 We have a special guest today, Steve Whittle, who is returning to the University of Chicago. Where he spent how many years, Steve? Ten years. Ten years. Did Dick say plenty? No, he's ten years. Steve is the Professor and Chief of the Division of Transplant Surgery at the University of Cincinnati. His MD was from University of Texas Medical Branch in Galveston, and he did his residencies in California, as well as fellowships in renal, pancreatic, and hepatic transplantation, which he did here at the University of Chicago. His research interests include solid organ transplantation, paired kidney donation programs, chains, and immunotolerance questions. In preparation for this introduction, I went back and I looked at a paper that Lainey Ross and Steve Whittle did. I think Dick was on it called Ethics of a Paired Kidney Exchange Program. There was a New England Journal paper in June of 1997. The idea of Paired Exchanges had been introduced about ten years earlier by Paul Terasaki at a conference, but nobody had ever really moved forward on the concept. And this paper in the New England Journal, Lainey was the first author and Steve was the senior author, really galvanized the field. And so many of the things that you see happening today, not just about pairs, but a sequence of pairs which have emerged as chains, I think derive not just from the Terasaki suggestion of the 80s, but from the revival of that in this New England Journal paper of 1997. Steve's topic today is Ethics of Kidney Exchange, past, present, and future, and it's a pleasure to welcome you back, Steve. Thanks, Mark. Can everybody see if I stand over here? I'd rather stand out here than be hiding behind that lectern. So it's fun to come back where you spent a large portion of your career. Really, my transplantation career was really formed and shaped by some of the people sitting around the table here. And so if you hear some things that sound a lot like the University of Chicago, it's because I haven't forgotten everything that I learned when I was here. So I want to take you on a journey starting when we first started thinking about this issue and take you through those period of years when we're here in Chicago and then what we've done in Cincinnati. I'm not going to be able to talk as much about the future because there's just not enough time in the talk, but for those of you that are interested in talking about the National Kidney Registry, which is probably the predominant program in the United States now and some of the ethical issues associated with it, I'm happy to talk to you later on about it. We did hear a talk by Garrett Hill. Yes, so Garrett's been here. But he didn't tell you about the ethical problems that he has with the registry. He has not. Yeah, yeah, yeah. So from my perspective, this is one of the real cradles of transplantation. If you look at this institution and its contributions, they're substantial. There's been 10 surgeons within the Nobel Prize in Physiology and Medicine. Two of those 10 won the Nobel Prize for work they did here at this institution. One in a building in a lab just over here with Charles Huggins for hormonal responses to cancers. But Alexis Carell came here just a few years after the university was founded at the turn of the century and in a building in a laboratory a couple of blocks away actually transplanted, learned how to sew vessels together and transplanted organs and animals and small animal. And his citation on his Nobel Prize is that he won that for recognition of his work on vascular suture and the transplantation of blood vessels and organs. This is a guy that I learned surgery from. His name is Bill Blaisdell. And Blaisdell was actually a real giant in the field of surgery. He actually did some of his training with the Bakie and Cooley. He invented the axolofemoral bypass graft, which solved the problem of infected grafts that the Bakie and Cooley were getting. That was his job. He went in the lab. But he was the founding chairman at the U-D-C Davis of Surgery. The library there at that institution is named for him now because of his scholarly contributions that he made. And he actually trained, I was actually one of his residents. And I actually got my job here as a fellow and I was really, really wanted that job because at that time back in 1983 when I was looking for transplant fellowships, I wanted to do kidneys, pancreases, and the livers. And there were only three programs in the country where you could do that. And this was one of them. And so he called this fellow who was the guy who started clinical transplantation here. And Frank Stewart was one of his chief residents, one of his first chief residents at the Fort Miley VA in San Francisco. And I didn't even have to interview. I had a job based on the phone call. And so that's where my lineage goes back. These are some of the guys, I was really lucky. I think as Dick was that this guy came along in 1984-85 and established a liver transplant program that became really probably over the next 10 years the preeminent, innovative liver transplant program in the world. The first series of segmental liver transplants was done here. The first series of split liver transplants in the world was done here. The first series of living donor liver transplants in the world was done here. And it was done during that period of time that Dick was a junior faculty attending, and I was a fellow. And so these guys were all here at the same time. Not all of the guys that came through here are here, but I just wanted to point out a few of them. A lot of you know these faces, but I want to tell you where they are now and what they do. This guy was one of the first fellows. I'm not sure if Dick, really, you were the first fellow, but you were sort of a junior faculty, but not really a fellow, right? And then right behind Dick was Johnny Mone. John is now the Chief of Transplant at Columbia University in New York. I came and Osama Gaber was in between. Osama is now the Chairman of Chief of Transplantation at Methodist Hospital in Houston, and he's a vice chair there. Following me was Tom Heffern. Tom spent about 15 years running the Pediatric Liver Transplant Program at Emory University. He's now starting a program in Denver. Behind Tom, there was this guy here who, as you know, is now the... Giuliano Testa is now the Director of Living Donor Liver Transplantation, one of the largest programs in the country at Baylor University Medical Center in Dallas. George Loss is now the Chairman of Surgery. He was the Chief of Transplant for a number of years at Oxner Clinic. He's now the Chairman of Surgery at Oxner Clinic in New Orleans. Dave Cronin is the Head of Liver Transplantation Medical College of Wisconsin. This guy's IVA Rosiers was just behind these guys. He is actually now Chief of Transplant at the University of Louvain in Belgium. Max Milago is the Head of Heptobiliary Surgery at University College of London. And this guy, Ken Newell, is a transplant surgeon at Emory in Atlanta and has just been elected the Chief of the Incoming President for the American Society of Transplantation. Quite a group. And so this is the legacy that this surgical transplant fellowship has. And if you look, there's a lot of these faces. A lot of these guys wrote papers with people sitting around the table on the ethics of transplantation. So the concept of research ethics consultation was started by Mark. And he and John Lantos published the first paper. It was used prior to segmental liver transplantation. It involves an extensive consideration of ethics involving a new surgical procedure prior to an IRB proposal and clinical implementation. And so this is a quote from the paper that Mark talked to you about, the New England Journal of Medicine paper that Laney first authored. And it talks about research ethics consultation. And we referred to it in that paper specifically because we wanted to write that paper to create the appropriate discussions that should be held before a clinical trial of kidney exchange procedures. In 1989, we described a process of research ethics consultation for surgical innovations to evaluate clinical and ethical acceptability of transplantation program involving living liver donors. This type of consultation entails a more extensive ethical analysis, greater than that usually provided in a standard review by an IRB. It involves open discussions with the institution. It involves publication, peer review, and public discussion. And so that process, which was started by Mark and John here for the innovative liver transplant procedures, we then had deliberately applied to kidney exchange. The concept of equipoise was actually also used. Equapoise has a number of different types of definitions depending on what you're considering. But really what I've done is sort of paraphrased it. Is equipoise involves the balance between the need to delay the introduction of procedures so that you gain more knowledge about the procedure. And it's balanced by the urgent need to clinically apply that so that you can save lives. And so paraphrasing it is basically the time to start is when enough is known and the clinical need is dire enough such that it is time to start the clinical procedure. So the concept of kidney exchange in the literature, there's no appearance before that of Felix Rappaport in 1986. And he actually had a publication, and it involved mainly talking about living unrelated donors and the results needed to be good enough. And once they were good enough, then one could exchange those kidneys. So what we needed was the immunosuppression to get good enough that the rejection rates were down and the graph survival was good enough that we could start to exchange kidneys between complete strangers. He envisioned a registry. He envisioned two donor recipient pairs, separate transplant centers, simultaneous procedures, and exchange of kidneys by courier. Now what he talked about in this was a very small paragraph. And it was really short on details. And it was a small paper as you can see here only about four pages. And this basically stayed in the literature without anything else appearing for a long period of time. And as you can see here in 1994, in the U.S., there was about, in terms of other living-related or spousal-unrelated, there was less than 10% of living donors were done with those types of transplants. However, the growth out to 1997 had gotten to the point if you added the two together, it was about as frequent as a parent or an offspring type of transplant. And so clearly this, and actually this increase here happened to coincide with the introduction of mycophenylate and really the use of tachromos and mycophenylate combination when the rejection rates got down into the teens and graft survival got very good. Well, I happened to be at a meeting at the ASN in about late 1995. And this guy, who really fathered, was one of the major formative people in the development of human tissue typing, was giving a lecture. And he mentioned in passing very briefly the concept of exchanging kidneys. And so I actually walked out of the lecture and bumped into a nephrologist who I've worked with for a number of years in Cincinnati now. I wasn't in Cincinnati then, but I knew Roy first, and I said, Roy, have you heard of this before? And he says, you know, Steve, people have talked about that often on, but nobody's really written about it and nobody really knows what to do with it. And I said, well, this really sounds like a good idea and I'm surprised it hadn't taken off. And I actually went, as I normally did, and went into Dick's office and I said, Dick, what do you think about this? And so we sat down and we talked for maybe half an hour an hour about the pros and cons of it and what we should do. And this was one of my favorite things about, that I recall the most about being here in Chicago is you could always walk down the hall and have a discussion with somebody on an intellectual level that was just a pleasure to have. And it was so much fun. And so Dick said it, I said, we probably ought to talk to Mark. And he said, yeah, talk to Mark. So then we talked to Mark. And Mark said, yeah, I think this is a really good idea. And he said, and I got this young person that I'd really like to work on this that I'd like for you to work with, Steve. And so Lainey really did all the heavy lifting on this. I did some of the background scientific data and everything. And so she really, it was really a pleasure to do that. And what happened was, is about halfway into, we'd been working on it for a few months. And Mark came up and said, you know, I think we may be able to get this in the New England Journal. I said, no way. And he said, yeah, I got some connections. And it is novel. I said, well, yeah, it is kind of novel. So anyway, it wound up in the New England Journal. And the real, so the purpose of this was to establish the ethics and set about a proposal to do a clinical trial and using research based consultation as an approach. And so that was the first paper and so it was a proposal and in it we proposed the pilot study. What we did was we proposed something very similar to what Felix Rappaport had envisioned. We took the simplest example of a kidney exchange because we thought that to lay out the ethics and stuff, you need to really start off very simple. And so what we proposed was an exchange between two pairs who were ABO and compatible, donor A to B, B to A. And then we changed the kidneys and you achieve identity. The problem with this particular issue was it represented only a small percentage of the combinations and really in an active transplant program only about 5% of your living donor volume can be expected to do this. So you need to have the only, no other donor is compatible for a patient. All of the donors are ruled out and you've got this as one of your potential donors to be able to move forward. So the original definition by this was two living donor recipient pairs who cannot undergo transplantation because of ABO or cross-matching compatibility and they are paired so that the donated kidneys are transplanted into the matched recipients, not the original intended loved ones, thereby circumventing the immunologic barriers and allowing both recipients to receive a compatible living donor transplant. So the issues that we identified in our first paper are as follows, coercion, right to withdraw consent, privacy, confidentiality, commercialization. This has turned out to be a big issue, even bigger now than it's ever been, informed consent and altruism balance. So in coercion, where coercion comes in is that we live in a real world and living donors don't all come just wanting to lay down and give up a kidney. A lot of them are ambivalent. A lot of them may have a lot of hesitation or reservations. And when you take away and some of them are relieved to find out that they're ABO incompatible, say, oh, I don't have to do this now. Well, now you've taken away that excuse. And so what you have to do is build into your program and teach your coordinators and have it and built into the social worker and the coordinators and the living donor advocates that this has to be watched and protected and you have to have a constant, ongoing conversation with the donors throughout their work. If they're not returning phone calls, the next time you talk to them, you have to say, are you having second thoughts? You have to have to pick up on the little details and this is really critical. We didn't talk about that in the paper, but it's the practical implementation of this that's really critical for programs. So there's the right to withdraw consent, sort of the same issue. Now we're actually going to be having formal training programs for our living donor advocates. Now every program in the country has a living donor advocate. But now we're actually going to have to develop training programs and this will be a part of their training programs. What do you do with privacy and confidentiality? If you've got two pairs, they don't know each other. How much do you tell them about each other? They have a right to privacy, but they also have a right to have a certain amount of medical knowledge so that you can get true informed consent. The issue about whether or not they meet is an issue that's been, we did not address in our papers, but it's been an issue that has been created back and forth in a number of different stances on that exists now. Medical legal protection, when you consent them, they need to understand that that kidney is coming from someone that they may not know and that there's always a chance for transmission of disease that was unexpected and so you have to take care of that issue also. Commercialization and exploitation is a real issue. We didn't envision it back then, but now there are kidney exchange programs in the United States where the donor and recipients pictures will be put on a website afterwards. And I'm not sure that all of the proper protections are in place, but those examples are used to try to recruit additional people to participate. So there's a potential for a note of violation with this. We actually considered that in the paper. We rejected the possibility that this actually violated note, but it remained an issue for a while and the U.S. Department of Justice actually kept an eye on this for a number of years. So here's what we said about the future. We were worried that some support groups may seek to assemble their own paired matches. People might advertise on the Internet. Transplantation teams had to accept that such exchanges had to take on the responsibility of ensuring that participation was voluntary and that the members of each donor and recipient pair had a personal and not a commercial relationship. In other words, there weren't donors that were being paid. So our proposal for a registry, we didn't support that. We actually, what we supported was individual centers like our own should initiate their own small programs and do it under controlled setting. The problem with this was that we didn't understand how few patients there would be and that small transplant programs probably couldn't generate the volume of patients necessary to achieve the matches. And this is not so much for ABO, but much more important when it comes to the highly HLA-sensitized patient. So after that, Laney got invited to write a book chapter and so the next thing I knew, we were writing a book chapter. We then came into the issue to address the issue of participation of compatible donor recipient pairs and altruism imbalance. So the idea with this is that you may be able to drive more matches if you don't have to wait for two pairs that are incompatible. If you have a compatible pair that can participate, then you can get more matches and get more transplants done. For example, in this scenario, this is the first scenario we talked about, both of these pairs can't have a transplant. So the amount of altruism in these pairs is equal. But if you have a transplant, for example, if you have an O recipient that needs an O kidney, this O donor can donate not only to their recipient, but also to this one. So this transplant could go ahead. So that's participation by a compatible pair and the amount of altruism required on the part of this donor is substantially greater than this one. So we considered that and it created a problem and this actual O donor problem remains an unsolved problem today in kidney exchange. One of the things that is the greatest demand in a kidney exchange program is the demand for O blood group kidneys. It's the same as the national weight list. So this problem is not completely solved. We've come up with a few strategies. This participation of compatible pairs is one of the most effective ways to deal with this. There's a balance that's starting to swing ethically in the transplant community. We won't be able to touch on it all because of the time limits today. But the original rejection that Laney and I published has been under somewhat of an attack, if you will. It's intellectual and what's driving that is the perceived need to drive the transplants. So a couple of the approaches that we proposed to mitigate this O blood group shortage was allowing patients to participate who had a positive cross match against their donor. In other words, they had HLA antibodies. They were ABO compatible but they had HLA antibodies. So that has a group of O donors that are in it. And so some O kidneys can come from theirs. Another approach that we suggested, if you take families where there's multiple donors upfront before you evaluate everybody, you tell the family and consent them and tell them that if one of you has an O blood group we're going to encourage you to be the one to donate. So that's a thing you have to be really careful about but those two solutions were things that we proposed and talked about. And so the next thing that we dealt with was weight list paired donation programs where this is a situation where you have a living donor and a recipient and you donate a kidney to the weight list and then your recipient goes up in priority and gets a kidney from a deceased donor. The problem with this is the quality of a deceased donor is nowhere near that of a living donor. We actually rejected this in the same paper and despite the fact that we rejected it it actually got incorporated in the first multi-center kidney exchange program in the United States of the New England program. So then the next thing that happened is the economist got interested and so we're going to talk a little bit about economists you know there's a lot of kinds of economists crawling around this place when we got it when they heard about them they consider all these things a market they don't understand what ethics is really that well. They view the whole world as a market they're really not that bad but so Stephanos actually ended up calling Laney and saying hey I can model this issue about the referential use of an old donor within a group of donors and so he did some modeling and looked at what the negative effects were on the old wait list with wait list exchanges and found that indeed this old preferred type of living donor thing can help mitigate these effects. So when New England got ready to establish their program they had a conference they brought together all of the programs in the New England organ bank which is UNOS Region 1 and I strongly advocated against a wait list exchange in that program despite my best efforts they went ahead and did it anyway and they published those effects and they saw that they saw that there was a deleterious effect on the old blood group and the way that people the people that don't have kidney exchange programs that have built in protections for the old blood group wait list justify it by saying that the volume of increased transplants that's being done justifies that small but significant effect on the old blood group wait list. So what we suggested to them was that if they were going to have a wait list paired donation that the real issue was how long do you make the pairs wait here to find a match so what happens is if everybody is allowed to bail out very quickly and just donate to the wait list you'll never build up a big enough pool of potential donors and recipients to have significant match rates. So what you really need is this type of scenario where you've got a lot of patients waiting here, a fine filter and highly restricted access to wait list paired donation. The overall ratio of kidney exchanges to wait list exchanges is a function of how frequently you find the matches up here. So little did we know but in 1991 there was a program that was started in South Korea. 20 years later they actually published their experiences so there were people in South Korea that had been doing this for six years. The problem is that the Koreans really didn't set out the ethics. They didn't perform this under a rigid prospective protocol. There was no IRB. They first used it to circumvent cross match positive and they first used living related donors. They did not use living unrelated donors. They actually used it to improve HLA matching. So there were a lot of ethical issues with this program. And they still there's still ethical issues today with that program. So when we went to Ohio people had known about our work. There was interest in a couple of centers and establishing one. Now the Ohio Solid Organ Transplant Consortium is something you don't have an equivalent for in Illinois and be glad you don't. It is a state mandated group where we have to approve every center has to approve every patient listed for a non kidney organ. So pancreas, livers, hearts and lungs all have to be approved by every center before they can be listed. It can be painful. But when we started working together this was an obvious medium where we could establish a kidney exchange program. So we got together and we did it the right way. We established a program. We established a protocol. We had rules. We had ethical protections for patients built into it. It took us a good while to get it. Another thing that we did is we developed one of the first computer matching programs. These are actually the programs that were there. These are the programs that exist in Ohio. One of the things that is really critical here too is that we had programs such as Ohio State, our programs at the Christ Hospital and the University Hospital and Cleveland Clinic that had substantial numbers of living donors. So we had over 200 plus living donors a year being done in the state which gives you a good volume to help drive these types of exchanges. Here's our policy and procedure manual. And this is our matching software. This was actually not really sophisticated matching software. Not nearly the type of stuff that's done today. These are fake names and stuff in here. But this is what you would see when you put in all the data. This is actually would be the patients were ranked based on a ranking system. The matches were ranked. And so this is 408 tentative matches and a match run back. So that was a fake one. But this was actually what the match would look like in the points. So it was a very, it was a nice system and then you could check to make sure that you weren't putting an EBV positive into a negative and those types of things. So, and this is actually the first kidney exchange that was done through the high solid organ transplant program. It was done between our program and Toledo. This young man wanted to give a kidney to his mother but she was sensitized by the pregnancy and had antibodies to his paternal HLA antigens. This gentleman had his wife wanted to give to him but he was an O blood group she was an A but she could give to her and he could give to him. And we did that transplant. And she died about six years later she had diabetes and cardiovascular disease. He is alive today and doing well with an excellent creatinine. So then we started to sort out when we started to do this we started to sort out that there's the issue of critical mass that you need a certain number of donor recipient pairs to drive the match rates. And so these are actually the numbers of donor recipient pairs in every match run that was done for the first year in the Ohio program. So we started off with 7. We ended up with 22. The number of potential matches is here so you can see 231 potential matches. The number that got excluded because they were ABO incompatible or they had an antibody that would have rendered a virtual cross match was 97.8% but look at these so with your just your computer looking at the match 98% of all potential matches all theoretical matches get excluded and that's the reason why you've got to have large numbers of pairs to really drive the volume. As you can see the number of paired donations here was four out of the first 22 an effective transplant rate on the order of about 10%. I'm sorry about 20%. So if we plotted the number of donor recipient pairs here on the x-axis and the number of matches this is the number of matches with a two paired type of exchange. This is the number of matches with a three pair. When you go and actually this is so that this is the number of different combinations you can put together. So you see you need at least 20 pairs to really start getting mathematical power, exponential power. Then when you have the computer rule out the ones that don't match you have to get to 100 to 200 pairs to start to get to where the computer says it's a reasonable match to go forward with. And this is what we mean by critical mass. And then when you actually do the cross match in the lab then you need actually around 200 pairs. The problem one of the problems is that the one population that even today remains to be inadequately addressed with this is the very high PRA patients patients who have HLA antibodies that react with 95 to 100% of all potential donors that are out there. These patients are going to need desensitization, they're going to need approaches to lower their antibody level so that they can effectively be treated and transplanted. One of the nice things about kidney exchange is that the first time you go into kidney exchange if you have 200 people in your exchange that recipient will see a kidney donor on that match run alone. So there's a very good chance that that person may see a kidney that's pretty well matched but not perfect and if you're dealing with one antibody or two then you can desensitize that. And this is the type of approach that Bob Montgomery has advocated from Hopkins. The real problem with that and we won't get into this today is that the desensitization mechanisms that are currently available today are woefully inadequate to really address this problem. We really need better desensitization mechanisms. So next to come along in the field and was the computer gurus and the economists. And they started coming up with mathematical approaches and different strategies for trying to enhance these match rates. And I want to go through some of these for you because some of them do raise ethical issues. So here's a multiple pair matching approach. Instead of just two pairs here you could have a three pair donation. Now the problem is once you get out to four pairs we had previously noted that the donors have to go to sleep simultaneously. So it eliminates the possibility of reneging. So if you do one transplant one day and one donors recipient gets done and they back out the next day you got a problem. So simultaneous induction of anesthesia is something that we advocated it's not always done now but it's something that we advocated. When you've got eight people that need to be in eight operating rooms simultaneously and coordinated everybody nobody can have a cold. Everybody has to be there on time and you have to have operative strength. If you're doing this type of transplant so we've done one of these in our institution we had six operating rooms going simultaneously. So I had three laparoscopic donor surgeons operating simultaneously and three recipient surgeons. And so logistically it really in our institution it becomes a bit of a problem. So computer based optimization has really been championed initially first by Dory Segev for those of you that don't know Dory he's an incredibly brilliant transplant surgeon that's not an oxymoron. He actually is the only physician to have ever graduated from Johns Hopkins School of Epidemiology and passed every bit of the board all of the parts of the board. He's also graduated from Rice with a degree of electrical engineering so he's really savvy. He happens to be married to a mathematician who did her graduate work PhD graduate work at MIT so it's quite a powerful couple for this field we're really lucky they're in the field so they actually said we can actually use optimization types of algorithms and so if each one of these is a donor recipient pair each line here is a potential match and this approach from an area of mathematics is called graph theory but to try to make it understandable for a person like me you can see that if you take these three patients out look at how many matches you have left so really what drives the match rates here are these three and they're critical okay so what you ask the computer to do is look at all the various combinations that you can create and look at the order in which you do the transplants so that you maximize the total number of transplants that you do for example if you did pair three and pair four and pair five and pair six right here is the first two matches you do transplants two transplants okay but if you did all of these first and save them to the end you would do eight transplants so rank order optimization provides the greatest number of transplants and the greatest number and you can actually optimize this to where the computer will give you a solution that it'll give you the best transplants with most HLA matches it'll it'll give you the best size weight discrepancies between you can make any rule you want and computers can be used to optimize the results so what they did was they actually created using UNOS data pools of patients and living donors and recipients up to a 5,000 here and a first accept matching scheme versus an optimized you can see that it drives about 10% potentially more matches and it also improves the number of HLA it also reduces the number of HLA mismatches okay and so that's the Hopkins type of approach then two programs came out and they suggested the possibility of allowing non-directed donors to participate and what a non-directed donor is there's about 300 of these a year in the United States as a person comes forward says I want to give a kidney to just anybody now normally those kidneys are donated directly to the wait list but these these programs came up with the idea of allowing those patients to donate in start and initiate a cascade of kidney exchanges this guy right here is from Harvard and he actually just won the Nobel prize in economics and he won it for his work he created the national resident matching program and he also did for this work that he did in kidney exchange he was specifically cited in his Nobel for his work in kidney exchange this is the way it works a non-directed donor donates here this donor then donates to the wait list that's the simplest type of exchange now this is good because this these people on the wait list this is the only way they'll ever get a living donor kidney okay they're on the wait list because they don't have living donors the problem is is if this is a no kidney it's probably going to get used right here and this kidney will be an A kidney so this approach may disadvantage once again the O blood group no blood group wait list and so we run into another stumbling block now that consideration has been largely ignored because this is a very powerful means but it still remains an issue that remains unaddressed ethically in the field so this is Alvin getting his Nobel prize and this is Alvin that transplant remember that transplant we did he actually came and watched it he'd never been in an operating room before you can actually kind of tell he's probably he looks sort of out of place there but he actually he's really an economist observations on what goes in in the operating room is certainly something to to experience so it occurred to us that when all of this happened that there was a need for ethical foundations and so I called up my buddy Mark and told him that we had put this stuff together through the Ohio Solid Organ Transplant Consortium and really didn't think that I could write an ethics paper on my own because I didn't feel like I was really qualified and so he helped us with this so we created a number of definitions now and rather than read them to you I should just show you what they are and the really critical thing here is the bridge donor this is the person this is the individual that within the concept of kidney chains and non-directed donor facilitated kidney exchanges that is the most vulnerable to be disadvantaged so this is what it looked like with two pairs going to the wait list so this is a closed exchange it gets closed it's all done in one day done you can also have a situation where you have the wait list but you have one of the donors wait so there's nobody for him to donate here he waits six weeks three months and another kidney exchange is found and he donates there then this donor becomes a bridge donor and starts another kidney transplant procedure this is a chain so now you can see things are starting to multiply and you're coming up with ideas and approaches where you can do more transplants then the important thing here is this terminates with the kidney to the wait list now I guarantee if that's an O donor here this is not going to be an O kidney coming off down here it's going to be an A kidney or a B kidney and sometimes if that's an AB kidney that kidney has nowhere to go but the wait list and you can't even generate another chain then along came the concept of a never ending altruistic donor that is a chain that never stops that just keeps on giving and you've seen the paper in the front page of the Wall Street Journal where several dozen patients were actually transplanted from one non-directed donor donating their kidney and those chains continuing over a period of a couple of years and so this is a very powerful approach the NKR which is probably the most efficient and the best kidney exchange program in the country is exclusively non-directed donor initiated chains okay they are not needs but there's a problem one guy is the guy who decides when it terminates and that guy is not a physician he's the guy who runs the program it's a major problem there are no ethical rules and no guidelines as to decide when a chain gets terminated how and when if a chain gets broken how does that get repaired the decision is not made by a physician there is no policy that governs that so that's one of the problems with the NKR so these bridge donors there's a number of issues that they have how long should they wait what is the chance that they'll back out in the NKR the back out rate is somewhere between 3 and 5% okay so that means that you're actually going to lose 3 to 5% of those kidneys they're never retrievable so one group actually proposed an honor system and so this particular so this was another kidney exchange program I think it was the alliance and so what they wanted to do is when a bridge donor came in the thing they did is they came to them after the transplant and said listen it's really important that you don't back out a few ethical problems with that and so we actually rejected those honor systems in the paper we actually suggested that what you do with a bridge donor is you let them know upfront before they make the final decision and commit you educate them in the very beginning at the first time that you talked to them about participating kidney exchange that they may become a bridge donor that they may have to wait a few weeks to several months to be able to donate that they have the right to demand at any point in time that they can donate directly to the wait list so you have to build in protections to protect those donors okay so there was a lot of issues with these perpetual kidney chains we talked about the AB donors the non directed donors and the old blood groups we talked about those so what we think is really good for these bridge donors is you provide them you talk to them about how long they want to wait in the beginning you check with them every month to see if they're still okay how they're doing I can tell you that I know for sure that one surgeon actually had a bridge donor who was thinking about backing out in Florida he got on an airplane went down there and took him for a steak dinner to try to talk him out of backing out and these are the types of things that go on the things that we really is that single incident that prompted us writing this paper so I won't go into all of the other issues here but there's a lot of issues so I mean just go right here so now Bob Montgomery has talked about combining kidney exchange and desensitization there's a number of issues with this that's being done at Hopkins it's been done all the time it's probably going to be done more and more at other programs in fact there's another number of programs that have done this in the United States there are no ethical foundations for this the issues is what is the acceptable level of incompatibility for transplantation in other words if you find four donors and a patient maybe got two antibodies against one three against another but they're different levels and the cross matches there let's say I'm going to go ahead and do the transplant because the higher the level of antibodies the greater the risk to the kidney and the higher the level of the antibodies the greater the risk is with desensitization in terms of infection and graft loss so these are very difficult issues to get at so what about long term outcomes what we really need to know is that for a given level of incompatibility what's the half life of the kidney how long is it going to last because if I'm going to transplant that guy and be back on dialysis in six years was it really worth it and so these are issues that we don't have the answers to but people are going ahead and doing this okay so I want to leave you with a kidney exchange the current definition of kidney exchange the 2011 definition is that kidney exchange is an exchange of kidneys from living donors between two or more recipient pairs who are not ABO or cross matching compatible so that the immunologic barriers are completely or partially avoided as in a when you combine with desensitization such exchanges may involve non-directed donors and possibly a deceased donor waitlist recipients that do not have a living donor that participates in the exchange quite a different definition we live in a really wild and crazy world these days but it's a real gold mine for ethicists so in conclusion there are several innovative approaches that have added substantially to the potential for kidney exchange we've come a long way since that initial paper we were in areas now that we never dreamed of back then clinical experiences there are worldwide programs there is a national program that is an excellent program in Canada there's an excellent program in Australia there's a very very good program that's basically run and governed by the national health service in Great Britain and these guys have really done it well they've done it better than we have so far the faculty of the UC McLean Center for Medical Ethics have shaped much of the ethical foundations for kidney exchange there is a mark that's left on this field that is indelible and will still has effects that reverberate today the unbalanced altruism issue is constantly being debated significant ethical issues remain and will require ongoing efforts for us to enhance the benefits and minimize risk for patients and I look forward to future collaborations with my colleagues here thank you very much it's a great presentation my question has to do with when you showed that nice diagram with the circle and the number of lines drawn across it and so depending on as you said the order in which you do things or what you're deciding you want to maximize the size of the organ and the recipient all those different things you get more or less transplants so what I'm curious about is what is the guiding principle by which the decision is made as to what should it be is it all based on maximize the number even if the size may not be identical etc so it depends on the group that's doing it each group sets their own rules and then the computer programmers the economist or who is doing your programming program the computer however you set the rules that's why you have to have a policy procedure manual and you have to have it set up so that that policy procedure manual only gets changed by vote of the committee and it gets documented and then that goes it's just like UNOS does things you get a policy it gets done and then it gets programmed well six months a year or two years later the programming gets done so you can set it to be whatever you want shouldn't it it should be some sort of balance between the numbers of transplants and the quality is how long are they kept off the dialysis you know and that's where the half life issue is really critical in this you really need to know what that individual kidney should do for that patient how long it will keep them off the dialysis because when you're looking at kidney transplant patients once you get a diagnosis of renal failure you lose life expectancy okay and how much life expectancy you lose depends primarily on how much time you spend with a transplant a functioning transplant off dialysis the longer time you spend on dialysis the more life years that you lose and so how long a kidney is going to last is a really critical decision when you've got a highly sensitized patient these are not easy things because you can get a kidney that's pretty well matched I know I could probably make that work they're probably going to have a significant risk of rejection the kidney is probably not going to last 20 years you can get 8 or 10 out of it if I'm lucky you know and move ahead the other thing that's important to understand the early data with desensitization with IVIG out of Hopkins indicates there's a 10 percent mortality rate at one year and a 10 to 15 percent graft loss at one year so the chances of being alive with a functioning graft at one year the best outcome is 75 percent now that's older data it's better the really good data is derived from patients that only have a DSA and a negative flow the ones that have a positive cytotoxic cross match the strongest degree of incompatibility results are really not very good and that's one of the reasons why we've been dissatisfied with IVIG for a number of years and have started to work on new types of therapies other than IVIG for desensitization where the responsibility for the donor lies and I ask that in the context of a selection criteria that we might have a different selection criteria than the people giving us the kidney kidney is going to be fine but I'm very concerned about the donor and their criteria in your opinion where does the responsibility for that donor lie well so if you're going to do the transplant it's ultimately you and your nephrologist I think that make the decision so you're going to make that decision and our program is really programmatic people sit around the table we look at every one of them we everybody's got a voice and a vote the ultimate decision you know basically is me because I'm putting the knife to the skin but I will rarely go against a strong recommendation by my nephrologist and that sort of thing one of the things that really worries us a lot when you see these big programs with 30 and 40 programs you get some donors going in and going oh my god how did they approve that donor we would never allow that person to donate a kidney and then you know there's times that people have said that you know about us and what happens I think sometimes is maybe a donors not perfect but you feel you listen to the recipient and the donor and they really want this to happen and you allow that to color your judgment I mean that's part of what we do we're not paternalistic in our program we listen to our patients and we make decisions with them you know and of course we have the final veto you know and they can go to another program but you know we try to make decisions together I mean I think that's I'm not sure I mean I think that's the way it was here before years ago I think Dick you may remember this is a real as you know we're doing more and more elderly donors now everybody in the country starting to go to where they're not hesitating to allow a 70 year old to donate a kidney some there were no gasps um you may remember back in the mid 90's I had a pair of lawyers who worked downtown who were both 70 years old each husband and wife the wife was on dialysis just started dialysis and they came in and the husband was arms across he was not happy he says he says I'm telling you I want to give a kidney to my wife and if you don't do it we're going elsewhere and they were bound and determined that they were going to be trans well turns out they'd worked their entire lives they were both in really good health we'd never done a donor over like 64 or something like that and they'd worked all their lives and they wanted to travel the world together and now she was stuck with a dialysis machine and he was bound and determined he was healthy he was good and so we went and talked about it and we ended up doing that transplant and they did fine in the travel to the world for several years and my mind is shifting towards where you really have to listen to your patient sometimes and as a surgeon when you're doing something like that it's hard to let them talk you into something you've never done before that's actually stretching the limits but we did it and we still do it now we've done it a lot of times and we probably do somewhere between 5 and 10 70 year old trans 70 year old to 70 year old transplants program it may be the fastest growing group of living donor transplants that's out in the country right now I'm not sure but it may be that works for a single exchange how would that figure into somebody plugging into the chain from the 70 year old kidney that's a problem that's a real problem and so one of the things about kidneys I mean Dick you may comment on this or Michelle is that if you just take a kidney and ask how long would the kidney last and so there's a known ongoing rate of deterioration and renal function starting about age 45 or 50 it's about 1 ml per year so if you start out at 95 to 100 ml at the age of 50 at the age of 80 you may be around 50 to 60 ml that kidney will last several more years so there's extra mileage in these kidneys in the elderly patients am I too far off Michelle so these will outlast people in general if you're pretty healthy what I was getting at is you feel very confident when you get to know the pair get to understand their emotional link when you're in a chain situation where you're getting the kidney from someplace else you are relying on other people to do the job you would do and I respect the college in many ways but if our program does not accept donors who are hypertensive on medication so we will accept a hypertensive donor that's 50 years of age or above these are the examples of differences between programs if they are on a diuretic or an ace or a diuretic and an ace that's the first line of treatment for some patients and they have a 24 hour blood pressure monitor test that shows a good nocturnal dip and their pressures are very reasonable say borderline say 140's and they have no evidence of kidney disease if that's the only living donor if both the nephrologist and I agree that this is something that really needs to go ahead and if the donor and recipient are educated and they understand the risks and again that's in your center but when it's coming from another center that has different donor criteria than you have you don't have to accept that donor you can always turn that one down the thing that bothered us the most about NKR was having another surgeon take my kidney out for me and ship it from California to my center and having it land at my center with 12 hours of cold time on it so we've actually had DGF in the first two of those kidneys that we've done like that and you know living donor kidneys I don't like it when they don't make you run right away that's not an easy thing so if you look at the literature that's been published about how much storage time cold storage time is safe to put on a living donor kidney it was UNILS data, Dory Segev published it and they use that data to say it's okay to ship kidneys the problem is there was hardly no kidneys beyond 8 hours of cold ischemic time and when you're shipping kidneys in NKR from coast to west coast to west coast to over it's going to be 12 hours or more so we're really in uncharted ground and what I think and we've made a preliminary look at some of the data and talked to people, we actually think that there's a suggestion that living donor kidneys may be more sensitive to cold ischemia than a deceased donor a deceased donor kidney from a brain dead donor and so there's a lot of issues a lot of issues with the NKR and programs that are out there if you look overall I think the overall good is there's been what? this year they'll do 250 transplants Laney years ago we thought maybe that would happen and it's finally here you got hundreds of kidneys and well over a thousand worldwide will be done this year as a result of kidney exchange and it kind of feels a little good to have that one paper back there a long time ago it kind of started it all you mentioned that for non-kidney organ transplantation the Ohio Consortium requires all of the centers in Ohio to approve it and we don't have something similar in Illinois and that you found that problematic and I can imagine that there's probably politics involved and that's perhaps what you're getting at but it would seem that transplant surgeons should be able to agree upon criteria for being listed maybe you could answer that there are some programs in this country extraordinarily aggressive in the donors that they'll use and in the recipients that they will list I'll give you an example I got a guy that I've actually gotten close to he's actually we were talking about him at dinner last night so this guy got transplanted by Ron Busatill back in 84 one of the first guys had sclerosis and colonitis had recurrence about 20 years later and he actually had a very difficult transplant his wound was closed his wound was allowed to granulate in an open wound repeat transplant very difficult severe portal hypertension and he was turned down for technical reasons by surgeons in my program and so I actually didn't know it but I had bumped into him in town and I said how are you doing he says well I'm on Ron Busatill's list and I said you are he said yeah I was turned down in your program and so I said no way I said Tom we will transplant you here in Cincinnati we will put you on the list we get a liver transplant so I went to the head of the liver transplant program I said listen will you do this with me I said I think he needs both of us but I think it's reasonable to do if you don't want to do it that's fine so we transplanted Tom and Tom is alive today but that's an example of how some programs won't do one transplant about other programs might but even within my own program I had surgeons that wouldn't I came under a lot of criticism because they thought that the relationship that I had with that patient was coloring my judgment and so I had a lot of thinking to do with that whether or not I would go ahead and force that issue to happen but I truly believed it was the best thing for Tom and I actually bounced it off a number of my colleagues before I actually made that decision to go ahead but I wanted Tom transplanted it in our program I didn't want him to have to travel to California move his whole family and do that stuff and the waiting times were shorter in our place so it was a better thing for him that's just an example there are huge differences in what people will and won't do I've got programs 90 miles down the road in Lexington University of Kentucky and they have patients turned down for transplantation based on weight all the time I transplant about a fourth of them as they are the others we get them they go and get a gastric sleeve and we transplant them six weeks later if they had another alternative they would sit down there, stay on dialysis and have half the life expectancy smoking is a huge issue some programs no way some programs if you've gone through a cessation program you've tried the drugs and you've made a really sincere good faith effort we won't deny you the benefit of a transplant that's a very, very sticky issue so there's a lot of differences it sounds like there is a political component it sounds like there's a political component and there's also a little bit of variability among the centers but I feel like isn't having the conversation worthwhile to perhaps curtail cowboy transplant surgeons you're trying to get a bunch of cowboy transplant surgeons to agree on something you know those guys Dick you've been here in Chicago Chicago has how many transplant programs have you gone through you know through Roby and the Oregon Bank a lot of times they have to agree upon policies and a lot of that stuff is consensus easier today than it was back 15, 20 years ago? I think you've been saying this I'm not sure you want consensus because the way the field moves forward is by people extending the boundaries if we look back to when I started in kidney transplant I went over 50 in kidney transplant now how we did it then that was probably the safest thing but the field moves and with it you get improvement and if you force everybody to follow the same rules and it's the one of my complaints about where UNOS is going then you're not going to change you'll be in 2020 transplanting by 2010 standards and that's just not appropriate so I think you need to allow I think you want to amuse us and to the extent that there's oversight the oversight doesn't have to be in Ohio the oversight is by CMS now if you're making really lousy decisions they're going to can your program so it's not that there's not oversight but I think you need to allow people to try to continue to treat more people with therapies that are focused it's a very very good point I mean I think so if you look at the field of kidney exchange UNOS has is in the game now they've been threatening to be in the game for a long time I was you know I probably have taken a number of hits because I've said openly and strongly opposed UNOS being involved and the reason why is UNOS has a huge bureaucracy anytime you want to change a policy it takes six committees to approve it and a year to change the policy that's sort of bureaucracy and put it upon a program a field that is formative that's rapidly changing and you'll stifle innovation and so maybe in another five to ten years will be a time for UNOS to really get into this game but if you look at the UNOS program that exists now it's been in existence for going on it's fourth year they've done twenty transplants twenty five Garrett Hill's going to do three hundred this year that's the potential and the impact that stifling innovation can have give you another example so when we went to Ohio we submitted a patient to be approved for a liver transplant that had a carcinoid tumor carcinoid tumors are very indolent tumors there's a good literature not randomized but a good literature of several dozen patients or more largely from Tom Starr's group showing that they can have long term survival with a carcinoid and it's actually better than survival with the worst genotypes of hep C but my patients were turned down I couldn't get them approved because the other guys in the state didn't think we should be doing them and so that really put a bad taste in my mouth I never had that in Illinois and I had to get used to it in Ohio and what we had was a group of programs that were really really conservative and fortunately they've come back the best thing that ever happened to liver transplant in the state of Ohio was Charlie Miller going to Cleveland Clinic and John Fung really helped us shift the pendulum back towards being somewhat more aggressive for patients but patients were leaving the state and going to other places to get their transplants and it was very frustrating I came back in December from our conference on carcinoid tumors with the Patek metastasis the the results of that consensus conference including the issue of transplantation for patients with the Patek metastasis when the primary is resected and not resected will be coming out in nature oncology in about two months so but as you say there are no good controlled studies of it I want to thank Steve for a number of things first for making the trip from Cincinnati to Chicago second for the kind words you said about the ethics program here at Chicago third for your contributions and Lainey's to writing about and developing this field of exchanges and leading to the chain concept and also for the ongoing work that you're doing so thank you so much Steve