Hi, I'm Jim Finlay, and on behalf of myself and my co-chairs, Kim Watt and Dennis Balchi, I'd like to welcome you to this year's AASLD ILTS transplant course. Under the overall title, Optimization to Transplant Care, we have three excellent sessions planned for you. Session one is Enhancing Access to Transplant. Session two covers perioperative risk assessment and management. And session three will focus on the 10 years after transplant. And finally, don't forget to join us for the live question and answer session with the presenters and the chairs present. That will be on Monday, November 16th, from 2 to 3.30 p.m. We hope to see you there. Hello, my name is Mark Gattrell. I'm going to be giving a talk on living donor liver transplantation in the critically ill patient. I am a transplant surgeon at Toronto General Hospital. I've been with this program since 1993, and I am currently the surgical director of the Living Donor Liver Transplant Program. I have no disclosures to make. I have two learning objectives. The first is to understand the role of living donor liver transplantation in critically ill patients. And the second is to understand the requirements to perform living donor liver transplantation successfully in this population. Living donor liver transplantation has been with us now for over 30 years. The foundation for this surgery was provided by Bismuth and Picklemeyer, who reported the first reduced size and split liver transplant respectively. Live donor liver transplantation was originally developed to treat babies with liver failure. The first successful live donor liver transplant was reported by Russell Strong in Brisbane, who transplanted a left lateral segment graft into a baby with biliary atresia. It was then extended into the adult population by several surgeons in Asia. Mukuchi reported the first adult left lobe transplant in 1993. Fan from Hong Kong reported the first adult right lobe transplant. And Dr. Lee reported the first dual live donor liver transplant in 2000. The rationale for a live donor liver transplant is summarized here. We know that in the donor, the liver remnant will eventually return to full size and full function. In the recipient, we know that the liver graft will ultimately restore full function. And underpinning the procedure are the principles of beneficence, autonomy, and justice. To date, somewhere between 35,000 and 40,000 living donor liver transplants have been performed worldwide. It has flourished in the East, and it has grown significantly in India, Saudi Arabia, and Turkey. It has remained relatively uncommon in the West. In the United States, the number of living donor liver transplants performed increased significantly in the late 1990s and peaked in 2001, at which point it represented about 10.1% of all liver transplant activity. Following this, the numbers dropped precipitously. And this was attributed to two main factors. One was the introduction of a mail system for the allocation of deceased donor livers. And the second was a well-publicized living donor death in New York City. It has remained relatively uncommon until recently when a number of programs started to increase their activity. In 2019, living donor liver transplants accounted for about 5.9% of all activity in the United States. And this year, it looks like the numbers will be somewhat similar. In our own program in Toronto, the first living donor liver transplant was performed in 1996. The adult program began in 2000. And since then, we've done close to 1,000 living donor liver transplants. Overall, they account for about a third of our activity. And we typically perform somewhere between 50 and 70 a year. This year, we may do 80 despite COVID. There are a number of advantages to a living donor liver transplant. First of all, the wait time is shorter. And this results in a lower risk of weightless mortality. In our own program, we know that the LDLT recipients have about a 20% to 25% survival advantage. In general, the quality of the LDLT graphs are better. We also know that we're able to transplant patients before they become too sick. And this results in a much faster rehab. A number of years ago, the A2L group published the outcomes of patients who had LDLT versus DDLT. And whether the patients had a higher or lower mental score didn't make any difference. They always did better than the DDLT recipients. There is a problem of view that living donor liver transplantation should only be performed in low-risk recipients. We should first of all define what is a critically ill or high-risk recipient. Most of us would define this as a patient who has a high male score and a general cutoff as being a male score of 25. Patients with evidence of hepatorenal syndrome would be considered critically ill or high-risk, as would patients who have evidence of fulminant liver failure. Several concerns have been raised about proceeding with a living donor liver transplant in the critically ill patient. Some believe that a living donor graft is too little too late, resulting in an increased risk of graft failure and recipient death. Some are also worried about the compressed evaluation in the donor, which may lead to stress as well as coercion, and insufficient time for reflection, which might result in an increased risk for a poor decision and an adverse outcome. And some believe that the aging experience may not be applicable or replicable in the West. I'm going to show you data from our program, which should help dispel some of these concerns. In 2010, we published a report that looked at our experience in patients with a high male score. At this point in time, we had transplanted 44 patients with a male score greater than 25 and 227 patients with a score less than 25. The high male recipients represented about 16% of our activity. And as you can see here from the graft survival curve, there was no significant difference between these two groups of patients. I recently looked at our own experience in the super high male patients, that is male scores of 35 or greater. 27 of our recipients had received a living donor graft and 190 had received a deceased donor graft. And you can see from the survival curve that there was no significant difference in these two groups of patients. We've also looked at living donor liver transplantation in the setting of a paderino syndrome. In this study, we compared 30 patients who received living donor grafts versus a matched cohort of 90 patients who received deceased donor grafts. As you can see, both groups of patients were quite sick. Based on their INR, grating and bilirubin, the male transplant was high at 31. About a third of the patients were on dialysis prior to the transplant. When you look at graft survival, there is no significant difference between the two populations of patients. And when you look at return of kidney function, again there is no significant difference. And in fact, only one patient ended up on dialysis long term and that patient had received a deceased donor graft. We have looked at living donor liver transplantation in patients with fulminant liver failure. The study period was between 2000 and 2014. During that time period, we had listed over 1,100 patients for liver transplantation, of whom 46 had fulminant liver failure. Thirteen did not receive a transplant and all of these patients died. Thirty-three did receive a transplant. Twenty-six were deceased donor grafts and seven were living donor grafts. The demographics of these patients are summarized in this table. They were similar in all respects. Both groups were very sick, as shown by their high bilirubin, high male score. Over two-thirds of them were in the ICU on mechanical ventilation and many of them were on inotropic support. As you can see here from the survival curves, there was no difference in patient or graft survival. Since that study was published, we have transplanted five further patients with fulminant liver failure, all of whom have done well. Recently, the Pittsburgh group reported their experience in high-risk recipients. As you can see in this table, patients who had a male score above 25 had a similar outcome whether they received a living donor or a deceased donor graft. This table also shows the outcomes in patients who received re-transplants, another high-risk group, and again, there was no significant difference between the patients who received living donor and deceased donor grafts. For the next part of my talk, I'm going to be reviewing the requirements for the successful living donor liver transplant in the critically ill patient. I'm going to begin by looking at the graft. One of the concerns with a living donor graft is the potential of small for size syndrome, which is characterized by high levels of bilirubin, INR, ascites, the potential for graft failure and the need for liver re-transplantation. A number of years ago, Amadeus Markles looked at the main determinants of graft function. So in addition to graft size, the degree of portal hypertension and the adequacy of venous outflow are also very important. There are a number of techniques available that can be used to modify portal inflow, including splenectomy, splenic artery ligation, as well as portal vein banding and shunts. There's also techniques available to optimize venous outflow. The other factors that have to be considered in determining functional mass is age of the donor. Older donors are thought to have a reduced potential for regeneration, and the other factors include steatosis and graft fibrosis. To give you an example of the impact of graft size, I'm showing data from a paper that was published a couple of years ago that looked at left low grafts, which are generally much smaller than a right low graft. In this study, they found that the one-year graft survival was 59%. Urgent re-transplantation was necessary in over a quarter of the patients, and this was generally due to small for size syndrome in combination with hepatic artery thrombosis. And they identified a number of risk factors for graft failure, donor age greater than 45, a MELD score greater than 14, and a graft recipient weight ratio less than 0.6. So in general, left low grafts would not be sufficient for most patients who are considered critically ill. As far as venous drainage is concerned, it's important to make sure that segments 5 and 8 are well-drained. There are a number of techniques that are available today. Most groups have moved away from taking the middle hepatic vein from the donor and have used either vein grafts or blood vessel substitutes, such as PTFE, to drain these segments. As far as portal vein pressures are concerned, in general, you'd like to aim for a portal vein target pressure of less than 15. In some cases, this may require various surgical techniques that I described earlier, such as a portal vein shunt. So in summary, in high-risk recipients, you should aim for a graft recipient weight ratio of greater than 0.8. You need high quality parenchyma, and therefore, I would restrict the donors to an age less than 50. They also must not have any steatosis. And you need excellent venous outflow, and you should aim for a portal venous pressure less than 15. In Asia, there is a large experience in transplanting living donor grafts into high-risk recipients. Last year, Oh and colleagues wrote a paper and discussed the essential elements of a successful living donor liver transplant in this population. So the three main factors that they considered were the quality of the graft in terms of size and venous drainage and steatosis. They also thought that it was very important to identify futility. And as a rule of thumb, I would say that if there's any doubt in your mind as to whether the patient would survive a deceased donor liver transplant, you should forget about considering a living donor transplant. The third essential element was experience, and they focused on the surgeon. But as I believe it actually is the experience of the entire team, which includes surgery, hepatology, anesthesia, intensivists, infections, disease, as well as our allied health colleagues. So this brings us to a very important question. Who should perform high-risk living donor liver transplants? Should it be every setter? Should it be limited to a few setters? In general, we know that in highly complex surgery, volume and experience matters to the outcome. And we all, in all our considerations and deliberations, we must be always very mindful of the impact of our decisions on the donor. A living donor graft is a precious gift. It restores health, saves lives, but it must be used judiciously. We must carefully balance recipient benefit with donor risk. First and foremost is donor safety. And this not only includes physical safety, but psychological safety. I can say from our own experience that when a recipient dies following a living donor liver transplant, it has a huge negative impact on the donor. And this is one of the main reasons why we have to avoid futile transplants. So here are the key takeaways from my talk. I believe that a living donor liver transplant can be successful in critically ill recipients. But whether one proceeds with a living donor graft depends on a number of factors. First of all, you need a high quality graft. Secondly, you have to have the experience to perform this successfully. And third, you have to decide whether it's actually necessary. If you happen to be lucky enough to live in an area where there's a large number of diseased donors and the wait times are short, then there's probably no need to do a living donor liver transplant in this setting. I believe that experience matters. I think it's important to avoid futility. And it's always important to remember that donor safety is paramount. Thank you for your attention. I look forward to answering any questions that you might have. Thank you. Good morning. It's an honor for me to participate in this ASLD-ILTS virtual transplant course on the topic of using grafts with chronic viral infections. This is my background. These are my disclosures. In recent years, we've seen a substantial increase in increased risk donors based on epidemiological and clinical data, with a rate of 8.9% in 2010, increasing to 26.3% in 2017 in the U.S. Interestingly, there were no substantial changes in surface antigen positivity, anti-core positivity, or HIV antibody positivity. In contrast, there was a substantial increase in anti-HCV positivity, increasing from 15.9% to 21.6%, also with a parallel increase of varemic HCV RNA positive donors. Transmission is the norm if these viruses are varemic in the donor. We all know that the length of window period for all these different blood-borne viruses is different. And in particular, we need to understand that when we're using serological testing, the serological window is substantial for all of these viruses, whereas when we use biological tools, there's also an eclipse window where we can't miss the detection of the virus in the donor, and yet transmission may be possible. Today, I would like to talk on HCV positive donors, HBV positive donors, and HIV, just a minor point on HIV positive donors. I will start with HCV positive donors. In the US, there's been an increasing use of HCV positive organs in liver transplantation. This is data from the Scientific Registry of Transplant Recipients, and as you can see, the percentage of donors who are positive and who receive the percent of recipients who are either negative or positive and who receive a donor positive is increasing in recent years. And in fact, donor antibody positivity was 3.7% in the pre-DAA area, and it has increased to 7.1% in the post-DAA area. And most importantly, the use of these donor antibodies positives in recipients positive has increased in these years, but also the use of these donor antibodies positive use in recipients who are negative. And also, there has been an increase of these donors who are not only antibody positive, but who are viremic and who are being used in recipients negative. And what are the circumstances that have led to the expansion of this strategy? Well, I think the most important one, and as we all know, is the availability of highly effective antiviral drugs that can be used post-transplantation with very high success rates. In addition, with the use of these drugs, we have fewer and fewer HCV viremic recipients on the waiting list. This is clearly, and it's been shown to be a potential life-saving procedures. It's also been shown, particularly in kidney transplantation, to shorten waiting time. And as we will see, it's been shown to be associated with higher organ quality, as I will show just in a few minutes. And in addition, due to the opioid epidemics, there's been a significant rise in HCV viremic donors. But I would like to mention and to highlight that this is just seen in some parts of the world, but not in all countries. This is the data on the higher quality of donors in recent years. And again, I'd like to highlight that this comes data from the United States. And as you can see here, there was a marked decline in donor age among donors who were HCV positives. And in fact, this is related to this opioid epidemics with these donors being younger and thus with more recent infections and thus less likely to have liver fibrosis. And in fact, the discount rate in HCV positive and HCV negative donors was almost the same, reached the same number in 2016, with a marked decline in discount rate of anti-HCV positive organs since 2011. And this reflecting either the high quality of the donors and or the availability of DAA therapies. What is the published experience using all these graphs from viremic donors to non-viremic recipients, both in kidney and liver and heart and lung transplantation, where there's been an abundance of articles, particularly in more recent years. And overall, the results have shown that this is a beneficial, this is extremely efficacious. And while there is transmission of the virus, treatment post-transplantation is associated with, generally speaking, 100% SVR post-transplantation in many of these reports. In fact, in the two studies, longer studies, both in liver and kidney, in liver transplantation, it's been shown that two-year growth survival was the same regardless of the use of this donor positive including viremic donors. And the same has been shown in kidney transplantation in this large OPT-N study, where it was shown that H viremic, the use of these viremic donors, was associated with lower delayed graft function, also better allograft function at six months post-transplant, and similar graft failure risk at 12 months post-transplant. Where there is some controversy is on timing of HCV treatment. This treatment may be started preemptively to prevent infection. However, this might be tricky to give because of complications in the early post-transplant period. Liver function and renal function are less stable. And thus, in addition, there is a small chance you treat unnecessarily. The second option is to treat when viremia is confirmed to prevent disease development. But there may be a small chance to have a severe HCV before the use of DAA. I think the data in the literature shows that in the case of the liver, we tend to use a delayed treatment in contrast in case of other organs, particularly kidney, there is a trend to use a preemptive approach. And this was a very important study in kidney transplantation, showing really ultra-short term perioperative pangenotypic DAA prophylaxis used in these cases, using either one dose pre and post or one dose pre and three doses post the first three days post-transplantation, and showing that there was a transmission of the virus, but which was significantly reduced, particularly when four doses were used. And so, in fact, the four-day strategy reduced viral transmission to 7.5% and could result in avoidance of prolonged post-transplant DAA therapy. However, this has not been approved, and this is still an investigational strategy. So the key points in terms of HCV, and these come straightforward from this very good review published in General Hepatology from Wayne Farther and Reddy. Despite overall increasing rates of organ transplants, the demand for organs still far exceeds the supply, and HCV infection is still a reason for discarded organs in some areas. The advent of this very highly effective direct and acting antiviral therapies has really led to the rise in the utilization of organs from HCV viremic donors in HCV non-viremic recipients. Preliminary data suggests high rates of HCV transmission to recipients when we use these viremic donors, but then this can be effectively prevented and particularly treated in case of liver transplantation with a variety of different DAA regimens. We need no more data to determine the most efficacious and cost-effective DAS strategy, whether preemptive, whether delay, the incidence of treatment relapse and failure as we use more as this strategy may be expanded, and potential long-term complications. I would like now to move to HBV, and when I will touch upon the use of anti-co-positivity organs, a practice that has been in place for many years, and more recently and particularly in Asian countries, the use of surface antigen positive donors, even sometimes in surface antigen negative even sometimes in surface antigen negative recipients. So, in terms of the pool of potential donors, this is data showing really the rate of anti-co-positivity in different places of the world and surface antigen positivity in different areas of the world. And as you can see, in Southeast Asia and Africa, this is a very prevalent infection, and discarding organs from donors who are either anti-co-positivity but also surface antigen positive may result in really a significant loss of potential good donor, good grasp with good quality. As I mentioned before, we've been using anti-co-positivity positive donors for a long time. And so, here we show the relationship to HBV serological status before liver transplantation. So, the rate of acquiring de novo HBV based on HBV serological status before liver transplantation in the absence of HBV prophylaxis after liver transplantation. This is a study that was published several years ago. And as you can see, when HBV recipient was naive, the risk of acquiring HBV was very high, 50%. This risk decreased substantially when the recipient was anti-co-positive, both anti-co- and anti-surface positive, or when the recipient was only anti-HBS positive. When we use HBV prophylaxis, these numbers decrease substantially, such that in the HBV naive recipients, the risk is reduced from almost 50% to 12%. And in those who are anti-co-positive or anti-HBS positive, the risk is reduced to almost 0% using prophylaxis post-transplantation. This, I think, is a summary of the data that has been accrued so far in liver transplantation with the use of anti-viral monotherapy prophylaxis. This is a study where 964 liver transplants from 2000 to 2015 were assessed. Almost half were anti-co-negative, and the other half were anti-co-positive. And they received organs from both anti-co-positive and anti-co-negative grafts. And particularly, 108 of these grafts were positive or anti-co. Using anti-viral monotherapy for prophylaxis, only no HBIG was used. The authors reported only three de novo HBV infection with a risk of 2.8%, which was reduced to the group of lamivudine therapy. And no significant differences in terms of 10-year patient and graft survival, which was excellent, 80% regardless of the use of anti-co-positive or anti-co-negative grafts. What about the use of surface antigen-positive grafts? Well, this is a strategy that is mostly used in, as I mentioned before, Asian countries. There's been some case reports from 2006 to 2000 and recent years. But in general, these were case reports. And there was a very interesting paper published in Journal Hepatology in 2014, showing similar results regardless of the positivity of the surface antigen of the graft, either positive or negative, with five years of follow-up. And in fact, an editorial following this paper really showed that this was a potential strategy provided certain measures were undertaken, including strict donor selection criteria for the absence of delta co-infection and liver damage and adequate antiviral therapy, as we mentioned also for HCV. There are some differences when you use surface antigen-positive livers and surface antigen-positive kidneys. In both, these surface antigen grafts should preferentially be allocated to surface antigen-positive recipients. In the liver, this could be used in exceptional cases, very high MAP scores, very high risk of death. They could be used in HBS antigen-negative recipients. The same occurs in kidney. They could be used in exceptional cases to immunize surface antigen-negative recipients with high anti-HBS titers. In terms of the outcome, well, the outcome in both instances, liver in orange, kidney in green, it's been used that the use of these surface antigen-positive grafts is safe, and they have comparable outcome even in terms of long-term survival. In terms of prophylaxis, in terms of the liver, there's been data showing that despite the lack of signs of HBV disease and the use of immunoglobulins, most patients will continue to be surface antigen-positive in the long term. Thus, the value of using HPIC remains unclear. And prevention of HBV liver disease can only be guaranteed in these patients, in these recipients, by the use of long-term antiviral prophylaxis with high barrier to resistance. In surface antigen kidneys, there is no role for HPIC. And again, prevention of liver disease can only be guaranteed by the use of long-term antiviral prophylaxis. And we need to make sure that these patients are adhering to this long-term prophylaxis. I will finish with just one slide on HIV. Well, this all started in South Africa with the use of these HIV-positive kidneys in HIV-positive recipients. And the data showed, really, that there was undetectable virus in blood post-transplantation when using adequate treatment with all antivirals and no evidence of HIV superinfection with graft, excellent graft, and patient survival. And in fact, in the US, the HOPE Act really allowed transplantation of organ retrievals from HIV-positive donors to be used in HIV-positive candidates. And there is data now that is being recruited in many of the centers that are using this policy. So my key takeaways messages, the outcome using high-risk donors overall is similar to that what we see using low-risk donors, provided that there is access to new all-antivirals. And this is true for all the viruses. Potential recipients of HCV-viremic, surface antigen-positive, anti-COVID-positive, or HIV organs require a thorough discussion of the pros and cons of these practices with the recipients. And while affinite therapy is only required in those receiving HCV-positive organs, indefinite treatment is needed in case of HPV and HIV. And thus, adherence to all antivirals is essential for the success of these practices in the long-term. I would like to thank you for your attention, and I would like to thank ASLD and ILTS to allow me to present at this meeting. Thank you to the ASLD and the ILTS for the opportunity to present this talk entitled, Heart-Liver Combined Transplant, Does the Patient Really Need a New Liver? Here's my brief biography. I'm a transplant hepatologist at the University of Pennsylvania who does clinical health services and outcomes research. And here are my disclosures. Let's first talk a little bit about the background of combined heart-liver transplantation. Combined heart and liver transplant remains a very uncommon procedure in the United States and worldwide. The first combined heart-liver transplant was performed in the United States The first combined heart-liver transplant was performed in a six-year-old female with familial hypercholesterolemia and heart failure, secondary to coronary artery disease, and this was described by Starzl in 1984. This patient survived eight years. Since then, other early cases have been performed in children for various metabolic indications with poor survival. However, this has quite improved in more contemporary series, as I will show you. This is showing you numbers in the United States, as well as the University of Pennsylvania, which is my institution, from 2010 to 2020. As you can see, there are really not that many combined heart-liver transplantations performed. And for the last 10 years, we have performed nearly 250 in the United States and a total of 34 at our institution. Not surprisingly, these multi-organ transplants are generally done at high volume centers with significant experience. As you can see in the pie chart on the right, only a handful of centers represent nearly half of the transplants performed of combined liver and heart. And you can see my center, University of Pennsylvania, with 36 cases shown here in red. Graft survival has improved after combined heart-liver and is similar to that of isolated heart or liver transplantation alone, with one year survival of greater than 80% and 10 year survival greater than 70%. The three main categories of combined heart-liver transplantation are as follows. Primary heart disease with cardiac cirrhosis caused by hepatic venous outflow obstruction, hereditary transthyretin amyloidosis, FAP, leading to cardiomyopathy. In these situations, liver transplantation is needed to prevent recurrent damage to the cardiac allograft, as well as primary liver disease with concurrent significant enough heart disease where liver transplantation alone cannot be performed safely. Here's some more specific indications for combined heart-liver. As I mentioned, familial amyloid polyneuropathy is a common indication, as is familial hypercholesterolemia, homozygous beta thalassemia, hemochromatosis, decompensated cirrhosis with underlying cardiomyopathies, glycogen storage diseases, and another common category, which is increasing. After surgery for congenital heart disease, predominantly for single ventricle heart disease, or a Fontan procedure. I wanna touch a little bit more about the Fontan procedure, as this is a growing indication for combined heart-liver transplantation in the United States. To put things into perspective, there are currently greater than 900 Fontan operations performed each year for single ventricle heart disease, mostly in children ages two through five. And compared with other congenital liver diseases, there are about 500 to 600 children born with biliary atresia in the United States, half of which will receive an early transplantation. We don't know the exact proportion of Fontan patients that will require liver transplantation or heart-liver transplantation, but we do know that after 10 years of having a Fontan, the risk of liver fibrosis and decompensation increases greatly. It is now estimated that the global population of Fontan patients is 70,000 and is increasing. Unfortunately, we still have limited data on markers of long-term prognosis, how to risk stratify patients, how to potentially prevent any decompensations. And this is an area of ongoing and active investigation. In terms of discussing the pathophysiology of single ventricle procedures and how that causes concomitant liver disease, I will not go into detail in terms of the Fontan surgery, and there are several different types. I do have a reference here provided for you that you can look up after this talk. But in brief, the Fontan procedure is a surgical shunt that diverts blood away from the IVC and SVC to the pulmonary arteries without passing through the subpulmonic ventricle. This causes a chronic hepatic venous congestion, secondary to high-pressure non-pulsatile flow in the IVC. And as I mentioned earlier, a high proportion of liver fibrosis forms just after 10 years after Fontan and sometimes even sooner. Specific estimates are not really available, but the proportion of significant fibrosis ranges from anywhere from 30 to 60 or 70% after 10 years, depending on the series. Liver disease staging and evaluation of nodules, which can be regenerative nodules, perfusional changes, as well as HCC, which does occur in this population, is extremely challenging and is actually a topic for another talk. Emanuele and colleagues put together this very nice algorithm of how they conceptualize a patient with post-Fontan and an algorithm of the outcomes in these patients in terms of at least what's known about them. I would like to direct your attention to the right part of the slide in the red box. And here we have a patient, for example, who is greater than three years post-Fontan, who has developed liver complications, which could be ascites, splenomegaly, thrombocytopenia, PBGI bleeding, jaundice, or other complications of liver disease. This patient does require hepatology referral, transjugular venous biopsy with pressure measurements, and careful multidisciplinary consideration for heart-liver transplantation. Let's talk a little bit about patient selection for combined heart-liver versus heart-liver alone. This is a simplified algorithm put together by a group at the University of Pennsylvania. So obviously it is of utmost importance to have a multidisciplinary team, and actually it's two separate teams, usually the heart team and the liver team that work together to work up these patients. And here I'm gonna talk about patients with heart disease when deciding whether or not a liver transplant is needed. We will leave the topic of decompensated liver disease with concomitant heart disease for another time, and I think in a certain way it's a little bit more straightforward. But let's say we have a heart transplant candidate with either potential cardiac cirrhosis or significant enough concern for liver disease in the setting of significant heart disease. We do a careful evaluation of the patient for comorbidities for other sources of liver disease that are non-cardiac, perform a transjugular liver biopsy with pressure measurement, and this is really to minimize bleeding risk in these very congested livers. If there's no significant liver disease, no significant fibrosis, that patient can proceed to heart transplantation alone. If the patient clearly has cirrhosis or decompensated cirrhosis, this is when, at least in our center, a dual organ transplant with combined heart and liver is performed. Occasionally, the liver status is uncertain. The biopsy could be equivocal. We could have advanced fibrosis, evolving cirrhosis, and it's really not clear whether or not the liver could withstand the stress of a heart transplant or if a liver really does, in fact, need to be transplanted. In these cases, our center performs what's called the peak liver, where we evaluate the liver after the heart transplant and see whether or not that liver does need to be transplanted concurrently. And we've had good success with this strategy. Anecdotally, out of all the peak livers that we have done for indeterminate cases, only a handful, three or four of them, ended up in needing a heart transplant alone. We usually do end up transplanting the liver as well. There are no absolute contraindications that we can really speak of. This is an area where not a lot of transplants are performed, but we do have to think about age, poorly controlled HIV, AIDS, other comorbidities, BMI of greater than 38. Hepatitis C has special considerations and is no longer really a contraindication given the advent of DAA therapy, which should be used immediately after transplantation. And obviously, poor functional status is an important consideration. When we think about surgical considerations, we think about donor selection. Allocation for these cases is nearly always based on heart priority. Provisional acceptance has to happen by heart and liver teams. There are generally two recovery teams. The cardiac transplant begins with the median sternotomy. If a peak liver protocol is instituted, the incision is extended to the abdomen. And if it is perceived by the surgeons that a liver is not required, then that liver is allocated to a backup recipient. The liver transplant proceeds then in the cases of combined transplant after cardiac reperfusion, and the patient is off cardiopulmonary bypass. So the key takeaways from my talk are that combined heart liver transplant is an uncommon procedure with favorable graft outcomes in appropriately selected patients. Multidisciplinary teams and careful candidate evaluation with strict attention paid to liver function are key to optimizing post-transplant outcomes. And there's a growing population of patients with single ventricle and after congenital heart disease, and they present an ongoing challenge for risk stratification and outcome prediction. This group is of intense interest and is an area of study, and we look forward to knowing more about these patients, their prognosis. Thank you again for the kind invitation to discuss this topic. Looking at kidney and liver combined transplants, does the patient really need a new liver? Or in other words, what is the data on kidney transplant alone in patients with cirrhosis? I'm Sumit Dasrani. I'm a transplant hepatologist at Baylor University's Medical Center in Dallas, Texas. I have no disclosures. So the context is that, there's a high prevalence of metabolic factors, hepatitis B and hepatitis C in patients awaiting kidney transplantation alone. And in this context, I wanted to discuss the impact of liver disease, share data of kidney transplant alone in patients with compensated cirrhosis, and discuss monitoring of liver disease after kidney transplant alone. Now in stage five CKD, the question is, what is acceptable liver fibrosis? You know, if somebody is stage zero, we assume kidney transplant alone is fine. In somebody with decompensated cirrhosis, we assume that SLKT is fine, but where do we draw the line in the middle with regards to significant as well as advanced fibrosis? In an ASTS survey of 800 physicians, 20% of the surgeons replied, when asked about kidney transplant alone in patients with compensated cirrhosis, 70% said kidney transplant alone, and about one third said SLKT. 40% felt that there were more complications with kidney transplant alone in cirrhosis. 80% felt that there were favorable outcomes. Was HPPG greater than 10 a contraindication? 68% said yes, and 60% saw decompensation after kidney transplant alone in cirrhosis, and putting this all together, would they always advocate for kidney transplant alone in patients with cirrhosis? Only 8% said yes, and a majority said this decision should be case by case. What is the impact of liver disease, and what do we know from the literature? The assessment of liver disease prior to kidney transplant alone, there are many pitfalls. On one hand, serum testing is available, but normal transplants can be misleading. With imaging, due to the volume shifts, there's false elevation and stiffness with non-invasive imaging, such as elastography. Hepatic penis pressure gradient measurement is operator dependent, and even in 2020, biopsy remains essential for identification of cirrhosis. In patients with hepatitis B and hepatitis C undergoing kidney transplant, patients who have hep B and hep C, based on older data, tend to do worse in a couple of studies. The issue here in this study was that not all patients underwent biopsy, but again, age, hep C, and biopsy-proven cirrhosis was associated with worse outcome. There was also an association with cardiovascular events, liver failure, sepsis, and new onset diabetes. In a separate study, which put together studies up to about 2010, looking at the association of hep C and survival, survival was poor, and it was worse with diabetes. Same themes occurred here, is that presence of hep C was associated with a higher risk of liver-related mortality, cardiovascular mortality, as well as infectious disease-related mortality. With regards to hep B, though hep B versus no hep B, rates of graft failure were unchanged. However, rates of hepatic failure were increased in patients who had hepatitis B, and under adjusted analysis, similar factors, age and diabetes, playing a role. Now, what do we know specifically in patients with cirrhosis? There are only a few limited studies and few number of patients in each of these studies. In a study spanning 1990s and 2000s, though graft survival was similar in patients with and without cirrhosis, even if you look at the non-cirrhotic population, 10% developed cirrhosis. Whether this was not diagnosed at onset or this is new onset, we do not know. And in those with cirrhosis after kidney transplant alone, there was development of HCC. In another study looking at hep C cirrhosis, in 12 patients who had cirrhosis on adjusted analysis, again, older patients, low albumin, did not do well, and there was one new HCC in the apparently no cirrhosis group. Patient survival in a separate study, in the 1990s and 2000s, 18 patients with cirrhosis, survival was similar. The issue again was the presence of age and diabetics as the ones who did not do well. So to summarize sort of kidney transplantation alone in patients with cirrhosis, there's relatively limited published experience with cirrhosis. In selected patients, survival is similar. Age, diabetes, advanced disease, potentially indicated by low albumin, maybe prognostic. The risk of HCC persists. And the question remains that even though one may able to get them through surgery, but can cirrhosis-related factors be mitigated in the long-term? So let's say you transplant a patient who has cirrhosis. What happens after? What if cirrhosis is not obvious in patients undergoing kidney transplantation alone? Specifically, historically, our emphasis has been on hepatitis B and hepatitis C, but assessment of non-alcoholic fatty liver disease prior to kidney transplantation alone is minimal. The issue becomes is that our patients with cirrhosis no longer look like this, but it's usually more look like this, where there are shared risk factors. Age, hypertension, diabetes, metabolic disease and heart disease is prevalent both in the kidney transplant as well as the liver transplant population. And as regards to non-alcoholic fatty liver disease, the impact on cirrhosis and outcomes after transplant, kidney transplant alone are not well-known. So surveillance and vigilance for liver-related decompensation remains important. This was highlighted in the hepatitis B and hepatitis C studies that I presented. Surveillance is important for alcohol-associated disease as well as patients with diabetes. And a reminder that HCC and decompensation risk is not always abrogated after antiviral therapy, especially in patients with significant metabolic factors and presence of cirrhosis. And even though one may have improvement in non-invasive indices, this does not always imply regression of cirrhosis. Putting it all together based on society guidance and documents, the statement out there is that we recommend hep C infected patients with compensated cirrhosis without portal hypertension undergo isolated kidney transplantation. We recommend referring hep C infected patients with decompensated cirrhosis for combined liver kidney transplantation and deferring hep C treatment until after transplantation. So to sort of summarize for a patient who has stage four to five CKD, in this case, hepatitis C, one can start off with non-invasive assessment due to the high negative predictive value. If there's no fibrosis, okay to proceed. However, most of the time, there's usually either discordant results or false positive, or if there's concern for advanced fibrosis, liver biopsy with pressure measurement would be the recommended next step. Here's a suggested risk ratification for a patient with stage four to five CKD. If a patient has stage zero to two liver fibrosis, that is none to significant fibrosis, kidney transplant alone may be acceptable with the concern to still watch and modify factors such as alcohol and weight. For somebody with advanced fibrosis, kidney transplant alone, but surveillance for liver complications is important. For a patient with cirrhosis, but normal hepatic venous pressure gradient, if it's abnormal or they're concerning factors, then simultaneous liver kidney transplantation. But in this group, especially in the presence of advanced age, diabetes and specific etiology, even though we may choose kidney transplant alone, we still don't know enough about the natural history after surgery and surveillance for liver related complication remains important. There are many known unknowns and unknown unknowns. How will DAA change the natural history? What is the long-term benefit of eradication? If therapy is provided early and improvement is seen, does that last? Will non-alcoholic fatty liver disease replace hep C as the dominant concern after kidney transplant alone? And how much of the reported decompensation to date after kidney transplant alone is due to unrecognized liver disease instead? So the key takeaways are the role of liver biopsy and hepatic venous pressure gradient measurement still remains important. There remains limited experience with cirrhosis in kidney transplant alone. More recent recommendations suggest kidney transplant alone in select patients with cirrhosis. However, surveillance for HCC and vigilance for complications remains essential. Thank you. Good morning, everyone. First of all, I would like to thank the organizing committee from ILTS and ASLB for their kind invitation to participate in this debate on how far can we go with social media as a source for live donors. I don't have any disclosure. In an ideal pre-COVID world, at this point of the presentation, I would have asked the room and the participant to raise their hand for those who believe that social media is influential in facilitating matching of recipient and potential living donors. However, since this meeting is virtual, I will present the result of a survey of American Society of Transplant Surgeons that was recently published in Transplantation. 299 members of the ASTS were asked about their use of, their attitude toward, and their perception of social media. And one of the question that was particularly, that was pertinent to this presentation was their belief on the social media influence on facilitating matching of recipient and potential living donors. As you can see here, the responders were divided and about 55% say that social media can facilitate this matching. And interestingly, analysis of this group shows that younger age and fewer years of experience in the field of transplantation were associated with stronger belief that social media can facilitate matching. There is no doubt that live donor liver transplantation remains still a solution to close the gap between the number of the weighted listed patients for transplant and the number of the transplantation performed every year. And the outcome of live donor liver transplantation is excellent. This is the data from our own program in Toronto with now 20 years experience and follow-up of the live donor liver transplant recipient. As you can see here, the long-term follow-up is superior to disease donor liver transplantation. The traditional live donor search includes the ask from family and friends, word of mouth used in church or other worship places, an advertisement in a newspaper, or more creative forms such as a billboard in New York Times Square, or writing on a window of a car, or holding a pond card in a football stadium. The barrier to live donor liver transplantation remained around the discomfort with initiating discussion about donation, concern about inducing guilt or burdening family members or friends, concern about harming their relationship, and the desire to not place a family or friends at risk. All this barrier is around direct asking. Social media, in the contrast, have the advantage to have a low barrier to entry. Everyone can open an account. It's cheap. It has a greater dissemination power. It's an indirect form of asking and has been proven beneficial in awareness-raising approach in the past. The greater dissemination power of social media is known through this data. We now know that 3.5 billion people worldwide are actively daily using social media. That represents about 45% of the population worldwide. For example, in the U.S., 75% of the Americans are using Facebook on a daily basis. Social media has been proven in awareness-raising. For example, Pete's Face Ice Bucket Challenge for ALS a few years ago, where 7 million people, celebrity or not, uploaded their video on Facebook after dumping a bucket of ice on their head. This resulted in $220 million raised in 60 days for ALS research, and an increase by 3,500% compared to the previous years. Similarly, Facebook has shown beneficial in raising the rate of organ donors. This was an initiative between John Hopkins researchers and the Facebook leadership. Facebook agreed to alter its timeline platform to allow Facebook members to specify their status as an organ donor, just as they would specify whether they are married or not. In addition, once they have chosen their status as an organ donor, they were given a link to do a direct registration at the registration office, and also all their friends were made aware of their change of status. This work shows that within the first day of the Facebook organ donor initiative, there were 13,000 new online registrations to be a donor, which was a 20-fold increase compared to the 600 daily registrations. Social media is an indirect yet personalized approach, is more comfortable, less burdensome, emphasizes on a real person's needs and the ability to help that specific person. Once again, this has been shown through a research work that was done by the John Hopkins group together with Facebook. They have collaborated in collaboration with Facebook leadership. This group developed a mobile app that enabled wait-listed candidates to create a Facebook post about their experience with end-stage organ failure and their need for live donors. And in their work, they have shown that compared with the controls, the candidates who are using the Facebook app were six times more likely to have a donor coming forward on their behalf compared to the controls. Social media has also taught us other advantages that was previously unknown to us. One of the advantages was through the history of these Wagner twins. These are two adopted Vietnamese twins that are living in Toronto. They both had biliary atresia and needed liver transplantation. Their dad donated to one of the toddlers. However, there was no match for the second twin among the family member. The family created afterwards a Facebook page and made a public plea for a live donor. Within a few days of creation of this page, over 600 donors came forward to be considered as potential donors for the second twins. This donor came from all across the world, from all the way from British Columbia to New Zealand, Brazil, and the US. What this story shows us was the increased rate of indirect donation. Indeed, among those 600 potential donors, 50 have passed their initial screening test, and two of them went to donate anonymously to two other children on the waiting list in Toronto during the same year. Another lesson from social media is the celebrity appeals. This is the story of Eugene Melnyk, the owner of Ottawa Senator and NHL Hockey League in Canada. He was found a few years ago to have liver disease and needed liver transplantation. None of his family members was a match for him. Ultimately, Ottawa Senators made a public appeal for him, and within a few weeks of this appeal, he underwent an anonymous live donor liver transplantation after 500 people came forward to be a donor for him. The lesson learned in this situation was the motivation behind this donation. It was not a financial motivation from the anonymous donor, because it's now five years post-donation, and Mr. Melnyk is still unaware of the identity of his anonymous donor. The motivation was purely altruistic, and the wish expressed by the donor was only for Ottawa Senators to bring the Stanley Cup back to Canada, which we are still waiting for it to happen. There are a number of considerations to keep in mind with the use of social media, including lack of privacy, one-sided anonymity, unfair for unplugged beauty contests, and the requirement for appropriate resources to deal with surges associated with public appeals. Some or all of them may be discussed by my opponent, Dr. Jackson. So in summary, should the social media be used and how far we can go to increase living organ donation? I would say quite far. These platforms are cheap. They have low barrier entry. They have a greater rate of dissemination, less stressful. It's an indirect form of asking. It would allow to increase both direct and indirect donation, and would also help other recipients on the waiting list. Thank you very much for your attention. My name is Whitney Jackson. I'm from the University of Colorado. Thank you so much for the opportunity today to debate the con side to the question, how far can we go with social media as a source for liver donors? I have no disclosures. In the United States, the overwhelming majority of people are on social media in a diverse age range. Even worldwide, over 50% of people use some social media platform. The average user spends two and a half hours a day on social media. Clearly, it is ubiquitous and one of the best ways to share information to a wide audience quickly. At first glance, it seems indisputable. Transplant centers have to utilize social media or will be left behind. Patients are already using social media to recruit live donors, whether we are involved or not. The question is, to what extent should the transplant community be involved in these interactions and use social media for education, advertising, and recruitment of liver donors, specifically live donors? Will we be prepared to engage in issues that arise? During my time, I'll show you that social media is not beneficent, that there are opportunities for ethical dilemmas, some of which we may not be able to predict. When you encourage your patient to look for a live donor using social media, you are likely under the impression that this is a tool to communicate with family and friends. But today's social media networks are much broader. Large groups of like-minded people join groups to share ideas. The newsfeed is altered to display updates and advertisements based on personalized behavioral modeling. This is all with the purpose of increasing the information you want to see to keep your attention with the goal of increasing advertising sales. Hence, already the information shared through social media is biased. If that's not concerning enough, we know that false news spreads faster than the truth. In a study from MIT in 2018, a false news story reaches 1,500 people six times quicker on average than a true story does. Robots accelerated the spread of false and true news at the same rate, implying that false news spreads more than the truth because of humans and not robots. This speaks to an attraction to more sensationalized information. And conspiracy theories have always existed. Previously, they were something you heard about from a relative at a holiday table. But now your relative has a platform. Maybe he says the earth is flat. It seems funny and harmless. But other conspiracy theories become dangerous, that vaccines cause autism and are part of a scheme to cause mass harm. So it should concern you that conspiracies around organ donation have always existed because of how easy they are to dramatize. And now they spread quickly. This is false news that was spread through the UK, manipulating their organ opt-out policy. It said there is a deadline to opt out. And if you miss that deadline, your organs are the property of the government. False information exists because the internet and social media are not regulated. And while freedom of speech is important, protecting public trust is also important. Here are examples of false and damaging information spreading. In 2015, a meme was created and shared broadly. It promoted the idea that organs are harvested while patients are alive, that the procurement itself causes death, and that pain is felt during the process. People actually believe this. Fact-checking organizations cannot keep up with the amount of disinformation. And this false information continues to spread. This is an example of a website linked from a social media site, which exposes quote-unquote the truth about organ donation, as told by a physician. And while that may look extreme and unbelievable to you, these myths have even been picked up and then spread by reputable news sources. The Wall Street Journal here published an article that was entitled What You Lose When You Sign That Organ Donor Card. Giving away your organs sounds noble, but have doctors blurred the line between life and death? And as we've all experienced, head-on attempts to persuade our patients can sometimes trigger a backfire effect, where people not only fail to change their minds when confronted with the facts, they may hold onto their views more strongly now, no matter how incorrect they are. It's in this setting of minimal regulation and disinformation that recipients are looking for live donors, and there are reasons to already be concerned with what's going on. These are real examples that illustrate why our concerns are valid. As we go through, envision these posts or conversations occurring on a social media site or exchange that you're hosting or you are responsible for. Would you be confident in your ability to navigate and regulate these interactions? Recently, a transplant candidate posted her story on a social media fashion exchange site. An anonymous donor came forward and traveled across the country at her own expense to be evaluated for donation. During her evaluation, it was discovered that the potential candidate misrepresented the etiology of her liver disease. She said her genetics caused her end-stage liver disease due to hereditary hemochromatosis, when in reality she suffered from alcohol use disorder. The donor felt misled and withdrew. My concerns here are that these interactions are occurring everywhere. Feeling lied to discourages altruism, not only now but in the future, and transplant programs have an obligation to ensure that donors are not taken advantage of. I don't know if we can police everything that's going on. Another example involved one of our non-directed anonymous living donor liver transplant cases. The day of transplant, without our knowledge, the donor and recipient checked into our hospital online. For those of you who are not aware, this allows you to see other people in that location. The two were quickly able to identify each other as the donor and recipient, and post-operatively were visiting each other's hospital rooms before our transplant team was aware. And large interest groups form on social media. This is a living donor awareness group open to the public for anyone to join. A man posts that he wants to donate part of his liver after prior kidney donation. What ensued was a debate over if liver donation after kidney donation is even possible. Some people were accusing this man of getting other people's hopes up who needed a transplant. And one person even called him a pedophile for unclear reasons, possibly because he was interested in donating to a child. This just speaks to the quick spread of misinformation by laypeople and the possibility of bullying. Many people on innumerable websites post every day their story and that they need a transplant. There are concerns for popularity contests and the potential for coercion. This person on a public forum is asking for monetary compensation for donation. I don't know that that's something that we feel comfortable navigating on a social media site. While these examples may seem extreme to you, they are actually occurring right now. Carl Sagan said, I have a foreboding of a time when technological powers are in the hands of a few and no one representing the public interest can grasp the issues. When people are unable to distinguish what is true. And I think we have reached that point here. Few people design social media and didn't understand the ramifications of the system that they built. High school students are the age group which is likely to be the most adept at navigating social media. Yet when given this picture of flowers from Fukushima, the site of the 2011 nuclear accident, they accept these flowers as real. You may be suspicious of this because we're talking about the downsides of social media. But when you are getting large volumes of information quickly, you too are likely to have trouble discerning fact from fiction. In summary, I want to say today that social media is not beneficent. That false news travels faster than the truth. That there are unique opportunities in the setting of social media for misrepresentation, misinformation, coercion, bullying, and loss of anonymity. Not only should the transplant community not go any farther in promoting the recruitment of living donors using social media, but we have already gone too far. Thank you so much for your time. Good morning, everyone. First, I would like to thank the organizers for inviting me to talk about redefining cirrhotic cardiomyopathy and cardiac risk, impact on peri- and early post-transplant outcomes. I'm a transplant hepatologist and an assistant professor of medicine at Vanderbilt University in Nashville, Tennessee. My research focuses on cirrhotic cardiomyopathy and its impact on pre- and post-transplant outcomes. I have no financial disclosure. This morning, we'll be reviewing the definition of cirrhotic cardiomyopathy, its old diagnostic criteria, and the new ones, as well as the associated cardiovascular outcomes. Cirrhotic cardiomyopathy was first defined in 2005 during the World Congress of Gastroenterology in Montreal. It was described as cardiac dysfunction, systolic and or diastolic, in the setting of cirrhosis in the absence of known cardiac disease. Its pathophysiology is relatively puzzling, and it involves multiple processes that occur in the setting of hyperdynamic circulation, such as myocardial and vascular inflammation, which appear to happen, at least in the animal model, within weeks of the development of advanced fibrosis. Subendocardial edema, which is not surprising or unexpected in our patients with volume overload. Myocardial hypertrophy, which is thought to be closely related to sodium retention. And last, myocardial fibrosis, and that's likely a complication of prolonged myocardial inflammation. These concepts were demonstrated earlier this month through the study that was published, showing a comparison in cardiac MRI findings between patients with cirrhosis and healthy controls. And they evaluated multiple surrogates that indicate increased myocardial inflammation, myocardial fibrosis, and myocardial edema in patients with cirrhosis due to cirrhotic cardiomyopathy. Now, how can we diagnose cirrhotic cardiomyopathy echocardiographically? So the first set of diagnostic criteria was formulated in 2005. So the first set of diagnostic criteria was formulated in 2005, and it consisted of diastolic dysfunction and systolic dysfunction criteria. For the systolic dysfunction, left ventricular ejection fraction of less than 55% or blunted response to stress was diagnostic of systolic dysfunction. And for diastolic dysfunction, peak velocity flow in early systole and early diastole to peak velocity flow in late diastole, also known as EA ratio of less than 1, isopodiometric relaxation time of more than 80 or deceleration time of more than 200 millisecond. Any of these criteria was diagnostic for diastolic dysfunction. And for patient to have cirrhotic cardiomyopathy, they need to have either systolic and or diastolic dysfunction. As our knowledge about echocardiography advanced, we learned of multiple shortcomings for these criteria. For example, left ventricular ejection fraction has interim intra-observer variability of up to 10%, and that was demonstrated in studies in general population. And if we apply these findings to our transplant population, a patient with pre-transplant echo showing ejection fraction of 54% may have an actual ejection fraction of 45% given this variability. Additionally, ejection fractions inflated or augmented in our patients with systemic vasodilation and decreased afterload. The other systolic dysfunction criterion, which is blunted response to stress, is difficult to apply clinically. First, because a lot of our patients are on non-selective beta blockers for verticeal bleeding prophylaxis. Second, there is no universal definition or universal objective criteria for blunted response to stress. Back to ejection fraction, this interesting study that was published earlier this year evaluated the early post-transplant mortality defined as death within 90 days in relation to ejection fraction. And they found that a cutoff of 60% or less was associated with increased mortality, increased early post-transplant mortality in patients with MELD of more than 20. And that association was even more pronounced in patients with MELD of more than 35 and an ejection fraction of 60% or less. The diastolic dysfunction criteria also have shortcomings. EA is preload dependent and given the volume overload status that's common in our patients, EA may not be reliable. Additionally, it's confounded by age and importantly, it exhibits a pseudo relaxation phenomenon when patients with grade 2 diastolic dysfunction can have a very similar EA to that of normal individuals. Isovolumetric relaxation time can be prolonged in early diastolic dysfunction. But as the diastolic dysfunction advances, it shortens and that limits its reliability. So given all of these shortcomings, the sorority cardiomyopathy criteria were revised earlier this year. And the current criteria requires ejection fraction of 50% or less or global longitudinal strain with absolute value of less than 18% to diagnose systolic dysfunction. For diastolic dysfunction diagnosis, it's a little more complex. So we have four criteria or four measures to assess it, which are average EE prime more than 14, peak tricuspid regurgitation velocity more than 2.8, septal E prime less than 7, and left atrial volume index more than 34. If the patient has two of these criteria, the patient has diastolic dysfunction, but we cannot determine the grade of it with a standard of care echocardiographic testing. It may require additional testing that's, as I said, not standard of care. If the patient has three of these four diagnostic criteria, the patient does have diastolic dysfunction and the grade of it can be determined by additional testing that's available or it's done routinely in our patients. I would like to spend a few minutes to talk about global longitudinal strain because this is not something that we're used to as transplant providers. We are highly reliant on ejection fraction. But over the past few years, global longitudinal strain has emerged as a reliable surrogate of contractile function. And it's defined as percent of myocardial fiber shortening during systole relative to its length during diastole. So we're assessing shortening and therefore it's a negative number. Here in this video, you see these yellow dots are getting closer to each other, representing the myocardial fiber shortening. The recommendation of the American Society of Echocardiography is to consider strain as an absolute number when we're discussing the changes in it. And that's to minimize confusion. So the normal absolute value is more than 18%. Here in this slide, we see this figure which our cardiology colleagues often refer to as bull's eye figure. And the machine or the software makes these measurements of segmental strain. And based on them, the global longitudinal strain gets calculated. The global longitudinal strain has two major advantages. First, its impairment usually precedes that of ejection fraction. And second, it's more producible. So it's less operator dependent and there's less inter and intra-observer variability. Now if we apply all of these criteria that we talked about on or to our patient population, how common is cirrhotic cardiomyopathy? So in this study that we conducted in my prior institution, and it's currently under review by one of the hepatology journals, we reviewed records of 141 liver transplant recipients, all of whom had normal ejection fraction going into transplant, as you would expect. And we were able to assess global longitudinal strain retrospectively in 119 patients and diastolic dysfunction in all 141 patients. And we found that cirrhotic cardiomyopathy affected 141 patients, sorry, 49 of the 141 patients. So basically 35%. And that was mostly based on diastolic dysfunction, which affected 47 patients because systolic dysfunction represented by impaired strain was present only in two patients. Importantly, we then compared the cardiovascular outcomes defined as first occurrence of coronary artery disease, CHF, dysrhythmia, or stroke between patients with cirrhotic cardiomyopathy and those without it. And as you can see in the figure, there is significant difference in the five-year survival between patients with cirrhotic cardiomyopathy and those without it, and the divergence in the survival curve increases as years post-transplant pass. We then compared early versus late post-transplant outcomes in relation to cirrhotic cardiomyopathy. And we found that cirrhotic cardiomyopathy does not seem to have an impact on early cardiovascular outcomes defined as within the first three months post-transplant, but it does have an impact on late cardiovascular outcomes. So it increases the risk for late cardiovascular outcomes by almost three-folds. It did not, cirrhotic cardiomyopathy did not have an impact on mortality, which affected 27 of our 141 patients, and two of them or two of those deaths were intraoperative. Now, let's talk about the individual components of cirrhotic cardiomyopathy criteria in relation to outcomes. So first, global longitudinal strain, which we assessed, as I mentioned, in 119 patients. An absolute value of less than 20.6 was associated with six-time increase in post-transplant congestive heart failure, and an absolute value of less than 20.5 was associated with six-time increase in post-transplant coronary artery disease. Now, if you remember, the cutoff in general population was 18, but here it seems that our prognostic cutoff is 20.6 or 20.5, excuse me, and that could be because of the hypercontractile state of the heart of our patients due to decreased afterload and hyperdynamic circulation. So maybe their baseline strain is higher than that of general population. The correlation or the association between strain and post-surgical outcomes is not unique to transplant, but it was observed in other types of surgeries, mainly cardiac surgeries. So in this study that evaluated 464 patients with impaired strain but normal ejection fraction, impaired strain predicted prolonged need for inotropic support for more than 48 hours postoperatively, and it's predicted first month mortality. In another study that evaluated 125 patients undergoing valve floor surgery, strain or impaired strain was the only predictor of cardiovascular events within four years after surgery. In fact, the multivariable analysis included ejection fraction, but there was no significant association with outcomes, while impaired strain did have an association with outcomes. Let's shift gears to the diastolic dysfunction variables. So EE prime of more than 9.2 was associated with increased risk for the composite outcome of cardiovascular events, and it was associated specifically with atrial arrhythmias. Left atrial ventricular, I'm sorry, left atrial volume index of more than 34 was associated with increased risk of first year mortality and with congestive heart failure. The latter observation is not surprising because left atrial volume index of 34 is associated with adverse outcomes in general population too, but the EE prime cutoff in our patients was below what's observed in general population. So here it's 9.2, while what was observed in general population in relation to post surgical outcomes was 15 or more. So the study evaluated 965 patients, only 5.6% had liver surgery, which was non-transplant, and it showed that EE prime of 15 or more was associated with post surgical heart failure in the first week. And this number of like EE prime 15 or more was associated with adverse outcomes in other studies, surgical and non-surgical in general population. Now what about diastolic dysfunction in intraoperative outcomes? The data about this topic are very limited, and this is a study that we concluded in our current institution last week. These data are unpublished, they're preliminary. We reviewed the records, the intraoperative records of 190 patients undergoing liver transplant, 43 of whom had diastolic dysfunction. And it does not seem that there is increased pressure requirements or IV fluid administration in patients with diastolic dysfunction compared to those without it. There was an increased length of stay in case of diastolic dysfunction on univariate analysis. Again, these findings are preliminary, and this is unpublished data. To this end, there was a recent study that evaluated the evolution of diastolic dysfunction during liver transplant surgery. So it assessed EE prime as a surrogate of diastolic dysfunction in 40 patients, and measured it during dissection after removing ascites five minutes after unclamping when cardiocirculatory conditions were stable and at the end of the surgery. And it showed that EE prime declined by 15% in 11 patients out of the 40. And that decline was associated with cardiorespiratory complications, such as, or they defined it as, dyspnea or hypoxia associated with systolic or diastolic dysfunction during first week post-transplant. And the decline did not have an effect on fluid administration or vasopressor support. The focus of the study was the evolution of EE prime during surgery. So the study did not elaborate much on the pre-transplant diastolic function of these patients. In summary, cirrhotic cardiomyopathy was recently redefined to accommodate the advancement in echocardiographic technology. There is insufficient evidence to suggest an impact of cirrhotic cardiomyopathy on interoperative or early post-operative course, but further study is certainly needed. The takeaway messages are the following. Pre-transplant echocardiography should assess for the contemporary surrogates of cardiac dysfunction, which you see here on the right. Cirrhotic cardiomyopathy can increase the risk for long-term post-transplant cardiovascular events. Thus, pre- and post-transplant surveillance may be of benefit. Of note, the cirrhotic cardiomyopathy consortium earlier this year recommended that patients with cirrhotic cardiomyopathy who are listed for transplant get echocardiographic surveillance every six months up to two years post-transplant to detect any subclinical decline in ejection fraction, which may warrant initiation of guideline-directed therapy. And last, validation of these measures or these cut-offs in our patient population is warranted because all of these cut-offs were borrowed from the general population. Thank you very much for your attention. Hi, I'm Dr. Mitra Nadim from the University of Southern California. I'd like to thank the organizers and the ASLD for inviting me today to talk about extracorporeal liver support and acute and acute on chronic liver failure. My only disclosure is that I am not a hepatologist, and in fact, I am a nephrologist. As all of you know, there is enormous discrepancy between organ supply and demand. And because of this discrepancy, we need to find strategies to stabilize the liver function on the wait list so that you can bridge these patients to transplant or help the recovery of the liver so that they won't need a transplant. This is data of UNOS as of September 30, 2020. UNOS as of September 30, 2020. And if you look at this year's statistics, about 12,000 patients are on the wait list. Over 6,000 patients have been transplanted, but close to 1,700 patients have either died or too sick to be transplanted. This number is probably even more as several patients have died even prior to getting listed. But this approximately comes out to about six patients a day dying waiting for a liver transplant. But of note is this 760 patients whose condition improved and they were removed from the wait list. And so these devices may be of use to increase the number of patients who potentially can improve and not require liver transplantation. When we think about these extracorporeal liver support devices, we have to think how they'll help us in each of the different forms of liver diseases. With ALF, the primary goal is really to see if we can stabilize the liver function and potentially give the liver a chance to recover. So the goal is really recover a patient to their baseline, which was a normal liver function. From a pathophysiological perspective, patients with ALF are really the perfect group of patients that would benefit from these devices because recovery is likely to return them to their pre-liver failure state. In contrast, patients with ACLF, they already have underlying liver disease. So the primary goal is really recovery to the state they were before they decompensated. As you all know, the liver is never going to recover. As you all know, the liver is never going to improve because of the underlying fibrosis. So both of these ultimately, whether the ALF patient who doesn't recover or the ACLF that doesn't decompensate, who doesn't recover to the decompensated state, the alternative goal would be to bridge them to transplantation, try to prevent progression of liver failure and improve endorgan function in those who have multi-organ failure. There are currently three artificial albumin dialysis that people have used and studied. There's the MARS and Prometheus systems that remove protein-bound and water-soluble molecules. The MARS machine, you have blood that's dialyzed across an albumin and permeable membrane. Then the toxins then go first through a CRT circuit and then through charcoal and charcoal column and an anion exchange column, whereby then the albumin is regenerated here. In the Prometheus, you have a much larger cut-off membrane of 300 kilodalton. So it separates the patient's albumin and plasma from the blood. And it then goes through these two columns and finally goes through a dialysis, again, membrane. The difference here is with the Prometheus machine, you can only use it to connect it to a hemodialysis machine, unlike the MARS machine, where it can be connected to the CRT machine. The contraindications, again, severe coagulopathy and bleeding or severe sepsis. And when these two machines are being used, drug levels need to be monitored as these protein-bound drugs can be removed. With the single-pass albumin dialysis, it's basically using a CRT machine. And albumin is used as the dialysate solution in this machine. So this is starting with ACLF and the use of MARS. This is one of the first large randomized controlled trials looking at its use in patients with advanced cirrhosis. It was from a group by Hassanine. And this was only 70 patients. It was comparing MARS with standard medical therapy versus standard medical therapy and the MARS was given daily for six hours for five days until or until there was improvement in the grade 2 hepatic encephalopathy. It should be noted that this study was not sufficiently powered to reveal really any potential mortality benefit. But what they did show was that there was improvement in hepatic encephalopathy higher in the MARS group, 34% compared to just standard medical therapy and patients achieved this at a much faster. There was however a 20% there was a decrease in platelets in about 20% of the patients in the MARS group. This is then the relief trial was one of the largest trials, randomized control trials in the comparing MARS again versus standard medical therapy. Patients received up to 10 6 to 8 hour MARS session and even though this was randomized the proportion of patients with MELT more than 20 with SBP as their precipitating event was significantly greater in the MARS group. The results however, there was no difference in the 28 day survival between the MARS and control group either by intention to treat or per protocol analysis. On day four there was as expected a greater decrease in the serum cranin and bilirubin in the MARS group because that is what these devices do. However, there was a non-significant improvement in hepatic encephalopathy. There were four randomized control trials on ACLF and the use of MARS and in this meta-analysis they had data individual data on three of those studies and so the this study was designed to pull the individual patient data from these trial comparing MARS and standard medical therapy versus standard medical therapy alone in patients with ACLF. They also divided them into patients who received less intensity treatment that was four or less MARS sessions or the high intensity treatment which was more than four sessions and in the 285 patients that they studied the authors were confirmed basically what was previously described in all these randomized control studies which basically MARS improved the serum bilirubin and cranin and it showed a beneficial effect on brain function with a reduction in significant hepatic encephalopathy but none of them really were able to show any improvement in survival. However, when they did divide them into those patients who received higher intensity therapy, so more MARS sessions, they were able to find a statistical difference between the two groups. The study also showed that there could be a potential beneficial effect of MARS on short-term survival in patients with ACLF if it's given at an appropriate dose and here you can see in patients with ACLF grade 1, those who received more treatments at 10 days there was a statistical significance in survival in ACLF 1 and 2. However, they lost this difference by day 30. There was no difference in patients with ACLF 3. They also were able to demonstrate that the effect of high-intensity MARS was independent of other prognostic factors such as MELD or number of organ failure. So this is something that potentially could be considered in future studies. What about the use of the Prometheus machine in ACLF? This is the Helios study looking at the largest randomized controlled study looking at this device with standard medical therapy versus standard medical therapy and similar to the relief study of the MARS, there was no difference in survival between any of the groups. There was a reduction in bilirubin in the group that received the Prometheus. The baseline factors that were associated with poor prognosis were high SOFA score, GI bleeding, SBP, AKI, and the combination of alcoholic and viral liver disease. So what about acute liver failure? Well, this was one of the first large randomized studies of MARS in patients with acute liver failure and this is a study done in multicenter trial in France. It was a randomized controlled trial of a hundred patients. It was comparing again MARS and standard medical therapy versus standard medical therapy in patients with acute liver failure who met criteria for liver transplantation and the randomization was stratified also according to whether acetaminophen was the cause of acute liver failure and this patient population actually accounted for the majority of patients with ALF, which was 38%. Again, there was no difference in the primary endpoint, which was six-month patient survival. However, those patients who were in the MARS group had a better chance of getting transplanted with 73% compared to 55%. One of the major confounders of this study was that the median listing to transplant time was only 16 hours and this is much quicker than what we see in the US and 75% of enrolled patients underwent transplantation within 24 hours. The median number of treatments therefore was only one with and in the MARS group from the 53 patients who were randomized to the MARS group, 14 of them had to be excluded because seven never started the MARS and seven had less than one treatment of MARS really reducing the power of this study. So the beneficial effect of MARS on outcome may have been precluded by the fact that there was a very short period of time between randomization and transplantation and therefore the results of MARS in terms of efficacy were inconclusive in this study. This is a retrospective multi-center study again conducted in all French adult care centers that used MARS between 2004 and 2009. These are patients that were either ACLF or ALF and the objective was to see whether patient survival based on the liver disease would be affected by the use of MARS and the results what they found was that the survival of the patients really correlated with whether or not they were being listed for those that were listed. There was a survival benefit for the use of MARS in patients with acute liver failure and patients who had more than three sessions of MARS. They had a better transplant free survival compared to other etiologies of liver disease and less sessions of MARS. So what about single-pass albumin dialysis? As I mentioned earlier, this is just the use of a CRT machine. The patient's blood is dialyzed against a 4% albumin dialysis solution and it's the membrane is just basically the CRT membrane which is impermeable to albumin. This is a study from Dean Karvelis' group in Canada. It's a retrospective study, very small. They looked at patients who were treated with SPAT, six patients compared to the control. These were very high mild patients. The patients received one to three treatments and they found no complications, but again, no differences, significant difference in ICU one-year survival or any liver recovery in these patients with acute liver failure. So what about just the use of CRT as an extracorporeal liver device? As all of you know, in patients with acute liver failure, elevated ammonia level has been associated with hepatic encephalopathy, cerebral engema, intracranial hypertension, and higher mortality. The mechanism really by which ammonia causes this neurological dysfunction is still not fully understood. This is the first study by multicenter trial in patients with acute liver failure. There was a thousand patients and they looked at the use of CRT or intermittent renal replacement therapy in reducing ammonia level. As you can see here on the top, the patients on CRT were able to significantly reduce ammonia level much more than patients with intermittent or without any kind of renal replacement therapy. In patients and they looked at various cut-offs of ammonia of 100, 150, and 200 and they saw that it was associated with a higher mortality with the sensitivity of 77 percent, 58 percent, and 42 percent. The authors then derived three models to better assess the effect of renal replacement therapy on 21-day transplant-free all-cause mortality. After adjusting for a year of admission, age, etiology, disease severity, CRT use on day one was significantly associated with a lower 21-day mortality with an odds ratio of 0.47 compared to intermittent renal replacement therapy, which was associated with a much higher mortality at 21 days. And the ESLO guideline that came out in 2017 has included the use of renal replacement therapy, preferentially CRT, in patients with ALF. And this is one of their recommendations that states early institution of extracorporeal support should be considered for this persistent elevated ammonia, control of hypernatremia, and other metabolic abnormalities. And they gave this a level 3, but a grade 1 recommendation. So what are centers doing? This is members of the European ALF Consortium 88. They had 88 items and the questionnaire was response from 22 transplant centers in 11 countries treating between 300 to 500 cases of ALF. And these centers were performing more than a hundred liver transplants for ALF annually. And as you can see here, the indications for renal replacement therapy just for an elevated ammonia level was 55%. So one of the other extracorporeal liver support system is high-volume plasma exchange. And this has been reported since the 1960s in isolated cases of ALF and ACLF. And the rationale was removal of these toxins and replacing them with beneficial plasma proteins that is normally synthesized by the liver will help patients with ALF. And often the replacement is fresh frozen plasma, but albumin replacement has also been reported. This is the first randomized trial looking at high-volume plasma exchange in patients with ALF. And they showed compared to standard medical therapy and an intention to treat analysis, the survival was significantly better in patients who received plasma exchange. And in patients who ultimately ended up with transplant, the high-volume plasma exchange didn't really improve survival compared to standard medical therapy. But for those who did not receive a transplant, there was a statistical difference in survival. Looking at the SOFA score, CLIF score, and the systemic inflammatory response score, these patients who received high-volume plasma exchange over the course of the week statistically had improvement in these scoring systems. And in a subgroup of these patients with ALF, they also demonstrated a significant reduction in circulating levels of DAMPs, damage-associated molecular patterns, TNF-alpha, IL-6, and IL-8, suggesting that there could be a potential role of high-volume plasma exchange in combating the systemic inflammatory response that is associated with acute liver failure. So despite more than three decades of intense research, the results of these devices still seem to be limited. I think the challenges of these studies have been really in the patient selection and the timing of when these devices are started. ALF and ACLF are two different conditions. They are associated with very high mortality. And even though these devices have improved surrogate complications such as hepatic encephalopathy, improvement in creatinine, bilirubin, hemodynamics, there's really very little data to show improvement in either transplant-free survival or all-cause survival, except with the use of high-volume plasma exchange in ALF. We all know that these patients are very critically ill, and sometimes no matter what intervention we do, the outcome will not change. But I really believe that the timing of intervention with liver support is of critical importance in determining whether a device will improve outcome, and by the time we wait till multi-organ failure is manifested, it may be too late, and that may be one of the reasons why we don't see any benefit with these devices. Thank you very much for your attention. Thank you for the opportunity to present today. I have been tasked with the topic of integrating palliative care in the management of end-stage liver disease patients, and I want to thank the organizers. I also want to thank my palliative care colleagues in Edmonton and as well in North America, and a special thanks to my patients, actually, for really being the inspiration for why I think all of us need to push this work forward. So I have no relevant disclosures, and I want to bring this back just a little bit to integration and recognizing that this is a whole process that we need to do to integrate sustainably palliative care into our way that we work. So we'll spend a little bit of time on identifying the problem and determining the gaps today, but we're going to go through a focus on assessing barriers, and that's all in a way to get us down to eventually having sustained knowledge use and palliative care integration into practice. So my objectives will be to focus on some obstacles to integrating palliative care and to convincing you, ideally, that we need to find strategies together for getting around these obstacles. I want to start with a video, which is just a couple minutes, but I love it. It is a video about empathy, and it really brings to mind, every single time I watch it, why we absolutely need to take into account care with palliative principles into every patient that we see, particularly our cirrhosis patients. So that's an incredible video. This is a shortened version of the larger one, but really we can't stand emotions, can we? But we can really keep this in mind when we're seeing these patients, and I hope throughout the talk that that will be in your head. So first misconception or barrier is, I think, the biggest one, and it's a misunderstanding of what palliative care actually means. Palliative care, certainly we would all agree, means care at the end of life, and so avoiding distress and suffering in accordance with the patient's preferences in the last few days of life. But it is much broader than that, and according to the World Health Organization, palliative care has a focus on improving the quality of life of patients, as well as their caregivers or family members, across the trajectory of their life-threatening illness, and that's not only dealing with their physical symptoms, but also their psychosocial and their spiritual, providing them support in those domains as well. Palliative care, on the same vein, does not just mean consulting a palliative care specialist. It would be wonderful if we had so many palliative care specialists that all of our patients with cirrhosis could benefit from their care, but there's just not enough of these experts to go around, and so we need to be able to, particularly as the prevalence of cirrhosis is increasing, we need to be able to not only have more general palliative care specialists, those people who have some additional training, for example, several family physicians in our province, but we also need to step up to the plate and integrate. do a lot of support of our patients, and that's really the core of palliative care. Overall, palliative care looks at advanced care planning and goals of care designation, which we'll look at in the next slide, symptom assessment and management, and needs assessment and care coordination. So what is the functional status for our patients? Can we assist them with transitions in care like hospice? And underlying all of this is effective communication skills, which are essential. So advanced care planning is at the core of all of this. Advanced care planning is a process to really help your patient think about and talk about and then document wishes for healthcare in the context of who they are as a person and their values and their beliefs. And this leads to a written medical order, our goals of care documentation that reflects what their wishes are. And it also leads to a personal directive or a designation of a surrogate decision maker, which is absolutely essential in this population. Now, palliative care can occur alongside transplant listing, and there's several studies to suggest that this is beneficial. Many people, and this is supported by the literature, still see palliative care, again, as this curative, palliative. You're on the transplant list, there's no way we can consult palliative care. But I would suggest, and the literature would suggest, that there is a lot of data to support that we should. And we should start seeing it as palliative principles can occur alongside disease-modifying therapies like transplant, because our transplant patients, perhaps, have even higher degrees of psychological and physical distress and suffering, and they need that support despite being on the transplant list. There are models to suggest even proposed integration of palliative care alongside transplant. I really like this article from 2017. It wasn't specific to liver, but it did cover different organ failures and how to integrate palliative care. And what they suggested is palliative care should be started at the time of assessment, but even carried through all the way post-transplantation where there are still significant issues, and even down into the end of life. And so that idea of palliative care across the spectrum of the patient's trajectory in transplantation is an interesting one, and I think very valid. Sorry. Second misconception. There's an unclear understanding of why early care with palliative principles is so important in cirrhosis. And we know that our patients have a much higher symptom burden than we know or we ask about. And this data was actually taken from patients that we've published who were largely compensated, actually, compensated or Child QB. Look at the high degrees of pain, anxiety, and depression in this population, huge. These symptoms are on par with advanced malignancy. Mean quality of life score in this population of reasonably well, otherwise, patients was 59 out of 100. The amounts of distress when you talk to them, when you look at qualitative studies, their worries about family, the social stigma, the financial distress, and add onto that the stresses of being on the transplant list, this risk of dying of 20%. You know, their only hope being a transplant. At that point, those cause significant psychological issues. Physically, our patients are suffering. And so the Edmonton Symptom Assessment Scale is one of the symptom assessment scores that we can use. There's several studies that have looked at this. I'm just picking one from Bauman, which I'll also cover in the next slide. This looked at 50 patients, mean mild of 15. 85% of patients had more than one moderate to severe symptom on the ESAS. And very commonly, pain is one of the top ones. Good news is, and this is the Bauman study, when palliative care was integrated into the care of these patients at the time of transplantation, their symptoms improved. And so we have saw a significant improvement in symptoms like, sorry, like pruritus, well-being, appetite, anxiety, fatigue, and depression. We can make a difference with palliative care management. Across different diseases, this is not just specific to cirrhosis, but palliative care integration reduces anxiety, increases the patient's understanding of their illness. It improves quality of life and satisfaction. It reduces costs of care. And this was very nicely shown on a broader administrative data scale by Arpan Patel recently. And it reduces healthcare utilization, so readmissions. In non-cirrhosis patients, it's also been shown to improve survival. We know that the lack of advanced care planning can lead to inappropriate care. And this is clear in our cirrhosis patients as well, where patients who are listed for transplant have even lower rates of advanced care planning and palliative care consultation than non-listed patients. And it's because of that curative, palliative, those two black and white boxes, that misperception. Even patients who are delisted for transplant for being too ill end up having aggressive care and suboptimal symptom management. This is data from two sites. There are several studies now, but this is our local Albertan data showing that of these delisted patients, 28% had goals of care designations, 11% were referred to palliative care. Almost half of the patients were admitted to intensive care after delisting, and 17% had dialysis done. At UCSF, very similar theme, 17% of patients referred for palliative care, the majority of the referrals within 72 hours of death, and the majority of the referrals for transition to comfort care. On the same vein, our patients get referred to hospice uncommonly and late. So the mean hospice stay for cirrhosis patients in this study was 29 days versus 59 days for cancer patients. Non-informed surrogates, or not having a surrogate, leads to inappropriate care as well. And we know from the literature that in even non-cirrhosis patients, up to 80% of patients are unable to participate in their in-hospital, end-of-life decision-making. And this, of course, may be even worse with hepatic encephalopathy issues. Unfortunately, our family and friends may not know us as well as we'd like. So if you have not discussed your wishes with your family members, you have a non-informed surrogate. In this study, only 35% correctly identified the treatments the patient was willing to accept. Informed surrogates, on the other hand, really are involved from the beginning to know who the patient is and to work with the team to make the best possible in-the-moment medical decisions based on the patient's values. There's no way we can predict every single thing that might happen, but the informed surrogate knows what the patient would most likely want. Third misconception. Patients don't wanna discuss their disease. It's just gonna take away their hope or cause them major distress. And this is really far from the truth. So this is some work that we did in 100 patients who were, again, reasonably well. These were outpatients. I'm just gonna focus on the last two questions. How important is it to know the truth about your health, even if it's not good news, is what we asked them. Unanimously, they all wanted to know, okay? Oh, sorry. Second question, preferred timing of the advanced care planning discussion for the first time when we explained to them what advanced care planning was. And again, the majority of them was in clinic with a provider that they trusted and knew well, not at the time of hospitalization, which is unfortunately what is happening in many, many cases. There is much data to support that advanced care planning doesn't take away a patient's hope. In fact, it increases hope and reduces anxiety. There is an increase in disease-related knowledge, and there's a reduction in caregiver bereavement outcomes like stress and depression and anxiety. Fourth misconception is there's an uncertainty about when do we do this in patients? Which patients actually need palliative care? And I think this is framed by this figure really nicely. And so this figure looks at the life trajectory of our different conditions. And so you can look at frailty, for example, where there is a steady decline in a patient. Advanced cancer, where we have a decline and then that's more gradual, then we have a point where, yeah, that patient's getting worse and a steady decline. So then we know that hospice or additional supports definitely necessary at that point. Arthrosis patient and other organ failures, they have these dips in function where they can come out or not come out. And on top of that, they have hepatic encephalopathy, many of them. So it is so important to get to them early, early, so we can actually see what their wishes are and talk to them before it's too late to really understand what they want. There have been many suggested triggers for palliative care in the literature. And this is just some data from one of the studies, but I would say that many people would support decompensated cirrhosis, those patients awaiting liver transplantation, and those patients who are delisted from the transplant list. I would suggest that palliative care principles should likely be applied, given that many of our compensated patients are suffering as well, ideally across the trajectory of their illness, at least some of the principles around even providing information or prognostication support. But again, it will depend upon resources. Fifth misconception is this is really tough. It's just gonna require a change in practice. And it's how do we integrate a palliative approach to care into practice? And it is tough, especially if we're following this knowledge to action cycle where we do need to, you know, not only go from identifying the problem, looking at it in local context, tailoring interventions, evaluating how it works, et cetera, and going through this process. And maybe the process is a little bit different at each site. But integration most importantly requires teamwork and it requires role clarity. There's gonna be a lot of players. We are all going to have to participate in this and it's gonna require buy-in. Convincing our naysayers around why curative and palliative can occur together. That takes some time and it takes some discussion around that. But I think doing it together, it is possible to do so. And all of us, all of us in this figure will have a role in that. Now, the good thing is, is that we can improve our skillset. And so while we are working on integrating palliative care in, we can improve our advanced care planning skills, for example, to get ourselves a little bit better at communicating. Right now, two thirds of advanced care planning discussions occur in hospital with a median time of about one minute. That is not enough time to get to know your patient or their values or their beliefs. So it's wholly inadequate as far as really doing justice to advanced care planning and understanding our patients. We are very comfortable discussing things like diagnoses and treatments and procedures, but we are very uncomfortable, some of us, in discussing dying and maintaining independence and control, which patients and all of us really want to some degree in our lives. Spiritual wellbeing and impact on family, those sorts of things are difficult to talk about sometimes. It's difficult to prognosticate and prognostic uncertainty often leads us without that skillset to discuss it properly, to giving patients vague information or a tendency to overestimate outcomes. But thankfully, there are resources that we can access and there's many different courses that people can take. I've taken the Serious Illness Conversation Guide, absolutely loved it, really provides you with some of the language that you can start to practice around this. We can improve our communication skills as well when we are discussing with patients choices about is transplant something you should do? Is TIPS something you should do? And I love this framework. It's a best case, worst case scenario. And there's a really nice 10 minute YouTube video online that you can Google and as well, courses around this as well. But it helps us to really see how to take what we normally give patients as percentages for you have a 20% chance of renal failure after transplant and turn that into this is the picture of what you might look like after transplant. Best case, worst case, most likely case. Excellent tools out there for us to improve. We can all start taking some initial steps. So I would ask that we all keep that empathy video in mind when we're seeing our patients, that we routinely provide patients with resources about cirrhosis, that we ask about a surrogate decision maker. Those people are so important in the trajectory of our patient's care in general. Take courses, lifelong learning, take some courses to improve your communication skills and advanced care planning skills. Learn about local billing codes to actually account for your time when you're doing this extra stuff in clinic. Determine your local resources. And this is a team game, meet other players on the team like family physicians and palliative care colleagues. That will allow us to really work towards integrating these models of specialty palliative care into clinic, into transplant. And then contributing to guidelines in the area and obviously spreading the word about why this is important. So I'll end with a few take home points that our patients really need and want information about their condition and about their natural history. And many of them have unaddressed fears and a high, high symptom burden. Palliative care is often misunderstood as a term. And I think as a team together, we can work together to overcome barriers for our patients and our caregivers. And so we are all adequately supported along this very difficult cirrhosis journey. And I'd just like to acknowledge all of the people who have helped me along with this. So thank you so much again to the organizers and sorry for the glitches with the presentation. Management of small for size syndrome in LDLT. This is Deniz Balci, professor of surgery and chief of liver transplantation in Ankara University School of Medicine, Ankara, Turkey. I would like to thank ASLD and IITS education committee for this opportunity to present at ASLD. It's a great honor. I would like to disclose that I'm one of the developers and stakeholder in liver vision software. Nothing better describes small for size syndrome with Benjamin Franklin words. And also prevention is worth a pound of cure. However, once develops small for size syndrome required complex multidisciplinary interaction. Currently accepted definition of a small for size graft is a graft with GRWR ratio, that is graft to recipient weight ratio of less than 0.8. And in the living donor liver transplantation in adults, virtually all grafts are relatively small for size. For the small for size graft to work optimally with immediate great regeneration, avoiding sinusoidal injury is critical. Mechanisms of injury is related with portal hyperperfusion. That is the key factor leading to sinusoidal shear stress causing hepatocyte ballooning with cholestasis around the pericentral venous area. It is corrected in the recovery phase with liver regeneration. However, the patient will experience early allograft dysfunction and small for size syndrome. There are numerous definitions of early allograft dysfunction and small for size syndrome. And currently none of them has been accepted on a global scale. Most definitions concentrate on the timing of day seven or day 14 with total bilirubin of more than 10 milligrams per deciliter and INR over 1.6. With the clinical findings of encephalopathy, poor bile production, delayed synthetic function and intractable ascites and septic complications. The only meta-analysis in the literature is from Hong Kong group. It shows the midterm outcomes, which is three year survival is worse for small for size grafts. However, the long-term outcomes that is five year survival is similar. Hence the authors concluded that small for size grafts should be followed more closely than the regular size grafts. Small for size syndrome is related with factors that are linked and have an interplay with each other. In order to meet the metabolic demand of the recipient by providing a functional graft mass and preventing injury is important. However, small for size syndrome may develop even in the setting where minimum requirements are met. Here is a recent case from our group. We had a patient with 62 years of age, woman with cryptogenic cirrhosis. She was severely sarcopenic with a body weight of 39 kilograms and a history of very sealed bleeding. She had only one donor who was her brother of 52 years of age with a BMI 27, 10% macrostatosis. His left lobe volume to total liver volume was 21, which precludes him from right lobe donation and with the left lobe donation, estimated graft volume was 386 milliliter. But intraoperatively, actual graft weight was 347 grams and GRWR was 0.8. Keeping in mind the 52 years of age and 10% macrostatosis, after implantation, this graft functioned poorly. Intraoperatively, portal pressure was 31 millimeter mercury, which dropped down to 13 millimeter mercury after reperfusion with a normal portal. In arterial flow rates, here we see around 500 milliliters of portal flow and 60 milliliter. After an uneventful early postoperative period, patient had a progressively increased bilirubin and ascites while recovering. She developed an upper GI bleeding, leading a second peak only to resolve after three weeks. The postoperative course described that even when minimum requirements of graft selection and technically successful implantation, early allograft dysfunction or small foresight syndrome may develop. In order to better understand the multiple interactions of graft and recipient related factors, we need a better dynamic model. This is compound epicyclic GEER, I would call a hepatic GEER, and high efficiency model that explains multiple complex kinematic combinations. In the LDLT setting, the inflow and outflow hemodynamics are in a complex kinematic interaction with the liver graft in the perioperative period. The possible change in the components of the GEER that are inflow and outflow have an impact on the efficiency of the model, which has the end point of meeting the metabolic demand of the patient. Unfortunately, currently we don't have a mathematical model that accurately describes the outcomes of change of the inflow and outflow variables regarding with the graft size and graft compliance. In order to follow a step-by-step approach, I would like to divide my presentation with the following order. In the perioperative period, factors related with the recipient are sarcopenia, sepsis, and obviously the melsodium score. Donor age is critically important as well as the steatosis of the graft. And more importantly, the key factor will be the graft volume, which is determined by the graft size. Estimation of liver volume actually requires performing the operation by the computer perioperatively. This is better done by the surgeon rather than the radiologist. The division lines is... As we can see from the software here, it can be done and multiple scenarios can be implemented during the workup. And the software gives us the future lever remnant and the transaction line, which can be modified. Nowadays, we can calculate not only the future lever remnant, but the drainage territories of the portal veins and also the hepatic vein territories. This is critically important in the liver transplantation in terms of arterial flow at the time of closure. In a real-life scenario, we chose here a modified right lobe graft, segment 5 and segment 8 veins that are highlighted red, requires reconstruction for optimal outflow. Here we see the anterior section congestion area, if the anterior section veins are not reconstructed, which are closely more than 25% of total liver volume, which leaves the patient with the actual functional liver cell mass transplanted of only 30% of the right lobe graft, which is the right posterior section. So this can be avoided by defining preoperatively and during the operation. In order to tackle the size limitations, most experienced centers of the East use right lobe graft as the first choice. Here we see Asan Medical Center experience with more than 5,000 living donor liver transplant grafts, 90%, 80% are right lobe grafts, 10% are left lobe grafts, and they go to extremes of dual lobe grafts in order to provide sufficient liver cell mass to heavier recipients, as a picture from one of our recent dual lobe patients. Now we will concentrate on intraoperative factors that are related with the small for size syndrome. After implantation, the graft size becomes unmodifiable, but the inflow is modifiable. In the routine practice worldwide, graft inflow modulations correlate with portal pressures of a given graft after implantation. Actually, sphenic artery occlusion was described in one of the early articles in hepatology in 1980s by Japanese researchers from Kyoto University, that sphenic artery occlusion, they showed that with sphenic artery occlusion, sphenic vein flow decreases with a corresponding decrease in portal flow and portal pressure. Currently, sphenic artery ligation is widely accepted as the first-line procedure for graft inflow modulation, which can be inadequate with higher portal flows of more than 500 milliliter per minute. And if in the right side, a real-time flow meter measurement seen shows effect of sphenic artery ligation on graft inflow hemodynamics. This is before sphenic artery ligation, we see 1400 milliliter portal flow and 70 milliliter arterial flow. And after sphenic artery ligation, this portal flow decreases to less than 1000 milliliter and arterial flow increases to 94 milliliter. The second line is splenectomy. Splenectomy is mostly used by the Japanese centers, and this causes a significant drop in portal vein pressure and portal vein flow. This is used in situations with persistent portal hypertension, with portal flows over 500 milliliter per minute per 100 grams, despite sphenic artery ligation. Here we see a direct measurement of portal pressure with a needle inserted into the portal vein that is connected to the anesthesia monitor via the central venous line. Sphenic devascularization recently described by the ASAN group, an operative picture showing the marked spleen with limited functioning mass. The researchers reported that sphenic devascularization provides effective control on the total bilirubin and INR and SIDs on postoperative day 7, while causing less complications compared to sphenectomy. The third line surgical procedure is the hemopoietic cable shunt. When sphenic artery ligation or sphenectomy fails to reduce the portal hyperperfusion resulting with portal vein pressure over 15 mmHg, hemopoietic cable shunt can be attempted. The potential downsides are portal hypoflow despite shunt calibration and graft ischemia resulting with graft loss. The Medanto group described a portal inflow modulation according to the portal pressure and GRWR. They performed sphenic artery ligation or hemipoietic cable shunts for smaller grafts of GRWR less than 0.8 and 0.7 respectively in order to decrease portal pressure to less than 15 which resulted with small force size development of less than 3% and a comparable survival with patients having GRWR more than 0.8. Recently somatostatin was shown to provide a lower hepatic venous portal gradient at the time of graft hyperperfusion when infused intraoperatively. Now I'd like to share our approach briefly. In Ankara, we looked at our recent data with 95 patients with complete intraoperative measurements with a protocol that is before hepatectomy, 15 minutes after hyperperfusion, after arterial anastomosis and after the flow modulation if done. We are looking at portal flow, hepatic artery flow and portal pressure. Our indication for graft inflow modulation in LDLT is small force size grafts with GRWR less than 0.8 when they have portal flow over 300 milliliter per minute per 100 grams of liver or a low hepatic artery flow and portal vein pressure of more than 15 millimeter mercury regardless of the size of the graft. Our primary choice is sphenic arterial ligation that resulted with an average 30% increase in hepatic arterial flow, around 20% decrease in portal flow and 30% decrease in portal pressure. Interestingly, a portal flow to arterial flow ratio less than 20 was significantly related with better outcomes as well as arterial flow to graft rate ratio more than 6 was also related with better outcomes. And finally, final arterial flow of more than 53 milliliter per minute was related with better outcomes. Going back to liver GR model, graft inflow measurements enable us to better understand hemodynamics that translate into better understanding of graft functions in the postoperative period. Finally, postoperative graft modulation is possible using interventional radiology techniques for sphenic artery embolization. This is mostly in a scenario of hyperblubinemia and ascites in which portal hyperperfusion results with hepatic artery hyperperfusion due to hepatic artery buffer response. We have previously reported two cases and now here we see on the right side a real-life observation of hepatic artery buffer response where the portal vein is clamped while hepatic artery is open and there is a portal pressure catheter in the portal vein. Now here we see the high portal pressure of 36 mm and hepatic artery flow is increasing because there is a portal vein catheter and we will see that hepatic artery flow will climb up to 150 milliliters and portal pressure will increase and then portal clamp was released. This will increase the portal pressure and decrease the hepatic artery flow that is showing the hepatic artery buffer response with a corresponding decrease in portal pressures. What could be next? We have recently described a new approach for increasing liver grafts and donor safety in living donor liver transplantation using rapid procedure in the cirrhotic setting. It is accepted for publication by liver transplantation. Our recipient one with nephrosis, 90 kg BMI 39 with an HCC of 3 cm in segment 8. The donor was 43-year-old male, 70 kg and he had a FLR of left lobe of 367 milliliters which was 24% of the total liver volume. So he could not donate his right liver to his sister. This left lobe graft provided a GRWR of 0.4. So we planned rapid procedure in the cirrhotic setting and this is the left lobe graft. In the first stage operation, we cut the liver and take out the left lateral side and implanted the left lobe graft here and we diverted the portal flow to the left lobe graft using the measurements. We created a hemipolar cable shunt to decrease the portal pressure. This is the post-operative first week CT scan showing graft regeneration almost about 20-30% up to 437 milliliters and then after 3 weeks, this became almost 500 milliliters with GRWR around 0.8 and we were able to show the functional shift to the left lobe up to 70% with hepatobiliary significant CT graphy that we went back to take out the diseased liver. This procedure will potentially give patients with HCC or low MELD scores a timely curative operation option. So key takeaways of my presentation will be prevention of small forsythia syndrome is crucial for LDLT. After implantation, inflow modulation is critical for optimal graft performance and sphenic arterial ligation is effective in most cases, sphenectomy and portal cable shunts are used for refractory cases. Thank you. Good morning, everybody. I would like to thank the ASLD and the organizers of the IELTS course for giving me the opportunity to present today. I'll be talking about transition from pediatric to adult health care, the pediatric perspective. I'm a professor of pediatrics and a hepatologist at Emory University School of Medicine and Children's Health Care of Atlanta in Atlanta, Georgia, United States. And I have no disclosures. So let's talk about some facts. What is the current status of patients transitioning from pediatric to adult health care? Every year, 4 million young adults turn 18 and reach adulthood. Of these, an estimated 1 fifth are affected by chronic health conditions. Annually, approximately 750,000 patients with special health care needs will need transfer from pediatric to adult health care in the United States. Fewer than half of these patients receive the adequate support and services for their transition. Racial and socioeconomic disparities exist, but these children receiving suboptimal care during transitions. And of course, it's well known that transition from pediatric to adult health care can be associated with adverse health outcomes. So what's the status of children with a liver transplant? In 2019, based on the OPTN data, a total of 551 children received a liver transplant. And you can see the age breakout over here. How does that compare to the adult population? As you can see here, these numbers are from up to 17 years of age, and several pediatric facilities will transplant up to 21 years of age. So these numbers may be a little underrepresented. But if you look at this pie chart over here, children form a small percentage of the total transplants. Children form only 7% of all transplants. And though it may seem like a drop in the bucket, they actually form 100% of our future. And if we actually compare, children have a much longer lifespan ahead of them as compared to adults. So we created the UNOS database because we wanted to see what was a 20 to 25-year patient and graft survival. And as you can see here in figure A, this is a 20-year cohort, where the oldest possible patient is 41 years, who would be seeing Dr. Joshi by now. And this part B here is a 25-year cohort, which was transplanted between 1987 and 1990 with an oldest possible age of 46 years. And what we found was surprising and a little disheartening. We found that there was worst patient survival in children who were transplanted between ages of 11 to 15 and 15 to 17 as compared to children who were transplanted under five years of age. Older age of transplant in the pediatric population was associated with the worst patient and graft survival. And our own single-center data, which is currently under review, shows high mortality after transplant from pediatric center in the pre-transition clinic era. So why is that? Well, it's actually very clear. And we all know that by experience, because guess what? We've all been teenagers or we have teenagers at home. The teen brain is still under construction. The things which are last to mature are foresight, planning, and risk-reward evaluation. They're not able to dissociate decision-making and strong emotion. Not that they don't know what the risky behavior is, what the risk factors are. They do. But the strong emotion makes it very difficult to make the right decisions. And, of course, there's delayed maturation in children with chronic diseases in many different spheres. This has been shown eloquently in many studies, including this study, which was published in 2004, which showed dynamic mapping of human cortical development. So what type of patient do we, as pediatric hepatologists, transfer to our adult colleagues? So this is a patient whose long-term survival is already limited by chronic rejection graft loss, which is more common in adolescents. Substance abuse peaks and suicide rate is tripling in 18 to 24-year-olds versus that of the younger teens. Mortality rate of 18 to 24-year-olds is twice those of age 12 to 17. Up to a third of children or young adults may be non-adherent, which is also a known fact. So, again, the age range of 18 to 24 years is associated with a high-risk factor. And that is the age when most pediatric centers will transfer patients to the adult health care. So transition clinics are really needed. As you've seen, this is a high-risk age group. And there are many different models which have been shown. We can have combined clinics. We can have pediatric clinics visited by adult staff and vice versa. Pediatric member can accompany for the first visit. And some people also do a tour of the adult hospital. So when we started our transition clinic in 2011, we asked ourselves the question, what should we do? What should our transition clinic look like? And we went to our stakeholders. We went to the patients who had been transferred out of our facility when there was no transition program in place. And in the survey, we asked questions about what should be done to make the transition easier, how can we prepare you for transition, and what should be changed in our current routine workflow or care which would help with transition? And of course, we also asked questions. And we knew that these were special outcomes we had to focus on, time until first contact, year visits prior to first contact with adult providers, and if the patients were evaluated for a second transplant. And this was published in 2016. And this is what we based our transition clinic format and workflow on. So as you can see, our transition clinic actually consists of a multidisciplinary team. We stratify our patients into low, moderate, and high risk based on several different factors and a scoring system. These patients receive intensive monitoring, follow-up, and education, again, more intensive based on their risk. Contact is made with the adult hospital well before age of transfer. Then the eventual transfer happens, but this workflow doesn't stop here because we follow up on these patients after transfer to assess outcomes, all along giving ongoing preparation, education for transition with assessment for risk stratification, which helps us in determining the frequency of our clinic visits. We start this clinic at 14 years of age or at least a year from transplant when the acute medical issues have decreased so that the focus can be made on transfer and transition issues. 14 to 16 years with optional parent step-out as recommended by the AAP, 16 to 18 years with a parent update, and over 18 years of age with optional or encouraged parent update because we do want our parents to stay involved or provide a support system to our young adults, and if not parent, we encourage buddy visits. We all need some form of support system at any age, so we encourage that they should not try to maneuver this on their own but have some support system to help them with this process. So our program was named as Adolescent Program 101, so AP101, and we had several initiatives. One of the biggest things was we streamlined the multidisciplinary team approach. The clinic visit didn't take hours, and we were not all asking the same questions. We had a single MD provider, which was very important so that the patients could develop trust and the provider would develop ownership towards these patients. There was a patient navigator who helped navigate all the issues and was a liaison between the team and the patient. We had a dedicated social worker, which is so important in our country where patients are at a risk of losing their insurance at 18 years of age. We started a weekend camp just for teenagers where they could mingle and actually form support systems with each others. We have a self-awareness initiative, which I will talk about in a minute. We started a vaccination initiative, which was to make sure that all our patients were fully vaccinated with all the vaccines by the time they were transferred to adult healthcare providers. We started a young adult joint clinic, which I will talk about as well, and then telemedicine clinic, which was started well before this pandemic broke out and was mainly used for frequent touch bases and frequent follow-up with our patients. So this is an example of what we did in our first camp, which was started about six or seven years ago now. Not just the fun things, but it was also we taught them about career and healthy choices, things like housing, money, income tax, how to read a pay stub, how to make doctor appointments, how to know or read or understand health insurance, and of course, financial aid information, how do you locate internships and job training. And we also showed that this information was actually very well received during the camp. We also started a self-awareness initiative, which we administered a short questionnaire in the clinic itself, followed by tailored teaching. And as you can see at the bottom in the intervention group, which received the teaching, which was only five minutes of teaching based on the mistakes they had made, if you will, in the questionnaire, and then the others who received standard of care. And there was improvement in their understanding of their diagnosis, their medications, and also interpretation of common liver tests. But the biggest and the most gratifying part of our transition program, to me personally, and to many of us, has been the joint adult clinic. So at the Children's Hospital and the Adult Emory, we have a joint clinic, which is held at the adult center. It is a dedicated clinic. So there's an entire afternoon is dedicated to a patient who are transferring from the Children's Hospital. There's close collaboration with the pediatric and adult liver transplant teams. We have a designated transferring pediatric provider and a receiving adult provider. So we know who the patients will be seeing. And the person who's transferring them also knows these patients' history in great detail. There's pre-planning for eventual transfer. The clinic visit is attended by the two hepatologists, the pediatric hepatologist, which is myself, and my adult counterpart, Dr. Ryan Ford, who's been a great partner in this venture. And there's an in-person sign out with the patient and family present, which is absolutely a delight to watch because they are afraid, but then they see the pediatric provider and the adult provider together. And that just starts a different level of trust with the adult provider and a basis of a long relationship. And we continue to follow them jointly for one year. So of course, there are so many pros of this model. It is a closed location. So we are lucky that both our hospitals are located in the same area. It is highly beneficial for patients. There's ownership by both teams. We can keep track of missed patients so that no one falls through the crack. Outcomes are well-known to us. And then treatment protocols are also done in collaboration. So if there is a question, for example, there was a question about a patient with a 15-year history of autoimmune hepatitis post-pre and post-trace plan about the use of bortezomab, and it was easily communicated with adult providers. So to summarize, a structured transition clinic is very important to ensure good outcomes. We need a dedicated transition team. We have to recognize that the individual patient needs are different. One size does not fit all. And some teenagers need more help than others. Chronologic age really does not matter, but it is still critical to have a transfer deadline. Objective measures and checklists are important, but listening to the patient, having trust, and ownership of the patient is really the key. Thank you very much for your attention. I would like to thank our transition team, Lori Hall, our RN, who has been instrumental in this transition program, our adult healthcare partners, especially Dr. Ryan Ford, who is my adult counterpart, and patients and families. Thank you, and I'm happy to take questions. I'd like to thank the organizers of the ASLD and the ILTS for inviting me to speak and give you the adult hepatology perspective on the role of transition clinics. These are my disclosures. There are now increasing numbers of young adults with pediatric disorders that are surviving into adulthood. As a result, they will present to adult services and be seen potentially in your adult clinics. This is data from the ELTR database, which shows excellent long-term outcomes in patients transplanted between the ages of two and 18. What will be interesting will be that a number of these patients may go on to require re-transplantation and how one takes them through an assessment program remains to be seen. This is data produced by the team in Birmingham and within the United Kingdom, which highlights the importance of young adult services. You can see here that with the introduction of a young adult service, the overall survival rates in patients above the age of 18 improved and mirrored more that of the pediatric service. There are a number of models of care when it comes to introducing transition services. This diagram here shows the concept of pre-transition, transition and young adult. You can see that there are different age groups and the onus shifts from the parent and guardian to the young adult themselves by the time they are within the young adult service. I think it's important to state that these age groups are not set in stone and one needs to be a little flexible when looking after this cohort. When delivering a transitional young adult service, I think the key aspect to highlight is that of a multidisciplinary approach. This is what we do at King's. We have an adult and a pediatric hepatologist, a clinical psychologist who will provide care from the ages of 12 to 25, social worker, pharmacist, transplant surgeon and specialist nurses. We have a weekly multidisciplinary team meeting where patients are reviewed virtually and we provide inpatient in-reach care. The majority of our work is based in outpatients and you can see a number of different clinics that we offer per week and you can see that the majority of these clinics are based within the adult OPD, allowing the individuals to become familiarized with adult services. A number of adult clinicians may struggle or be weary of looking after a young adult so it's important to understand how they may be processing the information that you give them. The adult brain does not mature and sort of stop growing till the age of 25 so this certainly applies to the young adult group. They tend to be more immature and prone to high-risk behavior and are certainly more impulsive. They may not be able to process information effectively and they are certainly more excited by reward than consequence. So these are important ways of trying to get your information across to your young adult. In front of you is a word cloud with a summary of some of the issues that we will cover very shortly but more of the issues that tend to come up in clinic and when providing care for young adults. Some of these topics may be fairly difficult for one to broach, certainly those of sex, sexuality can be very difficult. So self-management is an important concept which can be applied to all aspects of our care as healthcare professionals and it is underpinned by the fact that information alone is not enough. One needs to be able to give the skills to the individual to be able to self-manage their healthcare. Now, there are developmentally-based skills checklist which allow the young adult to navigate health promotion and the management of their condition, their medications and how they gain further prescriptions and also the healthcare system itself. On the right of your screen is an example of some of the aspects we will cover with our young adults. I think it's important to highlight that more recent data has highlighted the importance of shared self-management with parents and carers because promoting self-management alone with the young adult can sometimes lead to poorer outcomes. When it comes to adherence, there's no doubt that young adults can have poorer adherence rates not only to medications but also to clinic attendance and some data has shown a non-adherence rate of greater than 50%. There's clearly an important link between non-adherence and psychosocial distress and the incidence of non-adherence can lead to increased graft loss in this cohort. So here are a number of sort of factors and risk factors for non-adherence and some of the issues that we will try and cover and address in clinic. More importantly, these are the approaches where you can help your young adult from simple things like asking one of the social workers to review them, patient passports, clinical psychology input and also the availability of clinics during the evenings which may be more convenient for them. So to improve physical health outcomes, we clearly need to improve adherence. To improve adherence then, we need to gain a better understanding of young adults' mental health and wellbeing. This is data from our group where we looked at nearly 200 young adults with either autoimmune liver disease or those that had undergone liver transplantation. And what we found was that there was an increased rate of anxiety and depression compared to the general adolescent population. Our data showed that anxiety levels were increased and associated with increased perceptions of their illness consequence, a reduced perception of control and perhaps they were worried also that they were defined by their illness. So this is important data highlighting the key role of mental health in the care of young adults. When reviewing young adults in clinic, I wanted to highlight the key role of the psychological screening tools. It gives good structure and allows you to gain the correct information from your patient. It's important to highlight the more recent introduction of the Thread screening tool which is probably more appropriate to young adults. So it's always good to reflect and see how we're doing. So this is data from the US looking at a national survey which showed some interesting data. Only 46% of patients had adequate knowledge of their condition. Only 16% of units had a documented transition strategy but it did highlight the importance of self-management. Not to feel left out, we conducted the same survey in the United Kingdom with the help of some of the authors in the previous publication. And our data showed similar findings. One of the key aspects again was that patient and families depended far more on their pediatric provider than on their adult team. So in conclusion, ladies and gentlemen, I think there will be an increasing number of young adults pre and post transplant that will be presenting to your clinics and you need to be able to have a structure and pathway in place to manage them. The importance of self-management and screening tools which give you that structure in the consultations has been highlighted. And I think one needs to have a holistic, collaborative and multidisciplinary approach if you're going to be successful. Personally, I find providing care for this cohort very rewarding and it's not as difficult as one makes out. Thank you for your time. Well, I want to thank the organizers for the opportunity to present on protecting the end organs for the long haul. My name is Lisa Van Wagner. I'm an assistant professor of medicine and preventive medicine in the Division of Gastroenterology and Hepatology and the Comprehensive Transplant Center here at Northwestern University in Chicago, Illinois. And these are my disclosures. So over the next 20 minutes, we are going to define the burden of cardiac and renal dysfunction after liver transplant, summarize the approaches for prevention of chronic kidney disease among transplant recipients, and then we'll move into discussing some strategies for prevention, particularly of atherosclerotic cardiovascular disease. And then we'll end by describing some major gaps in protecting the heart and kidney after liver transplant. So let's start by defining the burden of the diseases. To start, the prevalence of cardiovascular disease related mortality is increasing after transplant. And since 2002, there has been about a 66 percent increase in the prevalence of cardiac mortality among liver transplant recipients, such that cardiovascular disease is now the leading cause of early and the third leading cause of late morbidity and mortality after transplant. And this rise in cardiac mortality can be at least partially attributed to yet another unintended consequence of institution of the MELD score for liver allocation. This is a study that we conducted among about 38,000 liver transplant recipients, linking OPTN data to a large claims database in order to investigate the relationship between EGFR at discharge from the transplant hospitalization and both all-cause mortality shown on the left and cardiac mortality on the right. And what you can see here is that similar to what we observe in the general population, as EGFR decreases over time, both all-cause and cardiovascular mortality increase after liver transplant. Again, another contributing factor to the rise of adverse cardiac outcomes is that exacerbation of underlying traditional cardiac risk factors is extremely common in our transplant recipients. This is data from our own experience at Northwestern and over 600 transplant recipients over the past five years. And you can see that the pre-transplant prevalence shown in the green bars of hypertension, CKD, hyperlipidemia, and diabetes all increased substantially after liver transplant. And notably, the CKD prevalence was up to 78% at five years after transplant in this cohort. This is, of course, first demonstrated in a landmark paper by Ojo et al. in the New England Journal of Medicine that demonstrated that even after restoration of normal liver function, apart from intestinal transplants, liver transplant recipients, which are shown in the gray line here, have the highest five-year incidence of chronic renal failure of any non-renal solid organ transplant recipient. And of course, there are several consequences that are associated with chronic renal failure in liver transplant recipients, including limitations of drug dosing of not just our immunosuppressants, but our anti-infectious agents, increased frequency of hospitalizations, infectious complications, and of course, increased risk of non-renal allograft dysfunction. And it's been shown repeatedly now in several studies that there is about a two to fourfold increased risk of mortality among patients who have chronic renal dysfunction and those that do not after liver transplantation. So what are some of the approaches that we have for preventing chronic kidney disease in the liver transplant population? Well, the first step towards preservation of kidney function is to, of course, accurately estimate renal function. It's really well established that the blood-based equation, including both the creatinine and cystatin C equations, may over or underestimate measured GFR in liver transplant candidates, particularly in patients who have sarcopenia. In a recent meta-analysis, the solid organ transplant recipients, 35% of which were liver recipients, it was the CKD-EPI equation and the MDR-D4 equations, while they are imperfect, are likely the most accurate compared to measured eGFR. Alternate models are also being investigated in liver transplant candidates. And those two of these, the GRAIL model and the reverse model, were recently published last year in Hepatology. But regardless of the model that you use to estimate GFR, it's important to note that change in eGFR really provides the most prognostic value in this patient population. The second step is, of course, to recognize and accurately diagnose both AKI and CKD. And notably, most cases of early kidney dysfunction after liver transplant are related to AKI. However, as the comorbidity burden rises after transplant, as we saw in the prior slides, the ongoing effects of immunosuppression and CKD burden rises in parallel. According to published consensus guidelines, AKI is simply defined as an increase in baseline serum creatinine greater than 0.3 within 48 hours. And CKD, regardless of the equation used, should be defined as an eGFR less than 60 for a duration of greater than three months. The third step is to prevent AKI and control comorbidities and risk factors for CKD. And what we're going to focus on here is the modulation of immunosuppression, which, of course, as transplant providers, we have some of the most control over. So there are three main approaches to renal sparing strategies in liver-only allograft recipients with either pre- or post-transplant renal dysfunction. And those are to either reduce the calcineurin inhibitor, often through the use of mycophenolate mofetal or an mTOR inhibitor, to use induction therapy with consideration for a delayed emission of the CNI, and the third is to convert to a non-CNI agent such as Everolimus with or without the addition of MMS. So, of course, we would all love to just kick CNIs to the curb completely in order to preserve renal function in liver transplant recipients. And this question, of course, has been ongoing in the transplant community since the approval of Everolimus, which many of us hoped that CNI elimination would be possible. However, in this trial by Saliba et al., which compared Everolimus to reduced TAC versus early TAC elimination at 30 days post-transplant compared to the standard TAC group, it resulted in, of course, stopping of that TAC elimination arm early due to high rejection rates that were seen in that group. But what about leveraging induction therapy and waiting longer than 30 days in order to stop the CNI? Well, the PROTECT study tried to answer this question in which liver transplant recipients were given initial basaliximab induction and randomized at four weeks post-transplant to start Everolimus and taper off CNI therapy between eight to 16 weeks post-transplant or continue their current CNI-based regimen. And what they showed is that EGFR was superior for the Everolimus group using the MDRD formula, and the rates of the mortality, biopsy-proven acute rejection, and efficacy failure were similar between the two groups. Importantly, both a 24-month and a 36-month extension studies showed that continued renal benefit of Everolimus versus standard CNI therapy. But PROTECT did not include patients with immune-mediated liver disease, and the renal dysfunction, as you can see in the figure here, was fairly well-preserved at the time of randomization with EGFRs around 80 to 90. So there's a lot of unknown still in terms of our ability to eliminate CNIs completely in this population. And notably, in a recent sort of real-world analysis study called the Certitude Study that was recently published this past year, only about 50 percent of liver transplant recipients are actually able to maintain an Everolimus-only maintenance regimen. So we still have a lot more needed in terms of our ability to completely eliminate CNIs as a means of preserving renal function. So finally, what about late renal protective immunosuppression strategies? Well, unfortunately, there is no substantial evidence that reduction or elimination of CNI therapy in favor of mTOR inhibitors can improve renal function if you do it after a year after transplant. There is some low-to-moderate quality evidence that MMF and concurrent reduction of CNI therapy might possibly result in some modest improvement in renal function if it is done greater than one year after transplant. So there is some possibility, though the data is not very strong. So, of course, the final step in renal preservation is to ask for help. This is data from our own experience at Northwestern that we presented to ASLB last year, where we simply looked at our proportion of patients over the past five years who had a diagnosis of CKD who were being co-managed with nephrology, as shown in the green line. And then we looked at some guideline-recommended treatment of simple CKD risk factors, such as achieving a blood pressure of less than 130 over 80 in this population. And what you can see is that less than 45 percent of our liver transplant recipients with CKD were appropriately co-managed with nephrology. But I think the most important thing is that co-management with nephrology was actually associated with a 43 percent lower hazard in major cardiovascular events. Now, whether or not this was a result of increased adherence to guideline-recommended CKD care is unknown, but I think it provides an important area for future study. So what about atherosclerotic cardiovascular disease? How are we doing at controlling ASCVD risk after liver transplant? Well, we're doing pretty much as well as we are doing co-managing with nephrology for CKD. Again, if we look at our own experience here at Northwestern, you can see that looking at the orange line, that on average, only about 25 percent of our liver transplant recipients met a blood pressure threshold less than 140 over 90 within six years of transplant. If you look at the green line, only 10 percent, 10 to 15 percent of our transplant recipients were prescribed a statin for primary prevention. And if you look at the yellow line, we did a little better in terms of documenting lifestyle counseling or referral to nutrition therapy, and that 35 percent of our patients with obesity received that intervention. But by year two, we sort of petered out and our rate hovered around 20 percent of our recipients in the long term. So we obviously could be doing better. But does doing these things actually change cardiovascular risk in liver transplant recipients? And yes, it possibly does. This was a study that we published in AJT earlier this year in which we looked at patients who maintained a blood pressure less than 140 over 90 in the first year after transplant shown in the dark orange bar versus those who did not. And what you can see is that there was a 35 percent reduced hazard of cardiovascular events and a 52 percent reduced hazard of all cause mortality among these patients. So what I want to do over the next few slides is to just briefly highlight some of the current practice guidance for management of these cardiac risk factors in liver transplant recipients and where I think some of the major research gaps remain. In terms of measurement, blood pressure, of course, should be measured at every liver transplant visit, but we really should also be prescribing home blood pressure monitoring, which is very integral into adequately diagnosing and detecting hypertension. Finally, if we have elevated blood pressure or hypertension, we really do need to repeat assessment and potentially consider initiations of therapy. However, even though I showed you that blood pressure less than 140 over 90 is potentially beneficial in improving outcomes, the blood pressure target recommendations that we have in liver transplant recipients are not actually evidence based. We don't know whether a lower target, perhaps less than 120 over 80 or less than 130 over 80, are potentially better versus standard targets or whether you could go too low and potentially cause some unintended harm like to the liver graft or even to the kidneys. All liver transplant recipients should be counseled on lifestyle management, according to American Heart Association recommendations. But it's really unknown how much do we as practitioners continue to enforce sodium restriction after liver transplant for prevention of hypertension? And is this counseling actually effective for blood pressure control? In terms of pharmacologic therapy, there are many unknowns in our liver transplant population beyond the scope of our talk today. But in general, the pharmacologic approach should be based on comorbidities and two drug therapy should be and is usually required in order to adequately control blood pressure in this population. In terms of post liver transplant dyslipidemia, whether the risk based equations that we use in the general population for ASDVD risk prediction over or underestimate risk in liver transplant recipients is really unknown. But in general, lipid management should take a risk based approach. And due to the high prevalence of dyslipidemia in our populations, patients should be screened with a fasting lipid panel beginning around three months after transplant. And we should repeat this at least yearly. Treatment should really focus on risk and pharmacologic interventions must consider the drug-drug interactions and engage transplant pharmacy for any dose precautions, particularly early after transplant. Of course, many of our immunosuppression drugs, particularly the mTOR inhibitors that we discussed early and disease states such as NASH in our patient population have a really high prevalence of dyslipidemia and hypertriglyceridemia in particular. So in cases in which we have fasting triglyceride levels that are greater than 500 despite statin therapy, synthetic fish oil may be an acceptable second line agent, though it is definitely not as effective as phenofibrate for triglyceride lowering. There are a lot of concerns for drug-drug interactions between statins and fibrates and the increased side effect profile that we might see in our patient population who are also on CNI. So again, working with transplant pharmacy is incredibly important in this population. So finally, hyperglycemia is, and post-transplant diabetes, incredibly common in our patient population as we saw at the beginning of this talk in which over 50% of patients will develop post-transplant diabetes within six years after transplant. And so therefore screening early with both fasting blood glucose and hemoglobin A1C, acknowledging the limitations to A1C measurement in the early transplant period are indicated in liver transplant recipients. In most of our transplant recipients, targeting an A1C less than 7% is warranted, though some populations may consider less stringent A1C control. But we really don't know what the benefit and the harm is of tight glycemic control in this population and where the threshold actually might lie, especially in terms of timing after liver transplant. In liver transplant recipients, we do have good quality evidence that steroid-induced hyperglycemia is best managed with insulin therapy. However, there are a lot of unknowns in terms of the possible cardiovascular disease benefits in particular for SGLT2 inhibitors, given their new labeling indication. And of course, the potential role for GLP-1 agonists in this population, both for prevention of ASCDD risk, but also for prevention of potentially heart failure risk, which is a huge cardiovascular comorbidity in this population that we're not going to address today. So finally, in the last few minutes, I want to address some of the major gaps in care. If we have all this mounting evidence that cardiac disease and renal disease are so bad in liver transplant recipients, and we know the basic steps that we need to take in order to prevent adverse events, then why aren't we seeing improvements in this population? So we sought to address this. We surveyed 130 physicians, we had about a 70% response rate nationally, and asked them to review cardiovascular disease guidance recommendations that were adapted from evidence-based guideline documents across six domains. Lipids, blood pressure, tobacco use, weight management, glucose control, and renal function. And participants ranked the importance of the proposed guidance using a Likert scale and then assessed its accuracy in the liver transplant population. And they agreed on several things. They thought that cardiovascular disease risk factor screening was important, everybody should stop smoking, statins were important for secondary prevention, and blood pressure lowering and diabetes control is really important, and everybody should be getting lifestyle modification counseling. However, participants disagreed on a lot of things. One of the highlights is that they disagreed on how frequently we should be screening for cardiovascular risk factors. They disagreed on whether or not statins had any efficacy for primary prevention in this population. Everybody disagreed on the target blood pressure threshold, which we discussed previously, and less than 10% of respondents had any confidence in their ability to recommend weight loss pharmacotherapies, a type of diet, or bariatric surgery for liver transplant recipients. The practice guidance that we have in the general population has strong evidence. There's still a lot of uncertainty as to whether or not these metrics actually apply to our liver transplant population. And there's a significant lack of self-efficacy among providers to provide care for these risk factors. So we then convened a series of focus groups to ask patients, caregivers, and multidisciplinary providers about their perspectives on cardiovascular disease care after transplant. There were four main barriers to care that we identified, and there are some example quotes that I'm showing you here that highlight these themes. The first barrier was that there was a significant lack of awareness of cardiovascular disease risk after transplant, not just among patients and caregivers, but actually also among providers, particularly non-transplant providers. As one liver transplant recipient said, you're not worried about the heart at that point, you're worried about living. There was also a lack of confidence in the ability to provide proper care to cardiovascular disease recipients. One caregiver highlighted that the most frightening experience was them saying you're discharged. There was reluctance to provide cardiac care without transplant provider review. And the complexity of communication with the liver transplant team about cardiovascular disease care was highlighted by both liver transplant patients, caregivers, and providers. And one cardiology provider said, who is actually managing the health of these solid organ transplant recipients? I don't know who. So in a post-group survey, we asked participants then who should be responsible for managing risk factors for heart disease after liver transplant. And if you look here, you can see that the liver transplant recipients and the informal caregivers, greater than 80% of them thought that the transplant team or another specialist, like a cardiologist or a nephrologist, should be responsible for this care. Whereas the healthcare providers, the majority of which thought that the primary care doctor should be the appropriate leader of cardiovascular disease care. So in reality, we're all just sort of passing the ball back and forth, one to another, and nobody is actually taking care of these patients adequately. So there are many models that are being discussed, of course, for the long-term post-transplant care. And one of the things that we're trying to address here at Northwestern is, of course, to address the quality of care that we're delivering, in particular for cardiovascular disease care, though. Many of these things obviously have benefits for long-term renal care of these patients. And this is the CVD quilt study that we're running here at Northwestern, in which we're designing education. We're designing best practice alerts, care algorithms, and studying the implementation principles and actually getting this into the healthcare system to see if we can actually move the needle on care. But then, of course, it comes down to, what about our system of design of care? How are we actually managing not just cardiac risk and renal risk, but of course all the other prevention, sort of long-term, long-haul management in this patient population that we've been discussing in this course today? One care model, of course, that's been proposed is this idea of the post-transplant medical home. There are many other care models that are out there, but I think it really is time that we reexamine and redefine how we're providing care to this population in order to better manage this organ for the long haul. So in summary, cardiac and renal dysfunction contribute to greater than 60% of the long-term morbidity and mortality after transplant, and detection and surveillance of these risk factors is really paramount to protecting these end organs in the long term. Early control of these risk factors decreases mortality and cardiac events, and the treatment strategies really do need to take into account the underlying pathophysiology of disease. However, providers lack confidence in managing risk factors in liver transplant recipients, and the overall awareness of cardiovascular disease risk in liver transplant recipients is low. So I thank you for your time, and I look forward to your questions. Thank you to the ILTS Education Committee for asking me to speak about malignancy prevention in liver transplant recipients. And of course, if I knew how to prevent cancer, I would be in a much better station in life, but we will take the approach of trying to reduce risk of malignancy in liver transplant recipients. And here's my disclosure slide and looking at malignancy prevention with the idea that we're going to reduce high risk patients overall risk of malignancy. We're going to talk a little bit about lifestyle techniques, medication, optimization and surveillance or screening in our transplant patients. As we know, screening does lives. And we all know the reason we have to have this conversation is that malignancy is 1 of the leading causes of death after liver transplant and long term follow up. So non liver deaths over a 3rd of those tend to be related to cancers. 1 of the main reasons for the increased risk in transplant recipients is immunosuppression and it's a widespread belief and knowledge that immunosuppression certainly increases the cancer risk by reducing tumor surveillance. Essentially, in a normal environment, the T cell is needed to distinguish a normal cell from a cancer cell and in many different interactions within the tumor micro environment. The cancer cells themselves interact with T cells to effectively make them ineffective and have them ignore the cancer cells when we immunosuppress our patients, particularly with our focus on T cells. We effectively curtail the effects of these T cells and their cancer surveillance mechanisms. There's several different studies that have looked at the effects of our T cell mediated immune suppression. And these do show dose dependent effects they've shown to promote tumor growth. There's been studies that show shortening and double doubling time specific to calcineurin inhibitors. And there's several different studies that show increase in recurrence in HCC. All of these studies in general are flawed as many of them are retrospective. Some of the effects, though, of immunosuppression that we seldom ever even think about or talk about and certainly have impact on cancer are the metabolic effects. So hyperglycemia, hyperinsulinemia, low adipokines, chemokines, and other effectors, and then increased risk with malignancy, diabetes, other metabolic abnormalities that are certainly associated with higher risk of malignancy. In addition, we go from differing estrogen status in chronic liver disease compared to after transplant, and there can be certainly different effects on breast cancers and HCCs with hormonal imbalances, etc. Another specific effect that immunosuppression has that we also again seldom think about is the effect on, we think about it in the realm of infection, but we don't think of it in the realm of infection related malignancies. And there is definitely an increase in malignancies that are infection related in transplant recipients of all solid organ transplants. And if you just think about lymphomas, we all think about with EBV, liver cancers with hep C and hep B, which, of course, hopefully will be less in the hep C DAA era, H. pylori for stomach cancers, HHV8 for Kaposi's, and HPV for multitude of genital urinary cancers, as well as the oropharyngeal malignancy. And so we have to think about not just malignancies themselves, but perhaps even looking at the infections related to those malignancies. When we try to tease out what immunosuppression is, which specific immunosuppression is truly increasing these risks, it's really challenging to do. And we're sort of stuck with retrospective studies. And this is a study done with the SRTR database, trying to look specifically at patients discharged on cyclosporine based immunosuppression compared to TAC compared to mTORs and the exposure over that 1st year to antilymphocyte antibodies and the effects on all cancers, solid and skin and hematologic malignancies, and really only showed a difference in skin malignancies in patients on calcineurin inhibitors compared to the mTOR inhibitors. You do have to remember that many patients, this is all retrospective, you're not accounting for why somebody is put on those particular drugs. And so, of course, somebody that's higher risk was probably put on an mTOR inhibitor. And of course, that's going to make this entirely uninterpretable. What this study did show is that the degree of immunosuppression is what matters. And comparing 3 immunosuppressants to 1 or 2 immunosuppressants was dose-related, effect of more immunosuppression with higher risk of malignancy, less immunosuppression with lower risks of malignancy. And this is not a surprise, and we've had a fair bit of data, at least in the literature, looking to make that point. And so, the case to try to lower immunosuppression doses has at least some data around it, and this is 1 of the better studies looking specifically at lowering the calcineurin inhibitor dose and the effect of the calcineurin inhibitor dose on malignancy. And this is a French study looking at a fairly high amount of alcohol and smoking in their patient population of 249 patients, and found about 17% of these patients over a mean of 8 years did develop a malignancy, and that's a little bit higher than are normally seen with about 17% at 11 to 15 years, but again, high risk population. And what they did show beautifully with this curve is the mean tachrolimus dose, the higher doses, had an increase in the probability of developing a de novo malignancy after transplant. And it shows this quite well on the multivariate analysis. The mean tachrolimus dose, as well as smoking before transplant, were the independent risk factors for developing a malignancy after transplant. We've seen this in several different retrospective studies of HCC as well. This 1 in particular was able to identify low dose calcineurin inhibitor and high dose calcineurin inhibitor in patients that had otherwise a high risk of HCC recurrence with the factors listed here, high alpha-beta protein, microvascular invasion, and poor histology, and the addition of high risk calcineurin inhibitors exponentially increased their risk of recurrence. Compared to low risk, and specifically for those high risk individuals, really increased the risk of recurrent malignancy. So, which choices of our immunosuppression can we make that might help to reduce risk in our patients? And we do have plenty of data that has shown the association with azathioprine and skin cancer. This is all solid organ transplant recipients, multiple study meta-analysis. This really showed that squamous cell skin cancers were increased with azathioprine, not basal cells, melanomas, or keratin-based malignancies. So, this is probably what drives most of the attention away from azathioprine and more towards cell-sept or mycophenolate-based drugs. So, what about this case for mTOR inhibitors? We've all heard about the antiproliferative effects of mTOR inhibitors. In theory, they should reduce malignancies, and there's actually been several different meta-analyses. Many are negative, some are positive. This particular one is a little bit more positive than many. This was using individual patient data. It's all kidney data, 21 trials, almost 6,000 patients with 243 de novo malignancies. And you can see when you look at the data for overall cancers, it does look like there's a benefit to mTOR inhibitors. But it really is truly a benefit for the skin cancers, once again, not so much for the other cancers. And if you look at the details, there's a little bit of a benefit if there's a conversion trial from calcineurin inhibitor to an mTOR inhibitor, and they found that to be related to RCCs or renal cell carcinomas, which are mTOR-sensitive malignancies. But causes of death were actually, or increased risk of death was noted in patients with mTOR as well. And these patients died not of malignancy, but of infection and cardiovascular disease. So not a definitive help in deciding, do mTORs reduce the risk? What if you've already developed a cancer? Well, then an mTOR inhibitor may be of some benefit. And this is where everolimus has been looked at in a very small study of heart transplant recipients that had multiple aggressive recurrent melanoma skin cancers. And these patients were then added everolimus to their regimen or changed completely from calcineurin to everolimus. And essentially, before to after, there was reductions, mostly squamous cell carcinomas, less so the basal cell carcinomas and other skin malignancies. Another study looking at solid organ malignancies in liver transplant recipients, not including skin malignancies in patients that had a diagnosis, had a better outcome, so better survival in those patients that were on everolimus compared to those patients not on everolimus. We've had a couple of studies retrospectively in HCC recurrence, trying to determine if mTOR inhibitors reduce HCC recurrence. And the silver study was done as a prospective investigator-driven study that was to be the definitive answer. And unfortunately, this study was unable to prove that mTOR inhibitors reduce the risk of HCC recurrence. And they had over 250 patients in each group, no difference in overall recurrence rates and no real difference in overall survival. There were some subgroup analyses that showed certain groups having some benefit, but particularly unexpected ones. But important to think about why this would necessarily fail. And if you think about 15 to 25 or 30% of patients having recurrence, that's much smaller numbers, and only half of those are likely to have mTOR upregulated in that particular malignancy. So only half are even likely to have an effect, and it may be a numbers game. So not all tumors are driven by mTOR signaling. mTOR currently are cytostatic. They are not cytotoxic, so it might be more of a disease stabilization effect as opposed to tumor regression or not developing a tumor. mTOR2 pathway is just as important as mTOR1, and none of our current mTOR inhibitors affect that. So future mTOR-based medications will be looking to block mTOR2 as well and maybe have more benefit. So more to come on mTORs. So what else can we do to reduce the risk in our patients besides immunosuppression? Well, there's plenty of data out there in the general population on exercise and cancer. So not only with the diagnosis of cancer, but in preventing cancer, and this is one particularly large Australian study of 755,000 people that are followed with respects to their activity measures. They've had no previous history of cancer, and they're just followed for development of any malignancy. And 7 cancers had a reduction based on the effect of exercise. So with somewhere between 7.5 and 15 met hours per week, there was a reduction in colon cancer, more so for men than women. Reduction in breast cancers were noted, liver cancers. And so essentially the take home message is, is there can be a reduction just with simply inserting regular exercise into your regimen, which, of course, we all know the benefits of exercise. We just seldom think of it as cancer prevention. If you're diagnosed with cancer, many oncologists now are prescribing cancer, sorry, exercise treatments. And this is because there's actually strong data showing that you will have a reduction in the risk of developing cancer for certain malignancies. There's at least some data saying that you may have an overall improvement in survival in certain cancers if you're also add exercise to your regimen. So exercise is a good thing no matter what to our transplant recipients. We just need to convince them of that. So, what if you have diabetic patients? Is there something specific you can do? Well, this is a study from a large Taiwanese database that was able to show a very significant finding here with insulin use and a very high increased risk of HCC associated with insulin use compared to metformin or the PPAR agents that actually were found to have lower risk. And this fits with what's actually in the general population data. And there's plenty of data out there to suggest that insulin use may induce tumorigenesis and may increase risks for cancer. And there is plenty of data out there supporting that metformin has some benefits, a little bit less supporting the PPARs in the general population data. Metformin, though, is the go-to drug for treating hyperglycemia. And so there can be some benefits. And this is a meta-analysis, particularly looking at HCC events. And there is a benefit to reduction in HCC in patients treated with metformin. And metformin has some bona fide potential benefits in that it's a weak mTOR inhibitor. It has insulin sensitizing. It inhibits the IGF-1. Anti-inflammatory effects, anti-androgen and estrogen effects. And so there is at least some potential reduction that you may see. Having said that, they did just have a recall for carcinogenic contaminant. And so that's obviously going to need to be sorted out. But the drug effect itself may have some benefit. What about statins? Because we're going to put that into everyone's post-transplant medication pretty much universally. Now, if we add in the cardiovascular benefits and all of the other benefits to statins, now we can add in cancer. And there's definitely some potential with this. So there's colon cancer benefits. This was a New England Journal. And so an improvement in odds or reduced odds in patients that had been on statins compared to no statin. There was a relative risk reduction of about 39%. Another study similarly set up. 29% lower risk of dying from colorectal cancer if you were on a statin compared to not. Looking at HCC in specific, there's plenty of studies that were looked at. And there's even enough for a meta-analysis back in 2013 that did show some benefits to statins in reducing the risk of developing HCC. So if they need to be on a statin for another reason, by all means, there may be some benefits. And if it's sort of a borderline question, and it's a high risk for cancer, maybe give some serious consideration. And which statin you choose may also have some importance here. So there's lipophilic statins and there's hydrophilic statins. So the atorvastatin and simvastatin are the lipophilic statins that when looking at HCC protection or reduced incidence of HCC, there was a statistically different, or sorry, statistically reduced incidence of HCC using the lipophilic statins compared to no difference with the hydrophilic statins. And this is looking at over a decade of years in viral hepatitis patients. And this was needing at least two years of therapy to show some benefits, but picking atorvastatin or simvastatin over the other ones made some value. So importantly, screening is super important. And we're seeing more and more patients coming to transplant with a previous diagnosis of malignancy. And there's some new guidance that's just been published in AJT with David Aladra as the lead author. And this was a working group through AST of numerous oncologists of various different malignancies, as well as a lot of solid organ transplant people getting together and coming up with new guidance. And this is just an example of what's in these papers to actually help us determine timing to transplant. But this group also determined what kind of surveillance is going to be needed for these individuals, because there is definite data out there in the general population that patients with a prior malignancy are at increased risk of a second primary malignancy. And they're at increased risk of recurrence, of course. So we need surveillance for the recurrence. And there are some recommendations that are coming. This will be in, it's in submission at present. Screening, though, in those patients that have had a prior malignancy, they absolutely need to be diligent about screening for other malignancies. And our high risk population also need to be diligent about screening. And unfortunately, our screening recommendations are truly based on annual general population recommendations in most cases. Now, skin is a little bit different. We have our patients pretty universally being seen annually. Colon cancer is a little bit different in our transplant population that we have a lot of patients with IBD and PSC that get more frequent colonoscopies. And that's pretty standard, I think, across our community as well. What we don't know is what we do with the other patients. Who is at higher risk? And we're going to show you some data here that shows a group of NASH patients that may be actually at higher risk, and we should alter their screening recommendations as well. Lung cancer, I think our transplant community does a poor job at screening the way even the general population is supposed to be screened. Ex-smokers and current smokers require CT chest for screening, and very seldom do we truly do that. ENT, we have some different recommendations than the general population because we definitely have much higher risk of oropharyngeal malignancies, particularly in the alcohol transplant recipient and ex-smokers. And the genital urinary, breast, prostate, and renal cell carcinoma really are based on general population screening guidance. And there's now actually a publication specifically in cervical cancer screening for immunosuppressed individuals that is available through the NCCN guides as well. And so, looking just at colorectal cancer screening and transplant recipients, we all know that PSC patients are at higher risk. And we took a look here, and this is just in submission now being reviewed at NASH and alcohol-related liver disease. We looked at the other related diseases as well, but the 2 that seem to be at higher risk are NASH patients above the age of 50 with HCC, higher risk of developing a colorectal cancer. This gray line is a general population risk, and these are unscreened patients. Our patients are generally all screened, but we don't know their polyp status. So, within 5 years, males with HCC and NASH will have an increased risk, same as females at about 5 years. And for women over the age of 50, alcohol-related disease also showed an increased risk. And we need to look at why that would be, because most of these patients would have been screened. So, there's at least some data of what groups we probably need a little bit more data to be able to change screening guidance, but it is definitely a start. So, there's another population that may require a little bit different screening post-liver trend. Oropharyngeal malignancies, this is not something that's seen a lot in the general population, so there is no real screening guidance, but definitely in smokers are the highest risk. Smokers with previous alcohol-related disease are thought to be the highest risk. When you look at all the patients that develop oropharyngeal malignancies, HPV was underlying in about 75% of those in one particular study. And then just looking at our population of liver transplant recipients, who really is at higher risk and dividing it out by age, well, of course, age over 50 with the dotted lines are all unanimously higher risk, but what's surprising here is that PSC, in fact, is actually the highest risk in the earlier years and even higher than alcohol throughout. And whether this is because they're younger and maybe more HPV, it's really hard to know, but keeping in mind that it's not all just alcohol-related and smokers. So the key takeaways here are risk minimization and prevention is the key. So we'll expect more patients to come to transplant with a malignancy and we need to have strong surveillance recommendations. We need screening and we need immunosuppression minimization and metabolic interventions to help reduce the risk of developing a cancer in these patients. Hello, this is Paritosh Prasad from the University of Rochester Medical Center, transplant infectious disease, and I'm going to be speaking about infection in the immunocompromised traveler. I am a transplant infectious disease and critical care specialist up at the University of Rochester. I trained at Harvard Medical School and I'm the director of transplant infectious disease as well as the director of surgical critical care here at the University of Rochester Medical Center. I have no financial relationships with any commercial interests and no disclosures. So we're going to start with a bit of an overview. Obviously, when we think about transplantation, solid organ transplantation is all about trying to get our patients back to enjoying their lives. The patients have had an organ failure of some manner and the goal with transplant is to get patients back to a quality of life. Following solid organ transplant, the risk of infection, as we all know, is highest in the first year. It depends a little bit on the type of transplant, the type of immunosuppression, the course of the transplant in regards to issues of rejection, etc., the need for re-induction, but by and large the depth of immunosuppression is that first one year after transplant. Why this matters is that the immunocompromised traveler makes up about one to two percent of patients seen in travel clinics in the U.S., but about a third of transplant recipients will actually seek to travel outside of the U.S. after their transplantation and the vast majority, about two-thirds of these folks, won't go to a travel clinic, which is the standard approach that most folks will go for for pre-travel advice, but they'll seek pre-travel care from the transplant providers, which makes a lot of sense when you think about the complexity of transplantation, medications involved, all of the nuances immunocompromised host brings to the to the table. So we're going to focus on the pre-travel evaluation and the recommendations around care prior to travel and we're going to try and structure this in a very classical framework using infectious disease, which I'm sure everyone is used to, which is the structure of looking host to the pathogen and the environment. We're going to start with emphasis on the host. Obviously, a solid organ transplant patient, by definition, we want to think about the kind of immunosuppression involved. That's going to take into account not only the time since their transplant, as we said, the degree of immunosuppression impact on the body changes over time, further you are from induction of transplantation. That clock can get reset if a patient is on a developed rejection and undergone therapy for rejection, and it's very much mediated by the current regimen that the patient is being treated with for their immunosuppression. And that, obviously, in the degree of immunosuppression is going to vary to some extent based on the type of transplant involved. As we know, the degree of immunosuppression for a lung transplant is quite different than one would require for a liver transplant, etc. The other component that has to come into play a little bit, as you provide advice to a traveling immunocompromised patient from a transplant perspective, is the degree of organ function that they have and how that might impact issues around travel and infection in the traveler. Examples of this would be lung transplantation and the ability to travel by air. There are issues in regards to oxygen utilization and the types of support moment needed if they're going to travel by air, and that needs to be taken into account. Many solar organ transplant patients who've had issues, anatomic complications, liver transplants, kidney transplants, may have indwelling drains, percutaneous, post-osteotomy tubes, nephrostomy tubes. And it's important to take that into account when someone's traveling and the kind of supplies and the issues that arise around travel with those, because those are also, both anitis of infection can become occluded, issues can arise on that front that can lead down the pathway of infectious disease. We can also focus and think a little bit about the environment. This is a little more classical. When we think about the pre-travel advice, where is the patient going? When are they going? What are they going to be doing? Anybody who's worked in a travel clinic beforehand will have seen most travel clinics have some manner of software that's utilized that the patient fills out prior to their visit that includes information about their travel plans. And that shouldn't just be about which country, but where in the country, how long they're going to be in that environment. Is that a city? Is that more rural? It's important not just how long and where, but when, time of day, time of year, impacts some of the risk for seasonal infections, monsoon rains, for example. Certain arboviruses are at higher rates during certain periods. When they are traveling, where are they staying? A trip to a high-end hotel in New Delhi, arguably over the course of a weekend, arguably is going to have no significantly higher rate of risk of exposure than the same kind of travel to a high-end hotel in another developed part of the world. And then what is the total duration of their travel? And this feeds into the kinds of risks one might be considering they'd be exposed to and the role of prophylaxis. It also feeds into the decisions and recommendations around how much medication to take with them and to arrange potential support, medical support, in those areas should issues arise. And the last piece is really pathogen-specific, and there's two pieces to that, which is different for the immunocompromised host than it is for the average traveler. We all think about the exogenous risks, the need for vaccination against certain pathogens, and we'll go into details around that, but also the role of prophylaxis against certain endemic infectious processes such as malaria. But in the immunocompromised solid organ transplant host, we also need to think about endogenous infection and risk, and those things can also become issues when someone is traveling, the need to bring prophylaxis for endogenous infectious conditions such as CMV prophylaxis. Now let's go into some of the recommendations that are available and targeted against, targeted for the management of the immunocompromised host and specifically solid organ transplant patients when they're traveling. All solid organ transplant patients, when we think about ACIP vaccine recommendations, all solid organ transplant patients on active immunosuppression are characterized in the severe immunosuppression, not HIV-related category. And so when you look at the ACIP recommendations, that's the category you're going to want to be looking at. And basically the take-home component of that is really no live virus vaccine should be administered in solid organ transplant patients on active immunosuppression. So absolutely we do not want to administer yellow fever vaccine, the live typhoid TY21A vaccine, the MMR, the BCG, or the varicella vaccine, sorry, primary varicella. Now inactivated virus vaccines are largely, can largely be used as indicated in the solid organ patient, just as they would be used in a non-immunosuppressed patient. And there are a couple exceptions to that. So we'll touch on that briefly. As everyone who does this kind of care for solid organ transplant patients knows, influenza vaccine is recommended on an annual basis. And specifically when we talk about streptococcal vaccination, we recommend the PCV13 in conjunction with polysaccharide, poly-23-valent vaccine as well. The solid organ transplant population is a group in which PCV13 is recommended. If you have not seen the 23-valent vaccine previously, the recommendation is PCV13 vaccine followed subsequently by the 23-valent. If you've already seen the 23-valent, then after a period of time, your administration of the PCV13 to complete the series. If one is administering a single dose of hepatitis A in a solid organ transplant vaccine and solid organ transplant patient, remember that's a two-dose vaccine. If you don't have time to give the second dose prior to travel, there is a consideration of administration of immunoglobulin to provide some degree of protection against hepatitis A. This is a significant consideration when we think about liver transplant patients who can have extremely severe courses if they're exposed to hepatitis A. There's really, for Japanese encephalitis virus vaccine, something that's a consideration in Southeast Asia, there's really no data for safety or efficacy of that vaccine in solid organ transplant population, so one should exercise some caution there. When we think about the rabies post-exposure prophylaxis, both the vaccine, which is the five-dose, day zero, day three, day seven, day 14, day 28, and immunoglobulin should be administered regardless of previous vaccination status. All patients who are traveling to areas where the thought is they would have exposure for real risk exposure for rabies, so this is not just someone who's traveling to an area where rabies may be prevalent, but somebody who's going to be there for a duration of time, an extended duration of time, and somebody who's going to be in situations where they may come in contact with rabies, so significant field work, veterinarians, etc., that's a situation in which one would keep that in mind. And then finally, the recombinant zoster vaccine, which is completely separate from travel, but a consideration, the new recombinant zoster vaccine is often administered in the solid organ transplant patient population. It's absolutely fine in that population. There is no specific pre-travel indication, however, so just from a coverage perspective, in a travel visit, it might not be covered. Moving forward to prophylaxis, the most commonly considered prophylactic issues are around malaria. What we want to think about is, one, what is the risk of malaria, and to determine that risk, I would recommend using the cdc.gov malaria website. It has a link is right there, in a country-specific, and it's actually broken down not just by country, but also by region within the country, specific cities, and takes into account the the season as well. A consideration around prophylaxis is the interaction between the prophylactic medication and the patient's immunosuppression. So, mefloquine, chloroquine, primoquine, doxycycline can all cause elevation in the calcineurin inhibitors that are commonly used as post-transplant immunosuppression. Similarly, mefloquine, chloroquine, and tacrolimus can interact to cause prolonged QT intervals, so you want to be thoughtful about that. By and large, malarone, which is a tovaquan proguanol, and coartam are generally safe options and probably the ones that are most commonly used and would be recommended. Moving beyond just the vaccination and prophylactic medication prescription, it's very important to provide education around food and water safety. These are the primary mechanisms of infectious acquisition in travel when one puts aside arthropod-mediated disease. Many foodborne and waterborne infections can be extremely severe or become chronic in the immunocompromised host, and so it's important to give guidance around avoiding swallowing water while swimming or during water-based recreation, many cases of giardia and chronic herpes infection. Similarly, those with liver disease should take great care in the setting of salt water exposure due to risk for vivrio species. It's very common that providers will provide a prescription of antibiotics for self-treatment of traveler's diarrhea. Azithromycin is commonly used for this indication, but it's important to recognize that this can interact with calcineurin inhibitors. Fluoroquinolones, while they do have their own issues around risks for cdnf, risks for tendinopathy, and now long-term risks with vascular health, they do not interact with immunosuppression and probably are a reasonable alternative in this setting. Other non-infectious considerations to take into account, it's important to advise travelers to make sure they have adequate supplies of their medications, avoid taking medications purchased at the destination unless they're from a reputable source. There's lots of issues around counterfeit medications in certain environments. It's important to emphasize sun protection, especially for travelers going to warm sunny climates. Remember, calcineurin inhibitors decrease immune surveillance and patients that are post-solid urban transplant have much higher rates of squamous cell carcinoma. We just talked about food and water precautions, and it's also important to help patients identify facilities that are familiar with solid urban transplantation at the destination that they're traveling to in case an emergency were to arrive. It's much better to have that information ahead of time than to try and figure it out once those issues develop. Now finally, we're going to finish with infection in the return traveler. Now obviously, the most important piece here is to counsel all immunocompromised patients to monitor closely for fever or signs of infection in their post-travel period as well as while they're traveling, and to seek care immediately if those issues arise. If a patient that has traveled to a region with endemic malaria presents with fever, remember, check the malaria antigen if they get thin, and do so ASAP regardless of prophylactic use. As far as the bigger picture of evaluation, pursue the evaluation for travel-associated infection concurrently with standard workup for fever in the immunocompromised host. It's a potentially very broad evaluation that takes into account not just the host but also where the patient has traveled, so we won't go into too much detail there. All right, thank you very much, and I think that's my 15 minutes. Thank you.

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