 Thank you very much, Mark. That was a very generous introduction. I now get the privilege of introducing my co-conspirator over 20 years, Dr. Dick Thistlethwaite. Dr. Thistlethwaite recently retired as professor at the University of Chicago from the section of transplant surgery. And he also was before he retired a faculty member in the McLean Center for Clinical Medical Ethics and the Committee on Immunology. Dr. Thistlethwaite's bench research career was centered on immune activation and its controlling models of transplantation. His involvement in clinical medical ethics was formed by collaboration with Dr. Mark Siegler when they worked on the Living Donor of Liver Transplant Project back in the 1980s. Dr. Thistlethwaite has authored over 200 peer reviewed medical research articles with many focusing on ethical issues and transplantation. Since 1997, his work has been an ongoing collaboration with me and in fact we now hold together a grant from the Robert Wood Johnson Investigator Award in Health Policy and we're writing a case book on Living Donor Transplantation. And from part of our work is he'll be describing today which will focus on what should we do about ApoL-1. Please join me in introducing Dr. Thistlethwaite. Kidney disease in African-Americans is a difficult problem. The incidence of kidney failure in African-Americans has been estimated to be anywhere from about two and a half to seven percent higher than that in the Whites. It has many ramifications. In the field of transplantation, we see disproportionately African-Americans needing kidney transplants. We also see transplants surviving less long in African-Americans both in African-American recipients and kidneys donated by African-Americans surviving less long. This data is primarily in transplant and focused on deceased donor transplantation. And what I'd like today is to talk about the risk of living kidney donation where a person gives up half of their renal function to give it to someone else. And the risk specifically for the African-American population. What I want to talk about is a gene that's effect in renal failure has recently, in African-Americans has recently been discovered. As you can read as I will, that it's a one of a family of genes, the ApoL genes, lipoproteins that resides in a genomic hotspot meaning an area that has a lot of recent mutations on combs on 22. It's interesting that it's expressed only in humans and some hominoid apes meaning African-old world apes that are most similar to humans, but not all. In my earlier career, most of the immunologic questions I addressed we'd go to the lab and work in mice, you can't do that with this gene because it's not expressed in even chimpanzees which can be used for experimental animals. Grills is sort of hard to do experiments with. It confers what, why it exists is it confers resistance to a parasitic disease that is transmitted by trypanosome called trypanosoma. Brusee? Brusee basically. It doesn't exist because virtually every human has this gene so that it is a resistance gene to that parasite. Now they're interesting among the ApoL ones this exists both in a circulated form on a high density lipoprotein particle, HDL3, and probably has been shown to have functions not only in lipotransport but in innate immunity. That's our immunity, our resistance without developing what we call cognitive immunity, specific immunity. Intracellular ApoL is expressed on the vasodial lining of the blood vessels of many organs but also in the kidney cells in the glomerulus called potocytes and functions in sort of clean up. Autophagy is the sort of cells that destroy themselves and apoptosis is the mechanism by which that is sometimes done. It appears to have many health effects in humans that are related to this gene. Now I've just listed them here, we're gonna obviously talk about kidney disease today but there's no reason these are related that we know there clearly is a common mechanism but it's not known. Now what I really wanna talk about are mutants, mutations within this gene. G1 and G2, which are very close together and act almost as a single unit, as a single gene but they are separate. They're thought to have occurred very recently about 10,000 years ago in sub-Saharan Africa and because of that they're absent in Europeans, virtually absent in Europeans because the diaspora out of Africa to Europe and Asia occurred many, many years before this. They have occurred before the forced migration of Africans to America took place in slavery which is why it's a problem in the United States. It has a very high frequency in the Western African population and this is thought to be due to positive selection and the positive selection is that there is a variant, try Panazone, called Roudiz, I can't pronounce it, Roudizians that protects against a disease called African sleeping sickness. So these carried by the TZ fly, it's natural host as humans, also wild animals, livestock but it when infected and this is sort of a battle between the parasite and the host, the host develops a gene that will control the wild type parasite, the parasite mutates and has a variant that has a protective protein called SRA protein that now allows it to invade the host and the host now has mutated again to protect it and it's important that protection comes with a single copy of either of these two genes so that it's what's called a heterozygous advantage. This may sound very similar to sickle cell disease in malaria because it is, it's the exact same thing, different disease, different gene but the problem is that where the heterozygous, one copy of the gene is protective, two copies of the gene predisposed to immunofelier in Africans presumably but certainly in African-Americans. Just so you'll see on slides the nomenclature G1 and G2 with what we call the two mutations that are called, and I'll call those risk alleles and the wild type alleles is called G0. Now the demographics which show its prevalence is almost 40% of Americans carry either one or the other which to our knowledge does not cause disease in itself but 12% so more than one out of 10 carry two copies which is the two copies of what caused the renal disease in the United States. As I said, it's virtually absent in the European and the Asian community. One of the interesting things and I'll come back to this later is that and if you look at the bottom I've actually put in, if an odds ratio says whether this is better than or worse, number's greater than one, you have a worse effectiveness than one you have to have a better effect. If someone does not have renal disease and when I say someone here remember this is purely isolated to African-Americans, if someone does not have renal disease this gene does not work. Two copies of the gene do not hurt them. However, if they have other renal diseases and here's the list of them then it's much more likely to cause progression of renal problems. From HIV associated nephropathy which is the highest down to actually sickle cell nephropathy lost in here and somewhat in the middle is allograph loss following disease donor kidney transplant and as you can see that indeed if a kidney comes from an African-American doesn't matter if it goes into an African-American or someone of a different race it has a higher risk of early failure than an ultimate failure than kidneys that did not express this. So can they totally explain why African-Americans, can this gene, the humans totally explain why African-Americans have a higher rate of in-state renal disease than other races? Complicated slide, look at the bottom panels because this is where we'll have, get the answer. So for example look at the bottom left panel you can see this is a survival curve that indeed that if there are a black that has two of these mutations present that they have more graph loss than one. Warner zero which is called the low risk genes and the whites which are even better. So it accounts for about half of the words of the differences. Now something I'm not gonna talk about today is a whole set of literature of medical issues, socio-economic issues that contribute to why African-American transplants do wars and why people, African-Americans with renal disease do wars. So I think it's a combination of these factors, you know, medical factors as a higher incidence of hypertension, diabetes, et cetera in African-American, socio-economic poor healthcare that accounts for about half of it, this gene counts for the other half. The main effect that I said earlier is to promote not to cause renal disease itself but to promote accelerated development of other renal diseases leading to renal failure. Looking at the top left-hand panel here you can see that to be the case where if you have zero copies of the Able or one mutant of the adult versus R1, then there's a quite different pace to kidney failure than if there are two. The bottom panel's here, I'm not gonna discuss but what they show is that trying to control blood pressure doesn't help other treatments in the tribe and nothing that's been done so far in terms of medical therapy, close follow-up, hitting target goals affects the failure. So it's really not actionable in that sense. Now is there any data about African-Americans as living kidney donors? And there is for kidney failure because here we're introducing another variable. So far we've said you need two hits really to have the rapid progression of renal failure. You need to have a kidney disease, you need to have a double mutant and now what we're doing is we're taking away half of someone's kidney function and it has not been assessed that that is, can that be considered a kidney disease in itself, essentially, and accelerate? Well, what the data that exists, and again a complicated slide, the bottom left-hand panel is the data on African-American donors compared to a group that was selected to be thought to be equally as healthy as African-American donors. And when this came out in 2013, I believe, there was a lot of controversies whether those controls might have been even healthier than the donor population. We think of our kidney donor population as being incredibly healthy, otherwise we wouldn't expose them to the risk of losing a kid. But if you just accept the data as it is, you can see in the bottom right whites, they're in the control population over a 15-year follow-up period. There is actually no death, excuse me, no kidney failure, but there is in the last, excuse me, the last five years, you can see an increasing number of donors who have lost kidney function. In other words, losing a kidney, even when you're very healthy, is a risk to long-term kidney function. That was not appreciated before two years ago, the 1914, one year ago. For blacks, both the baseline comparison population and the test population are high. Now, if you read the legend, and I don't know if you can see it from there, but the legend is disease per 10,000. So to look and say, oh, it's almost 80, but that's 80 incidences per 10,000, so still very, very low. So the question is what role do, I want alleles play in the increased risk of donors? And is this something we should be discussing? The problem is there's no data about this in the donor population. They don't have disease, but they do have reduced kidney function. And will this, these gene risk alleles cause a problem? Plainly, it was about what three years, four years ago now, that we decided that there was a way to try to answer this question with existing data. Doing a prospective study isn't gonna work because you gotta wait 10 or 15 years. What are you gonna do for the next 10 or 15 years, right? Or 20 years. So we, when I say we, I mean, mainly, pestered the federal government and actually got them to release the identities cause this is all done through the Medicare system and through the trans minus control through HHS. And release the identities of people, what we got initially was people who had donated and subsequently developing with it. And we have systematically been approaching these people and Plainly has some wonderful students that do the initial approach to ask them if they wanna participate in our study. And it's just a collection of a blood sample to do genetic testing, basically. Plainy's gonna talk about some of the other interesting things that have come out of this. But this is purely a scientific quest. We have collaborators at the NIA, Cheryl Winkler, and I can't remember his first name, Kopp, who do the testing. They're blinded as to who the patients are and the results come back to us in a blinded fashion and so forth. Now we think there's a possible total of 300 subjects that we can do this testing on. Early on, Jeff Kopp, excuse me, decided he was interested to see what it was and so sort of without consulting his collaborators, ran the test for APOL1 alleles. And as you can see, the number of individuals are the percentage actually. So this was in our first about, I think they're 47 here if you had the numbers up, African-Americans, more than half of them had double the leaves, so at risk. The general population, the data I showed you earlier, that's 12%. So there certainly is an increase in frequency of this gene preliminarily. Now, I think we had to control for having one kidney versus two, I think we had to control for family effects because renal disease does tend to cluster. So there's a lot more work to be done. So if we wanna address ethical and policy issues when there's no direct data to support medical decisions, so what do we tell these people in other words? We have suspicions but we don't have any real data. First, we need the data. As I mentioned, it's gonna take a long time to get the data from prospective studies. We're hoping our retrospective study will be informative. Why is this important? I mentioned sickle cell disease earlier. In sickle cell disease, obviously the disease is much more virulent, it doesn't just cause kidney failure and a small portion of the population. But sickle trade is a much more analogous situation. Now for decades, the effect of sickle cell trade the effect of sickle cell trade on a normal function has been suspected to be very poorly documented. Nobody's made any attempt to study donors. In 2007, a survey was sent out to transplant centers to ask them what they did with donors with the people presented wanting to be donors with sickle trade. Most of us had no policies. Most of our transplant centers had no policies, so we're 80% but what's most interesting is over a third of centers reported excluding donors with known sickle trade, always or most of the time. One of the other problems with African-Americans in transplant is there aren't as many donors as there are among Caucasians, for example. A lot of that has to do with family diseases, a lot of that has to do with structured families because most of our donors come from related donation. But with no data, these people are being died, people are being denied the opportunity to help out family members and friends. So what are ethical and policy issues? What do we do when data's incomplete? Is there a stigma and is there discrimination based on genetic testing, something that exists in other areas, sickle trade, sickle disease, sickle trade is one of those? This is such a prevalent disease. I don't think that will be a problem, quite honestly, because when over half the population has a gene, how are you gonna discriminate against them? Should A4L1 screening be mandatory so we can learn? Now, the donors have the right to keep their genetic information private and if not, how should disclosure and sharing be done? And then the other thing is there is a potential negative effect on the number of African American living donors willing to donate. Transplant programs may do what they did for sickle cell trade and just say it's too risky without any data. Or individuals may not be willing. Now the first is unacceptable, the second is and if there's an attrition in the number of donors because donors decide they don't wanna donate when they're appropriately informed, they should not be forced to donate, obviously. So obviously, when information is incomplete, incomplete, the most important thing is counseling. And counseling is not convincing and counseling is not discouraging people to do something. It's giving them the information in a way that they can digest it and that takes time and that's what's gonna have to be necessary. That all living donors need to be informed of the results of the paper I showed you of the higher rate, not high low rate, but higher rate of African American living donors developing and stage renal disease. If they choose to go, if donors choose to undergo testing, then the donors that are at risk should be counseled that they're at increased risk of developing kidney problems, whether or not they know. That is known. And then they should be counseled that it's not known to the effect of reducing their kidney function. Am I overling? Okay. Before I go to acknowledgement, let me just, so we should counsel living donors about the risk of carrying two risk alleles. We should begin voluntary screening. Having two risk alleles should not programmatically exclude donation which should allow individuals to choose this. And giving our incomplete understanding of Apoal 1 and kidney disease, disclosure to potential donors should be accompanied by the counseling, including sharing of this information with their recipients and sharing, potentially sharing it with their family who also might carry the genes and also allowing data to be collected in a secure database. Sorry about that. Thank you. Given that living donation is largely beneficial because of better outcomes, and given the data you showed that kidneys from donors that have two risk alleles have a greater percentage of fatal on the recipient, do you need to notify the recipient as well? Well, the slides I skipped over talked about that. Our current rules actually don't give us the right to talk to the recipient about donor issues. However, the donor can talk to the recipient and the donor on the transplant team can talk to the recipient with their permission. I think we need to seek their permission to do this. The recipient has options. The recipient can look for another living donor. The recipient also may not wanna put their donor at any increased risk or implied increased risk because we don't know what that is yet, right? So yes, I think it's incredibly important that the recipient know. The data, however, we have about the effect of this gene on the survival of kidneys and recipients of a kidney is based on deceased donor kidneys, which go through a lot more ischemic damage and whatnot than a living donor kidney. So we don't know if it applies to living donors. So we have to be very careful on our discussions. I think I could probably convince anybody who's not a good idea to get a, do a living donor kidney transplant, any, anybody who had this, double risk mutations. That's not my job. My job is to let them know what the risks are to the best of my ability so that they can exercise their autonomy and make that decision themselves. And I think the recipient has to be part of that as well. It is very rare within families that donors want to hide their personal information. Occasionally it happens. I'm sure this is your experience also. With unrelated donors, it's a somewhat different situation and that may be more of a problem. So either we need to change the regulations to allow us to tell donors, physicians tell recipients information. As of now, what we need to do is to discuss it with the donor and get them to give permission.