رونوشت کامل Beyond the Operation: The complex decision making process

anesthetists, the intensivists, and of course the snobs, the nurses that make Caroline Verdon: 00:04:50 the approach for the donor family in that most incredibly difficult time. Caroline Verdon: 00:04:57 So, yes, far from being me with two or three people around me, Caroline Verdon: 00:05:01 just admiringly agreeing with me. Caroline Verdon: 00:05:03 Um, I'm pleased to say that that, that rather naive vision was, Caroline Verdon: 00:05:07 was, um, rapidly supplanted. Brendan Clark: 00:05:10 Right. Brendan Clark: 00:05:11 Let's meet some more of the team. Brendan Clark: 00:05:12 I'm Brendan Clark. Brendan Clark: 00:05:14 I'm consultant clinical scientist in histocompatibility and immunogenetics. Brendan Clark: 00:05:20 Um, that title doesn't mean a lot to most people. Brendan Clark: 00:05:23 So we also go by the name of transplant immunology, which probably explains Brendan Clark: 00:05:27 what we do a little bit better. Caroline Verdon: 00:05:29 So how does your role fit within the transplant team then? Brendan Clark: 00:05:32 What we deliver is, in colloquial terms, is Brendan Clark: 00:05:36 a search for a matched donor. Brendan Clark: 00:05:38 Do the tissue matching of donor recipient pairs. Brendan Clark: 00:05:41 We look at the, uh, the genetic fingerprint, if you like, to ascertain Brendan Clark: 00:05:45 the level of match that that exists between that donor recipient. Brendan Clark: 00:05:49 Generally speaking, better matches equal better outcomes. Brendan Clark: 00:05:52 We look at the immunology of the pair to assess compatibility. Brendan Clark: 00:05:57 People are, are aware of the basics around immunity. Brendan Clark: 00:06:01 If you are exposed to, uh, uh, foreign. Brendan Clark: 00:06:04 agent, a pathogen or bacteria, you form an immune response against that. Brendan Clark: 00:06:08 Well, that's the same if you're exposed to foreign tissue, you form Brendan Clark: 00:06:11 an immune response to that tissue. Brendan Clark: 00:06:12 So we look at pre existing immunity, which may get in the way of a transplant. Brendan Clark: 00:06:19 Um, and we look at That in, in terms of donor recipient compatibility, and then Brendan Clark: 00:06:25 following on from the hand transplant being performed, we look at the emergence Brendan Clark: 00:06:31 of donor sensitization, the development of an immune response against the donor. Brendan Clark: 00:06:36 Which would inform, um, clinical judgment around rejection episodes and, uh, the Brendan Clark: 00:06:41 management of those rejection episodes. Brendan Clark: 00:06:43 So, so we do three things. Brendan Clark: 00:06:45 Essentially, we do the tissue matching, we do the assessment of compatibility Brendan Clark: 00:06:49 between the donor and recipient prior to the transplant, and then post transplant Brendan Clark: 00:06:53 we monitor the recipient going out to make sure they're not developing

Brendan Clark: 00:06:56 immunity and are at risk of rejection. Brendan Clark: 00:06:59 So three areas of work. Caroline Verdon: 00:07:02 And is it more complicated looking Caroline Verdon: 00:07:04 at the immunology side? Caroline Verdon: 00:07:06 for a hand transplant than it would be a kidney transplant, for example. Brendan Clark: 00:07:11 So with a kidney transplant, we're standing Brendan Clark: 00:07:14 on the shoulders of others. Brendan Clark: 00:07:15 There's a massive literature going back into the 1950s that, that Brendan Clark: 00:07:20 deals with the immunology and the genetics of, of renal transplantation. Brendan Clark: 00:07:27 And we are surrounded by experts and guidelines and best Brendan Clark: 00:07:31 practice sort of instructions. Brendan Clark: 00:07:34 So, we work within a framework of knowledge that, that is vast. Brendan Clark: 00:07:39 We are guided in our application of that knowledge by national bodies, Brendan Clark: 00:07:43 NHS Blood and Transplant, and, and their requirements for delivery of Brendan Clark: 00:07:48 service by laboratories such as ours. Brendan Clark: 00:07:50 So, we, we have a lot of support, a lot of background support. Brendan Clark: 00:07:55 With the, uh, Um, what was at the time called the Hand Transplant Program, now Brendan Clark: 00:08:00 Composite Tissue Transplantation Program. Brendan Clark: 00:08:03 That background was not there. Brendan Clark: 00:08:05 There had been hand transplants performed in a few centers around the world, but Brendan Clark: 00:08:10 I think that at the time that Simon, was proposing to develop the LEADS program. Brendan Clark: 00:08:18 I think the worldwide experience was something like 10 hand Brendan Clark: 00:08:21 transplants, none of which had but occurred in the context of what Brendan Clark: 00:08:25 could be called a clinical program. Brendan Clark: 00:08:27 They had been single cases. Brendan Clark: 00:08:30 It was surgically led and the transplants had been done without Brendan Clark: 00:08:35 breadth of consideration that Simon brought to the question of Brendan Clark: 00:08:40 establishing the program in LEADS. Brendan Clark: 00:08:42 We were really working from base level. Brendan Clark: 00:08:45 We worked from the principles that we understood from our experience Brendan Clark: 00:08:50 of solid organ transplantation and brought those to the table and said, Brendan Clark: 00:08:53 well, by and large, we, we work to two rules in, in transplant immunology. Brendan Clark: 00:08:59 Matching is good and pre existing immunity is bad. Brendan Clark: 00:09:03 So if we, if we stick with those rules and behave in a precautionary Brendan Clark: 00:09:07 way, we will look for, we will look for matching and we will look to Brendan Clark: 00:09:12 avoid immunological sensitization. Caroline Verdon: 00:09:15 And when you say pre existing is bad, what does that mean? Brendan Clark: 00:09:19 So, as an individual, you can become sensitized to foreign tissues Brendan Clark: 00:09:25 through exposure to the antigens on those tissues, which are present in another Brendan Clark: 00:09:33 individual, but not present in you. Brendan Clark: 00:09:36 And, and generally speaking, you'll be exposed to those in one Brendan Clark: 00:09:38 of three, what we call classical ways in terms of everyday life. Brendan Clark: 00:09:42 You can be exposed to them through previous transfusions. Brendan Clark: 00:09:45 So people who have transfusions will have received a blood unit, which will Brendan Clark: 00:09:50 have obviously the red cells, which they require, but also carry a white blood Brendan Clark: 00:09:54 cells, which express these antigens, these, these things, which mark. Brendan Clark: 00:09:58 For what we call self and which are seen as foreign. Brendan Clark: 00:10:02 So if I receive a blood transfusion, maybe blood group compatible, but Brendan Clark: 00:10:06 the likelihood of it being tissue antigen matched in terms of the. Brendan Clark: 00:10:10 Antigens that we're interested in, very slim chance of that indeed, vanishingly Brendan Clark: 00:10:14 small, because we're not looking at that. Brendan Clark: 00:10:16 And therefore, through exposure, through transfusion, I may become sensitized. Brendan Clark: 00:10:21 Once your immune system has seen a foreign antigen, you develop Brendan Clark: 00:10:26 an immune response to that. Brendan Clark: 00:10:27 Everyone's familiar with that, that's how vaccines work. Brendan Clark: 00:10:29 You introduce a foreign antigen, you get an immune response to it. Brendan Clark: 00:10:33 But you also develop a memory. Brendan Clark: 00:10:34 You remember that you've seen that. Brendan Clark: 00:10:36 And so that when you re encounter that antigen at a later date, Brendan Clark: 00:10:40 you mount a much more vigorous response, higher magnitude response. Brendan Clark: 00:10:44 And so, sensitization through transfusion, for females through pregnancy, because, Brendan Clark: 00:10:50 in essence, the, the fetus is, is, is, is like a graft, it has special Brendan Clark: 00:10:55 status in terms of its immunity, but it shares half of its genetic Brendan Clark: 00:10:59 makeup with mum and half with dad. Brendan Clark: 00:11:01 The part that comes from dad, Is foreign to mom. Brendan Clark: 00:11:05 And so a female through pregnancy can become sensitized to these antigens. Brendan Clark: 00:11:10 And again, we'll develop an immunity, which we encounter fairly frequently in Brendan Clark: 00:11:15 ladies who've been pregnant, that they will have a preexisting immunity, which. Brendan Clark: 00:11:19 disbars the use of certain donors who have matches with the father of the child Brendan Clark: 00:11:27 that they've carried and therefore the female will have an immune memory

which Brendan Clark: 00:11:32 means that that particular donor there is a conflict in terms of immunity. Brendan Clark: 00:11:37 And then of course previous transplants so uh people who've had transplants Brendan Clark: 00:11:41 previously will be sensitized because they will experience these Brendan Clark: 00:11:44 mismatched antigens in that graft. Brendan Clark: 00:11:46 Contrary to common belief. Brendan Clark: 00:11:49 probably. Brendan Clark: 00:11:50 When we talk about matched drafts, they're not perfectly matched. Brendan Clark: 00:11:53 There will be a level of mismatching because of the complexity of the system, Brendan Clark: 00:11:56 and that may be smaller or larger depending on the graft and the graft type. Brendan Clark: 00:12:01 Um, so when we talk about matched drafts, it's very rare that you Brendan Clark: 00:12:04 have a perfectly matched draft. Brendan Clark: 00:12:06 So exposure to another tissue, if someone's had a renal transplant, Brendan Clark: 00:12:10 a liver transplant, skin grafting, they will all cause sensitization. Brendan Clark: 00:12:13 And so you carry that sensitization with you in terms of immune memory. Brendan Clark: 00:12:17 And so And classically, like I say, it's going to be transfusion, Brendan Clark: 00:12:19 pregnancy, previous transplant. Brendan Clark: 00:12:21 There are some other non classical ways of becoming sensitized, and we Brendan Clark: 00:12:24 do encounter those from time to time. Brendan Clark: 00:12:26 But those are the main ways in which people become sensitized. Caroline Verdon: 00:12:30 And so really stripping it back then, are you saying that if Caroline Verdon: 00:12:34 somebody has already previously had this response and then they have this Caroline Verdon: 00:12:39 um, hand transplant that gives them a higher chance of the body rejecting the Caroline Verdon: 00:12:43 hand transplant because it's already produced those antigens before and Caroline Verdon: 00:12:47 that memory, as you were talking about? Brendan Clark: 00:12:48 Yeah, precisely, Caroline. Brendan Clark: 00:12:50 Um, exactly that. Brendan Clark: 00:12:51 So there is, there is a A more significant risk for a rejection response to occur Brendan Clark: 00:13:00 in an individual into whom you perform a transplant where they've already seen as Brendan Clark: 00:13:06 a result of one of those other mechanisms, that antigen, they will carry that Brendan Clark: 00:13:10 immune memory and their memory, immune memory will be jogged by the re exposure. Caroline Verdon: 00:13:15 And so, does that mean then that there would Caroline Verdon: 00:13:18 be people who perhaps might want a hand transplant but who wouldn't be Caroline Verdon: 00:13:22 eligible on the grounds of that alone? Brendan Clark: 00:13:25 So, When we are doing the initial review, because I think Brendan Clark: 00:13:31 as will have been explained to you by others, the actual workup for the Brendan Clark: 00:13:34 transplantation takes place over a fairly prolonged period, and we spend time Brendan Clark: 00:13:39 looking at the pre existing immunity in the patients that have been brought Brendan Clark: 00:13:44 forward for consideration, and we establish a profile of immune reactivity. Brendan Clark: 00:13:50 We are told what pre existing sensitizing events, historical sensitizing events Brendan Clark: 00:13:55 have been, whether they've been transfused, transplanted, had children. Brendan Clark: 00:13:59 Um, and in the laboratory, we perform tests, which then disclose the way Brendan Clark: 00:14:06 in which that sensitizing event has impacted on their immunity. Brendan Clark: 00:14:11 And we can build up a picture of foreign antigens. Brendan Clark: 00:14:15 Antigens which are present in other individuals but not present Brendan Clark: 00:14:18 in the patient against which they already have sensitization. Brendan Clark: 00:14:24 Where they have formed that response, we are very cautious. Brendan Clark: 00:14:29 Really, we would not allow a transplant to occur because of the presence, the Brendan Clark: 00:14:37 pre existing presence of that immunity. Brendan Clark: 00:14:40 And so we have patients in, in the program who have. Brendan Clark: 00:14:45 Had extensive sensitization and, and yes, it does impact on their Brendan Clark: 00:14:51 chance of receiving a donor offer. Brendan Clark: 00:14:53 Um, all of that is, is fully explained to them. Brendan Clark: 00:14:57 Um, Simon goes through, uh, the detail of that with the patient and Brendan Clark: 00:15:02 explains to them what that means for their candidacy for transplantation. Brendan Clark: 00:15:07 Um, And essentially it means that for some they will wait a long time Brendan Clark: 00:15:11 before we say yes, this, this is a donor against whom this patient has no Brendan Clark: 00:15:16 antibody conflicts, there is no immune reason not to give this transplant. Brendan Clark: 00:15:20 And obviously Caroline Verdon: 00:15:21 the process of a patient joining the program and putting Caroline Verdon: 00:15:25 themselves forward and running through all the tests, it's long and it's very Caroline Verdon: 00:15:29 in depth and it takes, um, a minimum of a year, but obviously usually. Caroline Verdon: 00:15:34 considerably longer. Caroline Verdon: 00:15:35 You've done all those tests on the patient, but then you receive a phone call Caroline Verdon: 00:15:40 saying, look, here's a possible donor. Caroline Verdon: 00:15:43 What happens then? Brendan Clark: 00:15:45 Okay, so what we need to do is, if the potential donor has not Brendan Clark: 00:15:50 been through our hands, this laboratory, we've not done the, the tissue typing. Brendan Clark: 00:15:56 We need to find, we need to obtain a tissue type. Brendan Clark: 00:15:59 So we will get that from

NHSBTODT and we can reference that tissue type Brendan Clark: 00:16:05 to the immune profile that we hold. Brendan Clark: 00:16:07 We look at the profile of immunity that we have established for that patient Brendan Clark: 00:16:11 over the past year and we say either there are no immune conflicts that stand Brendan Clark: 00:16:18 in the way of this donor or Or we have identified an immune conflict as a result Brendan Clark: 00:16:25 of the longitudinal screening that we've done and we have to say that this donor Brendan Clark: 00:16:30 is incompatible on an immune basis. Brendan Clark: 00:16:33 If we have a compatible situation, we also identify The level of matching Brendan Clark: 00:16:38 between the donor and the recipient. Brendan Clark: 00:16:40 So we do two things at that point. Brendan Clark: 00:16:42 We assess the immunity and we say, this is the match level of that donor. Brendan Clark: 00:16:49 And then it's back to Simon for decision. Brendan Clark: 00:16:52 If we say, if we say incompatible, um, it's usually stand down. Brendan Clark: 00:16:56 It has been stand down to date. Brendan Clark: 00:16:59 Um, If we say compatible, then the decision goes back to them. Brendan Clark: 00:17:03 We've given them the green light on immune grounds to go ahead. Brendan Clark: 00:17:06 And now the decision is with them, whether they are going to go ahead. Caroline Verdon: 00:17:10 And if they do make that decision to then go ahead with Caroline Verdon: 00:17:14 the transplant, I think you described it as part number three of your role, Caroline Verdon: 00:17:17 then kicks in, uh, with the monitoring. Caroline Verdon: 00:17:19 Tell me a little bit about your involvement there. Caroline Verdon: 00:17:21 So the background to that is, Brendan Clark: 00:17:26 uh, slightly, slightly pre transplant stuff. Brendan Clark: 00:17:28 If you are exposed to foreign tissue and you're going to be exposed Brendan Clark: 00:17:30 to foreign tissue as a result of receiving this graft, then your Brendan Clark: 00:17:34 immune system will respond to that. Brendan Clark: 00:17:36 If it is unrecognized and not managed well. Brendan Clark: 00:17:41 can develop into a, uh, a rejection response. Brendan Clark: 00:17:46 And so it's important that as you move out from transplantation, you continuously Brendan Clark: 00:17:51 assess, as we do pre transplantation, the manifest immunity of the patient. Brendan Clark: 00:17:57 Initially, we'll do this at day 3, day 7, day 14, day 28, and then monthly out Brendan Clark: 00:18:03 to about 6 months, and then at every point that the patient thereafter makes Brendan Clark: 00:18:07 contact with the clinic, comes in for regular checkups, unless there is a Brendan Clark: 00:18:12 clinical event, and if there's a clinical event, the team will submit a, if they Brendan Clark: 00:18:15 say, we were a little bit concerned about X, uh, here's a sample, could Brendan Clark: 00:18:19 you look for evidence of new immunity that's donor relevant in this one? Brendan Clark: 00:18:24 The idea is there that you're looking for new immunity, de Brendan Clark: 00:18:28 novo immunity against the donor. Brendan Clark: 00:18:30 That will need to be met by some change to management if you are going to get Brendan Clark: 00:18:34 on top of that immune response and stave off the clinically manifest rejection Brendan Clark: 00:18:40 response that will probably follow. Caroline Verdon: 00:18:42 And are you always able to? Brendan Clark: 00:18:47 If you identify low level Immunity, well there will not Brendan Clark: 00:18:52 yet be anything that is clinically manifest usually in the graph. Brendan Clark: 00:18:56 So if you just pick that up as a result of routine screening, and flag Brendan Clark: 00:19:00 that back to the clinical team, they can titrate up the immunosuppression, Brendan Clark: 00:19:06 and low level antibodies, as long as you get hold of them fairly Brendan Clark: 00:19:10 quickly, tend to be more effective. Brendan Clark: 00:19:13 amenable to management. Brendan Clark: 00:19:14 There are, there are different ways of doing that. Brendan Clark: 00:19:16 It might not just be the use of pharmacologics. Brendan Clark: 00:19:21 You can do things like plasma free cistern If it's a patient who's Brendan Clark: 00:19:27 presented with something worrying to the clinical team, it looks like rejection, Brendan Clark: 00:19:34 you've probably got a bigger problem. Brendan Clark: 00:19:36 The antibody levels, the immunity will already got to fairly significant levels. Brendan Clark: 00:19:41 And that becomes a much bigger challenge. Brendan Clark: 00:19:43 Thank you very much. Brendan Clark: 00:19:44 That's not saying that it's insurmountable. Brendan Clark: 00:19:47 Um, as a center leads teaching hospitals as a incredibly good track record of Brendan Clark: 00:19:53 managing immunologically complex cases and turning things around, things Brendan Clark: 00:19:59 I would look at from my position as someone in the laboratory and go, Brendan Clark: 00:20:02 goodness me, they really are going to be struggling to get hold of that one. Brendan Clark: 00:20:06 But they do, so they've got a lot of background in this, particularly Brendan Clark: 00:20:10 Building on experience in the renal program of managing incompatible Brendan Clark: 00:20:14 transplants and patients that develop, um, antibody mediated Brendan Clark: 00:20:19 rejection following transplantation. Brendan Clark: 00:20:21 So, in some cases, You can. Brendan Clark: 00:20:25 In other cases, I'm afraid that things have gone too far by the time that we Brendan Clark: 00:20:30 are alerted to the antibody levels are rising, the immunity is kicking in, and Brendan Clark: 00:20:34 in some cases, that will not be possible. Brendan Clark:

00:20:38 I mean, so far in the hand transplant program, the composite tissue Brendan Clark: 00:20:40 allotransplant program, the experience has been good, where antibody responses Brendan Clark: 00:20:47 have developed, where immunity has developed, it's been manageable. Caroline Verdon: 00:20:50 It's a huge. Caroline Verdon: 00:20:52 decision to make, isn't it? Caroline Verdon: 00:20:53 When you're at that point, if you've been told, yes, this, this could be physically Caroline Verdon: 00:20:57 possible for you to have the transplant, but this side of things, um, and having Caroline Verdon: 00:21:03 to make that decision on whether for the rest of your life you will take those Caroline Verdon: 00:21:08 immunosuppressants, that must be such a huge decision because that's going Caroline Verdon: 00:21:12 to have a knock on effect, isn't it? Caroline Verdon: 00:21:14 For everything. Brendan Clark: 00:21:15 Yeah, yeah, absolutely. Brendan Clark: 00:21:16 From the very outside, it was reiterated that the difference between a hand Brendan Clark: 00:21:22 transplant, a composite tissue eye transplant, however you badge it, and a Brendan Clark: 00:21:26 renal or a liver transplant is that the, the composite tissue transplant is, is Brendan Clark: 00:21:32 life enabling, the others are life saving. Brendan Clark: 00:21:35 And we have to keep that, we have to keep that separation in terms of, you know, How Brendan Clark: 00:21:41 we think about the risks that you identify are met and addressed because what you Brendan Clark: 00:21:50 would do to try and save a graft, which is life saving, probably cannot be justified Brendan Clark: 00:21:56 to enable or to save a graft, which is life enabling, and that is matter, which Brendan Clark: 00:22:04 is Occupies the team, probably every meeting that I go to that, you know, how Brendan Clark: 00:22:10 are we doing the best out of this for the patient, whether it's to enable the Brendan Clark: 00:22:15 transplant or to preserve the transplant and what lengths will we go to here? Brendan Clark: 00:22:21 So that is, That is front and center in, in, in all of the thinking and Brendan Clark: 00:22:26 the complexities of patient management are rehearsed backwards and forwards Brendan Clark: 00:22:29 and argued out so many more times than I've experienced with, with colleagues, Brendan Clark: 00:22:35 you know, dealing with, with our bread and butter work, the renal work maybe. Brendan Clark: 00:22:39 Um, So that is very much in everyone's thoughts when we are trying to get a Brendan Clark: 00:22:46 transplant or we are dealing with a rising immunity or maybe frank rejection. Brendan Clark: 00:22:53 How do we best deal with this, giving consideration to the complexities Brendan Clark: 00:22:59 that you've identified, um, and, and weighing in that this is life Brendan Clark: 00:23:03 enhancing and not life saving. Brendan Clark:

00:23:05 It's, it's a, it's a real, you know, uh, I'm, I'm not a medic. Brendan Clark: 00:23:10 I'm a scientist. Brendan Clark: 00:23:11 It's a real wisdom of Solomon type thing that that discussion and uh, I I can Brendan Clark: 00:23:17 sit there and theorize and I I And I am guilty of throwing in my this is my view Brendan Clark: 00:23:22 This is a drug that looks like we should be looking at this with some seriousness Brendan Clark: 00:23:27 And then some little colleagues will then say but you're you're thinking Brendan Clark: 00:23:30 about that really as a scientist You're saying that's what it will do Actually, Brendan Clark: 00:23:35 it will also have these side effects and they are probably not as desirable. Brendan Clark: 00:23:39 You know, we need to shy away from that a little bit. Brendan Clark: 00:23:42 Um, yeah, it's, it's a balancing act, Caroline. Brendan Clark: 00:23:45 You're walking right along the knife edge, really, when it Brendan Clark: 00:23:49 comes to immunosuppression. Brendan Clark: 00:23:50 Go too far one way and you are compromising the patient's immunity. Brendan Clark: 00:23:55 greatly and and laying them open to all of the complications you've Brendan Clark: 00:23:58 identified under immunosuppressant. Brendan Clark: 00:24:00 You take the brakes off the immune system and the immune system gets Brendan Clark: 00:24:04 hold and it rejects the organ. Brendan Clark: 00:24:05 So it's it's a real problem that area. Richard Baker: 00:24:08 So my name is Richard Baker and I'm a Richard Baker: 00:24:12 consultant renal physician at St. Richard Baker: 00:24:14 James's but I also happen to be the physician helping with the whole program. Richard Baker: 00:24:20 I suppose sometimes I think of myself as the doom monger in a way because Richard Baker: 00:24:24 I have to talk about complications caused by the drugs, but I think it's Richard Baker: 00:24:27 important to get them in perspective. Richard Baker: 00:24:30 But equally, it's very important that during the evaluation, because it's such Richard Baker: 00:24:34 a long and hard journey to go through, everyone goes in with their eyes open Richard Baker: 00:24:40 and knows exactly what could happen. Richard Baker: 00:24:43 And as I say, because the numbers are so low, really, we haven't really seen many. Richard Baker: 00:24:48 of the more unusual complications in upper limb transplantation that we Richard Baker: 00:24:53 see in solid organ transplantation. Richard Baker: 00:24:55 With 1300 renal transplants being looked after in Leeds, we do see the Richard Baker: 00:24:59 rarer things happening all the time. Richard Baker: 00:25:00 So we quite frequently see cancers in relatively young people and infections. Richard Baker: 00:25:05 And I don't think we've really seen that yet in upper limb transplants, and Richard Baker: 00:25:08 I hope we never do, but I think it's inevitable as we do more, that you will Richard Baker: 00:25:12 see Um, complications, so the consent process and making sure that people Richard Baker: 00:25:17 have the right education prior to the transplant is absolutely essential. Richard Baker: 00:25:22 At the inception of the program I was asked to get involved because Richard Baker: 00:25:26 I had a lot of experience using immunosuppression because of course Richard Baker: 00:25:28 there's been a kidney transplant program at Leeds since the 1960s. Richard Baker: 00:25:34 When I've been there working in transplants since 2000, so obviously Richard Baker: 00:25:38 there've been I think over 6000 renal transplants over those years Richard Baker: 00:25:42 and we look after a population of about 1400 renal transplants. Richard Baker: 00:25:46 So obviously we had a lot of experience using the drugs that prevent rejection. Richard Baker: 00:25:52 And it was really one of the necessities of the program that they had someone Richard Baker: 00:25:56 who was used to using those drugs. Richard Baker: 00:25:57 So that's where I came along really, because I, I had that experience. Richard Baker: 00:26:00 It is a multidisciplinary team. Richard Baker: 00:26:02 There are lots of people doing various bits and pieces, but, um, I Richard Baker: 00:26:06 speak to people who are potentially. Richard Baker: 00:26:08 Interested in undergoing an upper limb transplant and I will talk to them about Richard Baker: 00:26:13 the medical aspects so I'll talk to them about the need to take drugs because if Richard Baker: 00:26:19 you have a transplant you will obviously have foreign tissue attached to your body Richard Baker: 00:26:24 for the indefinite future and that means that you're exposed to foreign tissue Richard Baker: 00:26:28 and you will mount an immune response against it so one of the important Richard Baker: 00:26:35 principles is that you'll need to take drugs to dampen down your immune system Richard Baker: 00:26:39 for the lifetime of the transplant. Richard Baker: 00:26:41 Otherwise you would reject it. Richard Baker: 00:26:44 So I talked to in the workup phase, I talked to all the potential recipients and Richard Baker: 00:26:48 I talked to them about immunosuppressive drugs and the side effects that Richard Baker: 00:26:52 they have, because obviously if you take a drug that dampens down your Richard Baker: 00:26:58 immune response that's going to have some side effects which will include Richard Baker: 00:27:01 reducing your resistance to infections and increasing your risk of cancers. Caroline Verdon: 00:27:08 And how much does that affect somebody who's had the transplant? Caroline Verdon: 00:27:14 You know, is it that they will pick up every single cough and cold or they can Caroline Verdon: 00:27:17 expect hospitalizations across the winter? Caroline Verdon: 00:27:20 How much is that likely to affect

them day to day? Richard Baker: 00:27:23 The vast majority of people who have immunosuppression Richard Baker: 00:27:25 don't suffer any consequences. Richard Baker: 00:27:27 We know that actually the commonest types of infection, well I suppose Richard Baker: 00:27:32 the commonest types of infections are viral infections and they are slightly Richard Baker: 00:27:34 increased in patients on immunosuppression but bacterial infections, for example, Richard Baker: 00:27:38 strep throat or scarlet fever, those sorts of things, there doesn't Richard Baker: 00:27:42 appear to be any particular increase. Richard Baker: 00:27:44 There is an increased incidence of some of the um, rarer infections. Richard Baker: 00:27:49 Things, that are caused by agents such as fungi and protozoa, which Richard Baker: 00:27:55 are rare anyway, but they are increased in transplant patients. Richard Baker: 00:27:59 So it's, it's a very small risk, which by virtue of being a transplant Richard Baker: 00:28:03 patient is increased a few times. Richard Baker: 00:28:06 So the overall risk is actually quite low, but it is much greater than Richard Baker: 00:28:09 someone who's not on those drugs. Caroline Verdon: 00:28:11 So how In inverted commas, normal, a life could a person Caroline Verdon: 00:28:15 expect to have post transplant in terms of, not the working ability of the hands, Caroline Verdon: 00:28:21 but in just in terms of everything else. Richard Baker: 00:28:24 Well, I think one of the reasons that they undergo such an Richard Baker: 00:28:27 intense psychological workup is because the first year is really very difficult. Richard Baker: 00:28:31 It's incredibly intense and you won't achieve maximal function Richard Baker: 00:28:36 from the, um, limb transplant probably for about two years. Richard Baker: 00:28:41 And there's an intense period of physiotherapy, particularly during Richard Baker: 00:28:44 the first um, year and perhaps some, you know, some psychologically testing Richard Baker: 00:28:48 things such as just being slightly frustrated by the slow progress. Richard Baker: 00:28:52 But it's important that people are resilient for that and prepared for Richard Baker: 00:28:55 it so that they can deal with it. Richard Baker: 00:28:56 So it does take quite a while. Richard Baker: 00:28:58 But once you get past that period, say at least a year down the line, Richard Baker: 00:29:02 then patients with transplants can lead relatively normal lives. Richard Baker: 00:29:07 They should keep up to date with cancer screening. Richard Baker: 00:29:10 They should have vaccinations like, um, the rest of the population or the ones Richard Baker: 00:29:14 that they're able to have, such as COVID and flu vaccines, those sorts of things. Richard Baker: 00:29:19 But otherwise they can lead a relatively normal life. Caroline Verdon: 00:29:23 And I've always wondered with things like this, when it comes Caroline Verdon: 00:29:26 to things, as you say, they're like, Caroline Verdon: 00:29:32 you know, the increased risk of, of cancer, what are Caroline Verdon: 00:29:34 the outcomes of that like? Caroline Verdon: 00:29:35 Because Along with the increased risk, obviously people are being tested Caroline Verdon: 00:29:39 more regularly and therefore is the cancer likely to be picked up earlier? Caroline Verdon: 00:29:43 So how does that compare to the outcomes with the general population? Richard Baker: 00:29:48 That's a very good point. Richard Baker: 00:29:49 And I think one of the difficult things about this whole area is Richard Baker: 00:29:52 that cancer treatment is improving all the time, very rapidly. Richard Baker: 00:29:56 So a lot of the data we have is old. Richard Baker: 00:29:58 The other problem we have in this case is that we, there just isn't Richard Baker: 00:30:01 a large enough database of people who've had limb transplants. Richard Baker: 00:30:03 There's only been probably somewhere between 100 and 200 Richard Baker: 00:30:07 in the world that we know of. Richard Baker: 00:30:08 So anything that's rare won't have happened yet. Richard Baker: 00:30:11 We have to extrapolate from the data in patients who have liver, Richard Baker: 00:30:18 Heart, kidney transplants and other solid organ transplants. Richard Baker: 00:30:21 And given that they're on the same drug, it seems reasonable to assume that Richard Baker: 00:30:25 the types of cancers will be similar. Richard Baker: 00:30:28 So we know from those populations and many thousands of patients who've Richard Baker: 00:30:32 received solid organ transplants that the risk of cancer is increased. Richard Baker: 00:30:36 And very roughly, it's increased by a factor of two. Richard Baker: 00:30:39 You're about twice as likely to get cancer if you're on long term Richard Baker: 00:30:43 immunosuppression for an organ transplant. Richard Baker: 00:30:44 So, Certain cancers, however, are much more likely to occur. Richard Baker: 00:30:48 And one of the main ones is certainly skin cancer. Richard Baker: 00:30:53 The good thing about that is there's a lot you can do about it Richard Baker: 00:30:55 by reducing your exposure to sun. Richard Baker: 00:30:57 So we're very keen to educate our patients about avoiding direct Richard Baker: 00:31:02 sunlight, using high factor block over 40, um, using long floppy hats. Richard Baker: 00:31:09 Staying in the shade, those sorts of things. Richard Baker: 00:31:11 And that, that can massively reduce your risk. Richard Baker: 00:31:14 But we know, for example, in Australia and New Zealand, that, um, the Richard Baker: 00:31:17 risks of skin cancer are probably somewhere around 20 to 50 times more Richard Baker: 00:31:23 common than the general population. Richard Baker: 00:31:26 Wow. Richard Baker: 00:31:26

That's huge. Richard Baker: 00:31:28 Well, it's very important to understand the difference between Richard Baker: 00:31:30 absolute and relative risk. Richard Baker: 00:31:32 And it's, I always explain this by taking the analogy of a lottery ticket. Richard Baker: 00:31:36 If you buy a lottery ticket, you're very unlikely to win, but Richard Baker: 00:31:39 if you buy two lottery tickets, you're twice as likely to win. Richard Baker: 00:31:42 And if you buy 10, you're 10 times more likely to win, but your risk Richard Baker: 00:31:46 of winning is still very low. Richard Baker: 00:31:48 So these, these risks of cancer are relatively high. Richard Baker: 00:31:52 The relative risk goes up by that, that many times, but actually the absolute Richard Baker: 00:31:57 risk still remains relatively low. Richard Baker: 00:31:59 And that, that remains true of other cancers as well, that are more common, Richard Baker: 00:32:03 particularly ones that are caused by viruses like skin cancer, genital Richard Baker: 00:32:07 cancers, and tonsil and mouth cancer. Richard Baker: 00:32:10 Some of those are increased and also certain types of lymphomas. Richard Baker: 00:32:14 are much more common. Richard Baker: 00:32:16 But as I say, it's the same story that the relative risk is high, Richard Baker: 00:32:20 but the absolute risk of getting it is still relatively low. Caroline Verdon: 00:32:24 So you meet patients very early on in the journey then, um, Caroline Verdon: 00:32:28 when they're sort of in the considering Portion of this process and considering Caroline Verdon: 00:32:33 whether or not they want the transplant and getting all the information and then Caroline Verdon: 00:32:37 when it comes down to them having made a decision that yes, this is for them, Caroline Verdon: 00:32:42 what's your involvement past that point Richard Baker: 00:32:46 at the time of the transplant? Richard Baker: 00:32:47 Really not not too much. Richard Baker: 00:32:49 I tend to see them afterwards. Richard Baker: 00:32:50 There's there's a lot of surgeries you can imagine in a very intense Richard Baker: 00:32:54 period which requires the. Richard Baker: 00:32:56 skills of a vast team, but there's not really much for me to offer other than Richard Baker: 00:32:59 to check that the immunosuppressive drugs have been given correctly. Richard Baker: 00:33:03 Um, then I would tend to review the patient before discharge and at least Richard Baker: 00:33:08 say hello, um, and check that they understand their drugs, look into some Richard Baker: 00:33:12 other things like whether their blood sugars are high and what the blood Richard Baker: 00:33:15 pressure's like, and check on some of the other medications that are given Richard Baker: 00:33:19 to prevent infections, for example. Richard Baker: 00:33:21 And then, you know, Once they enter the longer phase, then I will tend to see Richard Baker: 00:33:25 the patients every three to four months just to check that they're getting on Richard Baker: 00:33:31 okay with their medications, that the levels are about the right numbers and Richard Baker: 00:33:37 things like, as I say, blood pressure and blood sugars are all well controlled. Caroline Verdon: 00:33:41 So you must build up quite a relationship with the Caroline Verdon: 00:33:43 patients then, as you're seeing them over such a long period of time. Richard Baker: 00:33:47 Yes, you do. Richard Baker: 00:33:48 But of course, as a, as a kidney doctor, once you have kidney failure, Richard Baker: 00:33:51 you're with the renal team for life. Richard Baker: 00:33:52 So I sort of used to seeing people for a long journey, but that's absolutely right. Richard Baker: 00:33:57 It's a, it's a classic chronic care type model where you Richard Baker: 00:34:00 see people for a long time. Caroline Verdon: 00:34:01 Did you imagine sort of 20 years ago, 15 years Caroline Verdon: 00:34:06 ago, that this would be the sort of thing that, that you would be Caroline Verdon: 00:34:08 involved in, that you would be doing? Richard Baker: 00:34:10 Absolutely not. Richard Baker: 00:34:11 No, originally I worked, um, during my training in West London. Richard Baker: 00:34:15 Uh, where one of the, uh, surgeons was involved in the very Richard Baker: 00:34:18 first, um, hand transplant that was carried out in France and. Richard Baker: 00:34:24 Of course, that didn't end very well because the patient stopped taking Richard Baker: 00:34:28 their tablets and in the end they had to amputate the transplant. Richard Baker: 00:34:31 And I think there was a lot of cynicism generated by that about Richard Baker: 00:34:33 the whole and transplant process. Richard Baker: 00:34:36 And to be perfectly honest, that was cynicism that I shared, but I Richard Baker: 00:34:41 actually sat down and watch some of the videos of people in the United Richard Baker: 00:34:45 States, particularly from, um, Kentucky and what they'd been able to achieve. Richard Baker: 00:34:51 And I was surprised by the level of function that could be achieved Richard Baker: 00:34:54 by an upper limb transplant. Richard Baker: 00:34:57 There was also a lot of work going on still in France and some, Richard Baker: 00:35:00 I believe in Vienna with some really quite impressive results. Richard Baker: 00:35:03 And that's what changed my mind, having seen what was possible and Richard Baker: 00:35:07 also meeting the patients who wanted to have transplants and seeing how Richard Baker: 00:35:11 difficult their life had become. Richard Baker: 00:35:14 Because without hands, obviously very basic things that you and Richard Baker: 00:35:17 I take for granted, like eating, toileting, cleaning, they just Richard Baker: 00:35:22 can't do, or they need assistance. Richard Baker: 00:35:24 Um,

and the combination of the predicament with what I witnessed as being actually Richard Baker: 00:35:30 pretty good results was enough to convince me that this was a really Richard Baker: 00:35:33 worthwhile thing to get involved in. Richard Baker: 00:35:36 And I, to be honest, I haven't looked back. Richard Baker: 00:35:37 I think it's, it's been really impressive. Richard Baker: 00:35:40 And I have to say that I think I've met some of the most impressive. Richard Baker: 00:35:43 individuals that I've ever met in my medical career, um, in the recipients of Richard Baker: 00:35:47 these transplants, because the amount of adversity and the journey that they've Richard Baker: 00:35:51 had to go on is really quite remarkable and they are, they are quite remarkable Richard Baker: 00:35:55 characters, very resilient people. Caroline Verdon: 00:35:57 I think hearing from both Richard and Brendan, for me, has Caroline Verdon: 00:36:01 really put into perspective just what a gigantic decision it is to have or Caroline Verdon: 00:36:06 to not have a hand transplant, because it really isn't an operation, you're, Caroline Verdon: 00:36:11 in inverted commas, you're not alone. Caroline Verdon: 00:36:13 Fixed. Caroline Verdon: 00:36:13 And then you're done and free to go. Caroline Verdon: 00:36:15 This is a lifelong change. Caroline Verdon: 00:36:19 Prof. Simon Kay: It is a lifelong change. Caroline Verdon: 00:36:21 And there are a few things worth saying about that. Caroline Verdon: 00:36:24 The first thing is, as we've discussed before, we make all our patients, from Caroline Verdon: 00:36:28 the moment we identify them as likely to be suitable, we make them all wait a Caroline Verdon: 00:36:33 minimum of a year, whilst we assess them immunologically and psychologically. Caroline Verdon: 00:36:38 But also in part of the psychological assessment of that is that they Caroline Verdon: 00:36:42 have information exchange about the benefits, the risks, the Caroline Verdon: 00:36:46 things that will happen to them. Caroline Verdon: 00:36:48 And we test at every new meeting, whether they've retained that Caroline Verdon: 00:36:51 information, how they've interpreted it, what their feelings about it are, Caroline Verdon: 00:36:56 and whether their feelings about it is stable in the course of that year. Caroline Verdon: 00:37:00 Um, that's very important because we're asking them to make probably Caroline Verdon: 00:37:04 one of the most complex medical decisions a patient makes. Caroline Verdon: 00:37:08 because it's not mandated. Caroline Verdon: 00:37:10 If you need a heart transplant, you're not going to say, well, I'm not really Caroline Verdon: 00:37:14 sure, you know, maybe I won't, maybe I will, because if you don't, you'll die. Caroline Verdon: 00:37:20 Some people would say that, um, being handless, that is to say having Caroline Verdon: 00:37:26 lost both hands, is not an illness. Caroline Verdon: 00:37:29 Um, and I don't think that's a helpful way to look at it. Caroline Verdon: 00:37:32 We're not asking a healthy person to balance the risks of an Caroline Verdon: 00:37:36 intervention that's not necessary. Caroline Verdon: 00:37:38 We're asking a person who's not healthy because they're not living a normal life. Caroline Verdon: 00:37:42 They may have fallen into poverty, self image problem, relationship Caroline Verdon: 00:37:46 problems, unemployment, um, all sorts of things that afflict these patients Caroline Verdon: 00:37:53 that unless you stop and think about it, you don't realize they're there. Caroline Verdon: 00:37:57 And we're offering to, change that health status by giving them hand transplants. Caroline Verdon: 00:38:02 But like all interventions for all illnesses, there is a Caroline Verdon: 00:38:05 downside as well as an upside. Caroline Verdon: 00:38:08 And what I would say is that external observers, uh, including myself, Caroline Verdon: 00:38:14 and this was a revelation to me, are not competent to make the decision Caroline Verdon: 00:38:18 as to whether that's worthwhile. Caroline Verdon: 00:38:20 They haven't lived the experience of a patient with no limbs. Caroline Verdon: 00:38:24 Who's gone from having limbs to no limbs, and so they can by all means express an Caroline Verdon: 00:38:30 opinion, but in the end, the well informed patient who knows themselves, who's met Caroline Verdon: 00:38:35 other patients who's had transplants, who knows that for the first year of the Caroline Verdon: 00:38:39 transplant, they won't work very well, and they may be more disabled, and who Caroline Verdon: 00:38:43 understands the risk of infection, blood sugar problem, blood pressure problems, Caroline Verdon: 00:38:49 tumors, renal problems, all of these problems that we're very candid about. Caroline Verdon: 00:38:54 Can happen and then they can make that decision and that's why I I refer to hand Caroline Verdon: 00:38:59 transplanters certainly life rescuing Because our patients are as Richard I Caroline Verdon: 00:39:05 think makes the point that they're very resilient and gosh They have to be we we Caroline Verdon: 00:39:11 have had a couple of deaths on the waiting list from patients who I don't want to Caroline Verdon: 00:39:15 go into Why they died, but I think there was a you know, the illness of being Caroline Verdon: 00:39:21 handlessness Handless contributed that. Caroline Verdon: 00:39:25 So these resilient patients that survive all of that misery to come Caroline Verdon: 00:39:28 through and ask for transplant, those are very special people. Caroline Verdon: 00:39:33 So, we think the decision is one they have to be really well informed to take. Caroline Verdon: 00:39:39 And I think Richard, one of the things he does, apart from give us very good advice, Caroline Verdon: 00:39:44

um, is he, Walks the patient through once or more and in great detail and in an Caroline Verdon: 00:39:52 interactive way what the problems are and you'll hear him talk about renal failure Caroline Verdon: 00:39:56 and, um, and, uh, infections and fungal infections and all this sort of thing. Caroline Verdon: 00:40:02 Among the things that hurt everybody throws their hands up in dismay Caroline Verdon: 00:40:06 and says, but what about cancers? Caroline Verdon: 00:40:08 And Richard has a very nice way of explaining that, which is that, Caroline Verdon: 00:40:13 you know, most of the cancers that kill you are a already rare. Caroline Verdon: 00:40:18 I mean, the public perception is they're lurking around every corner, Caroline Verdon: 00:40:21 but that's just not the case. Caroline Verdon: 00:40:23 Um, and B, their increased risk is actually very slight Caroline Verdon: 00:40:27 with the immunosuppression. Caroline Verdon: 00:40:29 There are some cancers or tumors that have an increased risk that's Caroline Verdon: 00:40:33 significant and worth considering. Caroline Verdon: 00:40:36 And those are, by and large, cancers we can treat quite Caroline Verdon: 00:40:39 readily, like skin cancers. Caroline Verdon: 00:40:41 And one or two are the lymphomas. Caroline Verdon: 00:40:45 But I'm not dismissing them when I say we can treat them readily, but thankfully, Caroline Verdon: 00:40:50 the increased risk is very small for the cancers like breast cancer and Caroline Verdon: 00:40:54 lung cancer and bowel cancer compared. Caroline Verdon: 00:40:57 And in fact, I was at a meeting in the States some time ago and I was talking Caroline Verdon: 00:41:01 about this and saying that if you take a thousand patients with hand transplants, Caroline Verdon: 00:41:07 Probably we're going to reduce the average length of life by treating them. Caroline Verdon: 00:41:12 And this professor of, um, liver transplantation got up and said Caroline Verdon: 00:41:16 you don't know that at all. Caroline Verdon: 00:41:17 You might be increasing their life expectancy because first Caroline Verdon: 00:41:21 of all, some of them might kill themselves or die or have accidents. Caroline Verdon: 00:41:26 Or just fall into poverty and depression and substance abuse Caroline Verdon: 00:41:29 because of their limblessness. Caroline Verdon: 00:41:31 So you have no idea because we don't know what the normal lifespan of somebody Caroline Verdon: 00:41:34 with no limbs is and how it changes. Caroline Verdon: 00:41:36 But the other thing he said is that, um, a number of the drugs we use have been Caroline Verdon: 00:41:42 shown to actually increase the average life expectancy of a healthy patient. Caroline Verdon: 00:41:46 And I had no idea of that. Caroline Verdon: 00:41:48 So again, it's as if in my clinic, I have a big basket labeled, don't know. Caroline Verdon: 00:41:53 And every question a patient throws at me, I say, you know, this is my best guess. Caroline Verdon: 00:41:58 This is the team's best guess. Caroline Verdon: 00:41:59 This is the expert's best guess. Caroline Verdon: 00:42:01 But in the end, we don't know, and we won't know for 50 years. Caroline Verdon: 00:42:06 But I think Um, all my sort of doom and gloom was a little bit over theatrical Caroline Verdon: 00:42:11 because in the end what you're doing is taking what I believe to be a Caroline Verdon: 00:42:16 life ruining and a life threatening condition and ameliorating it. Caroline Verdon: 00:42:21 Coming up on our next episode we meet Sarah Taplin, a Caroline Verdon: 00:42:24 specialist practitioner in physiotherapy. Caroline Verdon: 00:42:27 She's worked with the team since the beginning and is responsible Caroline Verdon: 00:42:30 for its organization, as well as being that constant link Caroline Verdon: 00:42:34 between the team and patients. Sarah Taplin: 00:42:36 The hard bit of Organizing a transplant I feel is, apart from Sarah Taplin: 00:42:40 the donor issues, is then making sure that you can get all of the people in Sarah Taplin: 00:42:44 the right place, at the right time, in theater time, theater capacity. Sarah Taplin: 00:42:49 You can get a call whenever. Sarah Taplin: 00:42:51 The other day it was like, I'm in the middle of making cauliflower cheese. Sarah Taplin: 00:42:57 Just give me a minute. Sarah Taplin: 00:42:58 I'm just going to turn the cooker off. Caroline Verdon: 00:43:01 This podcast is an under the mast studio production.