Thank you, Bijan and John Renz, for inviting me. To be honest with you, I had a lot of trouble figuring out what I should talk about here. So I put together an assembly of thoughts that hopefully would be of interest to the group. And I'm covering a little bit of ground that was already covered in the other talk, but in a slightly different point of view. So no disclosures. So I really asked myself, well, how is, I've been rounding on liver transplant patients for about 35 years. And how is it changing in the last five years? Because I'm feeling that it is quite different. And the patients are getting sicker. Now, we've always been transplanting sick people, but consistently sicker. And there's more pressure on the donor system. And so we're going out and using fatty livers, as was discussed earlier. Increased risk livers, hep C positive livers, DCDs. And at the same time, the diagnoses of the recipients are changing. And we'll go into that a little bit. Now, some more specific things. We are here to talk about Nashian metabolic syndrome. CKD is married to that, since there's such a high correlation between those two. Alk cirrhosis and hepatitis are also joining the group, which, and those patients have a lot of overlap, certainly biologically, to the Nash patients. We heard a beautiful talk in the previous part about cardiac risk. I think this is a really big deal. I'll just make a few comments about that. Donor selection. More and more of the donors that we use have fat in them. I think most of us draw the line at steatohepatitis, and certainly fibrosis, but the amount of fat in the donor livers is an issue for debate. DCDs are important in some parts of the world. A quarter to a third of donors are DCDs, but that varies quite a bit. Of course, living donors and the perfusion systems, which may well change our practice quite a bit. Now, you saw versions of this slide from Tamer, but actually, if you look just in the past few years, the hep C is now plummeting as the number of transplants go down, in contrast to NASH. NASH with cancer, which together become the most common indication, and of course, alcohol is moving on up, too. We've already heard all about obesity, diabetes, cardiovascular risk, but renal insufficiency and oncogenesis are really intrinsic to what happens to the NASH patients, and therefore, both in the NASH patients as well as in the overall candidate pool, we're seeing a lot more renal insufficiency. This excellent review from Cotter and Charlton, I have borrowed quite a few ideas from that. In addition, and I don't need to go into this, the relationship between NASH as well as obesity and renal failure is not just mediated through the metabolic syndrome and diabetes, but is intrinsic, as was alluded to earlier, and the risk of renal failure in the NASH patient is doubled even when you control for the other risks. Now, CKD in liver transplant candidates is somewhere around 15% or even higher, and the whole issue about simultaneous liver-kidney is another part to this conversation, but whether or not the patient gets a kidney, probably a third to a half of the post-transplant patients were struggling with their kidney function in the early period. Now, the rich ecosystem of donation is, in fact, I love these slides, I put them in every talk, more and more fragile, and in fact, it's dog-eat-dog out there. So as we struggle with the donor pool treating more and more transplant candidates, we, in fact, are making more and more risky choices regarding the donor pool. So we've made our living up here in New York by using a variety of organs that are not particularly popular, accounts for about half of the deceased donors we use, and of course, we try to do as many live donors as we can in our activities. So if you take most of the definitions, are a little bit fuzzy, but certainly, we use older donors a lot. HCV-positive donors used to be popular. Now, they're very hard to get, especially the young ones because of the new programs. Everybody's grabbing those livers. So those are hardly marginal livers anymore. The cold time over 12 hours just simply reflects that livers that nobody wants, or you get them at the last minute out of ice, DCDs split. Now, the macrosteatosis, we've used quite a few of these very fatty livers, but unless we make a big mistake, and sometimes we do, the biopsies should exclude steatohepatitis and certainly fibrosis. Now, it's very easy to see fat bubbles on the frozen section of a donor liver. It's not so easy to pick up fibrosis or NASH, and we've made several horrible mistakes, in my experience, anyways. The NASH liver with a lot of fat has a very high risk of primary non-function. So that young lady's liver from the previous session would probably not be a good choice for us. Now, this was mentioned earlier that the key to using this growingly diverse pool of donors is to do donor and recipient matching. So the very excellent DCD risk score generated from the UK data and published in Journal of Hepatology last year, it's a fantastic paper, a really nice score, and like all of the most robust scores, uses both donor and recipient factors in terms of trying to optimize outcomes. And the same goes for older livers. So we have quite a lot of experience with using livers of people over 70, well into the 90s even, and those livers have to be matched. They don't regenerate very well. They don't tolerate very difficult recipient operations or long cold ischemic times. So they have to be used with care in optimally selected recipients. Halazin analyzed this, and Hagen et al. published another very nice study from Dori Segev's group showing that if you optimize the matching of recipients, you could get good use of old livers. And Segev's team did a recent similar analysis from the UNOS data of optimizing the use of steatotic livers. Everybody does it sort of anecdotally or clinically, empirically, but if you look at the data on a large scale, you can really see there are trends that ought to be followed to get the best results. Now, when patients have bad kidneys going in or even kidneys that were not so bad and get worse, we're dealing with the whole issue of SLK, which is well beyond the scope of this talk, simultaneous liver-kidney. A lot of our patients come out of the OR or even go in and then come out on CVVH, which leads to delayed initiation of immunosuppression, and I think that's a big deal. Complicated course length of stay. And then this baseline renal insufficiency leads to long-term risk of CKD. And in fact, that carries very high predictive relationships for long-term mortality. The seminal New England paper from 2003 from Ojo and Merian demonstrated the incredibly high risk of CKD in patients receiving non-renal transplant. That was really the first demonstration of this, something that we sort of take for granted. By a decade, a quarter of the patients have significant renal disease. A more recent look at this from Allen, published in Journal of Hepatology, shows both the relationship between the GFR or CKD and mortality risk, which increases five-fold as you get up into the lower... This is all-cause mortality after liver transplant, so this is a real deal. And more depressingly, I guess I would say, if you follow out after transplant out to five to a decade, you're looking at instance of GFR below 60, excuse me, of well over 60%, going up to 80% by 20 years out. So our patients, and it's not just the CNI, but of course, it's complicated. The CMI is being layered on top of intrinsic renal disease. So this plagues us in the hospital as well in the first index hospitalization, as well as over time. Now, we had a beautiful summary of the heart thing. I just wanted to make a few comments. The left-sided heart disease, when I was a young transplant surgeon, that was what we were always looking for, ischemic heart disease, coronary artery disease. But the real challenge for our patients is the occult cardiomyopathies, which are very hard to diagnose. We heard some very excellent talks. The right heart dysfunction, which is a huge deal, leading to a growing use of intraoperative echo and other much more dynamic pre-assessments, as well as intraop management, because we have about 7% incidence of newly either discovered or developed post-transplant cardiomyopathies, that some of which are quite devastating, leading to either death or mechanical heart support. Now, we've had a few. Our heart team is quite active in our place, and both for acute and chronic management of heart failure, we've had some of our liver transplant patients end up on ECMO. Now, there's a really nice paper that caught my eye from our yard, a very large single-center French study that was looking at variability in CNI exposure early on and the relationship between complications. I don't know that CNI exposure variability is the cause, because, but what happens when people are having trouble, we're fooling around with our immunosuppression quite a bit. And in their series, CNI in variable patients had a neurologic complication rate of up to 30%. It was half that in patients who were more stable. Again, it's a chicken and egg. I think they're related, because this is what happens when the kidneys or the brain are not working well, we delay CNI. We used to think that frail patients don't reject, but in fact, if you wait enough weeks, most of them end up rejecting. So now, they're off CNI. They're having, recovering renal function, if you're lucky. And now, they're rejecting. The alternatives, strategies, certainly basaliximab is non-toxic. Dr. Verna studied this in our series. A lot of people do this. It's helpful, but it doesn't solve the problem, because you don't have a what then, and these patients often don't recover brain or renal function in the timeframe we need to prevent rejection. Early mTORs, a lot of our patients have glomerulid disease, so they can't really have mTORs either. Velatacep was a great drug, but a total, I won't say total disaster, but a very disappointing high-risk drug. So we really still are a little bit stuck when patients are not able to take their CNIs. Now, frailty was alluded to. It's the huge, very popular thing to study. It's been in the liver transplant literature for about a decade. And certainly, up to a third of, this is from Liotol, up to a third of the liver transplant recipients will be clinically significantly frail. I know it's a little hard to see these tiny drawings at three months after liver transplant. So it's an ongoing problem that's very tough to tackle. There's not a lot of convincing evidence that prehabilitation works in patients other than the ones who are already strong enough to exercise. And what do we do afterwards? The idea of enhanced recovery is very appealing. It's very popular in colorectal and other types of abdominal surgery. But in fact, in my reading of literature, enhanced recovery only works when you're dealing with low-meld patients without a lot of comorbidities. And so a more realistic look is that about a third of the patients are gonna end up either with prolonged length of stays or back in the hospital for long periods of time, however hard you work to get them moving in the first hospitalization. This study from actually Loyola looked at rehab. So inpatient rehab is something that I'm quite pleased to use a lot. And a fair amount of benefit is derived from that. But about half the liver transplant patients are gonna have to go home with some kind of help if they're lucky enough to go home. I'm out of time here, but the only other thing I wanted to comment, which is emerging, is more and more teams around the world are having access to a machine preservation of the liver, whether it's normothermic from Friend and his colleagues and collaborators, as well using the resuscitation of marginal livers, which could be transformative. The hope, the end oxygenation from the Zurich group, as well as the hypothermic machine perfusion, which is now in clinical trials from Guerrera. This is gonna slow everything down and give us more chance to evaluate both the graft, as well as choose the best recipients. It will give us more hours to prolong storage time. In the UK now, they're taking marginal livers and waiting 12 hours. And then if half of them work, they put them in and they have beautiful outcomes. Graft selection, recipient timing. So this could be a game changer. It'll probably take another five to seven years until it's widely available. But it could be really transformative. So a few observations I guess I would sum up with. The candidate pool is changing. The increase in medical comorbidities are the norm. Not just from NASH, but certainly NASH brings a lot of that. The donor pool is changing. And we have increasingly sophisticated challenges in evaluating and supporting organs. And finally, our CNI immunosuppression, which we've all known and loved for the last 35 years, is just not enough. And we've gotta keep working to find better ways to manage patients without these drugs, or with much smaller amounts of them. Thank you very much. Thank you.

liver transplantation

challenges

donor selection

post-transplant care

research in liver preservation