to Dr. Bijan Ekterstad, I would like to welcome you to the transplant surgery workshop. This afternoon we will be exploring surgical options for expanding the organ supply for liver transplantation. The first session will look at the use of increased risk organs. Specifically, we will have talks from Dr. Kimberley Watt on the use of steatotic livers, Dr. Sasaki on donors with a history of cancer or malignancy. Dr. Ekterstad will talk about domino liver transplantation and who should receive it. Dr. Kim Althoff will talk about the use of older donors and into which specific recipients. Dr. Tanner will talk on DCD donors and the last talk will be by Dr. Lara Danziger-Isikoff on organ recovery from infected donors. There will then be a break and part two will be later on this afternoon. I would just like to remind attendees of the audience that audience Q&A will be taking place after part two. Thank you. I would like to thank the organizers for the chance as a hepatologist to speak at this surgical meeting about a fairly surgical topic, although it is about fatty liver, which is close to my heart. The topic is how much steatosis is safe. With this, I have no disclosures that are relevant to this talk, graciously. Just to remind everyone that the reason we have this talk is this is becoming more and more prevalent of an issue. As far as the overall incidence and prevalence of fatty liver across the world, the general population, 25% of the population, 25-30% has fatty liver. If you're looking at type 2 diabetics, this is going to be more in the 50-70% range. As surgeons trying to accept organs, you need to be aware that there are a fairly significant number of potential donors coming that will be fatty liver. Age is not necessarily going to be protective against the likelihood of finding steatosis. We've seen in our cirrhotic population where we have younger and younger patients showing up cirrhotic with a couple of decades of fatty liver, the donors in the age group of 20-40, over 20% of these donors may be steatotic. Even the young population, adolescents, up to 10% of those can be steatotic, so being aware. It gives me great joy as a hepatologist to remind the surgeons that you are not perfect at guessing the steatosis grade. One of the studies that looked at this by Ken Chavin a couple of years back in 2013 as part of their prospective observational study, they had 18 situations where the donor was thought to be by the surgeon's eyeball test steatotic and a wedge biopsy done showing about 12.6% steatosis, a range of 0-50%, but on reperfusion biopsy, it was in fact much more steatotic than that with a range upwards of 86%. But what's more important is 99 of these donors passed the eyeball test and did not have the pre-procedure wedge biopsy and their reperfusion biopsy had upwards of anywhere from 0-80% steatosis with eight of those graphs actually having more than steatosis. This just to remind that anyone looking at the graphs, you're not going to be able to really necessarily predict how much steatosis is there. What's important to know is how long does this fat stick around and how much trouble can this really cause? Some of the studies that do look at this, in general, it looks like somewhere between 80-90% of the fat disappears within that first 10 days or so and 100% within the first month and that's irregardless of having a very severe steatosis or mild steatosis. This really is a periprocedural issue and what the fatty liver increases the risk of is ischemia reperfusion injury and not to get into too much of the details about this in a short talk. This is largely shown in many different studies and this is just one of the representative studies that shows AST and ALT tend to be peaked to a higher level with the fatty liver, but that in general, most of the studies show INR and liver function to be relatively stable. This particular study by Ken Chavin did actually look at the factor 5 level. The actual function is affected by the steatosis with the greater steatosis levels of 60% or higher having actually lower factor 5 activity. There is certainly an impact on the function of the liver with the higher degree of steatosis. The big worry that we all have is primary non-function. What that reperfusion injury leads to is the potential of primary non-function and there's plenty of studies looking at this all case control or largely cohort studies. This is a meta-analysis of 4,000 patients, mostly cohort studies, so not super robust data, but certainly a combination of a lot of different studies to make it a little more of a reliable finding. What we do end up seeing, these are the steatosis grades in general, that mild group, no real difference in primary non-function. The moderate and severe group, that the patients with higher degree of steatosis do have a higher risk of primary non-function. Also an endpoint in many of the studies, although not all of them, only eight studies looked at early allograft dysfunction, so EAD, and again, the moderate group and the severe steatosis group, all at higher risk of early allograft dysfunction. This study did have a few, now this is only two studies here that you can see, that looked at graft survival and they looked at one year graft survival and there was no difference between the severe and moderate group and certainly obviously the mild group as well, which I'm not showing here, and no difference between control as far as graft survival. But this study by DeRoos is one of the ones included here and they actually did break it down that if patients had early allograft dysfunction, those individuals are at higher risk of graft loss or graft mortality. The risks that associated with this early allograft dysfunction was not just the steatosis grade, but also DCD liver and the cold ischemic time. There's clearly more involved than just the steatosis and there's some higher grades of steatosis livers that are probably going to do fine and there are some that may have lower grades of steatosis that are also not going to do well, so it's not just about steatosis. This study in 2014 tried to match cases with moderate, 30 to 60 percent steatosis, with all of the other factors that you can look for, so cold ischemic time, age, etc., and they do show what every other study shows, the decrease over time where it normalizes at seven days, so higher reperfusion injury, but that this was more likely in the situation where cold ischemic time was greater than eight hours in this particular study. So cold ischemic time along with steatosis is going to increase that reperfusion injury, which puts them at higher risk for the other outcomes. The study by Spitzer in 2010 also looked at additive factors, so this is a multivariate analysis of one-year graft survival, looking specifically at macrovesicular steatosis, and you can see that greater than 30 percent had a higher risk of graft loss and the 20 percent to 30 percent were not at higher risk, but if you add in cold ischemic time, which in this case is 11 hours, to that lower risk group, it now becomes a higher risk situation and gets pretty close to having the same risk as the higher steatotic livers. So cold ischemic time is a critical factor here, and you can see also DCD has similar age of the recipient and the donor are factors in this particular case, the donor, and so there's more than just the steatosis level, and this is shown also in Pierre Clevian's group in 2012, so the additive effect of steatosis to a already poor-ish graft, and so they looked at their bar score, which is a combination of recipient age, donor age, ischemic time, retransplant, and melt score, and their scores go from zero to 18, and this higher risk organs are certainly above 18 and the moderately high risk of anything above nine, and what they do show is that regardless of the steatosis, it can be higher grades of steatosis that there's not a significant impact on what's considered reasonable five-year survival. This is graft survival, five-year outcome data in the even the higher risk steatosis in a lower otherwise risked graft, but you add steatosis into the higher risk organs, and now you have very significant differences in the overall graft survival, so this isn't just PNF or EAD, this is actual graft survival, so this is all additive risk, so DCD is well identified as one of these risks of allograft survival and potentially for primary non-function, and then you add in steatosis to DCD, what's the effect, and this particular study from China, 807 DCD patients, but there were only 16 of these patients that actually had moderate degree of steatosis, but they didn't match them for all of those factors, age, BMI, melt score, and ischemic time, and what they ended up seeing was there was, yes, higher likelihood of reperfusion injury, higher risk for EAD, and no difference in primary non-function, and no difference in overall graft or patient survival. Similar study and also from China did show a difference though, much smaller numbers, but does show a difference that steatosis greater than 20% had a fairly significant impact on graft survival over probably two years here, it didn't go all the way out, and that the incidence of EAD was higher in that group, and from what we already know, patients that experience EAD are going to have a worse outcome. One of these studies was able to look at was a multivariate analysis that included the histologic findings, so not just steatosis over 20%, but this sinusoidal neutrophilic infiltrate has a fairly significant and arguably even more important role here, and this is one of the pathophysiologic postulates as to why the allograft dysfunction. If you have all this going on in the sinusoids, you're much more likely to have perfusion injury and cellular hypoxia, etc., so this was a definite risk factor and maybe should be included in some of the donor biopsy analyses, and then the donor bilirubin level above two roughly in the U.S. units and 34 in the European units was also a risk factor. And what about living donor liver transplants, so how much fat is okay in those? There's really not a lot of studies that are directly assessing outcomes in this. This is one of the larger ones from India, 623 right lobe living donor grafts. They in their program do not do anything above 20% steatosis, but they looked at 10 to 20 versus less than 10 and really found only a little bit of a difference in AST, but no other significant, sorry, AST, ALT, and a little bit of INR within that first week, but no other significant difference in early allograft dysfunction, morbidity, mortality, or otherwise, and they did even actually adjust for their operative intervention with respects to the middle hepatic vein, and there was no difference in overall graft survival in patients with very, very modest degrees of steatosis. Other data that's there for living donor patients as far as steatosis goes, this is actually looking at the donors, so this particular study was looking at regenerative outcomes, so irrespective of the remnant liver volume, the steatosis grade did not affect the regeneration within the donor, which is reassuring, certainly. There were very few patients, obviously, in the higher steatosis category, but at least their overall regenerative changes were not significantly different, though they look like they might be a little bit, so there was another study. You can only get the abstract for, ironically, 58 patients as well with a little bit higher of the steatosis, and they had no difference in mortality and regeneration, and it kind of makes me suspicious it might be the same data. Regardless, there is looking at recipient risks as well on top of the additional donor risks. There are certain recipient risks that can increase the likelihood of an effect of the donor's steatosis, so this particular study is looking from UNOS data in 2006 to 2011. They're specifically looking at graft loss in over 41,000 cases, and there was a donor biopsy available in 39% of those, and looking at graft loss in that 39% of the donor biopsies by steatosis level and then graft loss within 30 days, 90 days, and one year, and you can see that there is an incremental increase over time, but that 40% to 60% range seemed to have the highest risk, and if you look at graft loss over time, you can see the two that really separate out here are 40% to 60% steatosis, increasing the risk for graft loss. They did look at the recipient factors here and found that low MELD score, which is anything under 33, and high MELD score, which is 33 and above, by the varying degrees of steatosis were a significant factor with those higher, again, degrees of steatosis in the high MELD patient, and I think this isn't new data, although it is 2020, but most people are aware of this, but they did try to sort out high MELD by degree of steatosis that really breaks apart, and they found 40% macromuscular steatosis in the high MELD, that's again about 33, to be kind of the breaking point, and 50% for a small decrease in the patients that had a lower MELD score, so there's a solution to this that we have no time to talk about, unfortunately, and that's weight loss exercise, maybe some fibrates, there's some data, deceased donor liver, that's in living donor and deceased donor livers in machine perfusion, but we have no ability to talk about that today, so in summary, how much is safe, high MELD recipient, upwards of 40% may be safe, low MELD recipient, you might be able to get away with 50% if none of these factors exist, and in a DCD, liver less than 20%, the data would support, and living donor less than 20%, but that's all the data that we have, so a lot more data is needed, and with that, I will take any additional questions that may come up, and I'm 20 seconds over. Hello, my name is Kazunori Sasaki, Cleveland Clinic. Today, I will talk about donors with history of cancer or with malignancy, which one to use. I have nothing to disclose. The risk of cancer transmission from organ donor to the recipient is actually not so high. According to the previous literature, the rate of cancer transmission is just 0.1 to 0.5%, which means one to five cases per 10,000 transplants. However, under immunosuppression situation, the cancer transmission will be a critical issue for recipients. Moreover, the discrepancy between donor organ supply and demand is getting bigger and bigger. As a result, we are trying to use more and more older age donors. It means we will encounter more donor candidates who has history of cancer and donors with active cancer. So, understanding appropriate knowledge about donor with history of cancer or active cancer is important to increase donor pool and decrease unnecessary risk of cancer. Organ discard. Regarding cancer transmission from the donor to the recipient, there are two types of transmission. First one is transmission from donor who has a history of cancer or donors with active cancer at the time of organ donation. Basically, we can prevent this kind of transmission by appropriate donor selection. There are two commonly used guidelines about donor selection, one from UNOS and the other one from European Council. The second type of transmission is transmission from donor who has no history of cancer or assumed as no cancer at the time of donation. Unfortunately, this kind of transmission is difficult to prevent by donor selection only. Only things we can do are asking procurement surgeon to check colon and the lung at the end of procurement in the donor, older donor, in older donor case, and also routinely check CT, chest, abdomen, pelvis for older donor. This is UNOS guideline. In UNOS guideline, they stratify the cancer transmission risk from donor to the recipient into five categories. According to the transmission risk estimation, they made recommendation for clinical use. Briefly, according to their recommendation, we can use organ with minimal or low risk, and also we can use intermediate risk organ in case recipient is sick and organ quality is good. There's one thing I would like to emphasize. In their original paper published in 2011, the authors repeatedly claimed that this is not fully scientific evidence guideline because the rate of transmission is very low and the people intentionally try not to, try to avoid cancer transmission. So we cannot know exact transmission rate and the risk, and the only we can do is estimating the risk of transmission from non-knowledge. In UNOSCILINE, they pick up those tumor as low risk of transmission. Of course, nobody can remember all of them, but in summary, skin cancer as a melanoma is okay, and also resected small renal cell carcinoma is also fine. It means even if we find small renal cell carcinoma at the time of organ procurements, we can use organ if the tumor is solitary and well differentiated up to two centimeter. Also, small papillary or minimally invasive follicular type thyroid cancer are fine, and the WHO grade one or two CNS tumor are fine as well. Very difficult part of this guideline is those sentences. History of treated non-CNS malignancy more than five years ago with over 99% probability of cure. So we are liver surgeon or hepatologist, so we have no idea how high the probability of a cure of ovarian cancer or semi-normal or some specific type of informer. In UNOS guideline, they recommended to visit Memorial Sloan Kettering Cancer Center website to estimate probability of a cure. Some of those links have online calculators of reclaimed free survival or overall survival. However, they do not give you exact number of probability of cure, so you have to estimate the probability of cure from reclaimed free survival. Some of the studies shows exact probability of cure in some type of cancers, and you can find those information from PapMed or Google Scholar. However, it is very difficult if you get an offer, organ offer at 4 a.m. in the morning and wake up and Google it. In theory, most of the cancer will not come back after five years from curative treatments. However, some type of cancer, such as colon cancer or breast cancer, can recur even after a long time from curative treatments and need special attention. For example, even T1-Enzel breast cancer can cause distant metastasis even after 15 years from curative treatments. And the higher stage breast cancer can cause much higher chance of liver metastasis or distant metastasis even after long term after surgery. Those are a list of intermediates and high risk of transmission by UNOS guideline. UNOS guideline recommend to use intermediate risk organ, I'm sorry, intermediate risk category organ only if recipient is very sick and cannot survive without transplants. For example, if patient is 65 years old, male, 38, and intubated and on dialysis and in ICU, if you get an organ offer such as 45 years old female who had a history of stage one or stage two breast cancer and the donor received curative treatments five years ago, probably I will use that organ after informed consent to the family, a recipient family, because I think survival benefits by using that organ is way higher than cancer transmission risk. However, if the recipient is 35 years old, male, 32, PSC patient with good performance status, probably I will not use that organ and wait another offer. So whether we can use intermediate transmission risk organ is depend on the situation. On the other hand, UNOS basically does not recommend to use high risk, high transmission risk organ. In high risk category, active colon cancer and breast cancer higher than stage one, any stage of active leukemia, active melanoma, active sarcoma, and active lung cancer are included. Here, we have to be careful that any stage of CNS cancer or tumor with a history of surgery or radiation are categorized as high risk in UNOS guideline. Also in UNOS guideline, CNS tumor grade three or grade four are both categorized as high risk. This is the chart of WHO CNS tumor grading. Of course, as a neurosurgeon does not remember this chart and it is very difficult to remember which CNS tumor is grade three or four. Basically, something blastoma or anaplastic something are stage three or four. Other than that is grade one or two. And that if the donor became brain dead because of a surgery or intervention, you will need a special attention. Here's an European guideline, and I just pick up high risk or an acceptable risk donor. The basic concept is almost the same with UNOS guideline. The difference are they think organs from donor who had history of breast cancer, ovarian cancer, corneal carcinoma at any time before donation should not be used. And also any stage of melanoma is not acceptable. Other part is basically the same with UNOS guideline. There's one interesting study published in 2014. They investigated whether those high risk or unacceptable risk donor is really high risk or not. This study was conducted in UK using European guideline. This study included over 17,000 donors who donated at least one organ. 202 donors had a history of cancer. And of those 202, 61 donors were categorized as an acceptable high risk of a cancer transmission but used to the recipient. Of those 61 donors, there are many glioblastoma, breast cancer, lymphoma, colon cancer patients are included. And the total 133 recipients received organs from those high risk donors. But surprisingly of those 131 recipients, none of the recipient developed donor derived cancer. And the authors concluded that our current guidelines might be too conservative and we may discarded organ which we can use. Next slide. Those are key takeaway message. First, the risk of cancer transmission from donor to recipient is very low. It means our current guidelines and our practice is doing good. However, we might overestimate the risk of a cancer transmission from donor to the recipient and possible we discards precious organ which possible we can use. Considering increased old age donor in the future and actually already increased, we need a study to refine those guidelines. Also, if UNOS unit can provide a risk of a transmission or probability of a cure as a default, if the donor has history of a cancer or active cancer, those information is definitely help make right decision. Also in the near future, we should be able to use more accurate liquid biopsy or circulating DNA or circulating tumor cell detection. Those information will help us to estimate the accurate risk of cancer transmission from donor to the recipient. Thank you. Hello, my name is Bijan Ektesad with Cleveland Clinic. In this presentation, I will be focusing mainly on domino liver transplantation from patients with familial amyloid polyneuropathy. And at the end, I will present some limited experience on domino liver transplant from patients with other genetic and metabolic disorders. I have nothing to disclose. Liver transplantation is the preferred treatment for familial amyloid polyneuropathy. And first liver transplant was done in 1991. First domino liver transplant was done in Portugal in 1995 from patients with FAP. And domino liver transplant has become an acceptable practice in many countries and many transplant programs. There is a ward registry for amyloid disorders and they have collected over 80 different subtypes and genetic subtypes. And I should mention that criteria for domino liver transplant varies from country to country and center to center. Domino liver transplant also can be considered in patients with other genetic and biochemical disorders related to the liver. These patients today are treated by liver transplantation and livers from these patients ultimately make severe disease in their recipient while they look normal otherwise. And the primary and main indication so far has been familial amyloid polyneuropathy. And that there is a domino liver transplant registry which they have collected over 2000 patients. As we know, patients with familial amyloid polyneuropathy may present symptoms after 20 or 30 years in their lives and liver transplant is the first line treatment now for these patients. After transplant production of mutated transtyretin decreases by almost 98% and there is almost a halt in disease progression. But however, domino liver transplant from these patients, the recipient may develop signs of amyloidosis over a course of several years. And comparing to patients with familial amyloid polyneuropathy the disease recurrence has a more accelerated course and there is a need for informed consent and also some consideration of all the ethical issues. There are several studies with relatively large patient population which I'm going through them all now. In first, 23 domino liver transplant recipients were followed and of course majority of these patients, 19 were done for hepatocellular carcinoma and there was a five-year survival of 70% compared to the 64% survival in 670 recipients and 12 patients died over a course of almost 12 years and almost 50% of these patients died of underlying liver disease which was hepatocellular carcinoma and its static disorders. And biopsy proven de novo amyloidosis occurred only more of 23 patients over a 10-year period which shows a disease can come back but not universally in all patients. There was one retransplant for progressive disease and one patient was retransplanted because of cardiac issues related to amyloidosis. And interestingly, most patients who developed amyloidosis were on the older side. In another study by Mishima in Japan, 22 liver transplant with domino were followed and mortality six or six in four late metastatic disease that was cause of mortality and two early post-transplant mortality. They found amyloid deposit in eight patients and first appearance of amyloid was about eight years after transplantation and first symptoms appeared nine, almost 10 years after transplantation. And they noticed that early recurrence happened in those older than 50 at the time of domino liver transplant. And recurrence also for those older than 50 was about 5.8 years compared to those who were younger than 50, which was 8.6 years. And also more severe deposits happen in older patients. And this is a common pattern that we see in all the reported tests probably because more and more domino transplants are done on older patients with lower life expectancy. In another study of 28 patients, three patients developed neurological signs of neuropathy two to five years after domino liver transplant. And when we look at the survival of these patients, those who were done for hepatocellular carcinoma did not have a good survival because most of these patients had advanced hepatocellular carcinoma. But for those who were done for, this is other than hepatocellular carcinoma, survival was excellent and comparable to regular transplant of one, three and five year survival of 93, 93 and 80%. And as we discussed that development of neuropathy may occur earlier than expected in this case. In another study of 28 patients, eight patients showed new onset of new polyneuropathy and one patient with genetic glutamine 89 lysine developed cardiomyopathy. And interestingly, no patient with methametionin showed cardiac involvement is the main cause of liver transplantation, made indication for liver transplantation in these patients. And that shows that domino liver transplant from valine 30 methametionin donors seems to be safe regarding development of cardiomyopathy. Of course, these patients may present with some neuropathy. And in another larger study of 30 patients, 13 of 30 patients developed amyloid deposits over a mid eight to five years. And six of seven patients became symptomatic and they received a transthyretin stabilizers as a medical treatment and two patients developed ventricular dysfunction. And, but regardless of the presentation, it was noticeable that most of these patients did not show severe autonomic dysfunction as is the presentation in most amyloid patients. Out of 30 patients, 5 patients or 50% almost died of metastatic disease from cancer. So overall, despite chances of disease transfer to the recipient, domino liver transplant from donors with familial amyloid polyneuropathy is an acceptable procedure, needs careful selection and consideration of informed consent from both donor and recipient of domino liver and all the ethical issues. Rapid representation of symptoms in some patients could be due to recipient age, immunosuppression, or a combination of several factors that are present in the recipient, including TAF and tyrosine mutation. And we should know that the recurrence of amyloid deposition is faster in these patients, but progression is milder. Now, we switch gears and talk about domino liver transplantation from other metabolic and genetic disorders. I start with the homozygous familial hypercholesterolemia, which have been several transplants done from these patients. These patients share hypercholesterolemia despite aggressive treatment. However, a very low number of these patients developed cardiovascular diseases related to cholesterol because receptors in the body may play a role in uptake and metabolism of cholesterol. Of course, more follow-up is needed on these patients, but potentially it's a good source for transplantation. There have been living donor liver transplant from patients with heterozygous donor disease and in pediatric patients, which they have done well. Diseases from domino liver transplant from fibrinogen, alpha-chain amyloid, is non-trans-tyrosine amyloidosis. There is no neuropathy. However, it can cause renal amyloidosis. There have been four domino liver transplants from these patients with no renal impairment in more than five years of follow-up and potentially could be a good source for transplantation. Primary hypercholesterolemia is another genetic disease that liver oxalate overproduction and deposits of oxalate in the kidney. Rapid renal failure is the consequences of it. There have been several reports of transplanting these livers. Five from ureotransplant, one was retransplanted and four unfortunately died. There is another case that was reported and they had to keep this patient on hyperhydration and multiple medications for keeping the kidney intact, but not a good source. Liver transplant and kidney transplant from heterozygous patients for hyperoxaluria have been done to a child and this had a good outcome. Maple syrup urine disease liver transplant is a cure for these patients. Domino liver transplant has been done with excellent results. Most likely there is sufficient extra hepatic enzyme activity in these recipients that can take care of the problem. Living donor liver transplant has been done on two cases. One patient died after liver transplantation because of a muscular problem and the survivor of the second liver showed that the donor was heterozygous for the disease. Acute intermittent porphyria is another metabolic disorder which liver transplant has been done. However, patients develop all kinds of symptoms after transplant and that is not a good indication for domino liver transplantation. Other metabolic disorders that are not suitable for liver transplant are tyrosinemia type 1, which is a major risk for hepatocellular carcinoma, apolipoprotein A1 amyloidosis, which causes extensive involvement of the liver, and lysosome amyloidosis, which again causes extensive hepatic and renal insufficiency and good sources. Patients with Arnitin transcarbamylase deficiency and propionic acidemia, methylmalonic aciduria are not good candidates for domino liver transplantation. Only in heterozygous patients, liver transplant has been done which needed extensive medical treatment for it. For accidental or inadvertent transplantation from Arnitin transcarbamylase deficiency, it has been reported in three cases that all died. Transplants from hemophilia A patients, there are two case reports. One had to be retransplanted because of extensive bleeding after transplant and required retransplantation, and one case survived which shows there is sufficient extra hepatic production. Factor V Leiden is another disease that we have to be careful, especially with homozygosity of the factor V, which increases risk of thrombosis. Overall, the domino procedure is a viable source for liver transplantation. Risk benefits should be evaluated on a case-by-case basis, and the recipient fully informed about the outcomes. Long-term monitoring of recipients for the primary disease is essential. The outcome is strongly dependent on the underlying metabolic disorder and persistence of systemic enzyme disorder. There are a fair amount of data in international registry which is usable for evaluation and study. Thank you for your attention. Hi, I have been asked to speak about how old is old and who should be the recipient. I wish we could be in person, and I'm really looking forward to the time when we can do that again. So, my outline is that I'm going to talk about the aging population in the U.S., the aging of our liver transplant recipients, outcomes, factors impacting outcomes, and strategies and models for predicting and optimizing outcomes in older recipients. So, as you can see, America is aging. We've got now about, in 2020, we have about 15% of our population is age 65 and older, and in 2050, we're going to see about 20% of our population to be 65 and older, and that is about where we are in Florida right now. So, we're becoming a nation of Floridas. And if we look at our liver transplant population, we also have an increasing proportion of older recipients in both the U.S. and Europe. Recipients over 65 increased from 9% to 20% in this 15-year period of 2002 to 2017, and there was a 16% increase in Europe. Now, there's many potential reasons why. The most obvious is that it's the increasing percentage of overall population, but we've also gotten much better at the care of the older end-stage liver patient, as well as gotten really good at post-operative care and improving post-transplant outcomes. HCV is no longer a leading indication for liver transplant, but NASH is, and that's a disease of an older recipient with or without cancer. This is the most recent data from the OPTN database that shows that we literally more than doubled the number of patients with, that are over 65, that received a liver transplant in the last 10 years. And if you look at the most recent waitlist additions in the last five years, you can see that there is a slow increase in the number of patients that are over 70 as well, and that there's a slow increase in the number of patients over 70 that receive transplants. As a percentage, at 70 or older is about 4% of our patients, and about 40% of patients are 60 to 69. We looked at our own Penn data, and we mirrored that pretty well, and that we had about 3% of our patients were over 70, and about 45% were 60 to 69. Well, wisdom comes with age, but so does many other things, such as cardiovascular disease, diabetes, malignancies, cerebrovascular disease, renal dysfunction, respiratory illness, bone loss, muscle loss, and most important probably is our loss of physical strength and increasing frailty as we get older. And these things we have to take into consideration when we're talking about transplanting older patients. So let's look at outcomes. Our first is outcomes with waitlist mortality. Older age at registration is associated with a higher waitlist mortality, particularly in this 70-plus group, as you can see here that died while on the waiting list. As patients get older and sicker, they also become too sick to transplant, so these are patients that are removed from the list because they're too sick. And it probably often happens as their MELD increase, and they think they're too old and too sick. The combination is just too much to go forward with transplant, and it decreases the likelihood of them getting a liver transplant. This shows the association of MELD and age, and as you can see in these very older patients, it doesn't matter if your MELD is higher, over 25, or less than 25. There is a significantly increased waitlist mortality in this older group, whether it's a lower MELD or a higher MELD, and there's evidence that the older patients just don't tolerate higher MELD scores, but they also die at lower MELD scores for various reasons and causes. If we look at post-transplant outcomes now, these are some papers that were written over the course of the last 10 to 20 years, and as you can see, they looked at age cutoffs anywhere from 60 to 70, and you can see that the majority of these studies showed that there was significantly lower five-year survival for patients over 65 or 70, showing about a 10 to 20 percent lower survival rate. Now, if we look at the most recent, some of the most recent data from the OPTN database, transplants done from 2008 to 2015, it actually doesn't look that bad in that if you compare patient survival and graft survival, it's only about a six percent difference in patients at five years for those who are over 70, I mean, sorry, over 65 compared to the cohort beneath that, the 50 to 64 range. We wanted to look also at the even older group, and if you combine the patients that are over 70 with a high MELD score, you can see that their outcomes are significantly worse. This is a paper from 2014 looking at the UNOS database, where if you're over 70, your three-year survival is around 50 percent, significantly lower than those in the younger age groups. So, we wanted to look at this in a little more detail, so we pulled the most recent UNOS data from the last five to six years and broke it out by under 60, 60 to 69, and 70 and older, and the blue line is 70 and older, and you can see that this line drops below the other two lines by about 10 percent in the graft and patient survival when you get out to five years. Now, there's not very many patients out that far, but it's still a significantly lower survival in the more recent data, and you have to think that in the more recent years, we're doing patients with higher MELDs, patients that are sicker, with a different allocation and distribution system, which may cause it to be harder to transplant these older recipients. We looked at our own data, same time periods from 2014 to 2020, and currently, our mean MELD at transplant is 30, so you can imagine what it's like trying to get a graft to these older recipients, and as you can see, even though the five-year survival is about 60 percent until you get to that very end where we're down to only one patient, there is a significant drop in that first year post-transplant when we transplant these older individuals that are over 70, so it's making us take a very close look at the patients that we're transplanting and how we can choose the most optimal recipients. If we want to look at the contributors to morbidity and mortality in older recipients, I think it's pretty obvious. We know that heart disease, malignancy, and chronic kidney disease are the biggest contributors to post-transplant morbidity and mortality in these older recipients. There is also bone health, functional status that's independent of the MELD score that they get transplanted on, and we know that NASH patients have a higher cardiovascular mortality post-transplant as well. If we want to dig into this a little more deeply, we also look at what's associated with frailty, and age over 65 is a significant characteristic that's associated with frailty, as is chronic kidney disease, and we also see that NASH is associated with a higher liver frailty index. This is really nice data from three centers, Penn, Pitt, and UCSF, looking at cirrhotic patients that were admitted to the hospital. If you have a combination of both liver disease and enough kidney disease that you need a kidney transplant, there's also significantly worse outcome in these older patients. This is a paper by David Goldberg that looked at the combination of age and the presence of diabetes, and whether there was diabetes or not, those patients who were over 70 had significantly higher adjusted hazard ratios for post-simultaneous liver kidney mortality. That's independent of the presence of diabetes or not. Now, there's only three percent of these patients in the country, but there are a number of patients that are still being considered for combined liver kidney in this older age group. One group that does not seem to be affected by age are those patients who have HCC, and in general, these patients, because they get exception scores, also are a little better physically in the biological age category. This was a prospective database out of WashU, which looked at patients who got transplant or resection, and as you can see, the outcomes post-transplant are similar between those over 65 and those younger than 65. However, it was apparent that older patients were less likely to be considered for transplantation. So, who is too old? And I think when we think about it, we have to think about it as a combination of factors. There are two scoring systems, the soft score and the bar score, which have incorporated recipient age and other comorbidities into predicting what post-transplant survival would be. And as you can see, the strongest predictors of outcome are recipient age, whether it's a retransplant, if the patient's on life support, and they also incorporated donor factors, such as cold ischemic time and donor age. And if you have significantly high scores, that you can have outcomes that are significantly, survival scores that are significantly lower with a combination of factors. So, age plus a combination of factors does not lead to a good outcome. However, the C statistic was only 0.7, so we have to keep that in mind. And then a more recent publication that came out of Baylor in Dallas also looked at various characteristics, giving various points. As you can see, age gave a significant number of points, but in a combination of factors, if you get to a score of 8 or greater, your outcome is significantly lower than if you have less points. But when you add in graphed characteristics, like a high DRI or an older donor or a long cold ischemic time or a DCD, and you put a non-optimal graph into an older patient or a patient with a higher risk score, the outcomes are significantly worse, which leads you to the conclusion that older recipients with comorbidities just do not tolerate marginal graphs very well. So we must think about that when we're getting liver offers for these older recipients. And I also want to talk a little bit about allocation. Unlike kidney and lung, age is not part of the MELD allocation score. There's no age matching except for the very young where we match very young donors with young recipients. And the current US liver allocation policies do not really drive good age matching. Our sickest first allocation doesn't incorporate transplant benefit. And if we think about moving from a MELD-based system to a utility-based or transplant benefit approach, this may contribute to a more age-based matching of donors and recipients and could result in reduced life years lost. So it's something to think about as we consider how we allocate organs to these older individuals. So my final thoughts. We can achieve excellent outcomes in older recipients. We all know that, but it's still not as good as in younger recipients. And I don't think you can give a definitive how old is too old. Chronological age is different than physiologic age. We have to take into effect all those comorbidities and frailty. So one person's old is not another person's old. Outcomes are dependent on multiple variables and comorbidities, many that are outside our control. We can't cut corners or push the envelope when it comes to the evaluation of these patients or in the types of donors that we choose to do to put in these patients. Older recipients just cannot take a second hit after that first major hit of the transplant itself. We have to do what we can to minimize the risk by establishing uniform cardiovascular screening protocols, assessing frailty and nutrition and intervene when possible. We need to reevaluate our elderly patients often while they're on the wait list and also have very careful donor selection. And I hope that we can also rethink our allocation system when it comes to transplanting these older individuals as well. Thank you. Hi, my name's Laurie Danziger-Iskov and I'm exceptionally excited to speak today about organ recovery from infected donors. I wanna thank the organizers for inviting me to come speak. I'm professor of pediatrics at Cincinnati Children's Hospital where I'm the director of immunocompromised host infectious disease. These are my disclosures. So I figured that it would be a nice way to start with just some cases because there are certain things I'm sure that this crowd is very familiar with and other things that will be a little bit unusual. So let's start with case one right off the bat. So 34-year-old previously healthy person who presents to the hospital. They have fever and confusion. Subsequently, they develop intractable seizures and anoxia leading to brain death within two days of admission. The evaluation including an LP was negative except for an elevated white blood cell count and elevated protein. Do you accept this donor? Well, you might want some additional information about the donor or the potential donor before you make your decision. Things that you might think about asking include seasonality. Is it winter or summer? As this may affect the likelihood of certain infectious etiologies versus another reason why the patient succumbed. Where is the patient from? What donor region are they from? Have they traveled recently? Have they been to areas with other infections that would be more likely? Have they experienced any type of activity that would put them at higher risk? Such as being in a farm or having pets or specific animals. All of these things can have a role in understanding the risk that this is a potentially transmissible infection that caused the demise of the potential donor. So these are the things that you would want to find out in advance of deciding whether or not to accept the donor. In the circumstance of meningoencephalitis, UNOSA Ad Hoc Disease Transmission Advisory Committee has provided guidance on this, and that's a resource that's available. It suggests that there's caution when using any cases of undiagnosed or untreated meningoencephalitis as potential donors. That certainly an LP, as was performed in this case, with appropriate testing for infectious diseases should be performed. That geography should be considered as a risk factor. And if the evidence is suggestive of an unsuspected or untreated CNS infection, caution should be exercised. If it is encephalitis that is suspected and the suspected pathogen, the Eastern equine encephalitis or the like, where there's not a treatment option available for the recipient, extreme caution is urged in these circumstances. And certainly it's reminded that bacterial meningitis is not a contraindication to transplantation as there's therapy available for both the donor pre-donation as well as the recipient. Let's move on to the next case. A 45-year-old receives a deceased donor living transplant of obviously a liver. And this on post-transplant day two, the team is notified that the donor has positive serology for strongyloides. What's your intervention at this point? Well, I think it's important to understand several factors. First of all, what's the risk? Well, strongyloides is actually endemic in many regions of the United States, including in Appalachia and the Southeastern United States. And if your donor has been there and lived there, born there, it may be a consideration that this is a true positive. They could be foreign born from another endemic region of the world, as you can see from the map indicated on the slide. Also, they don't have to have been born there. They could have had significant travel or resided in an endemic country for a period of time. And for strongyloides in particular, as well as for others of these zoonotic illnesses, you have to consider that exposure could have been decades prior based on the life cycle of the parasite. So what should happen? Well, there's intervention suggested in this circumstance. Certainly the intervention already started when the organ procurement organization screened for an endemic infection in a patient who had risk. Other areas where OPOs may screen include certain regions of the country where there's highly populations that have higher epidemiologic risk for things like trypanosoma cruzii. And this screening can be performed based on those epidemiologic risk factors. And we know that hyperinfection related to immunosuppression after transplant is a significant risk factor for morbidity and mortality and has been reported as a donor-derived infection. Therefore, preemptive therapy can be given and is associated with a decreased risk for infection in the recipient. I think that this is an important thing to consider is that when you get information, you have opportunities. And if this information had been available before the donor organ was available and you knew this, you could work on preparing the patient to understand that, yes, this is a potential transmission, but we have a method to control for it and a method to mitigate this risk, which is what we're all trying to do in order to maintain our supply of donors. Now, case three probably is the most interesting and also the most topical issue that we're gonna address today. It is, you have a donor that's reported to be COVID-19 positive and they match with your candidate. How do you approach this? Well, this is not straightforward like strongeloides. Certainly. The Ad Hoc Disease Transmission Advisory Committee along with the AST, the ASTS, AOPO, CDC, and HRSA came together to address this issue in order to meet several goals. One, of course, to maintain access to safe transplantation for candidates. Two, to minimize the risk for donor-derived COVID-19 infections. And three, very importantly, to decrease unnecessary organ discard related to positive testing. We perform data review and create a consensus document looking at evaluation and recovery of organs from potential deceased donors and living donors related to SARS-CoV-2. Now, it's important to talk a little bit about definition so that everyone's on the same page as you're trying to figure out if you're gonna be able to use this donor. The disease, the date of disease onset is certainly essential. This is the date when COVID-19 symptoms started. And if the patient or the potential donor happens to be asymptomatic, it is the date of the first positive test for COVID-19. Mild COVID is when you detect the SARS-CoV-2 virus in the respiratory sample and the potential donor has a history of symptoms consistent with COVID-19, but they did not require hospitalization or supplemental oxygen related to that infection. COVID-19 becomes severe when a patient, when a donor, a potential donor who has a symptom consistent with SARS-CoV-2 as well as detection does require oxygen or hospitalization specifically for their COVID-19. Finally, resolved COVID-19. This is an immunocompetent donor who has a history of confirmed COVID-19 with resolution of symptoms and a period of more than 21 days from the date of the onset of symptoms. Now that we have the definitions in mind, let's think about how we would consider this potential donor. Well, initially donors should be screened epidemiologically and by symptoms and testing should be performed within 72 hours. Initially, this was only recommended as an upper respiratory diagnostic test, routinely a PCR. However, as many of us know, there was a proven transmission where an organ transplant recipient received a pair of infected lungs from a unknown COVID positive donor. And since that time, if a donor organs going to be offered from a specific donor include the lungs, a lower respiratory tract sample is required as well based on emergency UNOS policy. So the test is positive. What does that mean? There are certain things to consider. You have to consider whether this is the replication competent virus. So donors who've been known to have mild COVID-19 that's not admitted to the hospital and not requiring supplemental oxygen. After 10 days of the onset of symptoms, they rarely harbor replication competent virus particles in their respiratory tract. Having RNA positivity in your blood has not been associated with the presence of viable virus. And a positive test 21 to 90 days after the initial diagnosis is likely persistent shedding than replication competent virus in an immunocompetent host. Organ involvement is another thing to consider. Autopsies have shown sub-genomic RNA, non-replicating virus in heart, kidneys and livers. However, viable virus has been recovered from lungs and intestines. Additionally, it's strongly considered that you evaluate the testing platform on which the test was performed as there have been some tests reported by the FDA to have higher rates of false positive testing. You should look when and how the sample was collected and an emerging use may be the cycle threshold value of a PCR test whereby higher cycle thresholds indicate a lower viral load. So if a patient has a very low cycle threshold, they may have a higher viral load and therefore may be of a higher concern. Now, we're still talking about the specifics of accepting a liver. So in this construct, you can think about this as a matrix because there's not one right answer. You look at the date of disease onset of the potential donor for their COVID infection, the severity of their illness, whether or not they had any organ associated dysfunction, whether it be kidneys, if you're considering a kidney, cardiac disease, or liver dysfunction, including hepatitis and coagulopathy. You also have to consider the medical urgency of the transplant candidate. Is this a patient that can afford to wait for the next potential donor or is this medically essential to perform a transplant now? There's also the concern of unknown long-term outcomes related to donors who have COVID-19. And that's something that will take time for us to understand, but it has to be considered in the conversation. As well as understanding the systemic impact of COVID-19 and potentially some vaccines related to hypercoagulable states and how this may impact a potential recipient. Certainly the episodes of vaccine-induced thrombocytopenia and microthrombi have to be considered if that was a part of the donor's terminal event. And the final thing, if this is a living donor, you have to consider their risk related to undergoing a medical procedure, as there has been an increased risk, regardless of whether or not the potential living donor has symptoms or not, of undergoing elective procedures within the first six to seven weeks after a COVID infection. So once you have this matrix down, you think of their history of COVID, right? Did this patient have, did this donor have a mild infection? Remember they're unlikely to transmit COVID-19 to non-lung donors in that time period if it's been more than 10 days since their symptoms. Do they have resolved infection? And the decision in these scenarios, as we said before, rely on understanding the matrix of the candidate's risk for mortality or further complications in delaying transplant, as well as the unknown outcome related to COVID-19. So what do we know so far? Well, currently, based on reports to DTAC and analyzed by the CDC, there have been three proven or probable transmissions from three donors. All of these were into lung transplant recipients, and they had negative upper respiratory tract samples that on, at pre-transplant, but after transplant, retrospective analysis showed positive lower respiratory tract samples. Two of these had severe disease and there was one death. There were six non-lung recipients among these donors, and none of them had any events. Therefore, it is important to remember to consider that a positive test from a lower respiratory sample does not necessarily exclude use of these organs. And this has been shown in at least one study from a group in Italy where they took 10 donors, had symptoms within 21 days of organ recovery, five who had a positive BAL, but without any reliable symptoms. Interestingly, they were able to check their liver biopsies. All of nine of 10 of them, so 90% of them were negative for SARS-CoV-2. The recipients who were a median age of 56, but ranged from one to 70 and had a median MELD score of 13, ranging from seven to 35, with the pediatric patient having a MELD score of 29. All of them had a history of COVID-19. And the important outcome in this circumstance was that two of 10 did have a positive post-transplant PCR, both of which result by 21 days after transplant. There was one death, but this was not COVID-related, and there was no report of COVID transmission. This information has also been shown in the intended use of SARS-CoV-positive kidney donors by Koval et al in Cleveland, where they looked at 10 recipients between 24 and 55 years of age, two of whom were fully vaccinated. None of them had COVID symptoms, and their graph function was all adequate at 12 weeks. Interestingly, it's important to note here that they did use this matrix, as you can see in the bottom table, looking at the time from the onset of symptoms and the cycle threshold in order to choose these donors effectively. In addition, there have been more organs recovered and transplanted from donors with a positive lower respiratory tract sample. And you can see here, at least 15 livers have been recovered and transplanted with a utilization rate actually of 68% and no discards. So this is actually something that shows that this is happening in the community, and we look forward to hearing the results of these transplants so that we can continue to provide transplantation in a safe way. So what can we do for our candidates? Well, we can vaccinate them, we can improve their immunogenicity pre-transplants, and we can provide cocooning, ensuring that their family members are also vaccinated. We can use mitigation strategies, use symptom monitoring and testing, and evaluate patients for persistent viral shedding versus reinfection. All of these things make it possible for us to provide opportunities for transplant and prevent transmission of infection. Certainly, we know that this is applicable to other diseases, hepatitis B, vaccinating your transplant candidates ensures that you have a better chance of avoiding a donor-derived infection and being able to use a broader range of potential donors. What are the key takeaways? Well, it's really important to understand that donors remain a potential risk for transmitting infection, but this risk can be mitigated by vaccination of the transplant candidate, use of appropriate donor history, donor screening, and preemptive intervention. Preparation and preemption is obviously preferred as that allows us more flexibility. Certainly, we need careful attention to recent and remote donor exposures, and increased organ sharing across regions requires recognition and understanding, as well as appropriate mitigation for regional risks for infection that may not be recognized in a program that hasn't accepted donors from other regions previously. This is particularly true when we talk about things like risk for strongyloides, trypanomysiasis, also for things like tuberculosis, as well as other things, coccidioides, that may be very regionally specific related to risk that we can certainly avoid. And we are working toward the goal of offering safe and effective transplantation. The use of COVID-19 positive donors is something that people are pushing the edges on, which is an important process, as long as we are providing it as safely as possible, to as many patients using our understanding of the current scope. So I look forward to having conversations with you about other potential questions around potential donor-derived infections and taking the safest way forward so that we can maximize organ donation, as well as maximize recipient outcome. Thank you.

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