I am grateful to the organizers of the conference to honor me with the Starzl Lectureship. Here are my disclosures. I did not know Dr. Starzl very well. I met him at a variety of ASTS social events and clashed with him at times over organ allocation policy. I did spend time with him when I interviewed for a job in Pittsburgh in 1999. I read a lot of his early work regarding liver transplantation and recommend reading the collection of papers in the monograph, Experience in Hepatic Transplantation, which you can download online. The first description by Dr. Starzl of liver transplant in humans was of three patients in 1963. The first patient bled to death on the operating room table and the other two patients lived for less than three weeks after transplantation. There are many things to put into context in the early experience, such as remembering that all his donors were uncontrolled DCD because there was no definition of brain death at the time. Some of the donors were taken to the operating room with CPR in progress. Dr. Starzl's subsequent description of the first seven patients before 1967, all the patients had survival of less than three weeks. He states that the death of the subsequent recipients were related directly to quote technical surgical accident of one kind or another. By itself, for a surgeon, this statement must have been both humbling and discouraging. This graph demonstrates the outcome of the early experience in hepatic transplantation. As you can see, the first series, all the patients died within a month. The second series had much better survival, but then the third series of survival was again worse. Continued on after these series of cases with the knowledge that he had to improve the technical outcomes must have been daunting. The word passion is derived from the Latin root pati, meaning suffering or enduring. Despite these trials and tribulations, the fact that Dr. Starzl continued on with his work to promote liver transplantation demonstrates true passion and should be a message to us all about overcoming our failures. I'll move on now to my assigned talk about living donor liver transplantation. One of the basic tenants regarding living donor liver transplantation is that we would not perform it if there are enough deceased donor organs available. This is because the recipient benefit as a result of living donor transplant is only slightly better than that of deceased donor transplant, and we are putting a donor at risk when there is an alternative for the recipient. It is important to understand this relationship between the availability of deceased donor liver transplantation and the use of living donor transplantation. This slide demonstrates the relative numbers of deceased donor transplants and living donor transplants between 2006 and 2018. In the United States, you can see that there was a small increase in the number of living donor transplants from 2008 to 2018. As you can see in this slide, which demonstrates the number of living donor transplants since 2000, there was a sharp drop in the number of liver transplants associated with the introduction of the MELD score. While many believe that this drop was secondary to the highly publicized donor death in January 2002, it must be remembered that the MELD score was introduced in February of 2002. This slide compares the living donor number and the days waiting for transplantation. On the left panel, the median waiting time for liver transplantation in the United States took a continued fall after the introduction of the MELD score. During this time, you can also see that the living donor liver transplant numbers decreased. The same basic trend is seen here for pediatric living donor liver transplants that had a fall with the introduction of the MELD and PELD score over time. More support for the concept of the availability of deceased donor livers on the use of living donor liver transplantation comes from parts of the East, such as Taiwan and Korea. Professor C.L. Chen invited me to give a talk regarding living donor liver transplantation at his institution. I felt somewhat inadequate in that his institution had done far more living donor liver transplantations than we had done at the University of California, San Francisco, and he had performed about half the number annually that the United States had had. But you can see in this diagram that the use of deceased donor liver transplantation is very low in Taiwan. This theme is replicated in the annual number of liver transplantations in Korea, where you can see that approximately 1,200 living donor liver transplants were performed in 2009, but only 400 deceased donor transplants were done in that same year. This slide demonstrates the living donor liver transplantations per million population with South Korea doing approximately 23 per million population. Turkey did about 16 per million population. This is to be compared to the United States for deceased donor transplants at 26 per million, while in South Korea the deceased donor transplants were about 8 per million, and you can see Turkey is about 5 per million. To return to the United States, I would like to spend a little time looking at recipient need. It is clear from the A to All study in the United States that living donor liver transplantation decreases a risk of mortality as compared to waiting for a deceased donor transplant. As we can see from this slide, if you combine those patients removed from the waiting list with those patients who died, approximately 35% of the patients in the United States either die or are removed from the waiting list. This is similar to what Allison Kwong found at UCSF when we looked at patients who are listed with MELD scores between 10 and 22, excluding patients with exception scores, including HCC. About a third of the patients ended up being removed from the waiting list for being too sick or dying. The need for living donor liver transplantation is related both to recipient need and donor availability. Despite the apparent need for living donor transplantation, the need is affected by the significant disparity in MELD allocation score across the United States. Here is the median MELD allocation score prior to the institution of the acuity circles. You can see that there is a fair amount of variability. Parsi Aveghefi looked at the use of living donor liver transplantation in the United States in a paper published in 2012. He found that the adjusted odds ratio for living donor transplant was about 36-fold higher in those DSAs where the MELD score was also the highest. I was concerned that this data was quite old and looked to see if I could update it. If you go to the Scientific Registry of Transplant Recipients website, you have the ability to compare each center to the national rate. They use a 5-bar system with 1 bar being the worst and 5 bars being better or best. You can then sort the data on a variety of parameters. For example, here I sorted based on the number of living donor liver transplantations in one year. You can see the hospitals that perform the greatest number of living donor liver transplantation. This slide shows this information regarding the centers that performed the most living donor liver transplantation in the last year. You can see that approximately 26% of the total number of transplants done at these programs were living donor transplants. This excludes programs with less than 20 total adult transplants. In this slide, I sorted the results by those centers that have the greatest access to deceased donor transplant. You can see that all these centers have 5 bars. If you look at the number of transplants that were living donors, only 11 out of almost 1,300 or less than 1% were living donor transplants. In this slide, I sorted by those centers who have the least access to deceased donor transplants. It's somewhat surprising that their rate of living donor liver transplantation was less than 10% compared to the 26% of those centers that perform the most living donor transplantation. This is also true for the second worst tier access where the living donor percentage is about 12%. This suggests that there could be expansion of living donor liver transplantation within the United States for those centers that have trouble getting access to deceased donors. The next slide compares the median MELD score transplantation both before and after the implementation of the Acuity Circles allocation plan. While there are some changes, it is not clear that these changes will increase the local need for liver transplantation enough that centers will take up or increase living donor liver transplantation. One can imagine the opposite scenario where the increased availability across the United States could decrease the need for living donor liver transplantation. I do not think that the latter scenario is likely. The emphasis on allocation policy is to bend or provide livers for those patients who are most likely to die, i.e., have the highest MELD scores. As can be seen in this slide, the mortality for patients of MELD scores greater than 35 has been steadily falling related to changes in allocation policy, and I expect that this will continue. This slide demonstrates that the median MELD score has continued to rise in the United States. As most living donor liver transplants are performed in patients with relatively low MELD scores, the allocation of deceased donor livers to patients with progressively higher MELD scores will increase the number of patients with lower MELD scores waiting for transplantation. The patient's MELD scores for living donor transplant tend to be in the high teens and low 20s, but these still have a significant risk of dying or being removed from the waiting list for being too sick. An ongoing concern with living donor liver transplantation is donor death. Typical estimates for the risk of donor death is one to two per thousand donations, which can be compared to the risk of death with other altruistic acts, such as donating a kidney or donating bone marrow. Bone marrow. Data from the SRTR looking at donor death since 2002 demonstrates that there has been four deaths in the United States over this period of time. This slide demonstrates that there have been no deaths between 2011 and 2015, and one death between 2014 and 2018. I have been told that there have been no deaths in 2019. If we consider the total experience of living donor liver transplantation from 2002 to 2019, this would mean that there were four deaths out of almost 5,700 transplants, or a death rate of about one in 1,400. Given the recent 10-year experience where there was one death out of about 3,000 living donor liver transplantation, this would put the risk of death similar to the risk of death associated with donor nephrectomy. Obviously, these results can change over time, and it's hard to know that the risk of one in 3,000 is different than one in 1,400 or one in 1,000, but it's probably different than the one in 500 previous estimates. It is important to remember that as healthcare providers, we are quite risk adverse in regards to the donor's risk of death. This interesting study from New Zealand was performed on patients who were in the orthopedic clinic who answered a survey. The authors noted that the generally accepted risk of death to the donor in adult-to-adult liver transplantation is about 0.5% or one in 200. The mean acceptable risk of death in this study was 51% or 100-fold higher. There have been other studies that have suggested the same result, and it is important to remember this when we're talking to our donors about their risk of death. I now wanted to move to my enduring suffering, which is biliary complications. Biliary complications remain the most common complications in the body. The most common complication after living donor transplantation. Many years ago, Jim Pompaselli, Liz Pomfret, and I decided we wanted to look at biliary complications comparing the UCSF to the Lahey Clinic complication rate. Though the three of us were friends in our discussions, it was clear that we did biliary anastomosis differently. Mark Melcher wrote this paper, which compared 69 patients from the Lahey Clinic with 75 patients from UCSF. There were no differences in the rate of stricture or leak despite different methods of biliary anastomosis. This slide demonstrates the basic overlapping lines of the freedom from biliary stricture over time between our two institutions. Like many of us, I've tried a variety of interventions to try and decrease the risk of biliary complications. The problem with these interventions is that we can only look at them serially, and we don't have the numbers to have the ability to randomize patients. In centers where the numbers of transplants are in the hundreds each time, the ability to answer a number of these questions would be much better. Trying to answer questions like this in the United States, even with consortiums of transplant patients, is going to be hard to develop randomized trials. You can see from this diagram some of these interventions that we have made. Some of these interventions that we have made at UCSF over time, we moved to the use of a completely internal biliary stent placed at the time of transplant for those patients undergoing duct-to-duct anastomosis. The thought is that this is similar to what is done with the RCP, where stents are placed to manage bile leaks. Another intervention was to move to a steroid sparing regimen with the thought that the effect of steroids on healing the bile duct may be important, but also reflected a general dislike of steroids in transplantation. My most recent intervention was to minimize the number of sutures that I used in the anastomosis. This slide demonstrates the percentage of biliary complications over a five-year period as compared to the number of transplants per year. You can see the time points when we did the interventions, such as routine stents, steroid sparing, and minimizing the sutures in the anastomosis. Hopefully, in 2020, we have seen a step forward and a decrease in the number of biliary complications, though it would be of concern that we are just not seeing complications because the timing in the most recent transplant is too late. So, we have to be very careful too short. You have to remember that the median range of our biliary complications in terms of anastomotic stricture is 133 days, and leak, the median range is 24 days. So, we should be seeing at least the leak complications at the current time. Another topic that I'd like to talk about that we had experience with recently was non-directed donor chain initiation. We had a woman who came forward to be a non-directed donor. We had a woman who came forward to be a non-directed donor. She was a blood type O, and we had had a recipient who was a blood type O who had a donor who wished to donate who was blood type A. This would have been an incompatible transplant, but we did have the non-directed donor donate to the recipient of the blood type O, and the recipient's donor, which was blood type A, donated to a patient off the waiting list who was of blood type A. Non-directed donors are interesting in that there have been a total of 105 non-directed liver donors between 1988 and 2019 in the United States. In 2019, you can see that there are almost 40 non-directed donor transplants that occurred. This is similar to the trend that is in living donor kidney transplantation where there has been an increase in non-directed donors and also an increase in paired donation. Although living paired donation is not a new concept, it is an interesting concept that arises from the widespread uses of exchanges in kidney transplantation. Donation allows for expansion of the donor pool and has advantages over ABO incompatible transplantation. In kidney transplantation, donor exchange has almost replaced ABO incompatible transplantation. In living donor liver transplantation, paired donation has the opportunity to expand the donor pool, not only for ABO incompatibility, but potentially for inadequate graft volumes or with non-directed donors. MUNOS is developing a pilot program in living donor exchange that has been led by Ben Samstein. This would be similar to the kidney donor exchange programs where multiple centers would find potential pairs where exchange would be beneficial. Exchanges between the transplant centers would be done with the donor operations being done, say, in the morning at both institutions, and then each center would send the donor graft off to be transplanted and the recipient operations would be done after transport of the organ to each center. This has the potential of decreasing the resource needs that are necessary to do exchanges within a transplant center where two donor operations would need to be done simultaneously in the morning and two recipient operations simultaneously in the afternoon. I would like to thank the ASLD and the organizers for letting me give this talk. It is a great honor. I hope that I've been able to show some of the current state of living donor liver transplantation in the United States, plus some potential changes that we can make to improve this operation. I believe that we have decreased the donor risk, at least in terms of mortality and probably in terms of morbidity. We also are starting to decrease the complications in the recipients. Transplantation is a team sport, and I would like those who have been so helpful. This includes those who have helped me with this talk and other research topics, some of which I've described during this talk, and then also my clinical partners with living donor liver transplantation. Thank you.

Starzl Lectureship

liver transplantation

living donor liver transplantation

donor availability disparities

biliary complications post-transplant

non-directed donor chain initiation