51

       ... as rigorous. And so even in medical school, you would still attend that during your surgical rotations, but it, it, 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. Um, so this, this was kind of the story that, that I'll, that I'll tell that kind of always-- Uh, it just remains to this day etched in my mind. So, um, you and I-- This is-- 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 night-

   18. CSDr. Chris Sonnenday20:36

       [laughs]

   19. PAPeter Attia20:37

       ... 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, um, you're the ACS, [lips smack] and 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 y- y- you know, we both recall just how chaotic that could be, right?

   20. CSDr. Chris Sonnenday21:13

       Yeah.

   21. PAPeter Attia21:13

       You know, you've got people that are just getting shot two hours earlier. You gotta run to the OR with them, and you're being told about these all-- th-this patient, this patient, this patient. And, uh, 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-- and 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, uh, something that was missed. You-- 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, um, 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-

   22. CSDr. Chris Sonnenday22:25

       [laughs]

   23. PAPeter Attia22:26

       ... this patient came into our care. In other words, there was no blaming. There was no-

   24. CSDr. Chris Sonnenday22:30

       Yeah

   25. PAPeter Attia22:30

       ... "Well, you know, Mr. Smith was about to be discharged, but I decided to go and make sure he was okay and realized actually he 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 I, I, I-- H- honestly, it sounds crazy. That was one of the moments when I realized, I don't, I don't-- I'm not good enough to be in this profession.

   26. CSDr. Chris Sonnenday22:54

       [laughs]

   27. PAPeter Attia22:54

       [laughs] You know? Uh, maybe none of us are, but, but I, I don't know if you remember that case, but, uh...

   28. CSDr. Chris Sonnenday22:59

       Yeah. I do, actually, now that you recall it, and it was-- The circumstances were as you described. It was one of those crazy days where 35 things are happening and, you know, we, we were all over 34 of them. [laughs] Unfortunately, the 35th was this poor guy who was, you know, getting ready to be wheeled out of the hospital. Um, and, uh, yeah, I mean, I think-- You know, I don't remember the circumstances of the M&M discussion, but I, but I do certainly, um, carry the, uh, you know, philosophy in my work currently and, you know, certainly that, um, you know, uh, there is not value in kind of assigning blame to individuals. There's only, um, value in recognizing opportunity for us as a system, as a team to get better. And, and partially it's because, you know, I think, [laughs] you know, if, if I were to throw stones in that case, you know, uh, I could walk out of that conference and an hour later be the one responsible for kind of generating, you know, a, a similar or worse complication. So I think there's some humility that has to enter into understanding that no one has all the answers, uh, nor should be expected to kind of catch everything. Um, in fact, one of the things that I think has-- One of the-- 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, 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 can we, who's, you know, uh, who do we have to kinda string up for, you know, this particular mistake? Which is, which is number one, better for patients. Number two, sets a better example for the, for the trainees and learners in the room that are, that are, uh, trying to do this, and just is a, is an important piece of creating the right culture where everybody's kind of oars are moving in the

4. 25:15 – 31:10

   Why Chris chose a complicated field like transplant medicine

   1. CSDr. Chris Sonnenday25:15

      same direction.

   2. PAPeter Attia25:17

      At what point during residency did you decide that it was going to be transplant medicine, um, versus the other things that you had clearly shown, uh, you know, a fantastic predilection for, such as pancreatic surgery, liver surgery, and-

   3. CSDr. Chris Sonnenday25:33

      Mm-hmm

   4. PAPeter Attia25:33

      ... and all facets of surgical oncology in the GI tract?

   5. CSDr. Chris Sonnenday25:37

      Yeah, I mean, honestly, I was, I was greedy. I kinda wanted to do, do it all. I, you know, I, I ... When I entered Hopkins, I had, um, developed an interest in ki- in diseases of the hepatobiliary system and upper GI tract, so that was another thing that clearly drove my, my interest in that residency, where they had such expertise, uh, and, and, uh, uh, kind of a, you know, concentration of experts in those diseases. It was, um, you know, I, I did my, um, intern year rotation in transplant, and then again a third-year rotation in transplant. My, uh, fellow as an intern and then my junior attending as a third year, uh, was one of the people who's been, you know, one of the most important influences on my professional career, uh, uh, who's Bob Montgomery, now the head of transplantation at, at NYU, and a, you know, and a transformative figure in our field, uh, over the last couple decades. And, you know, partially it was his example of, um, uh, you know, what I thought I could aspire to be as a transplant surgeon. Partially it was realizing that, um, the distance from kinda bench to bedside in transplantation is really short, you know, is unlike anything that I had, had seen, uh, even in, in a very innovative, progressive, you know, surgical, uh, department. Um, and finally, you know, specifically speaking to my previous interest, I did see liver transplantation specifically as being completely complementary to, um, to being a comprehensive hepatobiliary surgeon and, and, and physician for patients with, you know, hepatobiliary disease. Um, you know, it's interesting. In other parts of the world, it's pretty commonplace for hepatobiliary 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 hepatobiliary surgery and transplant surgeons who may do some hepatobiliary surgery. But I clearly thought it would make me a more complete surgeon and physician to, to train in both. And, and I've been very lucky. I mean, I, uh, this isn't something that can happen necessarily at every institution, but I've, I've straddled that line in my career too. I- About half my clinical practice is, is, uh, hepatobiliary surgery, surgery of the liver, bile duct, and pancreas for mostly for cancer, but other benign diseases. And then liver transplantation. So, you know, I feel like I won the lottery, [laughs] you know, kind of walking that line, you know, uh, to be able to combine those disciplines.

   6. PAPeter Attia28:30

      Um, tell folks a little bit, uh, about what you mean by bench to bedside and that, that distance being short. Uh, it's a term we throw-

   7. CSDr. Chris Sonnenday28:36

      Yeah

   8. PAPeter Attia28:36

      ... around a lot in medicine, but its significance is huge. I wanna make sure people understand it.

   9. CSDr. Chris Sonnenday28:41

      Yeah, no, it, it's, it's a great point. I, I, I mean, part of it is just understanding the history, right? So, you know, transplantation as a field is very young. You know, 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, uh, all sorts of important changes, but particularly the development of effective immunosuppression. And then all of, once it became a, a feasible and successful, uh, medical intervention, then developing all of the systems around, uh, uh, making that a reality for more people and extending that to people with organ failure, uh, of various causes. So, so here we are, you know, surgical residents in the 1990s in a field that really is about 10 years old in terms of kind of being operationally, um, uh, uh, you know, expanding enough to, to, to really be a reality at most major medic- you know, uh, major medical centers. And so, you know, you would see, [laughs] you would see things being discussed kind of in morning report or rounds or like, you know, "Ah, this is a really, uh, tricky case of acute rejection. We haven't tried X yet." And then you'd would see we'd try X and, you know, it would work or not work, and we'd adjust. Or there were surgical techniques, you know, living donor liver transplantation, basically a part, a major part of my practice now was created in the, you know, 1990s and early 2000s. So, so I think the ability to see innovation become reality in very, um, you know, uh, rapid form was, was number one inspiring. I mean, you felt like you were doing something that was, that was new and innovative and just really incredible, but also, um, you know, I think to be honest, it made you feel like you could potentially have some impact in the development of a, of a field that, um, was nascent and, you know, uh, y- I would put myself in maybe the second or third generation of transplanters, you know, um, in terms of its history, which is, which is a very, you know, I feel very fortunate to be, uh, kind of a witness to that history and participate

5. 31:10 – 41:15

   Explaining kidney transplantation to showcase the challenge of organ transplantation surgery

   1. CSDr. Chris Sonnenday31:10

      in some of it, um, moving forward.

   2. PAPeter Attia31:13

      L- let's use kidney as an example to explain to people kind of the challenges. Today, um, y- you know, we take kidney transplants almost for granted because the success rate is so high. In fact, even when I was a resident, um, y- you know, if, if, if, if you demonstrated that you had enough of the skill and the interest, y- you know, even the transplant fellow would let you as the, you know, mid-level resident or the senior resident-

   3. CSDr. Chris Sonnenday31:42

      Mm-hmm

   4. PAPeter Attia31:42

      ... general surgery do kidney transplants. I mean, 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. Um-

   5. CSDr. Chris Sonnenday31:53

      Right

   6. PAPeter Attia31:53

      ... so the fact that, you know, kind of a knuckle dragger like me could've been doing this speaks to how well it works today. But as you said, this is a procedure that even in the 1960s carry- carried with it a, a mortality of, you know, more than 50%.

   7. CSDr. Chris Sonnenday32:09

      Yeah.

   8. PAPeter Attia32:09

      So-

   9. CSDr. Chris Sonnenday32:10

      Yeah

   10. PAPeter Attia32:10

       ... let's break down for people the evolution of this, uh-

   11. CSDr. Chris Sonnenday32:14

       Mm-hmm

   12. PAPeter Attia32:14

       ... from sort of the technical evolution, right? There was, it was only, what, maybe a little over 100 years ago that the anastomosis was even understood.

   13. CSDr. Chris Sonnenday32:22

       Correct.

   14. PAPeter Attia32:23

       Um, to then the complications of acute rejection, chronic rejection, and even understanding what the immune system is, is doing. So, and then we'll, we're gonna get to liver after because of course liver takes it-

   15. CSDr. Chris Sonnenday32:35

       Yeah

   16. PAPeter Attia32:35

       ... to a whole new level in, in all regards.

   17. CSDr. Chris Sonnenday32:38

       Well, I think, you know, kidney transplantation is kind of the, the best example of all the, the challenges that you just alluded to. It was also, um, the, the first solid organ at least that, that s- um, appealed to, you know, 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, you know, what we now do for, say, heart or liver transplantation, where you're doing an orthotopic transplant. You're literally taking out the prior organ and putting in a new one. That's a little different than a heterotopic kidney transplant, where you're giving them an extra organ and hoping that replaces the function of their failed kidneys.

   18. PAPeter Attia33:29

       Yeah, we should, people probably don't understand that, but when we do kidney transplants-

   19. CSDr. Chris Sonnenday33:33

       Correct

   20. PAPeter Attia33:34

       ... we don't go into the retroperitoneum, take out the old kidneys. We're putting the new kidney basically in their pelvis, attaching it-

   21. CSDr. Chris Sonnenday33:42

       Correct

   22. PAPeter Attia33:42

       ... to the blood vessels in the pelvis and taking the little tube that drains urine and just putting that into the bladder, the ureter.

   23. CSDr. Chris Sonnenday33:49

       Into the bladder, yeah.

   24. PAPeter Attia33:50

       Um, and, and obviously that's much easier than if you were gonna remove the old kidneys and put the new kidney in their place b- given the location of the kidneys. Um-

   25. CSDr. Chris Sonnenday34:00

       Yeah, and agreed. Yeah, I mean, I think it, it, it really was to make kidney transplantation feasible was a collision of, you know, 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, um, 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, into the recipient's body. So there's this whole concept of kind of the, the technique, the preservation, uh, and then the implantation, and then parallel to that was this whole question of, well, how do we handle the im- immunologic consequences of that? And so the, the series of events that occurred and allowed kidney transplantation to be a reality were really that the, the kind of technical and preservation, uh, elements came to fruition before we figured out the immunologic elements. And in fact, the first kidney transplant ta- as you know, performed in 1954 at, uh, Brigham and Women's Hospital by Joseph Murray, uh, who eventually won the Nobel Prize, was in identical twins, right? So it, they had, uh, two brothers, one brother who had kidney failure. Another brother who was healthy took one of the healthy brother's kidneys and, and transplanted it into, into the sick brother. And, um, you know, that proof of principle, um, was what created even kind of the possibility, the vision that transplantation could work because we understood the technical, uh, and preservation challenges of actually taking an organ out of one person's body and putting it into someone else. Um, and-

   26. PAPeter Attia35:55

       Murray was a plastic surgeon, wasn't he?

   27. CSDr. Chris Sonnenday35:58

       Yeah. [laughs] Joseph 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, 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, uh, on a, on a site, it would not, it would generally not live. And so, so there was this whole kind of cadre of, of clinician scientists who were interested in that question, including, interestingly, plastic surgeons like Joseph Murray. So, 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 in animals this, you know, idea of putting a kidney in the pelvis and attaching it to the blood vessels and bladder, and then pulled it off in a, in a human. And a lot of, if you look at the history of kidney transplantation through the 1950s and into the 1960s Uh, most of the kidney transplants performed were between twins, which, you know, there's a limited supply [laughs]

   28. PAPeter Attia37:13

       [laughs]

   29. CSDr. Chris Sonnenday37:13

       of available organs there. So you, you could see right there that that was gonna be a capacity problem. But, you know, for the f- for example, the first kidney transplant at the University of Michigan was performed in 1963 between two twin sisters who, uh, a few years ago we were celebrating our 5,000th, uh, transplanted organ at the University of Michigan, and those two sisters came back, you know, to celebrate that event. So I mean, it, it, it was a remarkably, uh, it was a remarkable achievement, but it was a little bit, uh, of a false pretense because none of the immunologic barriers were being confronted. And, 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, um, success stories. There, we, you know, the field worked out how to understand who had preformed antibodies to particular donors so you could avoid those and pick kind of, uh, pairs that might be more successful. There were increasingly sophisticated immunosuppression strategies that, that did work, you know, and drugs that were available, like, uh, like steroids and azathioprine, um, you know, were, 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 a- 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, you know, was, was, uh, making these procedures highly morbid and, and unsuccessful, at least at rates that we would think of as acceptable now. So, so the-

   30. PAPeter Attia39:24

       And what was the life expectancy if you opted for dialysis in the 1960s? How long could you be expected-
6. 41:15 – 54:30

   Overcoming the immune-based challenges of transplant surgery

   1. CSDr. Chris Sonnenday41:15

      for patients with, with organ failure in those, in those times.

   2. PAPeter Attia41:19

      So I wanna make sure people really get a sense of what these immune-based challenges were. Um, we take it all for granted today because we can rattle off all MHC II, MHC I complexes, and that stuff's been worked out in the most elegant manner. But in the 1960s, that was not the case. Uh, uh, uh, maybe start by explaining ABO incompatibility 'cause I think that's something people understand. If you, uh, if, if you came in the hospital and you'd lost blood and we wanted to give you a blood transfusion, we couldn't just willy-nilly give you anybody's blood. We'd have to make sure that the blood type matched. Uh, that's not entirely true. If you had... You know, we could give you O negative blood no matter what. But walk people through kind of ABO, which would be the s- uh, 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.

   3. CSDr. Chris Sonnenday42:18

      Yeah. So that's a great model to start with. So if you think about, uh, it in really basic forms, you know, our immune system has evolved to recognize self, recognize our own tissues, and is, has been primed to recognize things that, that do not look like, like us, um, mostly to be able to fight off viruses and, you know, other environmental challenges. But, um, that unfortunately makes it difficult for, for something like transplantation. So in the case of, of blood compatibility, we, we, um, uh, we carry, uh, a blood of a s- of a particular type. It has to do with the, the, uh, kind of the s- protein signature on the coating of those red blood cells, and they We know that if you give someone who, uh, 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 and someone who has blood type B, and you give the individual with blood type A blood from an individual with blood type B, the, they will, uh, have antibodies that attack those blood cells and essentially, um, 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, the Rh antigens, which are kinda what make blood positive and negative. And you're correct that, um, blood type O, um, y- you know, individuals who do not have blood type O do, do not have preformed an- uh, antibodies to, to those, um, uh, to that donor pool. So that, that is kind of the universal, uh, donor, uh, pool. But it was figuring out, um, that incompatibility, um, 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, you know, and, and this is still true to this day, that kinda step one in matching a donor and recipient is knowing their blood type, because that's kind of the, the first step. Um, it gets more complicated than that for all the reasons you alluded to, 'cause it turns out those are not the only proteins on the surfaces of those cells that are recognized by our immune system. And, and this in particular, this group of protein called human leukocyte antigens, which is what you were alluding to, um, or HLA types, is what kind of 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, so what, 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. If you took a skin graft from somewhere, somewhere else, from a s- 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, to destroy that new skin graft. Which-

   4. PAPeter Attia45:41

      Kinda sounds like a vaccine, huh?

   5. CSDr. Chris Sonnenday45:43

      Yeah, exactly.

   6. PAPeter Attia45:44

      [laughs]

   7. CSDr. Chris Sonnenday45:44

      So it was kinda the second ... Exactly. It's the same principle. So it was this kinda the second hit hypothesis that the body, the immune system, learned to recognize this foreign, um, tissue and, and the immune system was even more, uh, effective in eliminating it. And it was that whole series of experiments that led to this, um, these concepts right in the middle of the, of the last century, where the question was, and this was debated by individuals much smarter than us, many of whom who now have, you know, Nobel Prizes after their name. But, you know, so was there something circulating in the donor, in, sorry, in, in the recipient's serum that found the, this tissue, antibodies, uh, was the, 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, um, embryology from thymic development, was there some sort of priming event that had to take place where the, the body presented this foreign tissue to the immune system and then the immune system learned how to, to, uh, recognize it as self or foreign and destroy it? And, and that debate went on for decades.

   8. PAPeter Attia47:04

      Right. So, so, so just to separate that, right? The, in the case of blood incompatibility, it was pretty easy to figure out that it was just these-

   9. CSDr. Chris Sonnenday47:12

      Correct

   10. PAPeter Attia47:12

       ... soluble circulating antibodies. They weren't, quote unquote, smart. They were just-

   11. CSDr. Chris Sonnenday47:17

       Correct

   12. PAPeter Attia47:17

       ... floating around and-

   13. CSDr. Chris Sonnenday47:19

       You could do it in a test tube.

   14. PAPeter Attia47:20

       That's right.

   15. CSDr. Chris Sonnenday47:21

       You know, literally.

   16. PAPeter Attia47:21

       That's right. So you have a blood type A with its little A antigen, and if the recipient has an anti-A, uh, it grabs onto it, and these things precipitate out a solution of this reaction. And of course, now the question that you're posing is, is that how it works on organs?

   17. CSDr. Chris Sonnenday47:40

       Yep.

   18. PAPeter Attia47:40

       Or is there something more complicated where there's another actor?

   19. CSDr. Chris Sonnenday47:45

       Correct. And, and the reason that that was such a kinda 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 were gonna 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 a cross-match, so the idea of taking donor cells, recipient serum, mixing them in an assay, and determining whether or not the, that serum lyses those cells. Um, and that is more or less the technique that is used to cross-match, uh, individuals to, to, to match ind- you know, as you'll hear people talk about, "Oh, I wanna 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, uh, assay says that they have, um, that their uncle in this case doesn't have preformed antibodies that are gonna destroy their cells. So that would explain kind of that initial screening step. But what was conf- and, 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 were, 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, you, looks like you've, you know, won the game, and then it would immediately Start to thrombose and die essentially. That process called hyperacute rejection was figured out was because of the circulating antibodies to those HLA antigens 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. Um, 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, you know, are, are, are more sophisticated than I can explain, but it was figured out that what was actually happening was not this circulating, what we, we, we came to call antibody-mediated or humoral rejection, but actually was happening on a cellular level, so so-called cellular rejection. And as we learned eventually over time, that had to do with kind of what we now learn in basic immunology, antigen-presenting cell with carrying an antigen from the, the foreign tissue, in this case the donor tissue, immune, immune mediator cells, and we discovered and learned eventually they were T cells. That recognition, um, uh, priming the immune system to form, um, injury either, uh, you know, by various means, cytokines, eventual antibody formation, et cetera, and that was what was destroying organs in that kind of subacute phase. And, um, as we figured out over the course of decades, the, the drugs that we had to blunt that initial immune response, high-dose steroids, I, I've referred azathioprine, they tried total body irradiation at, at some of the early, you know, stages, um-

   20. PAPeter Attia51:32

       That was Franny Moore that was doing that at, up at the Brigham as well, right?

   21. CSDr. Chris Sonnenday51:35

       [laughs] Exactly, at the Brigham. Um, those weren't effective in preventing that cellular level rejection, and, and it was only later, you know, really the 1980s, that we, we developed immunosuppressive agents that were selective enough to interfere with that cellular reaction, and it was, it was then that transplant really became a reality 'cause now you had the ability to sustain an organ beyond just weeks to months, and you're, you know, looking at more long-term survival.

   22. PAPeter Attia52:09

       So 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, tr- transport a kidney, and put it in. By the way, was Wisconsin solution already around by the '80s or did that come later?

   23. CSDr. Chris Sonnenday52:26

       Yeah. Yeah, so the, or at least the predecessors of Wisconsin solution and, and the other, uh-

   24. PAPeter Attia52:33

       Tell folks what that is and why that matters so much as well

   25. CSDr. Chris Sonnenday52:36

       ... yeah, so, so the, the theory is, you know, you take an organ out of the, um, out of the donor body, whether deceased or living. Um, you flush the blood cells and such out of it so that it doesn't clot. Um, you then store it on ice and, you know, transport it to the recipient and, and put it in. And, and there were all kinds of in- initial thoughts about, well, do you just put it in saline essentially and transport it to the other room? And then-- And what they found was that, a- and this was, you know, experimentation that happened over decades, was that the, there was, um, there were cellular processes occurring both as kind of at the time from, uh, when ischemia begins, when the, you know, 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, and, you know, the, the history of all this is beyond me, but literally they tried, you know, it, it's like making Gatorade. They tried, you know, different electrolyte solutions and additives and, and, um, uh, other nutrients until they figured out which mitigated that, that ischemic time, uh, the best. And the, the crazy thing to think about, and this gets to alludes to something maybe we could talk about later in terms of, you know, where is preservation going in the future, but the crazy thing is we're pretty much more or less doing that now [laughs] . You know? So some of the fluid solutions and some of the, you know, 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,

7. 54:30 – 1:00:10

   How the discovery of cyclosporine transformed the field of organ transplantation

   1. CSDr. Chris Sonnenday54:30

      '70s, you know? Um, which is pretty remarkable that that was, that was one, as you said, one of the early barriers figured out in the field.

   2. PAPeter Attia54:38

      So once this notion of the HLA system is understood and we understand these different types of compatibilities, a drug is discovered, and it's, um, you know, 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.

   3. CSDr. Chris Sonnenday54:59

      Yeah, that's right.

   4. PAPeter Attia55:00

      Uh, the drug is called cyclosporine. And I think you could make the case, um, but I'd like to hear your take on it 'cause you know this field so much better than I do, but, but if I were telling the story, I would say that was the turning point, was the advent-

   5. CSDr. Chris Sonnenday55:16

      Yeah

   6. PAPeter Attia55:16

      ... of cyclosporine. Do, do you agree with that, or do you, do you think that I'm overstating that?

   7. CSDr. Chris Sonnenday55:21

      No, 100%. Um, you know, so, so a- as, as you said, and, and similar to the stories of drug development that happened in other circumstances, you know, this was a, a, a recognized compound, um, that, um, you know, had been experimented in a number of different, um, lines of investigation. Um, and an investigator, uh, who's really one of the central figures in the history of transplant named Sir Roy Calne in Cambridge, um, performed a series of preclinical experien- experiments that, that showed that using this medication, um, prevented rejection in, in transplant models. And what eventually was discovered is that it was interfering with the cascade that occurred when that foreign antigen was presented to the, uh, recipient T cell. And, um, in, 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.

   8. PAPeter Attia56:37

      And it specifically inhibited IL-2 secretion?

   9. CSDr. Chris Sonnenday56:41

      It, it, it, it affects IL-2 secretion, uh, but there, you know, there's actually some interesting, uh, debate about how the calcineurin inhibitors-

   10. PAPeter Attia56:50

       Mm-hmm

   11. CSDr. Chris Sonnenday56:50

       ... so cyclosporine and then its eventual cousin, tacrolimus, um, works. You know, the, they both, um, function at the level of what are called immunophilins, these, you know, soluble, um, intracellular components. And, 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 af- the affinity of the binding of the T cell receptor. They have, they have systemic effects that are kind of interesting, like for example, tacrolimus, the other medication I mentioned, you know, has a potent vasoconstrictor effect in certain organs. So, so we probably don't fully understand its impact, but certainly the, the, the central, uh, component of its mechanism was interfering with the cascade that occurs after T cell receptor binding. And you're, and you're absolutely right, like it literally was a game changer overnight. So, you know, 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 graft survival rates, even with kind of the best immunosuppressive regimens that had been figured out at that point, one-year graft survival rates probably in the 70-ish, 60% range. Boom, you know, 90% overnight just with the addition of cyclosporine and then, you know, eventually refining kind of some, some of the multi-drug regimens. Um, so it was a complete game changer. It not only revolutionized the, the impact of kidney transplantation, which from a public health standpoint is clearly the most impactful organ we transplant. You know, the, the, the number of patients with end-stage renal disease, the number of patients with chronic kidney disease, you know, from a public health standpoint, kidney transplantation is just a fundamental, uh, important medical therapy. But so not only did it make that a reality and make it, um, a preferred, uh, uh, alternative to dialysis, it also reinvigorated the other solid organ, uh, transplant, um, uh, other solid organ transplants as being a reality. So, you know, liver transplantation, which es- essentially had been on a more or less enforced hiatus through the '60s and '70s, heart transplantation similarly, lung transplantation as well, the, 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, you know, 90 days, um, you know, reinvigorated those fields completely. Um, and you know, again, you know, almost overnight, over the course of years, you started to see liver transplant programs, heart transplant programs, lung transplant programs pop up at major medical centers all throughout the country in the 1980s and into the early 1990s. So that was really the

8. 1:00:10 – 1:06:45

   Rising chronic kidney failure due to the prevalence of pre-diabetes and metabolic syndrome

   1. CSDr. Chris Sonnenday1:00:10

      revolution that occurred because of that drug development.

   2. PAPeter Attia1:00:14

      When we look at the, the, the, the demand for kidney, uh, transplantation today, what percentage of it is chronic versus acute kidney failure?

   3. CSDr. Chris Sonnenday1:00:24

      Yeah, so the, the vast majority is chronic. So there, there are, um, occasions where patients can get acute renal injury from, you know, uh, traumatic events, uh, other medical catastrophes where they get acute kidney injury in the chronic, in the case of sepsis or something that they otherwise recover from. Um, and that, that does, um, you know, we still see, and we still see occasionally patients who get, for example, post-streptococcal glomerulonephritis or other diseases that are more linked to kind of an acute event. The vast majority of kidney transplants, though, in the United States, the, the primary indication is diabetes or hypertension, so this is chronic kidney disease, um, as a consequence of those comorbid conditions, which is one of the reasons, again, from a public health standpoint, the, the impact of kidney transplantation is massive. You know, so you have 100,000 people roughly waiting for a kidney transplant in the United States. You probably have fourfold that or thereabout on dialysis.

   4. PAPeter Attia1:01:30

      Mm.

   5. CSDr. Chris Sonnenday1:01:30

      And then probably tenfold that number with chronic kidney disease. So the, the potential impact of, of having an effective and durable therapy for chronic kidney disease is, is remarkable. Um, and I think it's, it's really important to consider as a, as a, you know, a public health problem.

   6. PAPeter Attia1:01:48

      Yeah, I, I, I ca- I can't agree with you more, Chris. And about three years ago I sort of had this obvious epiphany. I say obvious because I'm sort of thinking, "Why did it take me so long to do the math?" But I realized if, if my interest clinically is trying to figure out how to help people live longer and live better, you gotta start thinking about what are the things that you have to plan for. So if you're flying a glider where you know you wanna 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, 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 glomerular 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's, that becomes a very unacceptable GFR. You're going to run into-

   7. CSDr. Chris Sonnenday1:03:07

      Yeah

   8. PAPeter Attia1:03:07

      ... trouble. And so y- y- you know, looking at cystatin C beyond just creatinine and other biomarkers and looking at microalbumin in the urine twice a year, I mean, we do all these things b- even though they seem kind of crazy, because it's how you sort of start to catch that early-

   9. CSDr. Chris Sonnenday1:03:24

      Yeah

   10. PAPeter Attia1:03:24

       ... early, "Oh, look, you know what? Your blood pressure of 130 over 85 is not really acceptable. That's, that's, that's gonna take you from a GFR of 95 to 85 in the next decade," and we consider that to be too precipitous a decline. Um, so unfortunately, my view is that I think the demand for kidneys is only going to go up as we see-

   11. CSDr. Chris Sonnenday1:03:46

       Yeah

   12. PAPeter Attia1:03:46

       ... the rampant explosion of pre-diabetes and metabolic syndrome.

   13. CSDr. Chris Sonnenday1:03:51

       Yeah, I, I totally agree with you. I think, and there's so many kind of wrinkles to that question to think about. I mean, the first is that, is the obvious statement that, as, as you preach better than anybody, we don't do preventative care, you know, [laughs] in, in this country very well. And, and, and we particularly don't do it for things where we don't have reliable measures, you know? So, so to your point, you know, we, we use serum creatinine as kind of our best guess at kidney function. There's lots of reasons why that's a poor indicator. Um, you know, it, it's, it's not, it's very dependent on muscle mass and, and other variables that, that, um, allow y- that prevent you from using some sort of kind of normalized number as a acceptable range. Uh, there are more sensitive markers, as you alluded to. There, there's now th- 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, 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. You know, as transplantation has gotten more successful, transplant centers around the country, transplant providers, and, and just the medical community in general has started to say, "Well, you know, why don't we provide kidney transplants for 70-year-olds if they're otherwise, you know, uh, healthy individuals?" 'Cause their life expectancy might be 20 years from that point. So, um, and that's, that I think, the, the collision of that and then the, what you alluded to, this pre-diabetes, metabolic syndrome, you know, um, progressive kidney dysfunction in an aging population is gonna create an enormous demand for kidney transplantation. Um, you know, we, [laughs] we, uh, transplanted an 81-year-old a f- a few weeks ago, and I remember as I was looking at the, the, uh, census, I, I, I don't do kidney transplant very commonly as part of my clinical practice, so I was looking at the census. I was like, "Wait a minute. Is that... Is, is this gentleman 10 years out from a transplant back in the hospital for some other reason, or did we actually transplant this 81-year?" But the point is there are individuals who are healthy, functional people-

   14. PAPeter Attia1:06:13

       Mm-hmm

   15. CSDr. Chris Sonnenday1:06:13

       ... otherwise who have a, whose life, you know, part of what we're talking about is survival benefit, right? You compare their survival on dialysis to their survival with a transplant. Transplant is gonna win almost every time, um, you know, as long as they, you know, can tolerate the operation and the immunosuppression. So, so it isn't a, it, it isn't a kind of remarkable to think of the scope of that problem, and particularly to take a longevity lens on it. You know, it's, it's really kind of an interesting, um, challenge to think about for the next, you know, 20, 30 years of transplantation.

9. 1:06:45 – 1:26:50

   Why living kidney donations are superior, and the possibility of a market for kidney donation

   1. PAPeter Attia1:06:45

      So before we get onto liver, which is, is, is such an amazing story, uh, as well, I wanna, I wanna wrap a few things up on, on kidneys. So let's, let's talk about the evolution from cyclosporine to, to Prograf or, uh-

   2. CSDr. Chris Sonnenday1:06:59

      Mm

   3. PAPeter Attia1:06:59

      ... tacrolimus, as you discussed, um, and where we are today on some of the most common immunosuppressive-

   4. CSDr. Chris Sonnenday1:07:06

      Yeah

   5. PAPeter Attia1:07:06

      ... regimens. And then I also wanna 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, sim- I- transplant was never even something on my radar before-

   6. CSDr. Chris Sonnenday1:07:29

      Yeah

   7. PAPeter Attia1:07:29

      ... residency. Um, and for the entire time I was in residency, it was always one of those things. I was like, "I could see myself doing this. This is so cool."

   8. CSDr. Chris Sonnenday1:07:37

      Yeah. Yeah.

   9. PAPeter Attia1:07:38

      And it was actually, um, 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 gonna beat a six out of six cadaveric 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, and more importantly-

   10. CSDr. Chris Sonnenday1:08:01

       Yeah. Yeah

   11. PAPeter Attia1:08:01

       ... explain why it's true.

   12. CSDr. Chris Sonnenday1:08:03

       Yeah, so it's, uh, um, it's pretty remarkable to consider the impact of living donation, uh, and, and the, um, to your earlier question, kind of figuring out the appropriate place for living donation as transplantation moves forward. So in kidney transplantation, in counter distinction to liver transplantation, but in kidney transplantation, living donation has been part of kidney transplantations from its origins, you know? So as I alluded to already, the first transplant done between identical twins, um, living donation remained a part of the development of kidney transplantation, and then really took off in the 1990s. We witnessed it happening, um, with the development of the laparoscopic donor nephrectomy operation, um, a, a procedure pioneered by two individuals at Hopkins, Lou Cavucci and Lloyd Ratner, um, who ... And that, you know, having a procedure that was of such tremendous benefit to the recipient that then was safe and, you know, a smoother recovery for the donor, you know, really allowed that to explode. And if you look at kidney transplantation in the United States now, um, you know, so, um, uh, uh, 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. Um, and, and that's probably with under-realizing the potential of living donation for all the reasons you said. So part of what you're alluding 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. You know, let's say the starting line is the same for all three of those, and let's say that they're similar age, similar comorbid conditions, similar immunosuppressive regimen for the transplant recipients. So the, the benefits are pretty clear. The dialysis curve's gonna drop off pretty quickly. So the, in fact, the studies that have shown that the, 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, 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 and 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. You know, the, the, um, 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 recipient's room, and sometimes it's sewn in in under an hour. You know, so the time, the ischemic time from coming out of the donor's body to, into the recipient. And 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, the consequences just of the ischemia reperfusion injury and kind of literally knocking off some nephrons just from that process. Part of it it also is, as we've learned, is that that ischemia reperfusion 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, the ischemia reperfusion injury, they're also more prone to rejection. You see a, more immunologic injury. They, they, there's, you know, depends on the circumstance. They often require more immunosuppression, you know, greater frequency of rejection. So it really is almost like two different products from a recipient's point of view. And so, you know, I think if you hedged your druthers, you know, as a person in need of a kidney transplant, you would, um, want to have the access and the opportunity to get a living donor any day of the week if you, if that is possible to you.

   13. PAPeter Attia1:13:01

       A- a- and this other point, though, is to narrow that gap between the two-

   14. CSDr. Chris Sonnenday1:13:05

       Correct

   15. PAPeter Attia1:13:06

       ... it's that w- with the, with the deceased donor, you at least try to maximize the immunocompatibility, and with-

   16. CSDr. Chris Sonnenday1:13:14

       Correct

   17. PAPeter Attia1:13:15

       ... the living donor you have much more flexibility.

   18. CSDr. Chris Sonnenday1:13:18

       Correct. That's exactly right. So you know, what you were describing is kind of a, the situation that you, the s- the story you alluded to with Bob is you're comparing a, a, um, 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 that ischemic hit, and, and we can't make up for that. So even the best immunologic situation can't mitigate that, which I think is a realization that doesn't always kind of Come to fruition, but is again one of the reasons why we feel comfortable really pushing every kidney transplant candidate to, to think very seriously about exploring options for living donation. Um, it's also what's led to some of the things you alluded to, you know, paired kidney exchanges and other things to try and expand the, the compatibility of donors and recipients in, in kidney donation.

   19. PAPeter Attia1:14:23

       L- let's, let's use an e- an example to, to explain that to people because it's really quite fascinating and, and we trained very close to some of the people who really did a lot of the work behind-

   20. CSDr. Chris Sonnenday1:14:33

       Yeah

   21. PAPeter Attia1:14:34

       ... um, optimizing the mathematical algorithms around that. So, um, let's pretend that, um, you know, you called me tomorrow and said, "Peter, you're not gonna believe this, but, you know, I'm kind of at the end of my rope with my kidneys, um, and I'm gonna, you know, I'm gonna need to have a transplant." And, and I, you know, I, I was sad. I thought about it and I decided, you know what? I- there's, there's no greater way that I want to 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-

   22. CSDr. Chris Sonnenday1:15:18

       Right

   23. PAPeter Attia1:15:18

       ... blood type, never mind HLA compatibility. What would be some-

   24. CSDr. Chris Sonnenday1:15:22

       Right

   25. PAPeter Attia1:15:22

       ... of the options we would explore?

   26. CSDr. Chris Sonnenday1:15:24

       Yeah, so the, so the circumstance you're talking about is this really kind of frustrating scenario where, 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, you know, 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. Um, it may also be that, that, uh, you, you know, I have preformed antibodies to HLA antigens that, that you have, and, and as it turns out, there's certain populations that are more prone to that, to that challenge. So it's a, it's a really frustrating challenge 'cause here it is. It's like you have this, you know, you've got this diamond in the rough, but you can't apply it, you know? 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, you know, 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, and those sorts of swap- kidney swaps or paired exchange, um, began in the 1990s and, 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 w- good care of yourself. I assume Jill has approved this at some point in the discussion.

   27. PAPeter Attia1:17:30

       I haven't asked her, but-

   28. CSDr. Chris Sonnenday1:17:30

       [laughs]

   29. PAPeter Attia1:17:31

       ... you know, she can't wait-

   30. CSDr. Chris Sonnenday1:17:32

       The, uh-
10. 1:26:50 – 1:31:15

    Designing a fair system of organ distribution

    1. CSDr. Chris Sonnenday1:26:50

       Exactly

    2. PAPeter Attia1:26:50

       ... through the course of that. Um, 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 or more likely to get, uh, an organ, like a liver, for example, than other states. How does that work? And-

    3. CSDr. Chris Sonnenday1:27:06

       Yeah

    4. PAPeter Attia1:27:06

       ... what would be the best states to live in if you're vying for an organ versus the worst?

    5. CSDr. Chris Sonnenday1:27:11

       Right. So fortunately, that is changing rapidly, and it's changing rapidly because it's been, um, a focus of intentional policy change in the way organs are allocated.

    6. PAPeter Attia1:27:20

       So it's not like when we were in residency where it was almost comical.

    7. CSDr. Chris Sonnenday1:27:24

       Correct. So I think part of the issue is, is simply, um, a supply and demand issue. So if you look, for example, at California, you know, a state with a huge population, um, and, uh, y- you know, there i- is such a demand for transplant that if you restricted, if you, 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, the demand. That's true in other major pop- 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, is modest compared to the supply of organ donors. Um, and I think that has, um, created this disparity where, depending on where you live, you may have better access to organ in s- in, in various places. The solution to that, obviously, is to change the system. So in other words, you know, um, the way that organ donation is coordinated nationally is through these organizations called organ procurement organizations or OPOs. There's 58 of them in the country. Some of them are pretty, uh, easily understandable, like Michigan has, for example, one OPO that covers the whole state. There's, like, six in Texas. So it's, it's, it, 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, and facilitating the gift from, from procurement to, to transplant. And then the, the waiting list, and you hear people say that they're, 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, the list is run according to a predetermined algorithm of, 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 kinda offered out more broadly. And so what has changed in, um, 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.

    8. PAPeter Attia1:30:08

       Mm-hmm.

    9. CSDr. Chris Sonnenday1:30:08

       So they offer it, you know, uh, based on distance from the donor hospital. And that has, um, created some interesting, um, you know, phenomena. I mean, the, the good news is, to your point, is that the geographic variation, uh, that exists across the country has decreased, so it's not as important now to, like, go to a certain place if you know you need a liver transplant, for example. Um, it, 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 gonna get transplanted quickly 'cause you've got access to this broad swath of, of organ donors. The, 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, uh, getting transplanted. And that's speaks to the kinda need for expanding the donor pool, alternative donor sources, more living donation in the case of kidney and liver transplantation to kind of meet that, that need. So, um, so the system has gotten more fair, but it's

11. 1:31:15 – 1:44:20

    The debate on what constitutes “death” when deciding when to take organs from a registered organ donor

    1. CSDr. Chris Sonnenday1:31:15

       only exposed the need even more, I guess, is the best way to say it.

    2. PAPeter Attia1:31:18

       That's good to hear because it definitely struck me as, as a pretty unjust system, you know, 20 years ago, um, especially with liver, um, where you could, you know, it was almost like the, uh, y- yeah, it reminded me of some great injustice. Um, you, you alluded to brain death earlier. Uh, we've been remiss in not, I think, explaining to people a little bit what that means, and, um, 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. Uh, the donors are, are, are non-living. Um, so what does it mean to be brain dead? And, and how does that factor into, um, the, from, from a legal standpoint, what does it mean? And then from a physiologic and biologic standpoint, what does it mean?

    3. CSDr. Chris Sonnenday1:32:06

       Yeah, so it's, it's a, it's interesting. You would think that this would be, like, something you could flip to page one in, you know-

    4. PAPeter Attia1:32:12

       [laughs]

    5. CSDr. Chris Sonnenday1:32:12

       ... a medical textbook and there would be, you know. But it's actually been a relatively kinda complex set of definitions to come to. Um, and And the, the importance of establishing brain death was in many ways driven by the development of transplantation. Because if we were going to use organ-- deceased organ donors for transplant, we needed to establish clear, clearly defined ways that these were individuals that could not recover, you know, were not going to, um, uh, to be salvageable such that they could be, um, then go on to be organ donors. And to be even more specific about that, the, the, the whole question of what defines death, you know? So is death when the heart stops or is, or do we consider death when the brain has lost function and control? And, and what has developed over time-

    6. PAPeter Attia1:33:16

       And so just to clarify that for people, right, the first thing you said is when the heart stops is what we call cardiopulmonary death.

    7. CSDr. Chris Sonnenday1:33:23

       Mm-hmm. Right.

    8. PAPeter Attia1:33:24

       So a person has a heart attack, the heart stops, cardiopulmonary death. A person has cancer, eventually leads to cardiopulmonary death.

    9. CSDr. Chris Sonnenday1:33:33

       Correct.

    10. PAPeter Attia1:33:34

        Um, this brain death thing, how-- what is it? How does it show up? Give people examples-

    11. CSDr. Chris Sonnenday1:33:39

        Yeah

    12. PAPeter Attia1:33:39

        ... of the physical way, the physiologic ways people get there.

    13. CSDr. Chris Sonnenday1:33:42

        Yeah. So it's a, it's a, it's a kind of confusing concept. How can the body be alive but the brain be dead? And there, there are a whole number of circumstances where that can occur. But essentially the, the kind of central, um, [lips smack] uh, component of the definition is that the brain sustains an injury. That could be from anoxia, from an anoxic event. It can be, it can be literally from a traumatic event, you know, a penetrating injury, a devastating head trauma. Um, it can be from an intracranial event, a bleed or such, such that the pressure in the brain, um, 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 are, have, have stopped. And you know, there, there are clinical ways to define that diagnosis. So there are characteristic neurologic, um, uh, manifestations of brain death. Um, you know, the, the kind of classic ones that you see on TV are the, you know, the blown pupils as someone's brain has swollen to the, uh, to not, to no longer, um, prevent, or sorry, to no longer allow blood flow into the skull. Um, you know, there are core bodily functions that the brain drives, such as respiratory drive, um, that are part of that definition as well as, as well as a bunch of additional primitive reflexes. And, and really what e- evolved over time is a clinical definition of brain death that includes multiple elements, including that the pa- that the donor has, or sorry, that the individual has to be, um, you know, hemodynamically stable. They can't be hypothermic. They can't be in some metabolic condition that could confuse the issue. Uh, b- 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, there are clinical brain death exams that, that, uh, 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. Um, and I think coming to a consensus on that definition was really critical to allow the establishment of what, what equates with death, so the loss of the function of that individual, even if their other physiologic functions, like their heart beating, are maintained. Um, and, and establishing that diagnosis then allowed the step to go from, well, if they are brain dead but they 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, their death, which violates all the principles of, of kind of autonomy and the principle of, of organ donation, um, that transplantation is built on.

    14. PAPeter Attia1:37:10

        So there's a couple things there I just wanna highlight before you go on, Chris-

    15. CSDr. Chris Sonnenday1:37:12

        Yeah, please

    16. PAPeter Attia1:37:13

        ... just so people understand. There-- Brain death still requires cardiopulmonary support, right? That's the, that's the very-

    17. CSDr. Chris Sonnenday1:37:20

        Right

    18. PAPeter Attia1:37:20

        ... important thing people need to understand. A brain-dead individual is not gonna be laying in a bed, their brain not functioning, yet somehow they're alive. By definition-

    19. CSDr. Chris Sonnenday1:37:29

        Correct

    20. PAPeter Attia1:37:29

        ... if your brain is dead and you are not on full cardiorespiratory support, you will be dead within moments.

    21. CSDr. Chris Sonnenday1:37:36

        Right.

    22. PAPeter Attia1:37:36

        So that's why this apneic test is done while they're hooked up to a respirator that is just turned off but not disconnected.

    23. CSDr. Chris Sonnenday1:37:43

        Turned off.

    24. PAPeter Attia1:37:44

        They will fail to breathe, as you point out. They will fail the apneic 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, um, you know, the appropriate levels of tissue health. But the other thing that's worth mentioning, [chuckles] it's so funny, 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-

    25. CSDr. Chris Sonnenday1:38:20

        Yeah

    26. PAPeter Attia1:38:20

        ... the kidney or liver and, 'cause that would seem, that would seem a little, uh, you know, a, a, a little, uh, grotesque, right? So ex-

    27. CSDr. Chris Sonnenday1:38:29

        Yeah

    28. PAPeter Attia1:38:29

        ... explain that sort of line between those two teams of physicians because you know, you and I have been multiple times on both sides of that. We've been taking care of those patients-

    29. CSDr. Chris Sonnenday1:38:39

        Yeah, right

    30. PAPeter Attia1:38:39

        ... in the ICU that are going to become donors, and then we've been the, you know, on the other side where you're now part of the team that's harvesting organs.
12. 1:44:20 – 1:51:15

    Reflections on the gift of organ donation

    1. PAPeter Attia1:44:21

       Y- you alluded to something earlier, which reminds me of one of the sadder stories when I was, um, I was in, I was in residency actually when this happened. So my mom, one of my mom's closest, closest friends, um, her son, who was five years younger than me So I knew-- we grew up together, uh, was, was, uh, driving home one morning after a night shift and fell asleep, um, crashed and died, you know, uh, an immediate brain death. And, um, his mom, single mom, no relationship to his father, um, you know, had to make this wh- you know, 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, I'll never forget, she, she made this decision to have every, every single aspect of her son donated. You know, corneas-

    2. CSDr. Chris Sonnenday1:45:14

       Mm

    3. PAPeter Attia1:45:14

       ... skin. L- he, he-- his liver was split into two, so two people benefited from his liver.

    4. CSDr. Chris Sonnenday1:45:20

       Mm.

    5. PAPeter Attia1:45:20

       His both kidneys, heart, lungs. [lip smack] Um, it, it's, it's, it's always stuck with me. Um, and, and if that wasn't enough, a, a couple years later I would go on to meet a friend, um, that I ended up working with actually, who lost his son to his-- He was in a Jeep accident.

    6. CSDr. Chris Sonnenday1:45:38

       Mm.

    7. PAPeter Attia1:45:38

       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, and without hesitation, they did the same thing, which was-

    8. CSDr. Chris Sonnenday1:45:50

       Yeah

    9. PAPeter Attia1:45:50

       ... you know, every piece of our son, Aaron, was his name, um, is, is gonna be, you know, uh, donated to help someone else. And what was especially amazing in the case of, um, of this couple, I think I can say their names. I don't-- I think they're actually quite vocal about this, Jeff and Tina Webster, um, is that they got to know every one of the recipients.

    10. CSDr. Chris Sonnenday1:46:13

        Mm.

    11. PAPeter Attia1:46:14

        Um, and as I got to know them and got to know the stories, I was just y- you know, I was just blown away by it. And, and again, I'm someone who's been around this stuff, right? Like, uh, it's not like I haven't-

    12. CSDr. Chris Sonnenday1:46:26

        Right

    13. PAPeter Attia1:46:26

        ... seen these things before. But, um, you know, the, the man who got his liver has a tattoo of their son on his arm. You know, it's that kind of stuff, right?

    14. CSDr. Chris Sonnenday1:46:36

        Yeah.

    15. PAPeter Attia1:46:36

        And it's, it's just-

    16. CSDr. Chris Sonnenday1:46:37

        Yeah

    17. PAPeter Attia1:46:37

        ... it's-- It is hard to believe. I mean, do people ever ask you, Chris, um, "Hey, should I, should I check that box on my driver's license?" And, and, and-

    18. CSDr. Chris Sonnenday1:46:46

        Yeah

    19. PAPeter Attia1:46:46

        ... like how, how do you talk to people about those decisions?

    20. CSDr. Chris Sonnenday1:46:50

        Yeah, it's a great question, and it is one that I, 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 transplant surgeon. But, you know, I think, um, you know, I, I think-- So what are the reasons that people hesitate to, to do that? And I think some of it is what w- we already alluded to, is kind of the, the concern or the mythology that somehow it'll affect their own healthcare. And, and, you know, sometimes I'll answer questions about that. But, but I always try to focus on the, the profound impact that transplantation can have, and try to share with them, uh, what I've learned from donor families over the year. I mean, one of the privileges of the, the position I am in now is that I do get to occasionally do advocacy work and other, um, other opportunities to meet donor families. So families like you just told of, the Websters, that have a, a history of a family member who was an organ donor. And many of them can, you know, poignantly tell of the, the process they walked through with that decision making and the memories of their loved one. Um, but one of the things that donor families, uh, you know, really universally share is that their experience of organ donation, whether or not they were able to meet the eventual recipients of their, uh, loved one's organs, but that the experience of organ donation and knowing that their loved one's organs went on, uh, live on in another individual and saved their life is the only good thing about what was otherwise the worst day of their lives. Um, and I've heard that actual phrasing repeated by multiple families, by multiple individuals who had to say goodbye to their, you know, son, daughter, sister, brother, you know, husband, wife, but took some solace in the fact that y- 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 is really a, a, can be a transformative gift. I think the other thing I share with people and let them make their own decisions is that, um, you know, there is an incredible need for organ donation. You know, so there are currently more than 100,000, you know, people waiting on the waiting list for the various organs and, and, you know, each year there are, you know, less than, uh, you know, f- 40% or so of that number done. You know, and the, the need only grows each year. The gap between, uh, donation and supply, um, [lip smack] uh, 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, you know, incredibly good. You know, restoring them back to, um, you know, life expectancies that approximate normal and qualities of life that in many cases are totally normal. So I, I, I mean, I think that's the vision I try to share with people when they're considering organ donation. Um, 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, that walking through that decision making with someone's loved one who is in, you know, the middle of the night in a foreign hospital trying to make the decision about the wishes of their loved one is an, is an impossible task. So the more that you can, you know, register yourself or, and communicate that to your family, the actual easier you make it on your loved ones, God forbid they end up in that situation, having to facilitate that gift.

    21. PAPeter Attia1:51:04

        Yeah. I, I think that's the point. You can think of this as an advanced directive, which-

    22. CSDr. Chris Sonnenday1:51:08

        Yeah

    23. PAPeter Attia1:51:08

        ... um, actually is the biggest service you can give to people around you so that they don't have to-

    24. CSDr. Chris Sonnenday1:51:13

        100%

    25. PAPeter Attia1:51:13

        ...

13. 1:51:15 – 1:58:45

    The history of liver transplantation and why it’s so complex

    1. PAPeter Attia1:51:15

       th- there's no ambiguity about what your wishes are. So we've talked a lot about kidney, but I, I, I, you know, 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, of your clinical practice, and it's-

    2. CSDr. Chris Sonnenday1:51:30

       Mm-hmm

    3. PAPeter Attia1:51:30

       ... certainly one of the most technically demanding operations in the field. It's no surprise then that, uh, uh, the most amazing surgical resident I ever got to train alongside is doing the pinnacle of what surgery offers. Um, let's go back to the 1960s. There's a young guy, 19- it's 1963. There's this guy nobody's ever heard of, Thomas Starzl. Um, he's, 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 Imuran and actually increase survival-

    4. CSDr. Chris Sonnenday1:52:06

       Mm-hmm

    5. PAPeter Attia1:52:06

       ... to levels that were still abysmal by today's standards, but reasonable. You know, I think he was getting 70% survival at one year. Um, but four years later, a three-year-old boy dies on the operating table, bleeds to death, and at that point, uh, people sort of had enough, and there was kind of, as you alluded to earlier, this moratorium on liver transplants until we-

    6. CSDr. Chris Sonnenday1:52:28

       Yeah

    7. PAPeter Attia1:52:28

       ... 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 i- implant?

    8. CSDr. Chris Sonnenday1:52:40

       Yeah. So I mean, the liver's the largest solid organ in the body. Um, 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, uh, as well as the portal vein, which is the blood drainage of all of the intestinal blood flow. Um, and it, the reason that returns through the liver is the liver is the filter, essentially the metabolic filter for the, the, uh, 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, uh, into the vena cava. So it's, it's, um, anatomically made not to be messed with in some ways is, is the way you'll hear people talk about it. I mean, and, and in addition to that, you then have the, all of the intrahepatic anatomy, which, you know, which can be, uh, 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, you know, fortunately with experience you learn how to navigate. It's the fact that liver failure, uh, at least the, 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 clot and other important functions. Um, but because the liver is become this scarred fibrotic organ, all of that blood flow that's returning from the intestines has to make its way through what used to be this soft compliance sponge and is now literally the consistency of a, of a rock. And so the, what happens is you develop this condition called portal hypertension, where the, the blood, the pressure in the portal venous system increases such that it tries to find other ways back to the heart. And so it, it forms collateral channels. Th- that's, those collateral channels are what, what form the varices or varicosities that, uh, that, uh, develop in the GI tract that can lead to life-threatening hemorrhage in liver patients. Um, it's what leads to the formation of ascites 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 rat's nest of collateral venous vessels. So, so you've got the challenge of a, a large, you know, uh, organ with challenging anatomy. You have the challenge of this condition that makes the dissection and the predilection towards bleeding even higher, and then you have the synthetic function, which is, occurs in the setting of a, uh, you're doing this operation in the setting of an individual who's not making norm- normal clotting factors. So it's really k- both the circumstance of the technical challenge, but more, more often the, the, um, uh, the circumstances and the, in which you're doing it. And, you know, as you know, liver failure leads to cachex- cachexia 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 Starzl and his contemporaries took that operation on in the 1960s when electrocautery wasn't really a thing, most hospitals didn't really have blood banks. We didn't even have kind of, uh, critical care anesthesia, at least with any v- you know- 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, um, 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 a immunologic setting that just was not successful. And so, you know, even the patients that survived the operation in the early recovery, there were really no survivors past 90 days in the first, you know, dozens of transplants done, which is what led to the moratorium on liver transplantation that occurred in the late '60s.

    9. PAPeter Attia1:57:29

       A- and I would add one other thing to punctuate everything you said, Chris, 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 extracorporeal support that is offered to them to at least bridge the gap or tune them up a little bit prior to surgery. Um, the liver remains the only major organ with no form of extracorporeal support. Now, I, 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-

    10. CSDr. Chris Sonnenday1:58:31

        Mm-hmm

    11. PAPeter Attia1:58:31

        ... to manage gluconeogenesis, glycogen storage. I mean, you have to be able to regulate something to the milligram level with, with-

    12. CSDr. Chris Sonnenday1:58:39

        Right

    13. PAPeter Attia1:58:39

        ... seconds to spare. Uh, there are probably a dozen other reasons, but, you know, every attempt at extracorporeal

14. 1:58:45 – 2:08:25

    Addressing acute liver failure and the amazing baboon experiment

    1. PAPeter Attia1:58:45

       liver support has failed in- including some crazy stories that, you know, I heard from, God, o- one of our, one of the transplant surgeons I remember, it might've been Montgomery, even told a story about the baboon.

    2. CSDr. Chris Sonnenday1:58:57

       Yeah. That's, that's a Mel Williams story.

    3. PAPeter Attia1:58:59

       Oh, that's right. That's right.

    4. CSDr. Chris Sonnenday1:59:00

       Mel Williams story.

    5. PAPeter Attia1:59:00

       Mel Williams. Why don't you tell folks that story, actually?

    6. CSDr. Chris Sonnenday1:59:02

       Yeah.

    7. PAPeter Attia1:59:02

       It's just the scariest thing.

    8. CSDr. Chris Sonnenday1:59:04

       Yeah. So, [laughs] so, um, you know, what you're alluding to is exactly correct. So there have been all kinds of, um, both mechanical and even, you know, anatomic models trying to address liver dysfunction or to bridge that gap, you know, from liver failure to transplant, and nothing has worked real well. I mean, essentially, we've tried, you know, um, what's been called liver dialysis, so in other words, trying to remove some of the toxins from the bloodstream that the liver's responsible for filtering. We've, 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, um, kind of conjectures, well, what if, well, then we need a, a physiologic solution to this. W- could we, um, 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, uh, 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, um... He, he was a contemporary and a student of David Hume, who was one of the godfathers of liver, or, or, excuse me, of transplant and transplant immunology specifically. Um, Christiaan Barnard, who did the first heart transplant, actually trained in his lab. Um, and Dr. Williams, you know, uh, worked there as well, and then eventually came to Hopkins and started the transplant program at Johns Hopkins. Um, he was a kidney transplant recipient eventually himself, received a living donor kidney from his wife, and unfortunately died recently, um, you know, later in age, not related to his, his transplant. A remarkable kind of luminary figure, and one of the best storytellers, you know, you've ever heard. But he tells a story of that they decided, "Well, why don't we address acute liver failure by hooking up the patient to a extracorporeal essentially, you know, bypass circuit, and put a baboon on the other side of the, uh, circulation?" So the baboon's 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. And so they worked on this prep, and they did all kinds of preclinical studies, and eventually they had somebody come in with acute liver failure. And, you know, I don't know the specifics of IRB regulations at that time.

    9. PAPeter Attia2:02:02

       [laughs]

    10. CSDr. Chris Sonnenday2:02:02

        But sure enough, they got approval to, um, 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.

    11. PAPeter Attia2:02:14

        [laughs]

    12. CSDr. Chris Sonnenday2:02:14

        You know? It takes Herculean doses of, you know, s- uh, sedatives. So, um, and you can't have a baboon running around the medical ICU unit at Johns Hopkins Hospital. So they decided, in 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, um, you know, unbelievably, it starts to work. So the, the patient's encephalopathy clears. The patient starts to wake up. So this poor individual wakes up in the ICU at Johns Hopkins. 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 at lines. So the solution they decided to that is they actually put him in a body cast too. [laughs] So there was a baboon and this poor individual in a body cast in the ICU next, uh, next to each other at, at Johns Hopkins. And that, that, um, was a short-lived series of experiments, but it did prove the principle that that would work, you know, that the, that if you had an, an actual functional liver in cross-circulation with an individual. And, and actually, he went on to do some preparations between, for example, family members. If a-

    13. PAPeter Attia2:03:33

        Mm-hmm

    14. CSDr. Chris Sonnenday2:03:33

        ... a family member came in with acute liver failure, you could put them in cross-circulation with, you know, a s- a sibling or something. And, and some of those did, did work and maintain those patients. It also led to the principle that is part of a investigational product now that created this essential, uh, a dialysis column populated with hepatocytes. You know, with, with, uh, kind of a, a hepatocyte stem cell line that populates the hepatocytes. And that has been shown, at least in some, uh, studies, to at least provide some limited short-term support, uh, as well. So, uh, but the principle behind what you said is absolutely right, that we have not figured out how to provide extracorporeal support for liver patients, so they really are the patients that face death if they are not able to be transplanted in a timely fashion.

    15. PAPeter Attia2:04:24

        One of the most stark memories I have from residency on the, um, on the side of patients that would ultimately need a transplant was, uh, probably my second year in the old SICU. And, um-

    16. CSDr. Chris Sonnenday2:04:37

        Mm

    17. PAPeter Attia2:04:37

        ... a, a 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. Um-

    18. CSDr. Chris Sonnenday2:04:50

        Yeah

    19. PAPeter Attia2:04:50

        ... you know, the-- You know this of course, but just for pe- 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-- O- 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-

    20. CSDr. Chris Sonnenday2:05:11

        Mm-hmm

    21. PAPeter Attia2:05:11

        ... take for your headache. And so-

    22. CSDr. Chris Sonnenday2:05:13

        Yep

    23. PAPeter Attia2:05:13

        ... the ease with which a person can end their life with, with Tylenol is, is, uh, is, is staggeringly high. And as was the case in, uh, with this, 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, is the following: Before she really went into acute liver failure and-

    24. CSDr. Chris Sonnenday2:05:43

        Mm

    25. PAPeter Attia2:05:43

        ... 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, it was, it, it existed. Um, now, we could've been wrong. Maybe she was gonna recover. But, but it turned out she ended up getting transplanted. Um, and it was, it, it was just amazing to see her wake up from that and realize, like, she had another-

    26. CSDr. Chris Sonnenday2:06:28

        Yeah

    27. PAPeter Attia2:06:28

        ... lease on life. B-- And, and you could say, I mean, I-- Look, someone could say, "Well, she made a dumb mistake," you know? "And maybe she didn't deserve another chance." But of course, I would say who among us hasn't done really dumb things?

    28. CSDr. Chris Sonnenday2:06:39

        Yeah.

    29. PAPeter Attia2:06:40

        Um.

    30. CSDr. Chris Sonnenday2:06:40

        [sighs] It's so true. It's, it's-- You know, fortunately, acute liver failure only accounts for about 5% of the liver transplants done in the United States, so it's a relatively uncommon situation, in part because the liver is pretty resilient. So sometimes even a catastrophic, you know, overdose if, with good critical care and, and other measures, um, many of those patients will recover. But, um, you know, 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 a s- you know, suicidal-type gesture. Um, and we have to make the decision with limited information about whether or not we think they're an appropriate transplant candidate. And, you know, occasionally, there are reasons why they're not. You know, uncontrolled comorbid disease or maybe, you know, other, uh, factors. But usually, it's exactly the circumstance you described. It's a, a y- young distressed person who reacted badly to a, you know, a particular event. And I think our, the approach of our-
15. 2:08:25 – 2:20:40

    The potential for the rising prevalence of NAFLD and NASH to overwhelm the liver transplant infrastructure in the US

    1. CSDr. Chris Sonnenday2:08:25

       uh, uh, from the transplant, so.

    2. PAPeter Attia2:08:28

       Chris, when you and I were in medical school, and residency for that matter, um, 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 NAFLD and NASH. Can you tell us the twin stories of these two things and, and, uh-

    3. CSDr. Chris Sonnenday2:09:02

       Yeah

    4. PAPeter Attia2:09:03

       ... how is it that, that, uh, that something that w- w- we believed could never be cured got cured?

    5. CSDr. Chris Sonnenday2:09:09

       Yep.

    6. PAPeter Attia2:09:10

       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-

    7. CSDr. Chris Sonnenday2:09:18

       Yeah

    8. PAPeter Attia2:09:18

       ... in the developed world?

    9. CSDr. Chris Sonnenday2:09:20

       It's such a kind of at once compelling but also humbling story, and I'll, in telling it, I'll add even a third actor that, you know, is, is part of this as well. So, um, hepatitis C as, as you alluded to, uh, you know, a viral illness, um, bloodborne illness that can, um, is, has kind of an interesting history. Some people that are exposed to, to hepat- it-- 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 viremia and subsequent, uh, inflammation, which is, which is silent for years and in some cases decades. So the, the kind of history of this in the United States is that people were exposed to this, you know, in the '70s and '80s, either due to a time when the blood supply was not really tested for, uh, 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 about their life, and then here they are, 20, 30 years later with cirrhosis and eventual complications of cirrhosis and, and indication for transplant. And the-- 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 graft failure, you know, and cirrhosis essentially of their transplanted graft. So it was a, it was a particularly frustrating clinical problem 'cause there was this enormous need, but also we were only kind of partially solving the problem. Um, and you know, what has happened and what you're alluding to is in the last 10 years essentially was the development of these, uh, direct anti- antiviral agents that have transformed the field of hepatitis C. And it, 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. Um, you know-

    10. PAPeter Attia2:11:43

        Yeah, I don't, I, I don't think I could think of something more impressive in my-

    11. CSDr. Chris Sonnenday2:11:49

        I mean-

    12. PAPeter Attia2:11:49

        ... adult life

    13. CSDr. Chris Sonnenday2:11:50

        ... maybe you could argue the, the, you know, retroviral regimens that made HIV a chronic disease-

    14. PAPeter Attia2:11:56

        Yeah, yeah

    15. CSDr. Chris Sonnenday2:11:57

        ... instead of a, um, could, could rival it. But, 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, 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-

    16. PAPeter Attia2:12:20

        Mm

    17. CSDr. Chris Sonnenday2:12:20

        ... needing transplant for hepatitis C. Um, because once they clear the virus, their liver does, you know, recompensate and repair somewhat. And the patients that are not cirrhotic or with advanced fibrosis yet are never gonna get there, so it, it is a, it is truly a curative, uh, situation. So that drop has happened precipitously over the last, you know, three to five years. It has been replaced, you know, nearly completely by actually two diseases. Um, the, the first and the one that has this kind of incredible broad public health impact is, is the, is non-alcoholic fatty liver disease or the concept of, um, fatty deposition in the liver that leads to chronic inflammation and kind of just like a chronic virus, you know, ongoing inflammation, fibrosis, eventually cirrhosis. Um, and with the obesity epidemic and other associated diseases, the prediction is that by 2030 or so, uh, it will become the leading indication for liver transplantation. Um, 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, uh, you know, at a steeper slope, and that is the r- the, uh, incidence of alcohol-related liver disease, which is, has always been, you know, a important cause of liver disease in the United States. But unfortunately, and, you know, whether you blame it on the economic downturn in the late 2000s or other factors, you know, really have seen an explosion of alcohol-related liver disease made worse, by the way, by the pandemic. Um, 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 l- a little less of kinda this terrible Spanish Inquisition kind of approach to, you know, you're either in or out, you know, if, if we think you're committed to sobriety. To a system where we have developed resources, um, mental health professionals, counselors, and such to support people in their sobriety to allow them to get transplanted successfully. So, you know, I hope that that curve plateaus. Um, we unfortunately don't have an intervention for fatty liver disease that I see breaking that, you know, the slope of that curve, uh, quickly. Um, and, you know, it has changed our field because, you know, the, the population of patients with fatty liver disease is much different than the patient, the population with chronic liver disease of other causes, whether it's alcohol, hepatitis C. You know, 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 patient population, they are, first of all, often obese, which, you know, 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, hyperlipidemia, et cetera, which poses, you know, 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, the, the-- you'll hear the comment said that we're, we've kinda converted our liver transplant population to look a lot more [chuckles] like our kidney transplant population because they're dealing with these cardiovascular comorbidities and other things that are just, um, that are threatening their long-term survival as much as their liver disease and immunosuppression is.

    18. PAPeter Attia2:16:12

        You know, I sort of think that the, the, the uptick in alcohol-associated, uh, liver disease, or AFLD, say, um, is kind of the parallel but gets less attention than what we're seeing with the opiate crisis.

    19. CSDr. Chris Sonnenday2:16:29

        Yeah. 100%.

    20. PAPeter Attia2:16:29

        So I think the, the opiate crisis is -- I, 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. Um, and you can throw the physicians under the bus who make-

    21. CSDr. Chris Sonnenday2:16:45

        Mm-hmm

    22. PAPeter Attia2:16:45

        ... who prescribe them too 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-

    23. CSDr. Chris Sonnenday2:16:57

        Yeah

    24. PAPeter Attia2:16:57

        ... 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-

    25. CSDr. Chris Sonnenday2:17:09

        Yeah

    26. PAPeter Attia2:17:09

        ... it becomes very easy to focus on that. But acute alcohol toxicity is virtually unheard of. Very few people will drink themself to death in a moment, right? Um, much more common, of course, is the chronic toxicity of alcohol. And I think that, you know, you're one of the few, um, 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-

    27. CSDr. Chris Sonnenday2:17:37

        Yeah

    28. PAPeter Attia2:17:37

        ... basically two en- two sides of the same coin.

    29. CSDr. Chris Sonnenday2:17:40

        Yeah, I totally agree with you, and I think we unfortunately, um, it, it's, it's 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. Um, you know, o- o- one of our hepatologists here at the University of Michigan, Jessica Mellinger, who's, who's really dedicated her career to understanding alcohol-related liver disease, um, as she has refined kind of her approach to the evaluation and management of these diseases, you know, she really makes the sense that the, the, um, [lips smack] emphasizes the point that this is a behavioral disease. You know, uh, you could 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. Um, and I think, you know, we have kind of largely turned a blind eye at, um, the impact of alcohol-related liver disease and alcohol use disorder in our society because of the, just the factors you said. It's a, it's a freely available, you know, um, substance. Uh, you know, it's, you don't have to go, you know, the, the machinations and just kinda destruction that people have to go through their life to get opiates, that's, that's not the case for alcohol. You can go to the 7-Eleven and get, you know, the, the, the kind of equivalently damaging dose, you know, there. And I think it's made the problem much harder to address, and I, I am glad to see the transplant community and the medical community kind of re-pivoting in our focus towards trying to help people address the, the, the reasons, you know, why they're, uh, involved in this cycle. Uh, 'cause it is tragic, and one of the things that's most notable about the alcohol-related liver disease population now is they are ridiculously young, you know? So not only have they drank enough to destroy their liver, but they've drank enough to destroy their liver in their 20s-

    30. PAPeter Attia2:19:48

        Wow
16. 2:20:40 – 2:30:16

    The importance of teamwork in successful organ transplantations, and the most tragic event Chris has ever witnessed

    1. PAPeter Attia2:20:40

       Chris, I think the last thing I wanna talk about from a transplant perspective, and there's so much I wanna talk about, but I wanna be respectful of your time, and I know you've gotta head off to a meeting shortly. Um, you talked about the team, right?

    2. CSDr. Chris Sonnenday2:20:53

       Mm-hmm.

    3. PAPeter Attia2:20:53

       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 encom- I mean, the only one that I could maybe think of would be, like, that would rival it might be pediatric cardiac surgery, where you just have-

    4. CSDr. Chris Sonnenday2:21:17

       Mm-hmm

    5. PAPeter Attia2:21:17

       ... such, you know, the, the overlap is huge. But, 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.

    6. CSDr. Chris Sonnenday2:21:33

       Yep.

    7. PAPeter Attia2:21:34

       It's an enormous team. Um, and you lost a number of team members a, a while ago.

    8. CSDr. Chris Sonnenday2:21:42

       Yeah.

    9. PAPeter Attia2:21:42

       Shortly, shortly after you got to Michigan. Um, I think that story is, uh, obviously tragic, but also highlights the incredible risk that goes into this. Um, do you mind telling that story a little bit?

    10. CSDr. Chris Sonnenday2:21:55

        Yeah, sure. So what you're referring to was a, um, in June of 2007, we had a team, um, that had flown from Michigan to Wisconsin to retrieve lungs for one of our recipients. Uh, they had actually procured the lungs. They had, um, just taken off from Milwaukee and, um, y- you know, s- had a tragic, um, 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, um, uh, that shortly thereafter, and all six individuals on board, uh, died. Um, and it does, um-- There's a, 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, uh, set of lungs to a recipient. Uh, there were two pilots on board who passed away. Um, two of our perfusion staff, so individuals who are responsible for the, 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, a fellow, um, who died in that accident as well. And I can tell you that, um, you know, first and foremost, it's, it's hard to speak about it now without, um, getting emotional. It was the, uh, you know, most devastating event that I've ever witnessed professionally, you know, directly. Um, 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. Uh, you know, one of our, um, 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 then had to tell our team, uh, you know, what had occurred. Uh, it was, uh, devastating, you know, to, to, to put it mildly. Not to mention, most importantly, the loss that those families sustained. Um, you know, I think, um, it, 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. Um, it did, uh, uh, you know, if there is any good news about that event, um, it did two things, one of a- one of which I think was, um, 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, you know, the-- each member of our team is and how important their contributions are and how much they put at stake to make these incredible, you know, events of organ transplants happen. The second thing is it made our field pause and figure out, you know, do we need to be doing things differently? You know, do we need to be shipping teams all over the country to procure organs when there are qualified surgeons, you know, right next to where that, that organ may have come from? Do we need to reconsider how we travel, you know, in terms of the, the, um, the expertise of the flight teams and such, and the, and the actual f-flight, uh, um, uh, the planes themselves. Um, and it's-- And it has motivated differences. For example, in the liver community now, we used to fly out every time there was an organ to get-- You know, we would go to wherever that donor hospital is. Now, um, 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, 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, that I think needs to continue to evolve. Um, but you're absolutely right that it, it puts a, um-- It, it's a-- It was a terrible event to remind us, uh, of the kind of sanctity and importance of our teams, for sure.

    11. PAPeter Attia2:26:30

        Well, Chris, I wanna thank you for, for, for sharing that story. Um, it's hard to believe it was 13 and a half years ago. I, I mean, I remember it like it was yesterday, so I can't imagine-

    12. CSDr. Chris Sonnenday2:26:39

        Yeah

    13. PAPeter Attia2:26:39

        ... how proximate it feels to you as well. Um, this has been wonderful to sit down with you and talk about this. Um, uh, I- I always enjoy, um, our times together, and I have-

    14. CSDr. Chris Sonnenday2:26:52

        Mm-hmm

    15. PAPeter Attia2:26:52

        ... the fondest memories of sitting in that empty cafeteria at 2:00 in the morning between traumas. And again, as long as I was sitting there with you, it was always enjoyable. It was never like, "Oh, I can't wait to get back to the call room and try to get 10 minutes of sleep."

    16. CSDr. Chris Sonnenday2:27:05

        Mm-hmm.

    17. PAPeter Attia2:27:05

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

    18. CSDr. Chris Sonnenday2:27:24

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

    19. PAPeter Attia2:27:53

        Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. To that end, membership benefits include a bunch of things. One, totally kickass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these. Monthly AMA episodes or Ask Me Anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this. The Qualies, which are a super short podcast that we release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed on previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to every one. Steep discounts on products that I believe in, but for which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of such companies. [outro music]

Episode duration: 2:30:16