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

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.740 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. My guest this week is Chris Sonnende. Chris is the transplant director

00:00:55.520 for Michigan medicine. He received his medical degree at Vanderbilt and went on to complete his

00:01:00.580 residency in general surgery at Johns Hopkins, which is where we met. He went on to complete

00:01:06.560 multiple fellowships. He trained in trauma surgery, hepatobiliary oncology, and of course,

00:01:12.680 transplant surgery. More than any of Chris's academic accolades, the thing that makes him

00:01:17.560 most special to me is just the kind of human being he is. And some of you may have heard me talk about

00:01:21.760 Chris in the past. I've spoken about him on multiple podcasts, both this podcast and other

00:01:26.960 podcasts where I've been interviewed. And I've always really referred to him as probably the

00:01:30.100 most special resident I ever had the privilege of working alongside. And he's frankly, unlike anyone

00:01:35.700 I've ever met. And I've long wanted to talk with him. And this podcast really served as an opportunity

00:01:39.880 to do two things. One was sort of showcase the type of leadership that Chris has developed and carried

00:01:45.160 with him from Baltimore to Michigan. And also to really tell the story of transplant medicine,

00:01:49.420 which is something that I think most people don't fully appreciate and understand. And yet it

00:01:54.180 touches so many lives. We, in this episode, go into great detail about it. Frankly, we talk about

00:01:58.760 the entire history of two organs in particular, kidney, which is illustrative of so much, and liver,

00:02:04.760 which is really Chris's specialty. And we talk about them from the lens of the surgical developments

00:02:08.800 and of course, the immunologic developments, which are probably the cornerstone developments.

00:02:13.900 We talk about some of the tragedies, of course, and the miracles that have been witnessed by this

00:02:17.120 field. So I think this is an episode you won't want to miss, even if you think at the outset,

00:02:21.140 the transplant surgery is something that's a bit too far removed from your day-to-day life.

00:02:25.080 So without further delay, please enjoy my conversation with Chris Sonnende.

00:02:34.280 Chris, we've been talking about doing this for probably two years now. So I'm really happy to

00:02:39.020 finally sit down with you though. We had always thought we'd be doing it in person,

00:02:42.740 but decided, just didn't want to wait any longer. No, I miss you dearly. And I think during our

00:02:48.980 discussion today, people are going to get to understand why you've played such an important

00:02:52.080 role in my development. I'll just state for everyone that you were one of my senior residents,

00:02:57.680 what we call chief residents, when I was going through my training at Hopkins. And I think on

00:03:02.260 other podcasts, people have probably heard me mention you. I've certainly talked about you.

00:03:06.420 I talked about you on Jocko's podcast several years ago. I've talked about you on this podcast.

00:03:10.560 And usually in the context of what I consider to be the most remarkable leadership, residency was not

00:03:17.440 without its stresses and stressors. And I think we have lots of great memories from it, but also

00:03:23.020 some not so great ones. And therefore, anything that could have been done by those around us to

00:03:28.420 make the process better was always appreciated. And I think we'll get to that later, but let's just

00:03:33.200 start by telling folks how you even got interested in medicine, let alone surgery.

00:03:37.160 Well, first of all, thank you so much for the invitation. It's awesome, even virtually to get

00:03:43.540 to hang out with you and reminisce a little bit, but also talk about our work. And I'm really proud

00:03:49.020 of the work you've done with this podcast. It's been so impactful to patients, providers. It's just a

00:03:55.220 cool way to see your leadership and impact extend. Yeah, medicine for me was something I stumbled to.

00:04:04.540 So I grew up in the DC area. My dad is a retired Presbyterian minister. My mom was a medical social

00:04:12.300 worker. The only other physician in my family is my grandfather, who was an internist and researcher

00:04:19.220 in St. Louis. And, you know, I went to college without a clear plan other than wanting to play college

00:04:27.860 soccer, which is what I was fortunate enough to do. And I had imparted to me by my parents that,

00:04:34.860 you know, they would support whatever I chose to do, but wanted it to be something that served other

00:04:40.640 people. And I, you know, through the course of my studies did come to medicine for some of the

00:04:48.480 somewhat cliche reasons. You know, it was a really exciting, challenging field that appealed to kind of

00:04:54.920 the problem solver or the scientist in me, but first and foremost was a way to serve people. And came to

00:05:02.400 surgery very late too. In medical school, I was one of those people that kind of liked everything and was

00:05:07.740 fascinated by kind of all fields, but really became attracted to what fortunately I think still sustains me

00:05:16.380 today. And that is that being a surgeon provides this really unique opportunity to enter people's

00:05:24.020 lives in their scariest kind of darkest moments. And to have the privilege to be able to walk that

00:05:31.780 with them and try to help them navigate that time and, and to have skill in some cases to solve the

00:05:38.840 problem. And I think that was remarkable to me. I was struck by the challenge of it and, you know,

00:05:46.020 was fortunate to make the decision to train in surgery and end up at Hopkins. Whereas I totally

00:05:51.560 agree with how you described it. It was like the one hand kind of forged us into the people we are

00:05:57.440 today, but, you know, also was difficult and challenging. And that's partially also what made it,

00:06:03.480 you know, the experience it was. Yeah. How did you pick Hopkins? I mean, I guess you could say

00:06:07.400 Hopkins sort of picks people and not the other way around, but how did you at least have the desire

00:06:12.140 to go to, to such a rigorous program? Was it something that said, Hey, once I've committed

00:06:16.680 to doing this, I might as well go to the best place. Yeah, it was, it was a combination of things.

00:06:21.680 You know, as I mentioned, I decided a little late in medical school that I wanted to train in general

00:06:25.720 surgery. And I, and I went and consulted with the program director at my medical school, who was

00:06:32.200 John Tarpley, kind of a legendary general surgeon at Vanderbilt who had spent a lot of his career

00:06:37.120 in Africa, actually doing mission work and surgery. And I went to meet with him. And to be honest

00:06:43.900 with you, the goal of that meeting was to have him tell me that I even had a shot at staying at

00:06:49.060 Vanderbilt. You know, that was, that was my kind of what I thought would be the best I could do. And we

00:06:55.180 talked for a long time. He's a wonderful person, wanted to hear about my goals. And he said, I think

00:07:01.120 partially in jest, but he said, you know what, I think we need to send you back to the mothership

00:07:06.400 because he had trained at Hopkins and he still carried with very passionate memories about the

00:07:12.280 training there and the standard of clinical excellence that that the training programs

00:07:17.380 there represented. And so, you know, I was fortunate enough to get an interview and was obviously

00:07:22.840 impressed with the history and the emphasis on clinical excellence. But like you, I think I was also

00:07:29.220 really attracted to the idea of mentorship and one individual in particular, Keith Lillamo, who was

00:07:35.420 the program director at the time, now the chair of surgery at Massachusetts General Hospital. I really

00:07:41.920 got the feeling that he was invested in the development and training of his residents, not only as

00:07:49.540 surgeons, but also as individuals and as leaders. And exactly like you said, kind of once I got that sense,

00:07:55.300 I wanted to swim in that pool, so to speak, figuring that I would gain as much from obviously the

00:08:02.640 terrific history and mentors and training environment, but also the individuals who we

00:08:08.100 were lucky to train next to. You know, I mean, I think when you feel like you're just running with

00:08:12.840 superstars every day, that does push you to be the best possible physician, surgeon, person you can be.

00:08:20.120 And, you know, I can think of so many individuals just like you that, you know, inspired me to push

00:08:26.600 myself to beyond kind of expectations that I probably even had for myself at that period of

00:08:32.160 time. There's no doubt during this discussion, Chris, I'm going to have to embarrass the hell out

00:08:36.080 of you because, you know, the reality of it is you were definitely, and you're just going to be too

00:08:40.520 modest to accept it, but you were certainly in a league of your own, even amongst that caliber of

00:08:44.960 individuals. So it's one thing to say you played for the Yankees. It's another thing to say you were

00:08:50.060 Mickey Mantle or Joe DiMaggio. And I think one of the things I want to dig into today is for many

00:08:57.100 of us, certainly myself, I'd put in that category. You show up with all of these ideas about what you

00:09:03.460 can be and what this process is like. And somewhere along the way, a tiny piece of you gets a little

00:09:10.540 broken. You lose a little bit of your humanity. Your tolerance for distress goes down. The empathy

00:09:18.060 goes down a little bit. Your tolerance for others around you, even on the same team goes down a

00:09:24.140 little bit, whether it's your tolerance for an error that a nurse makes, your tolerance for an error that

00:09:29.240 the lab makes. I mean, I just watched in myself over five years, a degradation of humanity that in my

00:09:38.260 case led to a very extreme outcome, which was departing. I can safely say you're the only person in whom I

00:09:47.360 didn't witness that. And simultaneously, you were the best of the best. So to me, that's just an unusual

00:09:55.380 combination that I definitely want to understand that a bit more.

00:09:59.380 Well, I mean, that's very kind of you. I didn't feel that way at the time, which is, I guess, true of all of us.

00:10:04.960 The battle you're waging within is, you know, different than what everybody sees on the outside.

00:10:10.260 You know, I mean, I think one way of asking that question is kind of what sustained me during that

00:10:15.360 time period, what, you know, kept all of us going, but me in particular. I definitely had a

00:10:23.540 overwhelming sense from day one of arriving in Baltimore. And this speaks to kind of my medical

00:10:32.000 training in general, but certainly specifically our residency, that I felt like I was very

00:10:38.320 lucky to be there. You know, that there were hundreds of qualified individuals who could have

00:10:43.460 taken that spot and probably thousands of other individuals who who didn't get the opportunities

00:10:48.700 I did to get to that spot. So I felt obligated, if that's the right word, to kind of maximize that

00:10:55.300 entire experience. I also felt the burden, if you will, of the expectations of those around me.

00:11:03.160 You know, I mean, the expectations of those that were training us, our colleagues, et cetera. You

00:11:07.700 know, I always, one of the things I said to Dr. Little Lone, Dr. Cameron, when I left was, you know,

00:11:13.980 thank you for your high expectations. Like that's really what drove me to achieve things that I didn't

00:11:20.520 necessarily think were within me. I will say though, that the last thing, and this, this is true to

00:11:26.700 this day. So it's not specific to residency is that I have always found, fortunately, that what

00:11:35.400 re-centers me when medicine gets hard, because it does get difficult, whether you practice in a,

00:11:43.440 you know, busy primary care practice where you're cramming through 40 patients a day, or you're doing

00:11:49.580 operations where a wrong move leads, can lead to somebody's death. You know, there are, there are

00:11:56.000 good days and bad days, and there are pressures that can do all the things to you that you alluded

00:12:01.860 to. But what has always re-centered me is the patience. I mean, to be honest, that privilege that

00:12:07.360 I was speaking of earlier of being invited into people's lives in these crazy moments and actually

00:12:14.480 having the opportunity to intervene. And somehow, even in the thick of residency, when you're like,

00:12:19.580 why is it that this lab I ordered 14 hours ago has still hasn't been done? Or why can't I find the

00:12:26.060 x-rays that were just on this desk like two hours ago? Or all the other crazy things that we had to

00:12:32.060 deal with? Or why, why is there no food to eat at 11 o'clock at a 24-7 operation? The thing that

00:12:38.920 always kind of re-centered me is reminding me that the people upstairs in those beds had it a lot worse

00:12:45.800 off than I did. And, you know, I think that the privilege of being involved in their care is kind

00:12:50.280 of what re-centered me and still does today. You know, when I have days like that, that is always

00:12:55.560 what is able to kind of pull me back to the right frame of mind. Another thing that I think made you

00:13:01.400 very special that wasn't, that I think was actually distinct from everything you're describing.

00:13:07.220 Everything you're describing was on incredible visible display. But you could have, I think,

00:13:12.080 had all of those characteristics and you wouldn't have created the magnet that someone like me felt.

00:13:16.860 Now, I can't speak for the other residents. It would be hard for me to imagine I'm the only one

00:13:21.020 that felt this way. But I just remember anytime my rotation card showed I was going to be your junior

00:13:27.220 resident, it didn't matter what the rotation was. I couldn't wait for that month to arrive.

00:13:32.900 So that speaks to something a little different. And let's go back to, you went to Northwestern,

00:13:37.940 if I recall, right, for college. And so you're a division one athlete, you're playing soccer,

00:13:41.860 were you the team leader? I was a captain. I was not the best player on the team,

00:13:48.000 at least on my college teams, for sure. But I do feel very lucky that I was elected to

00:13:54.260 represent the team and to serve in a leadership role, at least as it is within the context of an

00:14:00.500 athletic team. One of the things that has always been true for me, you know, and this dates back to

00:14:07.600 sports as a kid. And to be honest, as part of the reason why I chose to be a transplant surgeon

00:14:12.780 is that I always migrated to team collaborative activities. I was never an individual sport

00:14:22.560 athlete. You know, I swam a bit, I played tennis a bit, but I never kind of like was captivated by

00:14:27.820 those sports in the same way that I was of just being on a team. And in fact, there were multiple

00:14:33.840 times in my development as a young kid playing soccer in the DC area, which is a very competitive

00:14:40.540 kind of soccer environment, you know, where I was lucky to kind of be on some of the teams that I was

00:14:47.300 on playing with elite players. But being on that team, being in that environment seemed to pull the

00:14:54.020 best out of me. And I think that was true in residency too. You know, what I relished the most

00:14:58.740 was like, yeah, it was five in the morning, but you showed up and there was Peter and there was

00:15:03.840 Megan and there, you know, it was your team. And it was like, you felt like you were unstoppable to

00:15:09.040 some degree, even though you were doing what at times seemed a possible task. And I feel the same

00:15:13.600 way about transplant. You know, I feel like part of the reason I chose it, it was clear that no one can

00:15:19.080 accomplish what it takes to take a liver transplant patient from their diagnosis to listing to

00:15:26.360 operation, to recovery, to transforming them to a new life afterwards without a really highly

00:15:33.120 functioning team. And that is what always has inspired me to give my best because I feel like

00:15:39.160 I'm on a team where other people are doing the same thing.

00:15:42.940 I mean, there's a story I'll tell that I would imagine you don't recall because it was so

00:15:47.760 commonplace, but it really stood out to me as an example of what a great leader would do.

00:15:55.800 So you'll have to forgive me for explaining a process that you understand, oh, too well,

00:16:00.300 but most people don't. Actually, I'm going to have you explain it. Tell folks what the M&M

00:16:04.300 conference was every Tuesday morning. Yeah. So you're referring to what at Hopkins was called

00:16:10.360 morbidity and mortality conference, which is, you know, I think there are versions of that

00:16:15.940 throughout medicine, but in surgery, it is a unique part of the culture. So one of the things that

00:16:22.780 makes surgeons and surgery unique as a discipline is the sense of ownership, accountability,

00:16:30.900 responsibility for the outcomes of the patients that you're privileged to care for. And so

00:16:37.220 morbidity and mortality conference was a weekly conference where we reviewed essentially patients'

00:16:44.600 stories, patients' cases, particularly patients that had suboptimal outcomes, whether it was a

00:16:50.780 complication as hopefully routine as a wound complication or something, that they would

00:16:56.020 extend their recovery, but they would recover from fully to a death related to a surgical procedure,

00:17:02.040 or at least to a diagnosis that we tried to address with a surgical procedure.

00:17:07.380 My former chair here at Michigan, Mike Mahon, used to say that you can look into a department's soul

00:17:13.040 by attending their morbidity and mortality conference. It becomes the kind of cultural event

00:17:18.320 of the department because you get a sense for what that level of accountability is. Is the conference

00:17:26.180 spent kind of blaming the anesthesiologist or the nurse or the patient's comorbid conditions,

00:17:32.480 or is the discussion about what we could do better next time to make the patient's outcome better? And I

00:17:41.560 think there are lots of examples that I'm sure you and I could regale for for hours of kind of how

00:17:49.140 lessons learned in that room in the morning, you know, shape the way we think about medicine, the way

00:17:55.140 we think about responsibility, all kinds of other things. One thing I always admired is that the chair

00:18:02.060 who was there for most of the time we were there, John Cameron, he would often be the moderator of

00:18:08.140 Morbidity and Mortality Conference. And he always led, as you recall, with his own cases, which is,

00:18:14.200 you know, a remarkable example of the level of accountability that I think he was trying to

00:18:20.740 encourage among the faculty and residents there. Yeah, that's one of the things that stood out to me

00:18:26.960 because I went to medical school at Stanford and it was just a different culture. It wasn't nearly as

00:18:34.020 rigorous. And so even in medical school, you would still attend that during your surgical

00:18:37.820 rotations, but it, it was not the conference that I saw at Hopkins, which was, I mean, this was the

00:18:46.060 most intense hour of the week and it was taking place outside of the operating room. So this was

00:18:51.960 kind of the story that I'll tell that it just remains to this day etched in my mind. So by this

00:18:59.100 point, you're now the trauma fellow. So you have now finished residency. You are now staying at Hopkins

00:19:03.600 for another year to do what can only be described as the craziest fellowship ever. It's a hepatobiliary

00:19:09.300 oncology fellowship combined with trauma every third night, as if that weren't enough. And it's

00:19:14.800 either July or August. So it's very early in the academic year. I'm the third year resident. So I'm

00:19:23.160 kind of your most senior resident on that service. And you're the ACS. So you're functioning like the

00:19:30.640 attending. And we had just come on that morning to receive sign-off from the team that was leaving.

00:19:41.200 And we both recall just how chaotic that could be, right? You know, you've got people that are just

00:19:46.520 getting shot two hours earlier. You got to run to the OR with them and you're being told about these

00:19:51.620 all, this patient, this patient, this patient. And I mean, almost as a matter of fact, one of those

00:19:56.560 patients was being discharged that day. And it was sort of like this person on this floor is going to

00:20:01.500 go home in a couple of hours. Nobody needs to go and even see that person. You not only went and saw

00:20:07.180 that person, but realized something was wrong. And it pains me that I don't remember what was wrong.

00:20:12.660 But either you sense that this person had a compartment syndrome that got missed. I think

00:20:17.580 they'd been hit by a car that day before or something like that. You sense that something that was

00:20:22.160 missed. For you to be the one to go and catch it was out of this world, right? Never would the

00:20:27.140 attending go and be the one to go and check on the patient whose discharge paperwork is already

00:20:31.720 signed to go home. But you did that. You caught the misdiagnosis, took the patient to the operating

00:20:37.820 room, operated, you know, probably saved his leg. You then presented that case at M&M several weeks

00:20:44.240 later. But the part that blew my mind was you never mentioned the circumstances around which

00:20:51.340 this patient came into our care. In other words, there was no blaming. There was no,

00:20:56.460 well, you know, Mr. Smith was about to be discharged, but I decided to go and make sure he

00:21:01.260 was okay and realized actually he had a compartment syndrome and needed surgery to save his leg.

00:21:07.260 Instead, it was, you presented it as though it was your fault, as though you had missed it.

00:21:11.780 And honestly, it sounds crazy. That was one of the moments when I realized I'm not good enough

00:21:17.720 to be in this profession. You know, maybe none of us are, but I don't know if you remember that case.

00:21:23.120 Yeah, I do actually now that you recall it. And the circumstances were, as you described,

00:21:29.200 it was one of those crazy days where 35 things are happening and we were all over 34 of them.

00:21:36.360 Unfortunately, the 35th was this poor guy who was getting ready to be wheeled out of the

00:21:41.440 hospital. You know, I don't remember the circumstances of the M&M discussion, but I do

00:21:46.300 certainly carry the philosophy in my work currently. And, you know, certainly that there is not value

00:21:54.680 in kind of assigning blame to individuals. There's only value in recognizing opportunity for us as a

00:22:02.200 system, as a team to get better. And, and partially it's because I think, you know, if I were to throw

00:22:09.160 stones in that case, I could walk out of that conference and an hour later, be the one responsible

00:22:14.380 for kind of generating a similar or worse complication. So I think there's some humility

00:22:19.600 that has to enter into understanding that no one has all the answers, nor should be expected to kind

00:22:26.500 of catch everything. In fact, one of the things that I think has one of the, as you know, one of the

00:22:31.560 criticisms of the M&M morbidity and mortality culture is that at least historically, it had been

00:22:37.640 a little bit too much about assigning individual blame and not about recognizing opportunity for

00:22:43.620 change. But I do think that over time, I've seen that change. And certainly the way morbidity and

00:22:49.660 mortality conferences are run now, for example, at my institution and others that I've visited are

00:22:54.680 much more focused on what's right for the patient than rather, you know, who do we have to kind of

00:22:58.860 string up for, you know, this particular mistake, which is number one, better for patients. Number two,

00:23:04.660 sets a better example for the trainees and learners in the room that are trying to do this. And just

00:23:10.360 is an important piece of creating the right culture where everybody's kind of oars are moving in the

00:23:15.340 same direction. At what point during residency did you decide that it was going to be transplant

00:23:22.240 medicine versus the other things that you had clearly shown a fantastic predilection for,

00:23:28.740 such as pancreatic surgery, liver surgery, and all facets of surgical oncology in the GI tract?

00:23:34.660 Yeah. Honestly, I was, I was greedy. I kind of wanted to do it all. You know, I, when I entered

00:23:40.640 Hopkins, I had developed an interest in diseases of the hepatobiliary system and upper GI tract. So

00:23:47.400 that was another thing that clearly drove my, my interest in that residency where they had such

00:23:52.660 expertise and concentration of experts in those diseases. I did my intern year rotation and

00:24:01.000 transplant. And then again, a third year rotation and transplant, my fellow as an intern, and then

00:24:07.020 my junior attending as a third year was one of the people who's been, you know, one of the most

00:24:12.860 important influences on my professional career, who's Bob Montgomery, now the head of transplantation

00:24:18.440 at NYU and a transformative figure in our field over the last couple of decades. And partially,

00:24:26.560 it was his example of what I thought I could aspire to be as a transplant surgeon. Partially,

00:24:33.400 it was realizing that the distance from kind of bench to bedside and transplantation is really short.

00:24:41.200 You know, it was unlike anything that I had, had seen even in, in a very innovative, progressive,

00:24:47.120 you know, surgical department. And finally, you know, specifically speaking to my previous interest,

00:24:52.880 I did see liver transplantation specifically as being completely complementary to being a

00:25:01.080 comprehensive abatabiliary surgeon and physician for patients with, you know, hepatobiliary disease.

00:25:07.400 You know, it's interesting in other parts of the world, it's pretty commonplace for

00:25:11.700 hepatobiliary surgeons and liver transplant surgeons to be the same individuals. You know, in the U.S.,

00:25:17.120 just training tracks changing over time and such, there are, there tend to be surgical oncologists who do

00:25:22.300 hepatobiliary surgery and transplant surgeons who may do some hepatobiliary surgery, but I

00:25:26.700 clearly thought it would make me a more complete surgeon and physician to train in both. And I've

00:25:32.480 been very lucky. I mean, this isn't something that can happen necessarily at every institution,

00:25:38.140 but I've, I've straddled that line in my career too. I, about half my clinical practices

00:25:42.960 is hepatobiliary surgery, surgery of the liver, bile duct, and pancreas for mostly for cancer,

00:25:49.320 but other benign diseases, and then liver transplantation. So I feel like I won the

00:25:56.100 lottery, you know, I'm kind of walking that line to be able to combine those disciplines.

00:26:01.580 Tell folks a little bit about what you mean by bench to bedside and that, that distance being short.

00:26:05.800 It's a term we throw around a lot in medicine, but its significance is huge. I want to make sure

00:26:10.380 people understand it.

00:26:11.980 I mean, part of it is just understanding the history, right? So transplantation as a field is

00:26:18.480 very young. So the first kidney transplants were done in the 1950s, the first liver heart and lung

00:26:25.180 transplants attempted in the 1960s, none of which were particularly successful until the 1980s related

00:26:31.580 to all sorts of important changes, but particularly the development of effective immunosuppression.

00:26:38.160 And then once it became a feasible and successful medical intervention, then developing all of the

00:26:46.960 systems around making that a reality for more people and extending that to people with organ

00:26:52.660 failure of various causes. So here we are, surgical residents in the 1990s in a field that really is

00:26:59.900 about 10 years old in terms of kind of being operationally expanding enough to really be a reality

00:27:06.260 at most major medical centers. And so you would see things being discussed kind of in morning

00:27:12.660 report or rounds or like, no, this is a really tricky case of acute rejection. We haven't tried X yet.

00:27:19.740 And then you would see we try X and it would work or not work. And we just, or there were surgical

00:27:24.840 techniques, living donor liver transplantation, basically a major part of my practice now was created in

00:27:31.920 the 1990s and early 2000s. So, so I think the ability to see innovation become reality in very rapid form was

00:27:42.500 number one inspiring. I mean, you felt like you were doing something that was, that was new and

00:27:47.920 innovative and just really incredible, but also to be honest, it made you feel like you could

00:27:53.380 potentially have some impact in the development of a field that was nascent. And I would put myself in

00:28:01.720 maybe the second or third generation of transplanters in terms of its history, which is, you know, I feel

00:28:06.620 very fortunate to be a kind of a witness to that history and participate in some of it moving

00:28:12.240 forward. Let's use kidney as an example to explain to people the challenges. Today, we take kidney

00:28:20.560 transplants almost for granted because the success rate is so high. In fact, even when I was a resident,

00:28:27.560 if you demonstrated that you had enough of this skill and the interest, even the transplant fellow

00:28:32.560 would let you as the, you know, mid-level resident or the senior resident in general surgery do kidney

00:28:37.660 transplants. I mean, you mentioned Bob Montgomery, there was a stretch on transplant where Bob and I

00:28:42.120 did 13 consecutive kidney transplants together in a period of like four days. So the fact that kind of

00:28:48.340 a knuckle dragger like me could have been doing this speaks to how well it works today. But as you said,

00:28:54.460 this is a procedure that even in the 1960s carried with it a mortality of more than 50%.

00:29:00.200 So let's break down for people, the evolution of this from sort of the technical evolution.

00:29:07.620 It was only what maybe a little over a hundred years ago that the anastomosis was even understood

00:29:12.720 to then the complications of acute rejection, chronic rejection, and even understanding what the immune

00:29:20.240 system is doing. So, and then we're going to get to liver after, because of course liver takes it to a

00:29:25.420 whole new level in all regards. Kidney transplantation is kind of the best example of all the challenges

00:29:32.760 that you just alluded to. It was also the first solid organ, at least, that appealed to the earliest

00:29:40.780 pioneers in the field as something that, you know, it seemed feasible to give someone an extra kidney.

00:29:47.440 Like that, you could kind of imagine a way technically to make that work, as opposed to

00:29:52.540 doing what we now do for, say, heart or liver transplantation, where you're doing an orthotopic

00:29:58.760 transplant. You're literally taking out the prior organ and putting in the new one. That's a little

00:30:03.540 different than a heterotopic kidney transplant, where you're giving them an extra organ and hoping

00:30:08.540 that replaces the function of their failed kidneys.

00:30:11.720 People probably don't understand that, but when we do kidney transplants, we don't go into the

00:30:17.520 retroperitoneum, take out the old kidneys. We're putting the new kidney basically in their pelvis,

00:30:23.680 attaching it to the blood vessels in the pelvis, and taking the little tube that drains urine and

00:30:29.140 just putting that into the bladder, the ureter. And obviously that's much easier than if you were

00:30:34.620 going to remove the old kidneys and put the new kidney in their place, given the location of the

00:30:39.580 kidneys. To make kidney transplantation feasible was a collision of lots of hard work by multiple

00:30:46.440 individuals, some of whom thinking about what you just said, literally, what are the technical

00:30:52.140 details of taking an organ out of a either living or deceased donor, mitigating the injury that goes

00:31:02.220 from cutting off its blood supply until you're able to restore it into the recipient's body. So there's

00:31:07.320 whole concept of kind of the technique, the preservation, and then the implantation. And then

00:31:13.720 parallel to that was this whole question of, well, how do we handle the immunologic consequences of

00:31:21.140 that? And so the series of events that occurred and allowed kidney transplantation to be a reality

00:31:28.640 were really that the technical and preservation elements came to fruition before we figured out the

00:31:36.700 epidemiologic elements. And in fact, the first kidney transplant, as you know, performed in 1954

00:31:43.080 at Brigham and Women's Hospital by Joseph Murray, who eventually won the Nobel Prize, was in identical

00:31:49.820 twins, right? So they had two brothers, one brother who had kidney failure, another brother who was

00:31:56.120 healthy, took one of the healthy brother's kidneys and transplanted it into the sick brother. And

00:32:02.300 that proof of principle was what created even kind of the possibility, the vision that transplantation

00:32:10.460 could work because we understood the technical and preservation challenges of actually taking an

00:32:16.880 organ out of one person's body and putting it into someone else.

00:32:19.760 Murray was a plastic surgeon, wasn't he?

00:32:21.840 Yeah. Joseph Murray was a plastic surgeon. And interestingly, although he and his colleagues

00:32:26.300 figured out this technical piece, what attracted him to transplant was the concept of tissue transfer

00:32:32.960 and the immunology of that. So a lot of the early work in immunology was done with skin grafts and

00:32:39.080 kind of understanding why you could take a skin graft from your own body and put it somewhere and it would

00:32:44.220 live. But if you took a skin graft from someone else's body and put it on a site, it would not,

00:32:49.300 it would generally not live. And so there was this whole kind of cadre of clinician scientists who were

00:32:56.000 interested in that question, including, interestingly, plastic surgeons like Joseph Murray.

00:33:01.220 So he became involved in that with a group of other surgeons, including some folks who had vascular

00:33:07.040 expertise and others and kind of conceived and developed in preclinical models in animals, this idea of

00:33:13.600 putting a kidney in the pelvis and attaching it to the blood vessels and bladder and then pulled it off in a

00:33:18.920 human. And a lot of, if you look at the history of kidney transplantation through the 1950s and into the

00:33:25.620 1960s, most of the kidney transplants performed were between twins, which there's a limited supply of

00:33:33.140 available organs there. So you can see right there that that was going to be a capacity problem. But

00:33:37.640 for example, the first kidney transplant at the University of Michigan was performed in 1963

00:33:42.680 between two twin sisters who, a few years ago, we were celebrating our 5,000th transplanted organ at

00:33:50.320 the University of Michigan. And those two sisters came back to celebrate that event.

00:33:54.740 So, I mean, it was a remarkable achievement, but it was a little bit of a false pretense because none

00:34:01.860 of the immunologic barriers were being confronted. And really what happened over the next four decades

00:34:08.600 were the development of effective immunosuppression to make that a reality. And as you alluded to,

00:34:15.640 it's pretty remarkable to think that, you know, in the 1960s and 70s and into the early 80s,

00:34:22.360 kidney transplants were being done and there were success stories. The field worked out how to

00:34:29.040 understand who had preformed antibodies to particular donors. So you could avoid those and

00:34:36.020 pick pairs that might be more successful. There were increasingly sophisticated immunosuppression

00:34:42.480 strategies that did work, you know, and drugs that were available like steroids and azathioprine

00:34:50.420 were making transplantation a possibility. But it's pretty remarkable to think in comparison to what

00:34:57.480 we expect now that in the 1960s and 70s, if you look at some of the published series, there were

00:35:04.540 mortality rates, mortality rates, mortality rates, meaning the patient died after kidney transplantation

00:35:11.260 of 50, 60, even 70%. So it's not only that they lost their graft, but the consequences of the

00:35:18.280 operation, the immunosuppression, subsequent, usually infections, was making these procedures highly morbid

00:35:26.180 and unsuccessful, at least at rates that we would think of as acceptable now.

00:35:30.940 And what was the life expectancy if you opted for dialysis in the 1960s? How long could you be

00:35:37.160 expected to survive?

00:35:38.680 It's a great question. And the first and most important kind of answer to that question is

00:35:42.940 the assumption that you could get dialysis, you know, so dialysis was not available everywhere. It

00:35:48.720 was largely centered around hospitals that had the ability to provide that service. Dialysis care was

00:35:57.480 not routinely covered by insurers. In fact, it wasn't until kind of a quirky rider to the law that

00:36:05.280 created Medicare in the 1960s that patients with dialysis even had the option, the ability to get

00:36:11.680 health insurance. It was hard to get dialysis. And then the survival on dialysis due to the challenges

00:36:17.740 of infection from repeated access, the hemodynamic consequences and cardiovascular consequences,

00:36:25.060 as we know of what were then more crude, primitive dialysis machines, was such that the life expectancy

00:36:31.320 was probably measured in months to years, you know, so two to four years might be, you know, very successful

00:36:37.900 outcome for someone on dialysis. You know, the average life expectancy, if you take all comers for an

00:36:44.920 individual on dialysis now, is about 10 years or so. But again, that is partially affected by the fact that

00:36:53.660 dialysis is more freely available. People, elderly individuals and people with other comorbid disease

00:36:59.300 have access to dialysis they wouldn't have had. So there were no good solutions, you know, for patients

00:37:05.000 with organ failure in those times. I want to make sure people really get a sense of what these immune

00:37:11.300 based challenges were. We take it all for granted today because we can rattle off all MHC2, MHC1 complexes,

00:37:19.660 and that stuff's been worked out in the most elegant manner. But in the 1960s, that was not the case.

00:37:26.100 Maybe start by explaining ABO incompatibility because I think that's something people understand. If you

00:37:32.060 came in the hospital and you'd lost blood and we wanted to give you a blood transfusion, we couldn't

00:37:38.280 just willy-nilly give you anybody's blood. We'd have to make sure that the blood type matched. That's not

00:37:44.720 entirely true if you had, you know, we could give you O negative blood no matter what. But walk people

00:37:48.780 through kind of ABO, which would be this, in my mind, at least the simplest form of antibody mediated

00:37:55.840 rejection. And then let's use that as a way to explain what was actually happening to all those

00:38:01.480 non-twin transplants. Yeah. So that's a great model to start with. So if you think about it in really

00:38:09.120 basic forms, our immune system has evolved to recognize self, recognize our own tissues, and

00:38:19.020 has been primed to recognize things that do not look like us, mostly to be able to fight off viruses and,

00:38:26.960 you know, other environmental challenges. But that unfortunately makes it difficult for something

00:38:31.980 like transplantation. So in the case of blood compatibility, we carry a blood of a particular

00:38:39.260 type. It has to do with the protein signature on the coating of those red blood cells. And we know

00:38:45.960 that if you give someone who carries blood of a certain type a blood type that is incompatible,

00:38:51.720 so let's make it the simplest, someone who has blood type A, someone who has blood type B,

00:38:56.000 and you give the individual with blood type A blood from an individual with blood type B,

00:39:03.160 they will have antibodies that attack those blood cells and essentially destroy the blood cells because

00:39:10.100 they think they are recognized as foreign. It's more complex than that because there's also these

00:39:15.000 things called the RH antigens, which are kind of what make blood positive and negative. And you're

00:39:20.800 correct that blood type O, individuals who do not have blood type O do not have preformed antibodies

00:39:28.880 to that donor pool. So that is kind of the universal donor pool. But it was figuring out that

00:39:36.400 incompatibility understanding that was kind of the first step in understanding how you would

00:39:43.100 potentially take an organ out of one individual and place it into another. Because, and this is still

00:39:48.160 true to this day, that kind of step one in matching a donor and recipient is knowing their blood type

00:39:54.100 because that's kind of the first step. It gets more complicated than that for all the reasons you

00:40:00.240 alluded to because it turns out those are not the only proteins on the surfaces of those cells that are

00:40:05.460 recognized by our immune system. And this, in particular, this group of protein called human leukocyte

00:40:12.260 antigens, which is what you were alluding to, or HLA types, is what on a very crude way determines one

00:40:20.060 individual from another, that profile. And so the history of this is pretty interesting, going back to

00:40:25.940 my skin graft analogy. So what investigators around the turn of the century were figuring out is, again,

00:40:33.220 so you could take a skin graft from elsewhere in your body and it would tend to work. If you took a skin

00:40:37.760 graft from somewhere else, from another individual, it did not work. Then even more interestingly,

00:40:44.020 if you took a second skin graft from that same individual and put it on, it died faster. It's as

00:40:51.780 if the body was primed to destroy that new skin graft. Kind of sounds like a vaccine, huh?

00:40:57.620 Exactly. It's the same principle. So it was just kind of the second hit hypothesis that the body,

00:41:02.060 the immune system, learned to recognize this foreign tissue and the immune system was even more

00:41:09.380 effective in eliminating it. And it was that whole series of experiments that led to these concepts

00:41:16.780 right in the middle of the last century, where the question was, and this was debated by individuals

00:41:25.160 much smarter than us, many of whom who now have Nobel Prizes after their name. So was there something

00:41:31.200 circulating in the recipient's serum that found this tissue, antibodies was the theory, attacked this

00:41:42.340 tissue, set off the immune cascade, destroyed the tissue? Or was it more complicated than that? Was

00:41:48.200 there kind of like we've learned about in embryology from thymic development? Was there some sort of

00:41:54.180 priming event that had to take place where the body presented this foreign tissue to the immune system

00:42:01.180 and then the immune system learned how to recognize it as self or foreign and destroy it? And that

00:42:07.640 debate went on for decades. Right. So just to separate that, in the case of blood incompatibility,

00:42:14.260 it was pretty easy to figure out that it was just these soluble circulating antibodies. They weren't

00:42:20.120 quote unquote smart. They were just floating around. You could do it in a test tube, you know,

00:42:25.320 literally. That's right. So you have a blood type A with its little A antigen. And if the recipient

00:42:31.940 has an anti-A, it grabs onto it and these things precipitate out a solution of this reaction. And

00:42:38.060 of course, now the question that you're posing is, is that how it works on organs? Or is there

00:42:44.380 something more complicated where there's another actor? Correct. And the reason that that was such a

00:42:50.780 fundamental question, because if you believed it was like the blood analogy and that, okay,

00:42:57.520 so if we could identify the patients that had preformed antibodies, preformed proteins in their

00:43:05.700 serum that were going to ruin this opportunity, then, well, that's great. Then we can select out

00:43:12.360 the patients that have that reaction and use the organ to transplant others. So that's the concept of

00:43:17.800 what is now called in transplant a cross match. So the idea of taking donor cells, recipient serum,

00:43:25.180 mixing them in an assay and determining whether or not that serum lysis those cells. And that is more

00:43:34.500 or less the technique that is used to cross match individuals to match, you know, as you'll hear people

00:43:40.880 talk about, oh, I want to donate a kidney to my uncle or something. I wonder if I'm a match. That's to some

00:43:47.520 degree what they're talking about is whether or not that assay says that their uncle in this case

00:43:52.760 doesn't have preformed antibodies that are going to destroy their cells. So that would explain kind

00:43:59.300 of that initial screening step. And the other thing that that helped explain is why sometimes when you

00:44:05.500 would do a transplant, either in animals or eventually in humans, there was this phenomenon,

00:44:12.940 which came to be known as hyperacute rejection, where you would put the organ in, you would take

00:44:19.040 the clamps off, the organ would fill with blood, looks like you've won the game, and then it would

00:44:24.460 immediately start to thrombose and die, essentially. That process called hyperacute rejection was figured

00:44:32.920 out was because of the circulating antibodies to those HLA antigens of the donor. So that made some

00:44:39.940 sense. We can try to figure that out. What didn't make sense is you would do the transplant, you would

00:44:45.200 get past that hyperacute stage, the organs working. And then a day later, three days later, six months

00:44:54.520 later, the organ would fail from acute rejection. So basically the same process, but with a different

00:45:02.780 kind of lead time. And it was after much debate in the field, the nuances of which are more

00:45:09.920 sophisticated than I can explain, but it was figured out that what was actually happening was not this

00:45:16.240 circulating, what we came to call antibody mediated or humoral rejection, but actually was

00:45:22.620 happening on a cellular level. So, so-called cellular rejection. And as we learned eventually over time,

00:45:30.060 that had to do with what we now learn in basic immunology, antigen presenting cell with carrying

00:45:36.440 an antigen from the foreign tissue, in this case, the donor tissue, immune mediator cells, and we

00:45:43.220 discovered and learned eventually they were T cells. That recognition, priming the immune system to form

00:45:51.140 injury, either, you know, by various means, cytokines, eventual antibody formation, et cetera. And that was

00:45:58.700 what was destroying organs in that kind of subacute phase. And as we figured out over the course of

00:46:06.000 decades, the drugs that we had to blunt that initial immune response, high-dose steroids,

00:46:13.080 I refer to days of thioprine, they tried total body irradiation at some of the early stages.

00:46:19.040 That was Franny Moore that was doing that up at the Brigham as well, right?

00:46:22.300 At the Brigham, exactly. Those weren't effective in preventing that cellular level rejection.

00:46:28.700 And it was only later, you know, really the 1980s, that we developed immunosuppressive agents

00:46:35.780 that were selective enough to interfere with that cellular reaction. And it was then that

00:46:43.260 transplant really became a reality because now you had the ability to sustain an organ beyond just

00:46:48.740 weeks to months and you, you know, looking at more long-term survival.

00:46:52.920 Really, the turning points are twofold, right? One, it's the knowledge of what's happening because

00:46:59.460 certainly by the 80s, it was not a technical challenge to be able to remove a kidney,

00:47:04.640 transport a kidney and put it in. By the way, was Wisconsin Solution already around by the 80s

00:47:09.240 or did that come later? Yeah. So, or at least the predecessors of Wisconsin Solution.

00:47:14.300 Tell folks what that is and why that matters so much as well.

00:47:17.260 The theory is you take an organ out of the donor body, whether deceased or living,

00:47:23.480 you flush the blood cells and such out of it so that it doesn't clot. You then store it on ice and

00:47:30.900 transport it to the recipient and put it in. And there were all kinds of initial thoughts about,

00:47:36.960 well, do you just put it in saline essentially and transport it to the other room? And then,

00:47:41.460 what they found was that, and this was experimentation that happened over decades,

00:47:47.260 was that there were cellular processes occurring both as kind of at the time from when ischemia

00:47:54.260 begins, when the vessels are clamped and the organ is coming out. And before blood flow and oxygen is

00:48:01.360 restored to the organ, there were cellular processes occurring that could be mitigated by creating

00:48:08.840 preservation solutions, essentially saline, that was fortified with particular molecules. And

00:48:16.300 the history of all this is beyond me, but literally they tried, it's like making Gatorade,

00:48:21.540 they tried, you know, different electrolyte solutions and additives and other nutrients

00:48:26.180 until they figured out which mitigated that ischemic time the best. And the crazy thing to think about,

00:48:33.340 and this gets to alludes to something maybe we could talk about later in terms of where is

00:48:38.260 preservation going in the future. But the crazy thing is we're pretty much more or less doing that

00:48:42.840 now, you know, so some of the fluid solutions and some of the minor details of what additives are in

00:48:49.100 the fluid has changed. But that's essentially the way we've been preserving organs since the 1960s,

00:48:55.420 70s, you know, which is pretty remarkable that that was one, as you said, one of the early barriers

00:49:00.480 figured out in the field. Once this notion of the HLA system is understood and we understand these

00:49:09.400 different types of compatibilities, a drug is discovered. And it's my favorite drug on the planet

00:49:17.220 happens to come from basically a fungus. And this is another drug that came from a fungus, but a different

00:49:21.580 one. The drug is called cyclosporine. And I think you could make the case, but I'd like to hear your take

00:49:28.680 on it because you know this field so much better than I do. But if I were telling the story, I would

00:49:32.740 say that was the turning point, was the advent of cyclosporine. Do you agree with that? Or do you

00:49:38.940 think that I'm overstating that? No, 100%. As you said, and similar to the stories of drug development

00:49:44.940 that happened in other circumstances, you know, this was a recognized compound that had been

00:49:51.760 experimented in a number of different lines of investigation. And an investigator who's really

00:49:59.300 one of the central figures in the history of transplant named Cerroi Calm in Cambridge, performed

00:50:05.800 a series of preclinical experiments that showed that using this medication prevented rejection in

00:50:14.560 transplant models. What eventually was discovered is that it was interfering with the cascade that

00:50:23.120 occurred when that foreign antigen was presented to the recipient T cell. In other words, it was a more

00:50:31.400 selective immunosuppressant, so directly interfering with the cascade of events that happens downstream of

00:50:39.540 the T cell receptor. And it specifically inhibited IL-2 secretion?

00:50:43.920 It affects IL-2 secretion, but, you know, there's actually some interesting debate about how the

00:50:50.300 calcineurin inhibitors, so cyclosporine and then its eventual cousin, tacrolimus, works. They both

00:50:57.340 function at the level of what are called immunophyllans, these, you know, soluble intracellular components.

00:51:05.220 And although they affect both kind of the activation of cytokines after that T cell recognition,

00:51:12.320 including IL-2, they also seem to have other effects on the affinity of the binding of the T cell

00:51:18.180 receptor. They have systemic effects that are kind of interesting, like, for example, tacrolimus, the

00:51:23.900 other medication I mentioned, has a potent vasoconstrictor effect in certain organs. So we

00:51:30.920 probably don't fully understand its impact, but certainly the central component of its mechanism was

00:51:37.880 interfering with the cascade that occurs after T cell receptor binding. And you're absolutely right.

00:51:43.520 Like, it literally was a game changer overnight. So if you look at papers written in the 1980s about

00:51:50.580 kidney transplant outcomes, there's literally an inflection point. You went from recipients having

00:51:56.380 one-year graft survival rates, even with kind of the best immunosuppressive regimens that had been

00:52:03.500 figured out at that point. One-year graft survival rates, probably in the 70-ish, 60% range. Boom, you

00:52:11.360 know, 90% overnight, just with the addition of cyclosporine and then, you know, eventually refining some of

00:52:18.360 the multi-drug regimens. So it was a complete game changer. It not only revolutionized the impact of

00:52:26.560 kidney transplantation, which from a public health standpoint is clearly the most impactful organ we

00:52:33.360 transplanted. You know, the number of patients with end-stage renal disease, the number of patients

00:52:38.360 with chronic kidney disease, you know, from a public health standpoint, kidney transplantation is just a

00:52:42.480 fundamental, important medical therapy. So not only did it make that a reality and make it a preferred

00:52:50.700 alternative to dialysis, it also reinvigorated the other solid organ transplants as being a reality.

00:52:59.340 So liver transplantation, which essentially had been on a more or less enforced hiatus through the 60s

00:53:05.220 and 70s, heart transplantation similarly, lung transplantation as well. The confidence that

00:53:11.920 now that we understood some of the technical and kind of patient-related factors that dictated the

00:53:18.760 success of the operation, to now also have the promise that those organs would last more than

00:53:24.240 90 days, reinvigorated those fields completely. And, you know, again, almost overnight, over the course of

00:53:32.480 years, you started to see liver transplant programs, heart transplant programs, lung transplant programs

00:53:38.380 pop up at major medical centers all throughout the country in the 1980s and into the early 1990s. So that was

00:53:45.020 really the revolution that occurred because of that drug development.

00:53:49.060 When we look at the demand for kidney transplantation today, what percentage of it is chronic versus

00:53:55.820 acute kidney failure?

00:53:57.240 The vast majority is chronic. So there are occasions where patients can get acute renal injury from

00:54:06.060 traumatic events, other medical catastrophes, or they get acute kidney injury in the chronic,

00:54:13.060 in this case of sepsis or something that they otherwise recover from. And we still see occasionally

00:54:18.340 patients who get, for example, post-streptococcal glomerular nephritis or other diseases that are

00:54:23.440 more linked to kind of an acute event. The vast majority of kidney transplants in the United

00:54:29.300 States, the primary indication is diabetes or hypertension. So this is chronic kidney disease

00:54:34.400 as a consequence of those comorbid conditions, which is one of the reasons, again, from a public

00:54:40.220 health standpoint, the impact of kidney transplantation is massive. You know, so you have

00:54:45.200 100,000 people roughly waiting for a kidney transplant in the United States. You probably

00:54:50.980 have fourfold that or thereabout on dialysis, and then probably tenfold that number with chronic

00:54:58.560 kidney disease. So the potential impact of having an effective and durable therapy for chronic kidney

00:55:05.320 disease is remarkable. And I think it's really important to consider as a public health problem.

00:55:11.680 Well, I can't agree with you more, Chris. And about three years ago, I sort of had this

00:55:17.640 obvious epiphany. I say obvious because I'm sort of thinking, why did it take me so long to do the

00:55:22.560 math? But I realized if my interest clinically is trying to figure out how to help people live longer

00:55:28.800 and live better, you've got to start thinking about what are the things that you have to plan for.

00:55:33.900 So if you're flying a glider where you know you want to cross a 200-foot chasm, but now all of a sudden

00:55:41.720 you say, well, I want that chasm to be 300 feet, you have to start thinking about how much higher does

00:55:47.340 that glider need to fly. And one of the things that really occurred to me was kidney function.

00:55:52.620 We sort of have in the back of our minds, eh, you know, look, if a person reaches the finish line

00:55:58.260 of life and their glomerular filtration rate is 40, great. You know, they don't need dialysis.

00:56:03.640 They're doing just fine. And if we think that an average life expectancy should be 71 or something,

00:56:10.180 and we think that, hey, we're going to tolerate a person's GFR being in the low 40s when they're in

00:56:16.080 their early 70s, that's great. But if we're trying to figure out a way to help people live and live well

00:56:21.860 into their 90s or beyond, that becomes a very unacceptable GFR. You're going to run into trouble.

00:56:28.880 And so looking at cestatin C beyond just creatinine and other biomarkers and looking at microalbumin

00:56:35.840 in the urine twice a year, I mean, we do all these things, even though they seem kind of crazy,

00:56:40.320 because it's how you sort of start to catch that early, early, oh, look, you know what? Your blood

00:56:46.600 pressure of 130 over 85 is not really acceptable. That's going to take you from a GFR of 95 to 85 in

00:56:54.940 the next decade. And we consider that to be too precipitous a decline. So unfortunately,

00:57:00.180 my view is that I think the demand for kidneys is only going to go up as we see the rampant

00:57:06.340 explosion of prediabetes and metabolic syndrome.

00:57:09.140 I totally agree with you. I think, and there's so many kind of wrinkles to that question to think

00:57:15.100 about. I mean, the first is that is the obvious statement that as you preach better than anybody,

00:57:21.340 we don't do preventative care, you know, in this country very well. And we particularly don't do

00:57:28.400 it for things where we don't have reliable measures. So to your point, we use serum creatinine as kind of

00:57:34.480 our best guess at kidney function. There's lots of reasons why that's a poor indicator.

00:57:39.440 It's very dependent on muscle mass and other variables that prevent you from using some sort

00:57:46.320 of kind of normalized number as a acceptable range. There are more sensitive markers, as you alluded to.

00:57:53.060 There's now, I think, fortunately, finally being recognized the whole question of how

00:57:57.340 creatinine and GFR and race interacts and how that needs to be accommodated for. So you're right.

00:58:03.800 So number one, we don't measure it well. So therefore, we don't appreciate the size of the

00:58:07.680 problem. Number two is we, again, this is kind of a situation where transplant is a victim of its

00:58:13.600 own success. As transplantation has gotten more successful, transplant centers around the country,

00:58:19.560 transplant providers, and just the medical community in general has started to say, well,

00:58:24.280 why don't we provide kidney transplants for 70-year-olds if there are otherwise healthy

00:58:29.380 individuals? Because their life expectancy might be 20 years from that point. The collision of that,

00:58:36.280 and then what you alluded to, this pre-diabetes metabolic syndrome, progressive kidney dysfunction

00:58:43.100 in an aging population is going to create an enormous demand for kidney transplantation.

00:58:49.020 We transplanted an 81-year-old a few weeks ago. And I remember as I was looking at the census,

00:58:55.740 I don't do kidney transplant very commonly as part of my clinical practice. So I was looking at the

00:59:00.500 census, I was like, wait a minute, is this gentleman 10 years out from a transplant back

00:59:04.940 in the hospital for some other reason? Or did we actually transplant this 81-year-old? But the

00:59:08.220 point is there are individuals who are healthy, functional people otherwise, whose life, part of

00:59:13.940 what we're talking about is survival benefit, right? You compare their survival on dialysis to their

00:59:18.280 survival with the transplant. Transplant is going to win almost every time, you know, as long as they,

00:59:23.640 you know, can tolerate the operation of the immunosuppression. So it is kind of remarkable to think of

00:59:29.440 the scope of that problem and particularly to take a longevity lens on it. You know, it's really kind

00:59:34.760 of an interesting challenge to think about for the next 20, 30 years of transplantation.

00:59:40.360 So before we get on to liver, which is such an amazing story as well, I want to wrap a few things up

00:59:45.860 on kidneys. So let's talk about the evolution from cyclosporine to prograf or tacrolimus, as you

00:59:53.400 discussed, and where we are today on some of the most common immunosuppressive regimens. And then I

01:00:00.360 also want to touch on this idea of not just living donors, but the live donor swaps and stuff. Because

01:00:07.160 I'll tell you, one of the things that I'll never forget from my intern rotation on transplant, which

01:00:14.060 like you captivated me beyond words. I mean, transplant was never even something on my radar

01:00:20.780 before residency. And for the entire time I was in residency, it was always one of those things.

01:00:26.060 I was like, I could see myself doing this. This is so cool. And it was actually, I think it was Bob

01:00:31.740 Montgomery as well that shared this with me, which was a live donor zero out of six HLA match is always

01:00:39.520 going to beat a six out of six cadaveric match. And I remember thinking, how is that possible?

01:00:46.320 Now tell folks what I just said, explain what I just said to people and more importantly, explain why

01:00:51.960 it's true. Yeah. So it's pretty remarkable to consider the impact of living donation and to your

01:01:00.440 earlier question, kind of figuring out the appropriate place for living donation as transplantation

01:01:06.340 moves forward. So in kidney transplantation and counter distinction, deliver transplantation,

01:01:11.340 but in kidney transplantation, living donation has been part of kidney transplantations from its

01:01:16.740 origins, you know? So as I alluded to already, the first transplant done between identical twins,

01:01:23.460 living donation remained a part of the development of kidney transplantation. And then really took off

01:01:30.680 in the 1990s. We witnessed it happening with the development of the laparoscopic donor nephrectomy

01:01:37.160 operation, a procedure pioneered by two individuals at Hopkins, Lou Cavusi and Lloyd Ratner. And that having a

01:01:45.980 procedure that was of such tremendous benefit to the recipient that then was safe and a smoother recovery

01:01:52.880 for the donor, you know, really allowed that to explode. And if you look at kidney transplantation in the United States

01:01:58.440 now, let's say 18 to 20,000 patients a year undergo kidney transplant in the United States, and it's

01:02:04.040 actually about half and half living donors and deceased donors. And that's probably with under-realizing

01:02:10.360 the potential of living donation for all the reasons you said. So part of what you're alluding to is if you

01:02:16.960 kind of compare head to head, let's say you have a patient on dialysis, a patient who receives a deceased

01:02:23.120 donor kidney transplant, and a patient who receives a living donor kidney transplant. Let's say the start of the

01:02:28.420 starting line is the same for all three of those. And let's say that they're similar age, similar comorbid

01:02:34.460 conditions, similar immunosuppressive regimen for the transplant recipients. The benefits are pretty clear. The

01:02:39.940 dialysis curve is going to drop off pretty quickly. In fact, the studies that have shown that where the dialysis and

01:02:46.500 transplant curves cross, even with the risks of undergoing a surgical procedure and starting immunosuppression, occurs in less

01:02:53.340 than a year. It's probably in somewhere between 90 and 250 days, depending on patient characteristics.

01:02:58.980 So that's clear. Dialysis loses. What's interesting then is that there's a difference between the

01:03:05.280 deceased and living donor curves, and that's what you were kind of so fascinated about. And the reasons for

01:03:11.160 that are many, but it probably speaks to the fact that even with all of the best technique and advances, there is

01:03:18.800 really no way to mitigate the fact that a deceased donor that goes through the process and the trauma of brain death or

01:03:27.140 donation after cardiac death gets removed from that individual's body, preserved, put on ice, transported to another

01:03:35.460 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

01:03:46.580 living donor, elective operation, side by side or sequential operating rooms, that kidney is in a healthy

01:03:53.960 environment with a healthy normal person, normal vital signs. We dissect out the kidney, clamp the blood

01:04:00.580 vessels, take it out of the body, flush it, walk it over to the recipient's room. And sometimes it's sewn in in

01:04:06.660 under an hour, you know, so the time, the ischemic time from coming out of the donor's body to into the

01:04:12.480 recipient. And it turns out that ischemic period is critical and is really almost linearly related to

01:04:21.920 the graft survival. Part of that is probably due to the consequences just of the ischemia reperfusion

01:04:28.680 injury and literally knocking off some nephrons just from that process. Part of it also is, as we've

01:04:35.540 learned, is that that ischemia reperfusion injury cascade that starts is a priming event for the immune

01:04:42.080 system. So not only do deceased donor kidneys kind of pound for pound compared to living donor kidneys

01:04:49.020 take that initial hit from the ischemia reperfusion injury, they're also more prone to rejection. You

01:04:55.100 see more immunologic injury. Depends on the circumstance, they often require more immunosuppression,

01:05:00.060 greater frequency of rejection. So it really is almost like two different products from a recipient's

01:05:06.880 point of view. And so, you know, I think if you had your druthers, you know, as a person in need of

01:05:14.260 a kidney transplant, you would want to have the access and the opportunity to get a living donor

01:05:20.560 any day of the week if that is possible to you. And this other point, though, is to narrow that gap

01:05:26.980 between the two. It's that with the deceased donor, you at least try to maximize the immunocompatibility.

01:05:34.820 And with the living donor, you have much more flexibility.

01:05:38.880 Correct. That's exactly right. So what you were describing is kind of the story you alluded to

01:05:44.520 with Bob as you're comparing a living donor kidney, so optimal conditions of the transplant,

01:05:50.400 but not a perfect immunologic situation, at least from looking an HLA alone, versus a deceased donor

01:05:58.880 kidney that immunologically is a home run. That's about as good a situation as you can get,

01:06:03.580 but still takes that ischemic hit. And we can't make up for that. So even the best immunologic

01:06:10.680 situation can't mitigate that, which I think is a realization that doesn't always kind of come to

01:06:15.980 fruition, but is, again, one of the reasons why we feel comfortable really pushing every kidney

01:06:20.860 transplant candidate to think very seriously about exploring options for living donation.

01:06:27.260 It's also what's led to some of the things you alluded to, paired kidney exchanges and other

01:06:32.000 things to try and expand the compatibility of donors and recipients.

01:06:37.420 Let's use an example to explain that to people, because it's really quite fascinating. And we

01:06:41.840 trained very close to some of the people who really did a lot of the work behind optimizing the

01:06:48.160 mathematical algorithms around that. So let's pretend that you called me tomorrow and said,

01:06:53.060 Peter, you're not going to believe this, but I'm kind of at the end of my rope with my kidneys.

01:06:56.900 I'm going to need to have a transplant. And I was sad. I thought about it and I decided,

01:07:02.940 you know what, there's no greater way that I want to be able to thank Chris for all he's done for me

01:07:06.780 than to give him a kidney. And I've got two and I'm perfectly healthy and I'm willing to part with

01:07:10.940 one of them. So I call you up and I say, Chris, I want to give you one of my kidneys. I want to be

01:07:15.520 a living donor to you. So we would go and meet with the transplant team and they would do some tests.

01:07:21.360 And what if they discovered that I was a lousy match for you? We didn't even have the same blood

01:07:27.120 type, nevermind HLA compatibility. What would be some of the options we would explore?

01:07:32.500 So the circumstance you're talking about is this really kind of frustrating scenario where a kidney

01:07:38.760 transplant candidate has done the right things. They've taken care of themselves. They've gotten to a

01:07:43.340 transplant center. They're listed for transplant. We think they're a good candidate. They've even

01:07:47.860 gone to the effort that you just described of identifying living donors and the living donor or

01:07:54.300 donors that they identify are not compatible with them or at least safely. So as you said,

01:08:01.020 they might be of a different blood type. Let's say I'm an A and you're a B. That's just not a barrier

01:08:07.660 that we're used to crossing, at least with any kind of reasonable likelihood of the success rates we

01:08:13.040 were discussing earlier. It may also be that I have preformed antibodies to HLA antigens that you have

01:08:21.400 and it turns out there's certain populations that are more prone to that challenge. So it's a really

01:08:27.080 frustrating challenge because here it is. It's like you have this diamond in the rough, but you can't

01:08:32.060 apply it. And so what some really smart people figured out, well, if I've got two pairs and they're

01:08:40.180 incompatible with each other, but happen to be compatible with the opposite. So let's say that

01:08:46.540 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

01:08:51.340 are compatible. Is it reasonable to swap those kidneys? And those sorts of kidney swaps or paired

01:08:59.240 exchange began in the 1990s and really took off in the 2000s because it allowed people to avail

01:09:08.180 themselves of broader opportunities for transplant. Now, what you're alluding to in terms of the

01:09:13.540 kind of the mathematics of it is you can imagine there's some ethical quandaries there. So let's

01:09:18.800 say, so you come forward to donate me a kidney. You're an extremely healthy person. You've taken

01:09:24.580 good care of yourself. I assume Jill has approved this at some point in the discussion.

01:09:29.020 I haven't asked her, but you know, she can't wait to say hi to you after this podcast. So I think

01:09:33.940 she would let me donate to you happily. That's an important part of the discussion. But then let's

01:09:38.400 say the pair that we were talking about exchanging with is someone about our age who needs a kidney

01:09:44.720 and their 75 year old father. So I swapped to them this perfectly healthy kidney from someone who's in

01:09:53.400 good health and younger. And I get an exchange for that, a 75 year old kidney. Now, for some of the

01:09:59.180 reasons we just talked about, it might still be in my best interest to take that living donor

01:10:04.320 kidney. But you can imagine that there are differences in quality. And then to add even

01:10:10.400 more complexity to it, what if let's say the individual that you would be donating to across

01:10:16.940 the swap, you just by coincidence are a perfect match for HLA and match across the board. But that

01:10:24.340 individual that I'm swapping for, you know, we're mismatched.

01:10:28.040 It's three out of six maybe.

01:10:29.480 Exactly. Or there's very sophisticated assays that actually can look for low levels of what

01:10:35.220 we call donor specific antibodies. Let's say that I've got some low level antibodies to that

01:10:41.140 individual. Is it worth the swap? Is it worth the extra immunosuppression I would need to make that

01:10:48.300 a reality to make that pair exchange work? And so some smart people, including colleagues of ours

01:10:55.300 that we both know, Dory Segev and his wife, Summer Gentry, who's a mathematician, started thinking

01:11:01.360 about that. Like, so could we start putting some value on those exchanges and create networks of

01:11:08.240 individuals? It's kind of like the dating game for kidneys where you come forward with your donor

01:11:13.280 and the algorithm looks at all the other possible pairs and tries to match individuals in a way that

01:11:19.160 maximizes predicted outcome. And there are now national networks that facilitate those sorts of

01:11:26.620 exchanges and have really expanded kidney transplantation in ways that I don't think

01:11:31.380 even we would have predicted watching it back in the 1990s. You know, for example, there was a day

01:11:36.100 maybe three weeks ago where I did a laparoscopic donor nephrectomy operation, so removed a kidney

01:11:43.500 from an individual. That morning, one of my colleagues was doing a similar operation in another

01:11:48.840 room. Both those kidneys shipped out to other institutions. Two kidneys came back later and

01:11:55.580 our colleagues put them in later in the day into two of our recipients. So it was like we've completely

01:12:01.880 dissociated the donor operation from the recipient operation, which from a patient's perspective is

01:12:07.200 great. You know, and so the donors don't have to travel. The recipients have more access to organs.

01:12:12.240 And, you know, I think thinking about how that is applied and expanded has really been a game

01:12:18.200 changer for kidney transplantation access. Chris, is there any serious discussion about opening up a market

01:12:24.200 for kidney donation? So everything we just described is it's happening through altruism. I would give you

01:12:33.380 my kidney because I love you. But is there a serious discussion that says, look, what if I've just

01:12:42.520 decided, you know what, I'm willing to gamble that I don't need a kidney. I don't know a given

01:12:46.880 individual, but for a big enough sum of money, I'm willing to part with my kidney. Are those discussions

01:12:52.220 even entertained? Great question. And this is a frequently debated and never resolved kind of

01:12:59.360 debate in transplantation. So to put some framework behind that question. So when transplantation

01:13:06.280 started to become a successful medical intervention, so we're talking now, 70s into the 1980s, development

01:13:15.820 of cyclosporine, we then started to think about, so, okay, this is a successful venture. We now have

01:13:23.840 organ donation laws that exist around the country. We need to create networks to make sure that a liver

01:13:31.720 that becomes available in Utah is accessible to the patient in Michigan as to California or other

01:13:40.140 circumstances. So there was a whole infrastructure put around that challenge. The legality of it was,

01:13:46.720 and the decision that was made at the time these laws were passed, that it was illegal to sell an organ.

01:13:53.540 And the reasons that that principle was upheld as kind of central to transplantation, particularly in

01:14:00.120 the United States, but in most countries around the world, is that the belief was that organ donation

01:14:07.320 was a gift. The ethical principle was that the donor has autonomy over that decision and makes it freely.

01:14:15.900 The concern about allowing people to pay for organs, like on an open market, was that can potentially be

01:14:23.160 coercive and can create markets where individuals who have lower standing in society or are economically

01:14:31.540 disadvantaged, then are put in this position where they can be selling their organs to achieve

01:14:37.260 some game. And actually, just literally this last weekend, there was an article in the New York

01:14:41.160 Times about the growth of kidney transplantation in Afghanistan, and that is exactly what happened.

01:14:46.800 They have turned away from understanding relationships between donors and recipients, and that's what's

01:14:52.800 happened, that wealthy people who have the resources are paying poor people for their kidneys and then

01:14:57.760 not certainly caring for them afterwards. So as a general principle, the transplant community has decided

01:15:04.620 against paying for organs as the principle being that it's coercive. Now, there's lots of people that

01:15:12.760 disagree with that on general principle and say, well, why don't we just create a better system, allow some

01:15:18.460 exchange of compensation to donors? And I think we are slowly migrating towards some version of that. So to give

01:15:27.200 you a few examples. The legality of this has been so tight that it's been impossible even for donors to be

01:15:35.040 reimbursed for like transportation to the transplant center or time off work or other sacrifices that they had

01:15:41.740 to personally make that had nothing to do with the actual donation, but just to facilitate that occurring. And

01:15:48.960 there are now laws being passed in states and other initiatives, either through advocacy groups, there's a

01:15:57.600 national group that does advocacy for living donors, and provides resources and support for travel to

01:16:04.140 transplant centers and reimbursement for time away from work and such. But what if we created a principle

01:16:10.920 where, say, for example, a living donor is compensated with some agreed upon amount of money that compensates

01:16:19.800 for the time of their recovery? I think there may come a time that some version of that becomes reality.

01:16:28.560 There's also principles of should living donation provide special kind of health care benefits to

01:16:35.680 individuals over time. Maybe it qualifies you for discounted public insurance or something so that

01:16:42.600 you can never lose health insurance if you were to, God forbid, have a problem yourself down the road.

01:16:48.000 So I think there are some versions of this that will come to fruition gradually. But I think at least in

01:16:52.400 the United States, our medical legal environment and the principles behind transplantation will not

01:16:58.960 permit an open market for buying and selling of organs.

01:17:03.500 I like that idea, though, about providing ongoing medical coverage. It's funny, whenever the debate

01:17:09.340 comes up about whether we should be paying NCAA athletes, especially the football players,

01:17:13.840 they generate so much revenue for the university and then they get spanked if they accept a $50 gift

01:17:20.440 from a booster. I've always thought one solution to that is fine. If you don't want to pay athletes for

01:17:25.920 playing sports at a university, you should at least cover their medical bills for the rest of their

01:17:30.560 lives. Like if an athlete suffers some consequence as a result of playing sports, which many of them

01:17:35.740 do, we should at least make sure that we take care of them if we're going to profit off them to the

01:17:40.120 course of that. Tell folks a little bit about if it's still the case, I assume it's still the case.

01:17:45.780 There are some states in which you're better off or more likely to get an organ, like a liver,

01:17:51.840 for example, than other states. How does that work? And what would be the best states to live in if

01:17:56.960 you're vying for an organ versus the worst? Right. So fortunately, that is changing rapidly

01:18:02.660 and it's changing rapidly because it's been a focus of intentional policy change in the way organs

01:18:09.300 are allocated. So it's not like when we were in residency where it was almost comical.

01:18:14.220 Correct. So part of the issue is simply a supply and demand issue. So if you look, for example,

01:18:20.460 like California, a state with a huge population, there is such a demand for transplant that if you

01:18:29.660 restricted, if you kind of imagine California as just its own unit, it's almost like the organ

01:18:35.920 donation supply in California would never meet the demand. That's true in other major, particularly

01:18:42.660 urban population centers like New York and parts of the East Coast. There are other parts of the country

01:18:48.520 and they tend to be in the Midwest, but there's some other locations in the South as well, where

01:18:54.480 just based on population size, the amount of individuals in need of an organ transplant

01:18:59.900 is modest compared to the supply of organ donors. And I think that has created this disparity where

01:19:08.900 depending on where you live, you may have better access to organs in various places. The solution to

01:19:16.060 that obviously is to change the system. So in other words, the way that organ donation is coordinated

01:19:22.340 nationally is through these organizations called organ procurement organizations or OPOs. There's

01:19:27.280 58 of them in the country. Some of them are pretty easily understandable. Like Michigan has, for example,

01:19:34.300 one OPO that covers the whole state. There's like six in Texas. So it's a little bit of a confusing

01:19:40.480 network. But the point is, those are the organizations that nonprofit organizations that are responsible for

01:19:45.580 identifying organ donors and facilitating the gift from procurement to transplant. And then the

01:19:54.440 waiting list, you hear people say that they're on the waiting list for an organ. The way that an organ

01:20:00.320 is actually placed is every time an organ donor becomes available, the list is run according to a

01:20:06.920 predetermined algorithm of how that particular organ is prioritized. And the problem, at least historically,

01:20:13.480 is that that list has been run largely locally or regionally first and only then kind of offered

01:20:21.380 out more broadly. And so what has changed in heart, lung, and liver transplantation and is about to

01:20:29.720 change in kidney transplantation is those kind of relatively artificial state or regional boundaries

01:20:35.700 have just gotten destroyed. And so now the way organs are allocated are literally by concentric circles.

01:20:41.660 So they offer it based on distance from the donor hospital. And that has created some interesting

01:20:47.400 phenomena. I mean, the good news is, to your point, is that the geographic variation that exists across

01:20:54.820 the country has decreased. So it's not as important now to like, go to a certain place if you know you

01:21:00.600 need a liver transplant, for example. It also has created a system where if you're really sick,

01:21:06.740 you know, at the top of the list for liver transplantation, for example, you're going to get

01:21:10.640 transplanted quickly because you've got access to this broad swath of organ toners. The challenge

01:21:15.920 is kind of the people that are medium sick, some of whom are still quite ill from their disease,

01:21:20.740 who have all these sicker people kind of ahead of them on the list getting transplanted. And that

01:21:26.580 speaks to the kind of need for expanding the donor pool, alternative donor sources, more living donation

01:21:34.040 in the case of kidney and liver transplantation to kind of meet that need. So the system has gotten

01:21:40.180 more fair, but it's only exposed the need even more, I guess is the best way to say it.

01:21:44.720 That's good to hear because it definitely struck me as a pretty unjust system 20 years ago,

01:21:51.400 especially with liver. Reminded me of some great injustice. You alluded to brain death earlier.

01:21:57.720 We've been remiss in not, I think, explaining to people a little bit what that means. And especially

01:22:03.000 now as we sort of talk a little bit about liver, where a much greater number of the transplantations

01:22:07.740 are from non-living donors, the donors that are non-living. So what does it mean to be brain dead?

01:22:14.700 And how does that factor into, from a legal standpoint, what does it mean? And then from

01:22:19.320 a physiologic and biologic standpoint, what does it mean? It's interesting. You would think that this

01:22:23.280 would be like something you could flip to page one in, you know, medical textbook and there would be,

01:22:28.220 you know, but it's actually been a relatively kind of complex set of definitions to come to.

01:22:33.920 And the importance of establishing brain death was in many ways driven by the development of

01:22:42.260 transplantation. Because if we were going to use deceased organ donors for transplant,

01:22:49.360 we needed to establish clearly defined ways that these were individuals that could not recover,

01:22:57.620 you know, were not going to be salvageable such that they could then go on to be organ donors.

01:23:03.920 And to be even more specific about that, the whole question of what defines death, you know,

01:23:10.480 so is death when the heart stops or is, or do we consider death when the brain has lost function

01:23:18.260 and control?

01:23:19.580 So just to clarify that for people, right? The first thing you said is when the heart stops is what we

01:23:24.200 call cardiopulmonary death. So a person has a heart attack, the heart stops, cardiopulmonary death.

01:23:31.360 A person has cancer eventually leads to cardiopulmonary death. This brain death thing,

01:23:38.000 how does it show up? Give people examples of the physical way, the physiologic ways people get there.

01:23:44.100 It's a kind of confusing concept. How can the body be alive, but the brain be dead? And there are a whole

01:23:50.980 number of circumstances where that can occur. But essentially the central component of the definition

01:23:57.420 is that the brain sustains an injury. That could be from an anoxia, from an anoxic event. It can be,

01:24:04.620 it can be literally from a traumatic event, you know, a penetrating injury, a devastating head trauma.

01:24:10.560 It can be from an intercranial event, a bleed or such, such that the pressure in the brain and the

01:24:19.420 injury that evolves in the brain increases to a point that blood flow and oxygen delivery to the

01:24:26.740 brain stops. And so all the cellular processes that are occurring kind of from literally the skull base

01:24:33.320 up have stopped. And there are clinical ways to define that diagnosis. So there are characteristic

01:24:41.640 neurologic manifestations of brain death. The classic ones that you see on TV are the blown pupils

01:24:49.140 as someone's brain has swollen to no longer allow blood flow into the skull. There are core bodily

01:24:56.740 functions that the brain drives, such as respiratory drive, that are part of that definition as well,

01:25:03.380 as well as a bunch of additional primitive reflexes. And really what evolved over time is a clinical

01:25:09.200 definition of brain death that includes multiple elements, including that the individual has to be

01:25:14.960 hemodynamically stable. They can't be hypothermic. They can't be in some metabolic condition that could

01:25:20.700 confuse the issue. But then the central focus of it is this thing called an apnea test,

01:25:26.080 where they literally stop the mechanical breathing support and see whether or not the individual

01:25:31.580 generates the drive to breathe on their own. And so there are clinical brain death exams that

01:25:38.520 physicians are used to doing to document that. And then there are ancillary studies that can actually

01:25:43.720 show that blood flow has stopped into the brain. And I think coming to a consensus on that definition

01:25:50.480 was really critical to allow the establishment of what equates with death. So the loss of the function

01:25:59.000 of that individual, even if their other physiologic functions, like their heart beating, are maintained.

01:26:05.620 And establishing that diagnosis then allowed the step to go from, well, if they are brain dead,

01:26:11.840 but they still have present circulation, can we then move to organ procurement?

01:26:18.600 Because in the absence of that, you could kind of ethically equate organ procurement as prompting

01:26:27.420 death, right? So in other words, if these individuals are not yet dead, organ procurement is

01:26:32.540 expediting your death, which with their death, which violates all the principles of kind of autonomy and

01:26:38.240 the principle of organ donation that transplantation is built on.

01:26:43.220 So there's a couple of things there I just want to highlight before you go on, Chris,

01:26:45.780 just so people understand. Brain death still requires cardiopulmonary support. That's the

01:26:51.140 very important thing people need to understand. A brain dead individual is not going to be laying in

01:26:55.140 a bed, their brain not functioning yet somehow they're alive. By definition, if your brain is dead

01:27:01.440 and you are not on full cardiorespiratory support, you will be dead within moments. So that's why this

01:27:08.020 apneic test is done while they're hooked up to a respirator that is just turned off,

01:27:12.820 but not disconnected. They will fail to breathe. As you point out, they will fail the apneic test,

01:27:18.340 and then they'll be resumed on cardiopulmonary support because of course the goal is to continue

01:27:24.680 to oxygenate their body perfectly to maintain the appropriate levels of tissue health.

01:27:30.180 The other thing that's worth mentioning, it's like if you watch TV, you might be lulled into thinking

01:27:36.280 that the same set of doctors that are trying to understand if your brain dead and trying to take

01:27:41.540 care of you after whatever accident you had that led to the situation you're in have anything to do

01:27:47.560 with the doctors that are coming along to take the kidney or liver. Because that would seem a little

01:27:52.420 grotesque, right? So explain that sort of line between those two teams of physicians, because

01:27:59.060 you and I have been multiple times on both sides of that. We've been taking care of those patients in

01:28:03.500 the ICU that are going to become donors. And then we've been on the other side where you're now

01:28:08.300 part of the team that's harvesting organs. Correct. So it's a clear ethical principle that is central

01:28:14.780 to not only the kind of effective operationalizing of transplant, but also to the establishment of the

01:28:24.000 public trust that is critical to allowing transplantation to exist. And the way I explain that

01:28:32.060 to transplant families and organ donor families is that the systems are completely separate with an

01:28:40.060 opportunity for integration in between that only occurs when certain events has happened in the

01:28:47.520 individual's care. So number one, the concept of brain death has to be thought about to begin with,

01:28:56.360 you know, that that's part of the diagnostic evaluation of that individual. The brain death

01:29:03.220 exam needs to be confirmed. The family and or patient through previous documentation has identified

01:29:12.080 that individual as an organ donor. And only then after those steps is the transplant machinery or

01:29:20.520 specifically the organ procurement organization involved. So some people have the concern, well, gosh,

01:29:26.120 are the people that want more organs for transplant going to somehow interfere in the decisions that

01:29:32.960 are made about this individual who's undergone some tragedy that's leading to the end of their life.

01:29:38.920 And the reality of that is fortunately that we have no impact on that decision. I think the other

01:29:46.480 principle that occurs is that then the care of that individual body, because if there have been declared brain

01:29:55.640 death, we consider the individual, then passes from the caregivers, the healthcare team that's been

01:30:02.080 caring for them to the organ procurement organization and their team, and then eventually to the transplant

01:30:08.160 teams and to the procurement. So there's a clear transition from when they go from an individual under the

01:30:13.920 care of ICU team or, or the teams that are caring for them to the individuals whose responsibility it is to

01:30:20.940 facilitate the gift of transplant. And I think in situations that fortunately occur more and more

01:30:28.460 often, where either the individual themselves have already identified on their driver's license or

01:30:34.700 through conversations with their family that they, in the event of a tragedy, they want to be an organ

01:30:39.540 donor, or families come forward. And I always think this is incredibly generous. I mean, this usually occurs out of the

01:30:47.660 the worst day of their life, and they come forward to say that they would want their loved one to be an organ

01:30:54.380 donor. Nothing happens on the transplant side until all those steps have occurred. And so I think it's really

01:31:00.260 kind of critical to understand that. It is worth alluding to the concept of donation after cardiac death, which is

01:31:08.780 where that gets a little more confusing. So there are individuals who have suffered a life-threatening event,

01:31:16.780 a devastating head trauma, but that has not caused brain death, other medical conditions where the

01:31:23.740 care team and the caregivers have decided that their life is not salvageable, but they're not technically

01:31:30.940 brain death. And that's always been a conundrum, because what if those individuals want to donate their

01:31:36.440 organs, but they don't meet this very strict criteria that we've established as a, as a important

01:31:42.560 principle to allow organ donation. And what has evolved in the United States and around the world

01:31:49.540 over time is this concept of donation after cardiac death. And importantly, there still needs to be the

01:31:58.920 establishment of death before we can procure organs to, again, separate the process of declaring death

01:32:07.880 organs. And so what happens in a donation after cardiac death situation is the family chooses to

01:32:15.520 withdraw care. Care is withdrawn. The individual then expires over some period of time. And then depending

01:32:24.820 on the circumstances of that individual's death, how quickly it happens, et cetera, if we then believe

01:32:31.700 it's appropriate to still utilize those organs, organ procurement can occur. And those decisions are

01:32:38.240 all made before withdrawal of care. So in other words, the family has decided to proceed with pursuing

01:32:46.080 organ donation. The arrangements have been made to have the teams and individuals available there

01:32:51.560 to procure the organs and preserve the organs appropriately. But nothing happens until that individual

01:32:57.440 is declared dead by a provider that has nothing to do with the transplant team. So I think even in the

01:33:03.260 case of donation after cardiac death, we've kept that very clear delineation between individuals caring

01:33:09.660 for the patient and individuals processing the gift of the donor for transplant.

01:33:15.980 You alluded to something earlier, which reminds me of one of the sadder stories when I was,

01:33:21.620 I was in residency actually when this happened. So my mom, one of my mom's closest, closest friends,

01:33:26.620 her son, who was five years younger than me. So I knew we grew up together, was driving home one

01:33:34.040 morning after a night shift and fell asleep, crashed and died an immediate brain death. His mom,

01:33:41.220 single mom, no relationship to his father had to make this, what can only be described as, as you said,

01:33:46.840 the worst day of your life. And now you have to make a decision. And I'll never forget, she made this

01:33:53.460 decision to have every, every single aspect of her son donated, you know, corneas, skin,

01:34:00.880 his liver was split into two. So two people benefited from his liver as both kidneys, heart lungs.

01:34:06.720 It's always stuck with me. And if that wasn't enough, a couple of years later, I would go on

01:34:11.100 to meet a friend that I ended up working with actually, who lost his son to his, he was in a

01:34:16.840 Jeep accident, rollover Jeep. And same thing, you know, he and his wife had to make this awful

01:34:22.440 decision about their 21 year old son who had just died. And without hesitation, they did the same

01:34:28.660 thing, which was every piece of our son, Aaron was his name is going to be donated to help someone

01:34:35.500 else. And what was especially amazing in the case of, of this couple, I think I can say their names.

01:34:41.740 I don't, I think they're actually quite vocal about this. Jeff and Tina Webster is that they got to

01:34:47.080 know every one of the recipients. And as I got to know them and got to know the stories, I was just

01:34:54.160 blown away by it. And, and again, I'm someone who's been around this stuff, right? Like,

01:34:58.060 it's not like I haven't seen these things before, but the man who got his liver has a tattoo of their

01:35:04.340 son on his arm. You know, it's that kind of stuff. It is hard to believe. I mean, do people ever ask you,

01:35:10.060 Chris, Hey, you know, should I check that box on my driver's license when I'm at the DMV about,

01:35:15.380 do I want to be an organ donor? I mean, how do you talk to people about something like that?

01:35:19.840 Yeah, that's a great question. And it is one that I, that I get asked. And actually my oldest

01:35:23.620 daughter tells me she occasionally gets asked now, I guess, because people know her dad's a

01:35:27.860 transplant surgeon. But so what are the reasons that people hesitate to do that? And I think some of

01:35:33.580 it is what we already alluded to is kind of the concern or the mythology that somehow it'll

01:35:39.700 affect their own healthcare. And sometimes I'll answer questions about that. But I always try to

01:35:45.460 focus on the profound impact that transplantation can have and try to share with them what I've

01:35:54.340 learned from donor families over the year. I mean, one of the privileges of the position I am in now is

01:35:59.800 that I do get to occasionally do advocacy work and other opportunities to meet donor families. So

01:36:06.680 families like you just told of the Webster's that have a history of a family member who was an organ

01:36:14.060 donor. And many of them can poignantly tell of the process they walked through with that decision

01:36:20.620 making and the memories of their loved one. But one of the things that donor families really

01:36:26.160 universally share is that their experience of organ donation, whether or not they were able to meet

01:36:35.300 the eventual recipients of their loved one's organs, but that the experience of organ donation and

01:36:41.660 knowing that their loved one's organs live on in another individual and save their life is the only

01:36:49.780 good thing about what was otherwise the worst day of their lives. And I've heard that actual phrasing

01:36:56.340 repeated by multiple families, by multiple individuals who had to say goodbye to their son, daughter,

01:37:03.120 sister, brother, husband, wife, but took some solace in the fact that you were honoring their life by

01:37:11.820 passing on the gift of their organs to another individual. So I think it's important for people

01:37:17.280 to hear that it can be a transformative gift. I think the other thing I share with people and let

01:37:22.900 them make their own decisions is that there is an incredible need for organ donation. There are

01:37:30.800 currently more than 100,000 people waiting on the waiting list for the various organs, and each year

01:37:37.860 there are less than 40 percent or so of that number done. And the need only grows each year. The gap

01:37:45.660 between donation and supply grows each year. Furthermore, the outcomes of the individuals who get

01:37:53.200 transplanted improves each year. So not only do we have this tremendous need for individuals dying of organ

01:38:00.160 failure, but the life that they can look forward to is in most cases incredibly good. You know, restoring

01:38:07.300 them back to life expectancies that approximate normal and qualities of life that in many cases are totally

01:38:14.740 normal. So that's the vision I try to share with people when they're considering organ donation. But acknowledge that it's a very

01:38:22.060 personal decision and people have to be comfortable with that. I do encourage people, if they feel passionately

01:38:28.860 about it, to make the decision themselves. Because I can tell you, like you said, you know, we've been on both sides

01:38:34.880 of this, that walking through that decision making with someone's loved one who is in the middle of the night in a

01:38:42.840 foreign hospital trying to make the decision about the wishes of their loved one is an impossible task.

01:38:50.080 So the more that you can register yourself and communicate that to your family, the actual easier

01:38:56.020 you make it on your loved ones, God forbid, they end up in that situation having to facilitate that gift.

01:39:02.180 Yeah, I think that's the point. You can think of this as an advanced directive, which actually is the biggest

01:39:07.840 service you can give to people around you so that they don't have to, that there's no ambiguity about what your

01:39:13.520 wishes are. We've talked a lot about kidney, but I think I'd be remiss if we didn't spend some time talking about the

01:39:19.780 liver, which is really the bread and butter of your clinical practice. And it's certainly one of the most

01:39:25.440 technically demanding operations in the field. It's no surprise then that the most amazing surgical resident I ever got the

01:39:32.620 train alongside is doing the pinnacle of what surgery offers. Let's go back to the

01:39:37.760 1960s. There's a young guy, it's 1963. There's this guy nobody's ever heard of, Thomas Starzl.

01:39:44.920 He's plugging away at this operation. He actually, I think if I'm not mistaken, was the first guy to

01:39:51.220 figure out that you could add prednisone to Imuran and actually increase survival to levels that were

01:39:56.020 still abysmal by today's standards, but reasonable. I think he was getting 70% survival at one year.

01:40:02.860 But four years later, a three-year-old boy dies on the operating table, bleeds to death.

01:40:09.160 And at that point, people sort of had enough. And there was kind of, as you alluded to earlier,

01:40:13.580 this moratorium on liver transplants until we figure this out more. Let's start with the technical

01:40:18.260 aspect of it. What is it about the liver that is so difficult to surgically implant?

01:40:26.240 I mean, the liver is the largest solid organ in the body. It has some interesting anatomical

01:40:33.820 nuances. It has a dual blood supply. So it's supplied by the hepatic artery, which is a major

01:40:40.960 branch essentially off the aorta, as well as the portal vein, which is the blood drainage of all of

01:40:47.900 the intestinal blood flow. And the reason that returns through the liver is the liver is the filter,

01:40:54.140 essentially the metabolic filter for the metabolites absorbed in the GI tract. It then

01:41:00.040 lives on top of the vena cava, the major vein returning blood from the lower part of the body

01:41:06.780 back to the heart, and actually sits right below the diaphragm, right below the right atrium, where it

01:41:11.440 has this complex venous network that drains into the vena cava. So it's anatomically made not to be

01:41:19.860 messed with in some ways. This is the way you'll hear people talk about it. I mean, and in addition

01:41:24.240 to that, you then have all of the intrahepatic anatomy, which can be profoundly complex as well.

01:41:31.000 But the thing that makes liver transplantation really the challenge that it is surgically

01:41:36.120 is not so much the anatomy, which fortunately with experience, you learn how to navigate.

01:41:42.140 It's the fact that liver failure, at least the diseases for which we most commonly transplant. So

01:41:50.020 the development of cirrhosis or the end stages of chronic liver injury and fibrosis leads not only

01:41:58.260 to synthetic failure of the liver. So the liver loses the ability to process some of those metabolites.

01:42:04.660 It loses its ability to make new proteins, including some of the proteins that help your blood

01:42:10.040 clots and other important functions. But because the liver is become this scarred fibrotic organ,

01:42:18.280 all of that blood flow that's returning from the intestines has to make its way through what used

01:42:24.580 to be this soft compliance sponge, and is now literally the consistency of a rock. And so what

01:42:32.580 happens is you develop this condition called portal hypertension, where the pressure in the portal venous

01:42:38.940 system increases such that it tries to find other ways back to the heart. And so it forms collateral

01:42:46.220 channels. Those collateral channels are what form the varices or varicosities that develop in the GI

01:42:53.100 tract that can lead to life-threatening hemorrhage in liver patients. It's what leads to the formation of

01:42:58.420 ascites or the fluid retention that you see in patients with liver disease with these huge

01:43:02.860 protuberant distended abdomens. And it also makes the surgical field this kind of rat's nests of

01:43:11.060 collateral venous vessels. So you've got the challenge of a large organ with challenging anatomy.

01:43:18.360 You have the challenge of this condition that makes the dissection and the predilection towards

01:43:24.380 bleeding even higher. And then you have the synthetic function, which occurs in the setting of,

01:43:30.040 you're doing this operation in the setting of an individual who's not making normal clotting

01:43:35.180 factors. So it's really both the circumstance of the technical challenge, but more often the

01:43:40.960 circumstances in which you're doing it. And as you know, liver failure leads to cachexia and muscle

01:43:46.700 loss. So these are debilitated sick patients that you're then doing a big operation on in suboptimal

01:43:53.800 conditions. And so the fact that Tom Starzl and his contemporaries took that operation on in the 1960s

01:44:03.100 when electrocautery wasn't really a thing, most hospitals didn't really have blood banks, we didn't

01:44:09.060 even have critical care anesthesia, at least with any resemblance to what it is now. I mean, it's pretty

01:44:14.740 remarkable that that was even conceptualized, much less achieved technically. And as you alluded to,

01:44:22.120 it was really their realization that not only was the procedure so technically demanding that the

01:44:29.820 risk of early mortality was quite high, but you were doing it in an immunologic setting that just

01:44:36.280 was not successful. And so, you know, even the patients that survived the operation in the early

01:44:41.560 recovery, there were really no survivors past 90 days in the first dozens of transplants done,

01:44:47.920 which is what led to the moratorium on liver transplantation that occurred in the late 60s.

01:44:52.960 And I would add one other thing to punctuate everything you said, Chris, which is not only

01:44:57.380 are these the sickest patients I've ever seen, I mean, these patients are staggeringly sick,

01:45:03.780 but they lack something that every other sick patient has prior to a transplantation. So whether

01:45:10.520 we're talking about cardiac transplantation, pulmonary transplantation, pancreatic transplantation,

01:45:15.880 renal transplantation, all of those organs have some form of extracorporeal support that is offered

01:45:22.360 to them to at least bridge the gap or tune them up a little bit prior to surgery. The liver remains

01:45:30.360 the only major organ with no form of extracorporeal support. Now I could spend an hour giving you my

01:45:36.960 theories as to why that's the case. I think it speaks, I'll give you the punchline. I think it speaks to

01:45:42.620 one particular function of the liver, although I think there are many, but I think the one that

01:45:47.520 just can't be done by a machine is the regulation of blood glucose. It is so complicated to manage

01:45:54.140 gluconeogenesis, glycogen storage. I mean, you have to be able to regulate something to

01:45:58.340 the milligram level with seconds to spare. There are probably a dozen other reasons, but

01:46:03.960 every attempt at extracorporeal liver support has failed, including some crazy stories that,

01:46:09.700 you know, I heard from, God, one of our, one of the transplant surgeons, I remember it might've

01:46:14.640 been Montgomery even told a story about the baboon. Yeah. That's a Mel Williams story. Classic. Oh,

01:46:19.540 that's right. That's right. Mel Williams. Why don't you tell folks that story? Actually,

01:46:22.760 it's just the scariest thing. So what you're alluding to is exactly correct. So there have been

01:46:28.400 all kinds of both mechanical and even in atomic models trying to address liver dysfunction or to bridge

01:46:37.180 that gap from liver failure to transplant and nothing has worked real well. I mean, essentially

01:46:42.840 we've tried what's been called liver dialysis. So in other words, trying to remove some of the toxins

01:46:48.380 from the bloodstream that the liver is responsible for filtering. We've tried things that do address

01:46:53.860 the portal hypertension. So at least you kind of alleviate that problem, but nothing has replaced

01:46:58.780 the synthetic function that you described. So one of the obvious conjectures, well, then we need

01:47:04.520 a physiologic solution to this. Could we support patients, particularly patients with acute liver

01:47:11.480 failure where the injury is acute and the liver is this incredible organ in that it does have this

01:47:17.720 regenerative capacity. Hepatocytes will replenish over time. So the thinking was, well, if someone comes

01:47:24.040 in with a Tylenol overdose or an acute viral toxicity to their liver, could we just bridge them long enough

01:47:31.800 until those new hepatocytes start to come into play? And so it was under that principle that the concept

01:47:38.120 of, well, can we do some sort of extracorporeal model to support these patients? And so Mel Williams,

01:47:45.880 who was the, he was a contemporary and a student of David Hume, who was one of the godfathers of

01:47:52.200 transplant and transplant immunology specifically. Christian Barnard, who did the first heart transplant,

01:47:57.180 actually trained in his lab. And Dr. Williams worked there as well. And then eventually came

01:48:02.460 to Hopkins and started the transplant program at Johns Hopkins. He was a kidney transplant recipient,

01:48:07.260 eventually himself received a living donor kidney from his wife and unfortunately died recently later

01:48:13.100 in age, not related to his transplant. A remarkable kind of luminary figure and one of the best storytellers,

01:48:20.940 you know, you've ever heard. But he tells the story of that they decided, well, why don't we address

01:48:27.060 acute liver failure by hooking up the patient to a extracorporeal, essentially, you know, bypass circuit

01:48:35.020 and put a baboon on the other side of the circulation. So the baboon's liver would essentially filter the

01:48:43.480 toxins out. They'd be, the blood would be returned to the individual and that would address their acute liver

01:48:49.220 failure. So they worked on this prep and they did all kinds of preclinical studies. And eventually

01:48:56.280 they had somebody come in with acute liver failure. And I don't know the specifics of IRB regulations at

01:49:02.600 that time, but sure enough, they got approval to do this. And one of the things they quickly realized

01:49:08.020 is, and I don't know any of the veterinary medicine behind this, but you can't sedate a baboon

01:49:12.660 very easily. You know, it takes Herculean doses of sedatives and you can't have a baboon running

01:49:18.760 around the medical ICU unit at Johns Hopkins Hospital. So they decided, and maybe what wasn't

01:49:24.680 the most ingenious method, to put the baboon in a body cast. So they would, at least the baboon would

01:49:30.760 be frozen to the bed. So they do the preparation and unbelievably it starts to work. So the patient's

01:49:39.280 encephalopathy clears, the patient starts to wake up. So this poor individual wakes up in the ICU at

01:49:46.520 Johns Hopkins. He doesn't know what's happened to him. Looks over and there's a baboon lying next to

01:49:51.420 him in the bed next to him. So what does he do? He tries to get up and start pulling at lines.

01:49:56.500 So the solution they decided to that is they actually put him in a body cast. So there was

01:50:00.820 a baboon and this poor individual in a body cast in the ICU next to each other in Johns Hopkins. And that

01:50:06.800 was a short-lived series of experiments, but it did prove the principle that that would work.

01:50:14.560 That if you had an actual functional liver in cross-circulation with an individual, and actually

01:50:20.840 he went on to do some preparations between, for example, family members. If a family member came

01:50:25.840 in with acute liver failure, you could put them in cross-circulation with a sibling or something.

01:50:30.440 And some of those did work and maintain those patients. It also led to the principle that is part

01:50:36.280 of an investigational product now that created this essential dialysis column populated with

01:50:43.980 hepatocytes, with a hepatocyte stem cell line that populates the hepatocytes. And that has been shown,

01:50:49.940 at least in some studies, to at least provide some limited short-term support as well. But the principle

01:50:57.440 behind what you said is absolutely right, that we have not figured out how to provide

01:51:01.500 extra corporeal support for liver patients. So they really are the patients that face death

01:51:06.700 if they are not able to be transplanted in a timely fashion.

01:51:10.500 One of the most stark memories I have from residency on the side of patients that would

01:51:15.960 ultimately need a transplant was probably my second year in the old SICU. A young woman came in,

01:51:22.740 she was 21 years old, she'd overdosed on Tylenol. And it's funny when you realize how dangerous

01:51:29.620 Tylenol is and yet how willy-nilly it's available. You know this, of course, but just for folks

01:51:35.260 listening, the LD50, the lethal dose at which 50% of the population would be dead from a drug,

01:51:40.740 that's a, you know that, one would know that for every drug out there. What's the LD50 of fentanyl?

01:51:46.360 What's the LD50? Well, the LD50 of Tylenol might only be 10 to 20 times beyond what you would normally

01:51:52.000 take for your headache. And so the ease with which a person can end their life with Tylenol is

01:51:57.760 staggeringly high. And as was the case with this girl, you know, I think she broke up with her

01:52:02.660 boyfriend and took a bottle of Tylenol. And by the time she sort of realized that this was a bad

01:52:11.920 idea, it was too late. And there was the saddest memory I have, Chris, is the following. Before she

01:52:19.160 really went into acute liver failure and then suffered sort of the encephalopathy that would then

01:52:26.020 rob her of her cognition while we waited for a transplant, there was a lucid period of time

01:52:31.420 when her PT, you know, INR, PTT were through the roof, LFTs were through the roof. And it was very

01:52:40.500 clear she was going to die without a liver transplant. And yet she was cognizant enough

01:52:45.680 to know that. And I don't remember how big that window was, but it existed. Now we could have been

01:52:50.860 wrong. Maybe she was going to recover, but it turned out she ended up getting transplanted.

01:52:55.880 And it was, it was just amazing to see her wake up from that and realize like she had another lease

01:53:01.760 on life. And you could say, I mean, look, someone could say, well, she made a dumb mistake, you know,

01:53:07.080 and maybe she didn't deserve another chance. But of course I would say who among us hasn't done

01:53:11.460 really dumb things? It's so true. It's, it's, you know, fortunately acute liver failure only accounts

01:53:17.840 for about 5% of the liver transplants done in the United States. So it's a relatively uncommon

01:53:23.000 situation in part because the liver is pretty resilient. So sometimes even a catastrophic,

01:53:29.580 you know, overdose with good critical care and other measures, many of those patients will recover.

01:53:36.520 But, you know, we are often faced with the situation where just exactly like you described,

01:53:41.960 a person comes in with a Tylenol overdose, it's an intentional overdose, or at least a,

01:53:47.840 you know, suicidal type gesture. And we have to make the decision with limited information

01:53:53.060 about whether or not we think they're an appropriate transplant candidate. And, you know,

01:53:57.420 occasionally there are reasons why they're not, you know, uncontrolled comorbid disease, or maybe,

01:54:03.500 you know, other factors. But usually it's exactly the circumstance you described. It's a

01:54:09.380 young distressed person who reacted badly to a, you know, a particular event.

01:54:16.460 And makes a very impulsive decision.

01:54:18.840 Impulsive decision with a freely available drug, like out of their medicine cabinet.

01:54:24.320 You know, and I think the approach of our center, which I think is true of most transplant centers,

01:54:28.620 is to give those patients the benefit of the doubt and try and get them to transplant rapidly,

01:54:33.400 and then use all the appropriate resources afterwards to help support them and make sure

01:54:38.000 that any mental health issues and such are addressed. So they are tragic and dramatic

01:54:42.720 circumstances. They can be incredibly rewarding, you know, transplants, as you would imagine,

01:54:48.220 though, to see them literally get transformed from the transplant.

01:54:52.860 Chris, when you and I were in medical school, and residency for that matter,

01:54:56.740 it seemed abundantly clear that hepatitis C was going to overwhelm the liver transplant

01:55:03.200 infrastructure within the United States.

01:55:05.380 Today, there's good news and there's bad news. The good news is that hepatitis C is not going to

01:55:12.600 overwhelm the liver transplant infrastructure of the United States. The bad news is that something

01:55:17.880 else is going to do that, and that's NAFLD and NASH. Can you tell us the twin stories of these two

01:55:24.500 things? And how is it that something that we believed could never be cured got cured? And then how is

01:55:32.040 it that this thing that we didn't know existed 20 years ago is going to be, if it not already is,

01:55:37.740 the leading indication for liver transplant in the developed world?

01:55:41.060 It's such a kind of at once compelling, but also humbling story. And in telling it,

01:55:47.400 I'll add even a third actor that, you know, is part of this as well. So hepatitis C, as you alluded to,

01:55:55.020 you know, a viral illness, bloodborne illness, that has kind of an interesting history. Some people that

01:56:01.000 are exposed to, so hepatitis C rarely causes an acute illness, fortunately, some people that are

01:56:07.980 exposed to it can clear the virus, so spontaneously clear the virus, but the majority are left with

01:56:14.940 chronic viremia and subsequent inflammation, which is silent for years, and in some cases, decades. So

01:56:24.300 the kind of history of this in the United States is that people were exposed to this

01:56:28.760 in the 70s and 80s, either due to a time when the blood supply was not really tested as stringently,

01:56:35.420 and they acquired it through blood transfusion, or they acquired it from use of IV drugs or other

01:56:41.560 exposures. But then it went about their life, and then here they are 20, 30 years later with cirrhosis

01:56:48.080 and eventual complications of cirrhosis and indication for transplant. And for about 20 years,

01:56:55.920 that was the predominant indication for transplant in the United States, which was a challenge because

01:57:01.680 the medications we had to treat hepatitis C were not particularly effective, you know, response rates

01:57:07.240 of 15 to 30 percent or so. So every one of those patients got recurrent hepatitis C after their

01:57:14.300 transplant, and many went on to develop graft failure, you know, and cirrhosis essentially of their

01:57:20.340 transplanted graft. So it was a particularly frustrating clinical problem because there was this

01:57:25.620 enormous need, but also we were only kind of partially solving the problem. And what has

01:57:31.680 happened and what you're alluding to is in the last 10 years, essentially, was the development of

01:57:37.660 these direct antiviral agents that have transformed the field of hepatitis C. And it's, you know,

01:57:44.540 you can make some arguments about what's the greatest medical advance we've witnessed in our,

01:57:49.380 you know, medical career, but that's up in the top two or three.

01:57:52.700 Yeah, I don't think I could think of something more impressive in my adult life.

01:57:59.140 Maybe you could argue the retroviral regimens that made HIV a chronic disease instead of a,

01:58:05.700 could rival it. But I mean, this is transformative. So you take patients who were on a certain path

01:58:12.500 towards liver failure and death, cure their viremia. And what we actually anticipated would happen was

01:58:18.380 that all the patients who already had cirrhosis would eventually go on to need transplant anyway.

01:58:24.440 But what we've seen is a precipitous drop in the number of patients needing transplant for hepatitis

01:58:29.600 C, because once they clear the virus, their liver does recompensate and repair somewhat. And the

01:58:35.440 patients that are not cirrhotic or with advanced fibrosis yet are never going to get there.

01:58:39.480 So it is, it is truly a curative situation. So that drop has happened precipitously over the last

01:58:47.440 three to five years. It has been replaced nearly completely by actually two diseases. The first

01:58:56.120 and the one that has this incredible broad public health impact is non-alcoholic fatty liver disease,

01:59:02.480 or the concept of fatty deposition in the liver that leads to chronic inflammation.

01:59:07.840 And kind of just like a chronic virus, ongoing inflammation, fibrosis, eventually cirrhosis.

01:59:15.340 And with the obesity epidemic and other associated diseases, the prediction is that by 2030 or so,

01:59:23.920 it will become the leading indication for liver transplantation. And we've already seen that curve

01:59:31.160 start to inflect up pretty highly. The only thing that makes the story a little more interesting or

01:59:37.560 frustrating is there's another curve that over the last several years has inflected even at a steeper

01:59:43.480 slope. And that is the incidence of alcohol-related liver disease, which has always been a important

01:59:51.100 cause of liver disease in the United States. But unfortunately, and whether you blame it on the

01:59:56.860 economic downturn in the late 2000s or other factors, really have seen an explosion of alcohol-related

02:00:04.860 liver disease, made worse, by the way, by the pandemic. And I think that has occurred at a time

02:00:11.200 when transplant centers have adapted their approach to patients with alcohol-related liver disease to

02:00:17.960 make it a little less of kind of this terrible Spanish Inquisition kind of approach to, you know,

02:00:25.120 you're either in or out, you know, if we think you're committed to sobriety, to a system where

02:00:31.140 we have developed resources, mental health professionals, counselors and such to support

02:00:37.440 people in their sobriety to allow them to get transplanted successfully. So I hope that that curve

02:00:44.400 plateaus. We unfortunately don't have an intervention for fatty liver disease that I see breaking that,

02:00:51.460 the slope of that curve quickly. And it has changed our field because the population of patients with

02:00:58.860 fatty liver disease is much different than the population with chronic liver disease of other

02:01:02.800 causes, whether it's alcohol, hepatitis C. You know, most of those patients have liver disease and the

02:01:09.000 consequences of liver disease, but usually, fortunately, not much in the way of other morbidity.

02:01:14.400 Whereas you take the fatty liver disease population, they are, first of all, often obese, which,

02:01:20.360 you know, poses surgical risk and other challenges. But on top of that, they have all the other

02:01:25.580 manifestations of their metabolic syndrome. They have cardiovascular disease, hyperlipidemia,

02:01:30.040 et cetera, which poses, you know, medical management challenges, both for making sure we select

02:01:36.580 patients that are likely to be successful with transplant, but also with caring for them afterwards.

02:01:41.760 I mean, you'll hear the comment said that we've kind of converted our liver transplant population to look

02:01:47.980 a lot more like our kidney transplant population because they're dealing with these cardiovascular

02:01:52.480 comorbidities and other things that are just, that are threatening their long-term survival as much as

02:01:57.460 their liver disease and immunosuppression is.

02:01:59.700 I sort of think that the uptick in alcohol-associated liver disease or AFLD, say,

02:02:06.460 is kind of the parallel but gets less attention than what we're seeing with the opiate crisis.

02:02:12.580 So the opiate crisis is, I think it's easy and understandable that you would throw the

02:02:19.520 manufacturers under the bus. And in truth, they deserve to be thrown under the bus. And you can

02:02:25.200 throw the physicians under the bus who prescribe them too freely. And that's fair as well. But the

02:02:31.400 elephant in the room is the why, right? Like why is it that people are self-medicating with opiates

02:02:38.360 that are made too freely available, et cetera. And I think with opiates, because the outcomes can be

02:02:45.680 quite binary and stark in the nature of the overdose, the nature of the death, it becomes

02:02:51.260 very easy to focus on that. But acute alcohol toxicity is virtually unheard of. Very few people

02:02:57.600 will drink themselves to death in a moment. Much more common, of course, is the chronic toxicity of

02:03:03.320 alcohol. And I think that you're one of the few specialists within medicine as a transplant doc

02:03:09.260 or a hepatologist who actually gets to see what that looks like. But I think it doesn't really

02:03:14.100 register for most people that they're basically two sides of the same coin. Yeah, I totally agree

02:03:19.660 with you. And I think we, unfortunately, that perception that they're different or the fact that

02:03:26.060 we kind of both medically and society-wise treat them differently has prevented us from addressing

02:03:32.680 the problem with the appropriate attention it needs. One of our hepatologists here at the University of

02:03:38.880 Michigan, Jessica Mellinger, who's really dedicated her career to understanding alcohol-related liver

02:03:44.260 disease, as she has refined kind of her approach to the evaluation and management of these diseases,

02:03:51.820 she really makes the sense that, emphasizes the point that this is a behavioral disease. You could argue

02:03:57.940 NASH can be a behavioral disease in some cases as well, but therefore the resources have to be put

02:04:03.300 forth to address the behavioral disease. And I think, you know, we have largely turned a blind eye at

02:04:10.800 the impact of alcohol-related liver disease and alcohol use disorder in our society because of just the

02:04:17.780 factors you said. It's a freely available substance. The machinations and just kind of destruction that

02:04:24.560 people have to go through their life to get opiates. That's not the case for alcohol. You can go to the

02:04:29.560 7-11 and get the kind of equivalently damaging dose, you know, there. And I think it's made the problem

02:04:36.780 much harder to address. And I am glad to see the transplant community and the medical community kind

02:04:43.980 of re-pivoting in our focus towards trying to help people address the reasons why they're involved in

02:04:50.760 this cycle. Because it is tragic. And one of the things that's most notable about the alcohol-related

02:04:55.620 liver disease population now is they are ridiculously young. So not only have they drank enough to destroy

02:05:02.260 their liver, but they've drank enough to destroy their liver in their 20s and 30s, which is a little

02:05:08.840 different than kind of the classic 65-year-old guy who's been drinking all his life and, you know,

02:05:15.440 gets to the end of his life and has cirrhosis and complications.

02:05:18.380 That's right. Most of us think of the Mickey Mantle story where it's exactly what you described,

02:05:23.120 but it is the same disease. And yet one population numbs with an acute numbing agent,

02:05:31.240 opiates that have an acute toxicity and the other numbs with a chronic numbing agent that has a chronic

02:05:37.580 toxicity. And to somehow put those into different silos when I think the underlying conditions are

02:05:44.480 similar is probably slowing our progress. Yeah, I totally agree. I totally agree.

02:05:50.160 Chris, the last thing I want to talk about from a transplant perspective, and there's so much I want

02:05:53.620 to talk about, but I want to be respectful of your time. And I know you've got to head off to a meeting

02:05:57.100 shortly. You talked about the team. One of the things about transplant that attracted you to it

02:06:02.460 was the team. And I think it's probably not obvious to people how big that is. It's obvious to me

02:06:08.680 because I got to see it during residency. But I don't think there's a field of medicine

02:06:13.880 that has a bigger team when you encompass... I mean, the only one that I could maybe think of

02:06:18.900 that would rival it might be pediatric cardiac surgery where you just have such... The overlap

02:06:25.060 is huge. But even that might not be as big as what we're talking about here in terms of the

02:06:30.800 perfusionists and the surgeons and the anesthesiologists and the nursing and the ICU.

02:06:35.540 And then the logistics associated with organ procurement. It's an enormous team. And you

02:06:42.040 lost a number of team members a while ago, shortly after you got to Michigan. I think that story is

02:06:49.740 obviously tragic, but also highlights the incredible risk that goes into this. Do you mind telling that

02:06:56.680 story a little bit? Yeah, sure. So what you're referring to was a... In June of 2007, we had a team

02:07:04.640 that had flown from Michigan to Wisconsin to retrieve lungs for one of our recipients.

02:07:12.900 They had actually procured the lungs. They had just taken off from Milwaukee and had a tragic

02:07:19.540 set of circumstances that happened to the plane and tried to turn it around and get back to Milwaukee

02:07:25.320 and essentially crashed into Lake Michigan shortly thereafter. And all six individuals on board died.

02:07:32.780 There's a story in there about how important teamwork is in transplantation. So six people lost their

02:07:42.360 life as one small part of trying to get this set of lungs to a recipient. There were two pilots on board

02:07:50.780 who passed away. Two of our perfusion staff, so individuals who are responsible for the coordination of

02:08:00.220 kind of the procurement operation, the handling of the organ, its preservation, transport back to the recipient

02:08:06.960 team. And then two surgeons. There was a cardiac surgeon and actually a fellow who died in that accident as

02:08:14.700 well. And I can tell you that first and foremost, it's hard to speak about it now without getting emotional.

02:08:23.240 It was the most devastating event that I've ever witnessed professionally, you know, directly.

02:08:30.940 You know, there was a patient on the table, chest open on the table as the lungs were flying back.

02:08:36.260 That operation had to be stopped. One of our coordinators who was the person responsible for,

02:08:42.420 you know, sorting all these logistics was the person who figured out that the plane had gone down and that had to

02:08:46.960 tell our team what had occurred. It was devastating, to put it mildly, not to mention, most importantly,

02:08:53.920 the loss that those families sustained. You know, I think it shook us all in a way that I think is still

02:09:02.180 relevant. We still celebrate the lives of those individuals here at Michigan every June. You know,

02:09:07.940 if there is any good news about that event, it did two things, one of which I think was kind of more

02:09:15.120 immediate and personal. And that is it really made apparent to all of us here. And I think in the

02:09:20.920 broader transplant community, how precious each member of our team is and how important their

02:09:27.360 contributions are and how much they put at stake to make these incredible events of organ transplants

02:09:33.660 happen. The second thing is it made our field pause and figure out, do we need to be doing things

02:09:41.020 differently? You know, do we need to be shipping teams all over the country to procure organs when

02:09:46.700 there are qualified surgeons, you know, right next to where that organ may have come from? Do we need

02:09:52.400 to reconsider how we travel, you know, in terms of the expertise of the flight teams and such and

02:09:58.420 the actual planes themselves? And it has motivated differences. For example, in the liver community now,

02:10:05.560 we used to fly out every time there was an organ to, you know, we would go to wherever that

02:10:10.860 donor hospital is. Now, more than 50% of the time, you know, one of our colleagues at another center

02:10:16.900 procures that organ for us and ships it to us, which is the way that it should be. I mean, I think

02:10:22.620 if you were a layperson looking at the system, you're like, wait a minute, why are you shipping

02:10:26.060 teams all over the stuff when you have qualified people right there? So it has motivated change in

02:10:31.380 our community that I think needs to continue to evolve. But you're absolutely right that it was a

02:10:38.460 terrible event to remind us of the kind of sanctity and importance of our teams, for sure.

02:10:45.180 Well, Chris, I want to thank you for sharing that story. It's hard to believe it was 13 and a half

02:10:49.920 years ago. I mean, I remember like it was yesterday, so I can't imagine how approximate it feels to you

02:10:55.300 as well. This has been wonderful to sit down with you and talk about this. I always enjoy our times

02:11:01.480 together. And I have the fondest memories of sitting in that empty cafeteria at two in the morning

02:11:07.400 between traumas. And again, as long as I was sitting there with you, it was always enjoyable.

02:11:12.420 It was never like, oh, I can't wait to get back to the call room and try to get 10 minutes of sleep.

02:11:16.180 It was like, I'd rather be sitting here with Chris absorbing his wisdom, even if it means getting

02:11:21.320 no sleep tonight. So that wisdom continues. And I know that you're surrounded by patients that are,

02:11:27.660 I hope they realize how lucky they are to have you as their dog. I'm sure they do.

02:11:31.900 No, you're very generous, Peter. And I just want to say how grateful I am for you inviting me. I also

02:11:38.880 really am grateful for you using your platform to highlight the importance of organ donation and

02:11:45.940 the miracle really that it is that transplantation works. And so I'm grateful for the opportunity and

02:11:52.500 most of all, just to see you and reminisce a little bit. So thank you.

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The Peter Attia Drive - March 29, 2021

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

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