So, thank you. I want to thank the organizers of this course for inviting me to speak at this session. This is a topic that I have devoted a significant portion of my research and advocacy career to. And in this process, I have come in contact with and gotten to know many passionate advocates in the field of transplantation. It's been such a privilege to work with these colleagues and to understand the wider challenges in transplant that face all of our patients who find themselves waiting for a liver. As John says, if you're considering value, children have superior long-term outcomes. But what I want to touch on today is the reasoning and the justification on top of utility for priority for kids. The basis by which we think that prioritizing children for transplants actually benefits society as a whole and how we've laid out the ethical basis for that, and then really the gaps in which we can obtain our outcomes and be holding to those ethical principles in liver transplantation here in this country. So here are my disclosures. Let's talk about the current state, which is that children die on the liver transplant wait list despite the fact that they have excellent graft health and they have excellent long-term outcomes. Here in the United States, they're increasingly disadvantaged in our allocation algorithms. And at the same time, we have simple ways in which we can get closer to eliminating pediatric wait list mortality and really optimizing our long-term outcomes without significantly impacting adult wait lists and post-transplant outcomes. The tragedy of the commons is such that although the numbers of children requiring liver transplantation, and that's represented by the red line on the bottom, has remained the same for more than two decades, the number of older adults on the list have increased in linear fashion. So we transplant the same number of kids in this country every year. It doesn't go up. It doesn't go down. And really, it's about how much later are we waiting before they're getting their transplants. I often get the question, why? And why are children more deserving of organs than an adult? And I think of deserving as a really emotionally charged word. It's not that they're more deserving. And I think the question is, how do we want to dispense our resources in a way that that's the best use of our resources for all of society? So there are ethical arguments and a basis that exist for prioritizing children for liver transplant. They extend beyond that of optimizing long-term outcomes. They really state what is best for society, and they've been codified in multiple forms. So the Declaration of the Rights of the Child, whereby the United Nations General Assembly asked of its members and stated that the child, because they have physical and mental immaturity, they need special safeguards and care, including legal protection, and that mankind owes to the child the best it has to give, that we have to give our resources to the people who can't speak for themselves. And we should enable them to develop physically, mentally, morally, spiritually, and socially in a healthy and normal manner, and that we should enact laws and, in fact, policies to consider the best interests of the child. This has also been codified by the United Network of Organ Sharing Pediatric Transplantation Ethics Committees, where they provided guidance about how organ allocation policies should address pediatric patient needs. They provided these justifications that are really for the benefit of all of society. And I'm going to just touch on a few of these things as they help to set the groundwork for why we make decisions and make allocation policies the way that we do. So the first one is the Prudential Lifespan Account, which in a bigger scheme of things says that you have this limited group of resources, and you want to invest those resources across one life with a goal to make that life go as well as possible. Children with end-stage organ failure have this time-limited opportunity, and we call it quality of life, but I think it's very different quality of life in children versus quality of life in adults. Quality of life in children translates to lost opportunity for growth and development and actually to suffering lifelong consequences if we don't expeditiously transplant them. So it's very different than when we think about quality of life in an adult. So you have a life, and it starts with birth, goes through childhood, adolescence, young adulthood, during which time you're completing schooling, physical and social development, which then lay the groundwork for having and raising children and developing a career into the long-span middle age, and then retirement. And you ask, where do we want to put all of our dollars if we're going to invest in this lifespan? Do we want to put it after retirement, or do we want to put it where all of the basis will lie so that we can extend and serve a very, very high productivity for the person? The fair innings argument is that each individual has a right to experience a full life, and that children who die prematurely are denied opportunities in adulthood to complete their education, establish a career, and have a family. So really, cutting short that life in a full one is not fair, and that everyone should have kind of the equal opportunity to experience a full life. The maxim in principle is that of which you're giving the most benefit to the least advantaged members of society, maximizing the minimum benefit to the least advantaged, or giving the priority to the most disadvantaged groups. And it states that societies are judged insofar as they improve the lot of their worst-off group, and the priority should be in reducing gaps between the worst-off and the rest of the population. So this goes back to how John was talking about value. If you're increasing value, you really want to try to standardize and improve overall disparity across society. Pediatric candidates are disadvantaged. They are small in size, they have developing anatomy, and they do have a lack of availability of life-sustaining therapy. So things that are available for adults for sustaining life are not available to children. And I would make the argument that pediatric candidates are disadvantaged across all those things that disadvantage all the people in our system. So if you are poor, or you are non-white in this country, you experience disparity. These things are amplified, and they are amplified in pediatrics when there's already existing disadvantage. And then the final principle, which is that of utility. It's been commonly shown that pediatric liver recipients have better patient and graft survival than adult recipients. The most recent U.S. National Database statistics continue to show that long-term graft survival is far superior in pediatric recipients of liver transplant, and it's improving over eras. So that the 10-year survival of children transplanted before 2010 approaches 75%. And you can see in this graph on your left that it's on an improving trajectory. Adults on the other hand experience 10-year graft failure rates nearly double the failure rates in children. And with the shifting indications for transplant, we may not see the same improvements over the coming decades. When we talk about just within children, are we allocating correctly? I think that that's a valid question, but really the overwhelming majority of liver transplanted children are done for diagnoses that never recur. So hepatoblastoma, which can or can't have worse outcomes, accounts for in fact a very small proportion of our patients, and the vast majority of our patients have very good consistent outcomes. So once we get children to survival, the question of how to measure long-term quality outcomes for children comes down to ideal outcome, which encapsulates other aspects of long-term outcome, including life without cancer, renal failure, or rejection. But really given our current wait list challenges, if we adequately allocate for pediatric wait list survival, long-term outcomes will have the potential to improve for all children on the wait list and post-transplant. So this is our patient, CJ. CJ, this is him after his transplant, but he had biliary atresia, and he was at the highest priority, status 1B for a child with BA within our region. And before his transplant, he bled from varices, he needed a Blakemore tube twice, he was intubated, and he was on dialysis before and after transplant. He waited months before he was able to receive a technical variant to seize donor graft, and his outcomes post-transplant, with the exception of a course of extended HD, have been excellent. But not every child is as lucky as he is, and our team was very worried about him surviving because we all know that in the United States, children die waiting for liver transplants. Between 7% and 12% of children on the liver wait list die every year, and it's the smallest children that have the highest death rate on the list, exceeding that of adults. And this hasn't improved over the last decade. Children who survive now are sicker at the time of transplant. A large proportion of them are being transplanted and now the PELD score is above 35, and it's status 1A and 1B. Exception scores continue to rise, and they rise in geographically disparate ways. There's these non-standard exception requests that are becoming the majority of the ways that we're able to elevate PELD scores for our children. And when my colleagues at University of California San Francisco looked at these narratives, we showed that there weren't really any aspects that were predictive of approval, denial, or survival. But at the same time, we know that having exception is associated with nearly three times the rate of transplantation, as well as with survival preceding and post-transplantation. And this is even more concerning, as we know that exceptions are applied in geographically disparate ways, and they're applied in economically disparate ways, and they're applied in racially disparate ways. So we know that these issues are amplified across the courses, and that by not advocating for these children, we're actually not advocating for those who require the most voice, who are the most voiceless among them. So the children who are dying are poor and they're less resourced, and a lot of the children that we care for are poor and less resourced. On top of that, we know that PELD underestimates the pediatric weightless mortality when compared to adults, and it disadvantages all children as they wait, necessitating this artificial elevation of their score that we're not applying in an equitable way to all of the children. On top of all of that, the current system that we have deprioritizes children for the organs that they need the most. In this country, adults get livers from children rather than the other way around. Under the current allocation system, if a liver from a pediatric donor becomes available in a region or DSA and there's no pediatric recipient in that region, every single adult with any MELD listed in that DSA or region would come before critically ill children listed nationally, even in adjacent DSAs or region. So livers from children are being offered to every adult in the region before they go out of region to 1A children older than 12 years and all 1B children. So this leads to potentially 100% of some of the pediatric donors in some of these states and regions and DSAs being allocated to adult recipients. And you kind of look at this, and it all matters of whether or not we go out of region or not, whether or not there's a pediatric recipient within that region, and where these organs are going. And I think that these, you know, truly I think that there are unintended consequences of these allocation policies. So, you know, the number of these donors have remained stable to slightly decrease, and this is kind of the purple line represents the pediatric donors. But they account, and they don't account for the majority of total donors to all recipients, but they account for 80% of the livers that are transplanted into children. So these are the organs that we need for kids and that are not being allocated to kids properly. So the consequences of this is that in work done in collaboration with my fellow speakers and Dr. Jenga of the University of California, San Francisco, we found that in a five-year period where more than 1,500 adults received a liver transplant from a pediatric age donor, almost 300 children died or removed for being too ill while waiting. And then 25% of the adults were transplanted with a donor that was never offered to a child. The majority of these donors were adolescents, and the majority of the adult recipients were not of high acuity. And at the same time, 278 children died or removed for being too ill while waiting. And then with post-transplant outcomes, we could show that compared to adult recipients, pediatric recipients under 12 years of age transplanted with these organs had a 38% lower risk of post-transplant mortality in multivariable analyses. So I argue that prioritizing children for pediatric disease donor livers nationally could reduce or eliminate pediatric liver waitlist mortality. So this would put critically ill children listed nationally above those adults with any MELD listed locally and regionally. And this would have really pretty small impact on the adults in this country. But at this particular moment in time, access to liver transplantation for children is becoming even more challenging. As we established earlier, 75% of children now are transplanted with an exception score. Before the implementation of the PEDS NLRB, this was a 90% exception approval rate. And that was important because all of these children required exceptions in order to be transplanted. And now post-PEDS NLRB, this has dropped to 60%. I think that this is related to wanting to have a more consistent basis for exception scores, but I think that this is inadvertently going to lead to a decrease in our transplantation rates and an increase in death for children on the waitlist. Our allocation algorithm continues to disadvantage kids. So I just want to point out that the global standard of care is to put children at the front of the line. And in work that George Monserriegos and I did from several years ago, we surveyed our colleagues across the world to see how they prioritize children or incentivize splits. We talked to our colleagues in France, the UK, Spain, Italy, the uro-transplant countries and in Switzerland. So just to go stepwise, in France, donors under 30 years of age are first proposed to pediatric liver teams to encourage splitting, and they have access to emergency status with limited waitlist time for children. In the UK, children are prioritized for all donors under the age of 16, immediately after, of course, their super urgent local and national patients. And also donors under the age of 40, more than 50 kilos and a lower intensity of illness are prioritized for splits. In Spain, donors less than age 16 are offered to children first. In Italy, donors under the age of 18 are offered to children first, and there's more. Donors age 18 to 50 are allocated and offered to pediatric centers first to decide split feasibility. In the uro-transplant countries, children age 16, years and under, receive an allocation equivalent, so they receive an increased score with an automatic 15% monthly increase. And then they are designating donors for splits. And then in Switzerland, the liver can be split if the patient with the highest priority consents to the split, and then donors that are pediatric are offered to children first. So what are the results of prioritizing children or having a mandatory split policy? The Italian group published their experience wherein they had shown that they're prioritizing splits or mandating splits, and they showed that median time on the liver transplant waiting list for children reduced from 229 days to 80 days. Mortality decreased from 2.5% on their list to 1.8%. And then really drastically, they found that they were having a donor every two days offered for split to the pediatric liver transplant waiting list, and they were doing one split graft per week accepted. So I really do believe that we could prioritize children without significant impact to adults, and we showed this in LSAM modeling through the Society of Pediatric Liver Transplants Sharepede's task force. Waitlist deaths in infants and children significantly dropped under proposed schema that prioritized children, and these deaths dropped without significant impact to adult outcomes. My colleagues have done modeling that shows that similar increases in pediatric survival would occur if there's better utilization of split grafts. But really, unless there's a mandatory splitting policy or prioritization of children, the only way we can achieve better utilization is by prioritizing kids for these organs. So after transplantation and initial survival, our goal is ideal outcome for our pediatric patients. When determining factors that predict ideal outcome, we found that the strongest predictor, in fact, was race, which continues to suggest that any one disparity in our system is likely to be amplified over the stages of transplantation from pre-listing to long-term outcomes, and that we really have to continue to speak for those that are voiceless and disenfranchised when we advocate for children. So fighting for change on behalf of children is reminding the country and our colleagues that alternatives that are fair, equitable, and improve pediatric waitlist outcomes without significantly impacting the adult waitlist do exist. Improving pediatric long-term post-transplant outcomes ultimately improves adult waitlist outcomes, and we need to advocate in our community and correct misinformation at every step that we can. We can do this through just reminding society and our parent advocates and our colleagues that children are the world's most valuable resource and its best hope for the future. This is really coming down to the fact that the ethical bases for pediatric priority exist, and they have been outlined in a way that prioritizing children benefits society as a whole, but I really do want to acknowledge and thank the ASLD for supporting this session and the organizers for recognizing this important topic and giving it much-needed airtime. None of this would be possible without my colleagues and my partners that are listed here. They've all played a prominent role and continue to speak up and advocate on behalf of children, but most of all, I want to thank the pediatric liver transplant patients and families, some of whom are pictured here from the split meeting a few weeks ago, who continue to remind me and my colleagues never to give up and to continue to fight. Thank you.

children

liver transplants

prioritization

ethical justifications

pediatric transplantation