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Sure, we've got online.com. Um I, good evening, everyone. My name is Caitlyn Main. I'm the co president of British Transplant physician trainees. Thanks all very much for joining this evening. Um I'm going to begin by giving you a brief introduction to the society and then we'll move on to our agenda for this evening. Um And talk a little bit about our upcoming education program. Um So BTP T um is an organ organization very much aiming to bring together physician trainees across disciplines across the UK, bringing together trainees from nephrology, hepatology, cardiology and um and other disciplines. Um really any form of solid organ transplantation, aiming to provide education, training and mentorship opportunities. And we're also hoping to be able to facilitate um research opportunities in a collaborative trainee led fashion. Um Another of the aims of BTP T is um that we will be able to increase representation of physician trainees on national transplant groups and hoping that we able to therefore engage with other key organizations in the field of, of solid organ transplantation. Um and hopefully building relationships between physician and surgical trainees which will ultimately strengthen the future of the transplant, physician workforce. Um Our, this is the second event in our education series. Our intention at the moment is to have one of these sessions on a monthly basis for the first few months, then have a break over summer and resume an education program thereafter. Um Our first session a month ago um was on um the theme of acute transplantation on the med on the acute medical take, um or transplant patients presenting on acute medical take, which was really well received. And the recording if you miss that event is available via the medical platform. Um Our education series is aimed at doctors from all specialties are interested in transplant. Um We've got a range of medical students, foundation trainees, core trainees, as well as a more senior specialty trainees attending the events. And we hope to provide educational content which is engaging for all and in time will cover across that, that broad spectrum. Um It's our intention to invite speakers from across the UK and further afield to share best practice um and help us develop our careers essentially as future transplant physicians. Um We also just wanted to briefly use this opportunity to mention um mentorship, which is one of the priorities for BTP to going forward. And before we continue to introduce our speakers this evening, I want to just hand over to Yy Chung and another of our members who Hepatology journey who just going to briefly mention mentorship and then we'll get on with the education program for this evening. So I just wanted to briefly mention that as BTP T we want to try and set up a mentorship program for our members. So in order to try and plan this, I'll be grateful if um members and people on the talk today can just take a few minutes to fill out a Google form, which we will put the link on, on our website and um you can access the Google form and it only takes about a couple of minutes just so that we can try and plan this. Great. Thanks for that. And um and it's membership is definitely something that trainees have told us again and again that they're interested in and something that we hope to be able to deliver it, they do BTP T and it's something that BT S and um E thought Y PT group are also really interested in. So, and we hope to be able to get up and running and that, that will be of real value to our trainee members. Um So without further do, let's move on with our um talks this evening. It's my pleasure to introduce our first speaker. Doctor Caroline Drill. Um Doctor Drill is a consultant nephrologist at Guys in London. Um She's previously trained in Paris where she undertook her nephrology training and she's got a special interest in immunology and transplantation and has been awarded a number of prestigious awards including for research in this area from OX. Um and um has received funding from the MRC and various other organizations. Um We're delighted that um Caroline's going to speak to us this evening on the topic of um rejection um in kidney transplant recipients. Hello, good evening. Uh Thank you very much for inviting me to this uh to this wonderful webinar. Um So I'm gonna try to wrap up around, you know, acu and clinic uh graph reject, give you a graft rejection in, in, in 20 minutes, which is a bit of a to the fall. So, uh we'll try to be uh quick and, and effective. Um So, first of all, um and, and this is part of, I think uh the remits of, of this uh new uh BTP T um society. I'm, I'm, I'm involved in different society, uh the BT S and the uh the er young professional in, in transplantation board. Um And I think I just wanted to highlight that there is a lot of resources already available um through ES O and through um membership and affiliation to a young professional in transplantation. Uh So I invite you to just follow them on Twitter and just go on their website, et cetera. There is, there, there will be a lot of, you know, opportunity for extra training, uh some grants to um attend a little uh uh a couple of different events uh for the year. So, um yeah, please please do go and, and, and come because you need to be enough to, to receive, you know, mailing list, etcetera to, to invite you to New Zealand. And last, but not least Ezo is coming to London next year. Uh And of course, this is, this is an amazing opportunity to uh be involved in, in such a great um congress and conference. So, um so we're gonna talk about rejection tonight and, and this is a bit of the concept of the outline of this talk. Um And, and so we're, we're gonna go through this about, you know, why rejection, how the immune system works uh quickly uh and then acute and chronic uh rejection. So why rejection? Uh I think it's important to sort of, and there will be a little bit of about immunology just to so understand and pave the way for the rest of the uh of the talk because um i it's, it's just we, we need to go back to basics to understand how things are working. So, the, the immune system recognize uh of course, antigens are different cell blood group and HLA a um what we call a uh minor antigens as well, which are very important. Um There is a concept of immunogen and I II sure that uh uh Professor Sanchez, we will, will talk about that as well. But, but the, there, there, there is a y hierarchy in terms of what is uh more immunogenic than, than than others. And of course, um kidneys is quite immunogenic compared to liver, for example. And, and, and last, but not least, the same organ can have different immunogenicity. Uh immune neicy depending on, on the circumstances. And of course, a living kidney um who uh which hasn't, you know, had a lot of uh long co called ischemic time will do much better than a cadaveric kidney. Um So how the sys the, the immune system works and the importance of HLA. So what is HLA A as you know, HLA proteins are complex proteins uh that are present uh on, on the surface of, of the majority of the nucleated cells. You have class one and class two II wouldn't go that deep into this. Um um uh tonight. Uh but they, they also called the AM HD molecules and they're very, very much like the I identi identity count of your body. So what, what happens when, when the organ is sort of plugged into, into AAA allogenic um system? And I think this is quite important just to remember. So this is a kidney which is, has just been plugged to you uh uh in your recipient vessel. Um And um what is uh quite important is, is to I, is to understand that first of all, you have the innate uh immune responses uh which is like um just the rec eus and, and, and the uh ischemia reperfusion and then um the, the, the cells will go um the, so the adaptive immune response will start and, and cells will go to the lymph nodes being educated and, and basically develop a response and go back to the, to the, to the transplanted kidney. Um So this is quite a busy cartoon. Uh but I think it's important just to sort of highlight what's what's happening, um what's happening in, in more in deep. Um So on, on the top, you have uh the antigen process and presentation to uh dendritic dendritic cells which um as we said, will go to the, the, the lymph nodes and, and basically, the, the, those A PC will just tell the lymphocyte that something is foreign and something needs to happen. Um It's again, very busy and quite small, but it's important to see that, you know, of course, the, the, the, the beginning of the immune response is then very much like T cell dependence. And, and you will have based on this, you know, initiated uh responses and activation than that of, of, of the more uh what we call uh humeral pathway with antibody production uh uh potentially, you know, complement activation. And so this is much more like the, the B cell type humoral pathway. But there is as well at cell mediated pathway which involves uh of course, um CD eight but involves as well, other other, other cells like macrophages and NK cells. Um And if this is, if, if if you're interested in that topic there, there is a lot of literature uh starting to emerge on, on uh NK uh rejection, for example. Um So what, what is the concept of alloreactivity? Um Again, I think it's quite important to understand how, how things work. So, uh initially, uh your, your and, and, and what is uh preponderant initially in the acute phase is what we call direct uh recognition. And this is the cartoon here and on, on the top left as well. So what is direct uh recognition? It's in red and A PC from the donor presenting some imagery from the donor to a CD four from the recipient. And that will lead to of course activation uh of, of CD eight. Um This is very much what's happening in the acute phase, of course, uh on the more chronic phase. And as the donor, A PC is just uh are just uh killed or get rid of, there is no more um AP CS from the donor, but you have uh AP CS from the recipients who will, you know, constantly um uh take on and process uh some, some uh pet peptide from, from the, from the donor from the transplanted organ and present it to the um to the um cells from the donor. And this is what we call the indirect pathway. Uh There is even a more complex process happening uh on the long run uh which I will just mention today, but it's quite complex. It's what we call the semi direct pathway. Um And this is basically some uh the, the A PC from the, from the recipient are able to express some of the images from the donor uh and activate and continue this, you know, immune response on the long term. So this is very much of an active process which will continue if you don't give any immunosuppression. Um Again, a, a brief summary of what is the, the activation of a lymphocyte and the different signal of activation. Um So, different signals are presented here and the different molecules uh that are basically targeting those different signals. And, and quite importantly, it's quite uh important to understand that those signals are redundant. So even if, if you, one of them is, is, is is blocked by uh by some of the drugs, it may still bypass and still and, and the the immune system is, is, is made in a way that it can still potentially activate the lymphocytes. So, hence the necessity of having a couple of different drugs. Uh This is a very famous um cartoon, I'm sure you've seen it already just presenting the A PC on the top and the uh lymphocytes on the, on, on the bottom with the different signals of activation and where the different drugs are working as well. Um If we, if we continue to move forward about um how can we, you know, treat and how can we target all these human cells? This is another cartoon just presenting which drugs work where and I think this is important. Then when, when we have a look at what, what, what is working and how do we treat, you know, rejection on the long run. So on, on the top, you have the T cell and we already mentioned that but um you have B cells which are of course targeted by the riTUXimab. But as you can see, riTUXimab doesn't, doesn't work on plasma cells. Um you have drugs like bortezomib which could work on, on plasma cells. Uh and plasmapheresis is just removing the antibodies. Um IV uh IV IG uh work a bit everywhere. They have a sort of some sort of pleiotropic effect which we don't understand. Um totally. And then you can have of course some molecules like, you know, Eculizumab, which is a complement inhibitor, et cetera. As you can see, eculizumab is much more active uh at, at the very end of all this activation sort of process. And eventually uh this is this, this is my sort of last slide about uh pure, pure immunology. Um But uh if we talk about suppressing B cell responses and particularly, you know, if we want to talk about suppressing antibody production, uh I think it's quite important to, to make the difference in a non sensitized in the individual where basically it's possible uh to stop the antibody production by sort of uh in theory, stopping the lymphocytes to uh to activate a B cell. But it's a very, very different story in sensitized individuals because of course, those individuals have known a response against some those potential um alloantigen and their memory details. Um and as we saw the different treatments are not very uh working very well on those. So uh quickly and very briefly how the system work and the importance of, of HLA A. So, HLA A ma matching and how it influences the outcome. So, of course, it is uh HLA A matching improves uh graft survival and, and it is important to prevent allosensitization for the long run. So this is a very, very old study but um you have on the top uh basically mid 00 Dr uh mismatch and on the bottom, more than one, more than zero Dr mismatch, HLA Dr and as you can see, people who have no mismatches in Dr are doing much, much better than the ones who have uh more than um one. This is the same cartoon with uh uh basically mismatches in A and B HLA A and B and, and same thing. Of course, it's better to match uh to HLA and, and on the long run, um when we talk about, you know, HLA matching and HLA antibodies, we, we definitely know that patients with uh donor specific antibodies which are uh anti HLA antibodies against the donor uh do much uh less well than the patients who don't not have any D SAS. And this is for preform D SAS, not, you know SAS. So I thi I think we, we, we, we've understood a bit of the basics of immunology and, and now we can move on, on, on the mechanism and uh of on different cases of acute and chronic rejection. So one entity that needs to be mentioned, even if we don't see it anymore is what we call hyperacute rejection. Um So nowadays, it's very rare and this is because now we we don't transplant patients who have a positive crossmatch uh or who have, you know, d SAS apart from the listing process, which is a bit complex, but basically, we don't uh we don't transplant uh a cross positive cross match crossmatch anymore. Um And so basically, hyperacute injection is caused by performed antibodies which could be a BO I or uh antiendothelial antibody or uh anti HLA antibodies. And basically, it's like uh an intrarenal uh crop with thrombi occlu occlusion of the small um renal arteries and, and ultimately, some renal cortical necrosis. And this is basically, you know, rejecting the organ within the 1st 24 hours with all graft loss. Thank God, it doesn't happen um anymore. So, uh we're gonna move on to acute rejection. Um So what is acute renal um allograft rejection? And, and it's defined as an acute deterioration of allograft function? Uh this cartoon is, is sort of presenting um on the top the, the, the first year survival with the um the little round uh uh white round and on the bottom, the oneyear acute rejection. And, and, and throughout the years, as a and as you can see, there has been a drastic drop in the one-year acute rejection uh throughout the year and particularly um after uh the initiation of cycloSPORINE and nowadays with in sort of normal um uh mode, what we call the M and era immunosuppression. And it's around, you know, 50 15% at the moment. Um The, if, if, if we, if, if the question is uh do we need to diagnose and treat acute renal allograft rejection? The answer is, is, is, is, of course, yes. And this is a very, very old uh cartoon as well. But it's just showing that of course, if you have acute rejection, uh your, your, your uh graft survival is much less than if you don't have it. So I'm just gonna move on very quickly to a case, much more like for illustrate um illustration more than anything. So it's a patient that's uh who was on, on the ward when I was on call a couple of weeks ago. So it was uh a lady in her fifties. Um interestingly, she, she was coming for a living donation. So had a lot of, you know, a very thorough workup and, and, and, and cross match, etcetera. Her donor was in her fifties. Uh the recipient had uh she had the background of diabetes and hypertension. She was a IC before the transplantation. She didn't have any D SAS at any point and a negative cross match. And what we called uh CRF of, um which is the calculating uh frequency of 0%. But she had a history of CRF of 44% which means that maybe she had developed at some point, some anti HIV antibodies mismatch were 110. Uh And, and, and the based on, on the fact that she had previous uh CRF of 44% she uh would get at guys uh in our unit, what we call a standard immunosuppression regime, which is basiliximab tacrolimus with at uh uh a level, a target level, a bit higher than if she was uh low immunological risk and some, some mm um So day zero or just after really just after the transplant, uh urine output went up to 200 ml per hour. Uh creatinine dropped like the, the normal leading donor uh transplants. But day one, the urine output tails off and the creatinine is starting to, to increase. So of course, she could have, she could have a rejection and we're gonna talk about that later. But uh I think it's important to understand at, at this stage, what are the different things that, that, that, that, that, that could be. So it could be, of course, uh hypovolaemia, it could be ca urine inhibited toxicity. And this is a little cartoon just showing that um whe when tacrolimus uh or or cycloSPORINE at, at a too high level that, that induce some vasoconstriction of the um arterial of of, of the kidney leading to acute kidney injury. Of course, it could be uh acute tuber injury. Uh even though in the in the living done, they are much, much less likely. Uh And, and it could be surgical complications like uh vascular thrombosis hematoma and uh urological complication and infection or recurrent disease. Not really in that case, of course, but uh that's all the sort of differential. And so a tacrolimus was quite high. Um but it was trims. Uh so I wasn't sure it was, it was really the cause the scan was normal. Uh and she didn't have any urine leak and because she was a living donor, basically, uh they went back to theater quite quickly to make sure there wasn't any, any thrombosis or anything and there wasn't any surgical complication, but the kidney looked quite, quite inflamed and, and they took a biopsy because we were worried about, you know, rejection. Um So this is a, a cartoon presenting uh a, a normal kidney. Uh and, and, and now I'm gonna talk about, you know, the different type of, of rejection. So, uh T CMR uh typically occurs between uh one week to three months after transplantation and it's very much at cell in infra infiltration within the tubules, the initio and sometimes uh in, in the vessels as well. And the treatment is uh is uh p of methylprednisolone and usually it works uh quite well. Uh I'm gonna go quickly through the histology slides uh because I'm worried about the time, but basically, you shouldn't have all these cells in the incision here. And this is T CMR. So these are uh tubulitis. So cells um cells where they shouldn't be and this is an infiltrate as well. And this is a kidney with a lot of infiltrated cells. So this is T CMR uh very briefly. Um whe when we talk about rejection, it, it's almost impossible not to mention the band uh classification, which is uh uh histopathology, classification of rejection. Um And this is the last uh T CMR uh sort of uh classification. And as you can see, you have what we call just normal T CMR. And after when there is some in involvement in the vessels, uh we have uh V one V two V three which is more severe T CMR. And, and so basically, when there's some vascular manifestations of, of, of T CMR, uh the treatments uh is, is usually ATG uh as, as usually steroids doesn't work that well. This is another slide. OK. Um So ABM R, uh ABM R uh typically occurs in, in previously sensitized individuals uh either uh D who had D SAS who are highly sensitized. It could be A B and or in patients who develop AD SA in the context of a impression. So they're caused by antibodies bending to the donor endothelium. And they're diagnosed with, with, with the renal allograft biopsies and, and they are much more complicated to sort of control. Very importantly, uh you need three C two out of three criteria to, to, to call ABM R. So you need morphological evidence of acu tubular tissue injury, um acute tissue injury, uh which is uh microvascular inflammation, some arteritis, potentially some acute thrombotic uh m microangiopathy. So we're gonna talk, we're gonna see a few slides about that, but you need um as well as some indirect evidence of antibody interaction with the uh vascular, not tell. And this is the complement CT Scan and we usually have a look at C four D which is a product uh of this, you know, complement activation and you did uh circulating donor specific antibodies. So you need two out of those three criteria, just call that an ABM R. And this is again, the bone flex justification of what, what you call a uh acute A DMR. So again, a few slides about what you can see. So uh here you can see that this glomeruli is quite full of cells. So this is what we call glomerulitis. Again, this is uh peritubular capillaritis, there is a lot of cells around the, the the capillaries here. Um And, and I'm just gonna talk uh stop very quickly about the C four D and A A, as we said, the CC four D is a complement product and it's a immunological footprint of complement activation. However, uh C four negative A DMR is possible. Um And uh and you can still have what we call a DMR with AC four negative. Uh This is just a cartoon presenting uh what's the, what we call the C four D deposition in Paular Capari um specific uh of the ABM on the top and a nonspecific staining on the bottom. Uh ABM R is a very poor prognostic if not treated. Um and, and particularly uh when a complement is involved and this is what you can see on the slide and, and what is the treatment? So the, the the treatments uh involves steroids even though uh usually they, they, they don't work that well. Uh The, the, the, the majority of the treatment is to remove the antibodies uh by using plasma exchange. And uh IV IG uh because of their uh immuno uh modulatory um function and the fact that because you are just removing the um immunoglobulin, you need to replace them and then you need to try to stop the antibody production. And this is a bit of uh a zone where you know, different people are doing different things. So, of course, uh you have to optimize immunosuppression with MMF and tacrolimus, you could use riTUXimab, you could use doom. Uh And some people even use ATG particularly in the con of mix rejection. We're gonna talk about that. Um This is a slide just comparing uh you know, uh the, the cell mediated rejection and the antibody mediated rejection and where the cells are. Um So what is next rejection? Next? Rejection is the combination of A Mr and TMR and the treatment is uh using ATG, which is like uh just knocking off any sort of T cell response. Um So just for your information. OK. So the, the, the, the patient, she had a mixed injection uh and she was, even though if she didn't have any, you know, D SAS uh in, in the past and she was treated uh with ATG and, and she's currently under treatment. A creatinine is static at the moment and she may need another biopsy. Um I will skip this one. So um this is a sort of summary of what is the treatment of acute rejection. And, and on the left hand side, you have a table, on the right hand side, you have of course, the Kygo uh and which has been endorsed by BT S as well. And this is what is recommended uh at the moment and it's just summarizing what you just said before. So uh very briefly, chronic rejection. So, chronic rejection is just the reason why uh basically for even now in the new era of with the new immunosuppression, there is not that much improvement in terms of how long the kidneys are, are lasting. And, and what proportion of, of late allograft loss is immuned. Again, this is a very uh complex cartoon, but it's just showing that on the long run. Uh the fact that you had some uh donor specific antibodies make a huge difference. So it's definitely immune related. So what, what would you see? So it's a bit of a mixed bag. But basically, you will have uh some trans glomerulopathy, you can have a bit of uh PTC, you may have some C four D deposition and you may have some uh viable amounts of circulating adenos specific antibodies. So this is uh the f these are features of um of chronic um immune uh um injury. Um So, going back to the flexi classification, which is, you know, changing every couple of years. Uh we've, and, and I think it's quite important just to know that it is changing again and again. Uh So there are new features of what we can call chronic active ABM R and even, and even now in entity which is chronic active T CMR and this is the late sort of presentation from the, the last report. Um and, and, and, and to finish, I will go back to the, the BT S um sort of uh guideline about uh what, what do we do about chronic rejection and Um So, of course, it's recommended to biopsy the patients when they have rejection and the creatinine is not going back to normal or the new proteinuria. And in terms of the treatments, uh basically, if, if, if there are some features of CNA toxicity, the CN I needs to be removed. Uh but it's much more uh about uh an intensification of immunosuppression and depends how active the rejection is. But the truth is the majority of the time treatment doesn't work very well. And I think this is almost my last slide. Uh So this is the band. Uh it's, it's, it's coming from the last band paper. Uh on the top, you have the website of the band classification. And just to, to, to let you know that this specification is much more uh you know, moving forward and check with uh biomarkers and with time to time there is more and more uh different sub features of the classification. The bump meeting is coming to Paris in September and I think it's a great opportunity potentially to be involved and, and attend this event. So in summary, we've seen that uh basically HLA are very important in immune responses. Um And, and that's, you know, matching that HLA A is very important and we talk about different type of injection and different treatments. And uh I would like to thank you for your attention. Thank you. Uh Well, great. Thank you very much for that. Um fantastic overview there. Um We're just gonna move on to the er liver talk now and we'll come back to questions at the end. Um So, um it's with great pleasure and now introduce um Professor Alberto Sanchez Puer from uh King Scottish Hospital um where he's a professor of Hepatology and academic head of the Institute of Liver Studies. Um His research has focused on understanding the mechanisms of immunological tolerance and transplantation and developing novel immunomodulator therapies for which he received uh funding and various grants from uh NIH R uh NIH in the Eu. Um And he's the only transplant hepatology consultant at Kings. Um A professor. Thank you very much uh for the introduction and thank you for the uh invitation and thank you to the organizers for having placed the liver talk after the kidney talk. This is a very wise thing for two reasons. The first one is that it actually saves me the need to kind of um um explain a basic uh transplant immunology. But the second is that the force it forces those kind of um uh members of the audience who are only interested in liver transplantation to actually go through the kidney transplantation talk as well. And this is actually very, very important because um um uh uh while the kind of immunological process are common in liver and in kidney transplantation, they are actually much more clinically apparent in kidney transplantation. And we have traditionally somehow copied what uh what kidney colleagues have been doing. So I think it's very important for a transplant hepatologist to really understand how kidney transplantation works. Ok. So uh very good. So as I said, the same process that applied to kidney transplantation uh happened in liver transplantation. In liver transplantation, we can have um immunological damage uh mediated by, by, by lymphocytes, by T cells uh emotion. This is what we call T cell mediated rejection and the classical um uh rejection that happens over the next, over the first kind of a few weeks after transplantation, what we uh uh traditionally used to call uh acute sero rejection. This is uh an example of T cell mediated rejection. But we also have um uh immunological damage to the liver allograft mediated by uh antibodies. And, and as you will see, this is still a slightly kind of a contentious uh entity. But I think it's, it's unquestionable that it can happen. Although it's rare and this is kind of uh uh the cases of uh either uh acute or chronic antibody mediated rejection. Now, uh um traditionally, we have uh we have um we have used these um these categories of hyperacute, acute or chronic rejection. Now, hyperacute rejection, uh this is a rejection that happens when there is a pro positive cross match. So when there are preexisting antibodies in the recipients that recognize the donor antigens and they actually activate complement. Now, this this this can happen in kidney transplantation, if someone does a transplant across a positive course match. But because they know that this can happen, nobody uh uh does uh a kidney transplant in the in the face of a positive course match. In liver transplantation, we do not do course match. So we do not know whether there is a positive uh crossmatch or not. We just performed transplantation. And even if there is a positive crossmatch, hyperacute rejection is almost never seen, I have never seen a case of hyperacute rejection in all my career. Now, we we still use this kind of a terms of acute and chronic uh rejection. But they can be some uh somehow misleading basically because they don't, they do not correspond to a specific chronological phases after transplantation. So acute rejection tends to happen during the first few weeks after transplantation, but it can happen at any time during the natural history of the allograft and chronic rejection. Although it's called chronic uh uh usually happens relatively early after transplantation. So not many years after transplantation. And in fact, rather than being a separate identity tend to be the final result of an untreated uh persistent immunological damage. It's probably kind of a wiser to, to think about rejection on the basis of the mechanisms that are causing rejection. And, and the, and the modern terminology kind of uh is is is, is is recommending to actually use the terms of um t cell matter rejection. And antibody matter rejection. And then to kind of differentiate within these two categories of whether uh we are dealing in the case of TCA rejection with early T rejection. And this is a rejection happening. Uh uh There is no agreement there either during the first three months or during the first six months after the transplantation versus the T cell mediated rejection. That happens after that kind of uh a chronological cut off. And the decision is important because these two types of rejection, they look histologically different. We also have, as I mentioned before, uh uh antibody media rejection. The hyperacute rejection is an antibody made rejection. But we never see uh uh uh uh this. As I said, we do see very rarely, but we do see cases of acute uh A R antibody made rejection. Uh And II think that we, we are still kind of coming to terms with this uh histological entity of chronic antibody rejection. I think this is still, this is probably where the there is still a significant degree of disagreement between some pathologists and some uh clinicians. Now, the term of chronic rejection uh from a pathogenesis standpoint is not clear where it lies within this category of T cell and antibody related rejection. And then we have some other kind of uh uh uh terms that we still use and whose uh uh pathogenesis uh is still not entirely uh uh understood. One would be this term of uh idiopathic posttransplant, hepatitis, which is probably a form of late a rejection. Although, so people believe that there could be a component of antibody me damage. And then there is another histological entity, uh uh which uh which we, we call plasma cell which uh rejection, which again, there is a, a little bit of kind of a disagreement of whether this could be uh uh an autoimmune response or a recurrence of an autoimmune uh uh hepatitis and or uh uh some sort of kind of immunological damage that is facilitated by the presence of, of uh of um Antigraft uh antibodies. Now, uh um you've heard everything about rejection in kidney transplantation. It is very important to keep in mind that uh that the liver behaves quite differently from the kidney. And that this explains why the monological consequences of uh of, of um o oo of rejection are actually quite different in liver. And in kidney transplantation start with the liver is much bigger than the kidney, but it also has a much, much greater regenerative capacity. And this is very important because in some instances, the liver might be being rejected, being attacked by the recipient immune system. But this might not become clinically apparent unless we do a biopsy. And in fact, because the liver also uh has many um cells that are somehow uh uh uh of the they somehow the have have the capacity or the function of, of, of neutralizing or inhibiting the immune system, we can actually have episodes of rejection that are spontaneously solved without requiring, adding more immunosuppression. Now, there is there is also kind of a, an inner uh uh uh uh lower immunogenicity uh in the liver. This is due that there is kind of a lower expression of uh M or HLA class two. And also because the the liver kind of um excretes produces lots of uh M or HLA class one molecules. And this have the capacity to absorb uh circulating uh uh anti HLA antibodies. As you will see shortly. Now, this kind of uh anatomical and immunological uh unique features of the liver explain why livers behave very differently after transplantation. In the first place, there is not a very clear effect of HLA matching. You actually heard from Caroline how HLA matching a kind of is associated or the degree of HLA matching with survival after kidney transplantation. This has never been demonstrated in the case of liver transplantation. Now, the second, very kind of a spectacular uh uh uh uh uh manifestation of the unique immunological character of the liver or grafts is that we don't, we, we, we, we don't kind of uh do a uh AAA cross match, we do transplant, we transplant kind of our uh uh livers across process crossmatch. And it is actually very, very rare, absolutely exceptional to see a case of uh hyperacute rejection. A A A AAA, an additional difference as compared to kidney transplantation is that is that most of our recipients uh eventually sometimes as early as kind of a 3 to 6 months after transplantation, they can, they can lower their need for immunosuppression down to tacrolimus monotherapy. So the majority of our recipients are actually kept long term on tacrolimus monotherapy. And this is actually very, very rare in kidney transplantation. Another kind of a unique feature is that uh even when patients develop rejection, uh in fact, only a minority of the rejection episodes require treatment with high dose immunosuppression. Some of the episodes just by doing nothing, keeping tight, the kind of a spontaneously uh uh improve. Uh Another uh uh uh uh a unique uh uh feature is that that uh and although this has become a little bit kind of uh uh uh debated uh lately, but traditionally, we have considered that to have an episode of dis her rejection, particularly every, every transplantation has no impact uh into the um long term survival of the liver uh allograft. And uh uh in addition, as you will uh uh you will see uh uh uh shortly uh the the the capacity of circulating anti donor antibodies to damage the liver is much, much, much less vigorous than what happens in the setting of kidney transplantation. And probably the most spectacular kind of a manifestation of these um unique properties of the liver is the fact that in many years after transplantation, this is rare but it does happen. Uh some liver, liver recipients can stop completely their immunosuppression and they do not reject. So they, they, they gradually kind of become tolerant to their transplanted liver. Allo let's see if I can change to the next. Ok. Now this is a an old but, but, but very, very kind of uh influence uh paper from the Mayo Clinic published in 1998 that actually show that the liver recipients who had an early episode of rejection. In fact, not only they did, they didn't do worse over time, but they actually did better. So those recipients who had an early episode of rejection, they actually had more prolonged long term survival, probably due to the fact that um uh even though they kind of uh uh uh rejected, the overall burden of um immunosuppression was actually reduced as compared to do those recipients who did not reject because they were receiving higher doses of immunosuppression. And this is kind of a a a AAA very influential paper because it was the first one to actually highlight the fact that uh most of our uh re uh recipients, they actually encounter problems because of the side effects of immunosuppression and not because of the side effects of rejection. Now, this applies only if anything to early episodes of rejection. It was also shown uh a few years ago that in fact, when rejection happens late after transplantation and by late, I mean, more than six months after transplantation, then developing rejection is actually bad. And those patients who develop late rejection, they tend to be more likely to eventually lose their grafts. Now, this probably has to do with the fact that every rejection is, is diagnosed very, very fast because it tends to happen during the first few weeks of the transplantation. When patients are admitted to the hospital. While late episodes of rejection, they tend to be diagnosed late uh because patients are actually outpatients. And because um uh uh uh uh uh because of this regenerative capacity of the liver, the liver needs to actually be severely damaged in uh before the kind of um um the clinical manifestation of rejection becoming apparent. Now, there has been a recent paper and this is what is shown uh on the on the right from the US suggesting that even early episodes of rejection uh in liver transplantation could be associated with uh worse prognosis. But this is still kind of AAA little bit a contentious uh uh matter because none of the kind of uh uh uh a randomized control studies ever conducted ha have actually uh ever observed a a negative impact of every episodes of rejection. Now, uh let me just kind of uh uh mention uh uh something about donorspecific antibodies. We do see donorspecific antibodies in liver transplantation uh uh uh as well. This can either be kind of uh antibodies that are there at the time of transplantation, for instance, in patients who, who have received previous transplant or in, in women who with history of kind of um uh uh uh uh a pregnancy. And then we can also see uh as that our kidney colleagues do uh patients who did not have antibodies after transplantation but who developed the no antibodies after transplantation. Now, what is actually uh quite uh striking in the case of uh uh liver transplantation is that most of the perform uh donorspecific antibodies disappear after transplantation. Now, this is AAA paper uh tracking what happens with circulating uh antibodies, anti HLA antibodies directed against HLA molecules expressed from the donor in in in red or HLA molecules uh that were not expressed by the donor. Now, this was kind of a a case of simultaneous uh liver and kidney transplantation in a highly sensitized uh um uh recipient. So a recipient with very high levels of donor specific antibodies and and as you can see, and this happened just kind of a few minutes after the liver allograph is placed, the donor uh specific antibodies, they drastically uh drop and they actually disappear over over time. And they kind of uh they, they, they, they, they, they, they, they, they are maintaining these very low levels over time. Now, this is what happens with about 95% of the cases of perform antibodies against HLA class one. And it also happens in about 70% of uh the patients who have antibodies against class two. And, and it's important to keep this in mind because uh if uh someone is highly sensitized uh pretransplantation, and we are concerned about what is the potential pathogenicity of this sensitization. Something that is useful is actually to investigate a few days after transplantation, whether these antibodies have disappeared or not. And if they haven't disappeared, this indicates that this individual could be at risk of developing antibody rejection. But as you, as you see from the, the, the the the the high rate of disappearance of the antibodies, this is gonna be uh uh um unlikely. Now, uh because of these observations that antibodies disappear after liver transplantation transplant, hepatologists have usually kind of uh not care much about uh antibodies. This is despite the fact that there were some kind of um cases in the early literature that suggested that um that antibodies could actually damage uh uh the liver. Now, in, in, in what regards the most kind of um uh recent uh uh uh data and what is the prevalence of uh antibody rejection? I'm I'm gonna uh describe 222 studies. The first one is this paper in liver transplantation from 2014 from, from, from Houston where they basically reassess all of there uh uh uh um livers that have been lost early after transplantation for unknown causes. And they actually, they were kind of uh uh a able to determine that uh six of uh uh um of, of, of those uh uh uh liver. So, in this case, was kind of uh uh um uh uh six out of kind of uh 60 cases that were suspected we had kind of a antibody made rejection as a, as a, as a, as a cause or a potential uh contributor. Now, I think uh a couple of years ago, we, we assessed our, our experience uh uh over the previous kind of a five years. And we basically kind of asked the question of whether the, the criteria for antibody media rejection defined by the BF group was actually uh uh um um um accurate or specific in our case. And we actually review everybody who has had um uh um a full course, a liver biopsy. It, it, it over the previous five years, it was a total of kind of um more than than 900 patients. Now, in, in 55 for those cases, uh uh uh the, the, the clinician had actually requested um a measurement of uh um um um donors specific antibodies and those uh donor specific antibodies have actually uh uh turned out to be positive. As you can see, only five of those cases actually met the BF criteria of uh antibody rejection. And this is a very, very low uh prevalence. This is kind of a below 1%. Now, of course, the, the the problem is that we don't routinely uh request donor specific antibodies uh uh for, for everybody. So the incidence is probably a little bit higher since then, that we are actually investigating the, the, the development of antibody rejection. Uh much more intentionally. We, we, we, we tend to diagnose approximately one or two cases a year. So the prevalence uh uh according to the criteria we use at Kings uh is probably one or two case uh one or 2% So very, very rare. But, but, but, but it's still kind of uh occasionally happening now. Uh um the the the the long term consequences of having donor specific antibodies uh are are, are, are, are, are are probably also negative in liver transplantation but much, much, much less than in kidney transplantation. So, on the left, this is a very famous uh uh paper from the Paris group that Caroline has shown on the negative impact on kidney transplant. Uh survival of habito specific antibodies. On the right is a paper in liver transplantation. And as you can see the overall effect of having donor specific antibodies in uh liver survival is much, much less than in kidney transplantation. And here I have just highlighted the most positive study ever published. I would say that most of the kind of additional studies suggest that the effect of tumor specific bodies in the long term is probably even lower than what this graph shows. Now. OK, let's see what happens when patients develop. Uh uh uh rejection. Now, uh in what regards um uh the the most traditional form of a rejection, what we used to call acute cellular rejection and now we call early rejection. What happens is that uh well, uh uh over the next uh first few weeks after transplantation, the liver function test start to increase at some stage. The kind of uh transplant hepatologist decides to perform a biopsy and there are no good biomarkers for rejection in liver transplantation. We kind of use arbitrarily defined uh liver function test cut offs, but there is not a single cutoff that has been associated or has been kind of as shown to have high sensitivity and specificity. So this is done in a very empirical manner. And then if there is rejection, we we come across with a picture such as this one where we see mostly kind of a portal inflammation with um ad to the endothelial of the uh portal venous uh tracts and also uh a damage to the small kind of um um uh biliary ducts in the portal tract. Now, we also use a AA a AAA grading system that was defined by the Banff pathology uh uh group. And this is kind of uh how we grade rejection from 0 to uh uh 9. Uh what is important is that um and not all of the episodes of acute uh or acute or early Decem rejection actually require a significant increase in immunosuppression. In fact, when we have mild rejection, the kind of a recommendation is not to increase immunosuppression just to kind of optimize at the levels. And we only give uh high dose steroids in cases of moderate to severe uh uh rejection. And this is actually approximately 30% of the cases of disseminated rejection that we diagnosed. Now, the overall prevalence of Decem rejection ranges between 10 to 25% depending on which kind of uh uh uh immunosuppressive protocol each unit. And as a general kind of uh rule of thumb, if you have lower than 10% rejection, you are probably doing something bad because you are over immunosuppressing your patients. And if you have more than 25 30% rejection, then probably you are doing something bad as well because you are giving too little immunosuppression. Now, we there, there are kind of a although I said that there, there are no of a good biomarkers as a kind of a general rule of thumb. If we, if we see kind of a raising bilirubin and raising uh uh um circulating eo eosinophil count, this is associated with moderate severe rejection. So this is kind of a, a good indicator to consider doing a biopsy because it's likely that if rejection is diagnosed, it will require a treatment. Uh uh It's very rare for these episodes of rejection not to respond to, to, to, to, to just optimization of of, of immunosuppression or, or uh uh a prednisoLONE uh passing and a refractory rejection is rare. And as you will see later, chronic rejection is very, very rare. Now, this is early rejection. However, when acute rejection or TME rejection happens late after transplantation, it looks quite different. Uh we see less inflammation in the portal tract, more inflammation in the lobular areas of the biopsy. There is less endocel, there is less bile duct damage and some pathologies have difficulties as diagnosis this as rejection because it doesn't meet the criteria. In fact, it looks more like an acute and acute or chronic conventional hepatitis. And in fact, uh biopsies taken by pathologists who are not expert in transplantation, usually do not uh diagnose these biopsies as having uh rejection. Now, chronic rejection is an entity that we see uh uh very, very unfrequently these times since we switched from cycloSPORINE to tacrolimus. Uh the pathogenesis is still not completely understood. Uh uh how much there is an an interaction or a contribution of T cells vessels. Antibodies is not perfectly kind of uh understood, but we tend to see chronic rejection as the end result of a persistent either cellular or humoral damage that has not been adequately treated. And it kind of uh uh uh the histological hallmarks of the disappearance of the bile ducts in the portal tracts and kind of evidence of uh of of, of transplant vasculopathy, very important. And this uh this is again, this is something unique about liver allografts. About a third of the patients who develop chronic rejection, they actually respond to conventional treatment. And by conventional treatment, II mean, I mean, just keeping a, a AAA relatively strong uh uh minded immuno suppressive uh regime. So there there could be under the doses of a, a spontaneous improvement which is not something that happens in in other transplant settings. Now, going back to, to, to how antibody me rejection looks like. This is actually quite difficult to uh uh diagnose because um uh in most circumstances, antibody me rejection coexist with other uh pathologies. And also because histologically, it can look quite similar to many other types of injuries that we tend to see early of the trans such as preservation uh injury, outer obstruction, sepsis or biliary or vascular complications. And, and, and this, this kind of um results in often uh uh as transplant, hepatologists and pathologists having quite heated uh arguments as to whether someone has acute A Mr uh or uh uh uh or not. Uh um Now, the, the, the kind of a, a canonical criteria uh according to BF BF is to have evidences of um of endothelial damage uh OK. Of um uh uh um um uh either kind of a endothelial uh hypertrophy or some kind of a vascular changes combined with evidence of uh vascular inflammation. And this is very different from the vascular inflammation we see in this rejection where the inflammation is seen outside of the endothelium. In these cases, we are seeing inflammation inside the vessels and this is kind of a a useful thing to kind of. Remember, we also require of course to have circulating donor specific antibodies. And also some evidences that the antibodies have activated complement by the kind of a uh uh diffuse kind of a staining or the position of C four. And in liver transplantation like kidney transplantation, we still haven't been able to kind of clarify whether is there is any form of antibody me rejection that is actually uh C four D negative. So we require C four D to make the diagnosis. Now, there is a theory out there in the literature that suggests that uh and that, that could explain potentially why antibody rejection is so rare in liver transplantation that antibodies in fact, are not really terribly pathogenic for the. And that we actually need a second hit. Uh some, some sort of of other histological damage that increases the expression of HLA class one and class two and facilitates the damage mediated by antibodies. And this is a two key hypothesis. It has never been kind of adequately demonstrated. But if true could explain why we tend to see antibody made rejection in the setting of other coexistent type of histological damage that makes the diagnosis actually quite difficult. Now, uh what do we do uh when we see uh antibody rejection? So we have no idea how to treat antibody rejection. But we just kind of a copy what our clinical colleagues uh in kidney transplantation do. So, basically, because in liver transplantation, most of the cases of A MR are actually mixed T cell made rejection and antibody made rejection. We we we tend to kind of try to eliminate the the the T cell component as aggressively as we can either with conventional immunosuppression, high dose or A TG. And once we have done this, we just again, look at what the kidney uh transplant do and try to remove the antibodies, either using plasmapheresis and uh IV or some other type of immunoabsorption uh strategy. This is the protocol we have at, at, at, at, at, at kings which basically kind of uh uh summarizes what I've just said. And um and, and just to kind of uh uh uh highlight the fact that we have used this protocol in very rare cases. In fact, probably over the past uh eight years, we have used this protocol in five cases. And retrospectively, we, we, we think that probably only three cases actually require uh and uh uh this treatment because they were actually uh uh uh real cases of acute A Mr. Uh Now, there is another entity in the bank classification which is chronic antibody me rejection. Uh uh And this is a very contentious uh type of um histological definition. We have never diagnosed a case of chronic antibody me rejection at Kings. This does not mean that it doesn't exist. But uh but, but uh uh but this is something that, that we find very, very difficult to uh to identify. This is basically kind of uh the coexistence of chronic inflammation in the portal tracts with uh with signs of uh of um uh diffuse uh uh uh antibody uh activation or complement kind of uh uh uh the position. Now, the this is also very controversial because um the kind of a recommended management of these cases is not to remove antibodies, but just to, to increase conventional immuno suppression. So it's actually very, very difficult to be convinced that this is a separate entity from uh uh from those cases of late deem rejection. Now, I'm I'm gonna end with a, with an other kind of uh uh uh uh uh entity that that is out there that is still AAA little bit controversial, which is uh what, what is likely to be subclinical rejection. Now, in liver transplantation, most units uh they do not do uh protocol biopsies. But if we actually do protocol biopsies in patient who have normal liver function test, we actually uh observe that a large fraction of them about 30 to 35% they have actually subclinical inflammation. And in fact, if you look at this plot is, is, is actually using some sort of uh gene expression markers that are very, very specific of this elevated rejection. And what this kind of um uh uh uh um um graph shows is that uh um from, from, from, from patients who have completely normal liver function tests. If we do AAA liver biopsy, as I said, a third, they have inflammation, but about 70% of them, they have a gene expression markers that are actually indistinguishable from what happens at the time of clinically apparent. Uh uh These are rejection. Now, what happens with this, with these, with these cases? These are our kind of uh patients who are doing the best because they have normal liver function test. What is the kind of a what are the long term consequences of this subclinical inflammatory infiltrates is something that is still not clear and I think that I will end here and uh be happy to take any questions. Great. Thank you for another very engaging talk. Um So we've obviously just run over time. So we'll try and uh group some questions together. Um I thought if I could start, there's a few questions relating to um sort of what, what are the outcomes is better for patients who are having uh combined uh liver kidney transplantation versus uh isolated kidney and sort of the relationship with rejection there as well. So, um um if I may start from, from, from, from um yeah, II think that we, we, we tend to, well, there are different schools of thought, there are some units where kind of uh the immunosuppression management is um completely led by the um kidney transplant under the assumption that uh that they need immunosuppression is much greater for kidneys are than from livers. And that with, with the traditional uh kidney transplant uh immunosuppressive regime, it's almost kind of uh never seen a case of um uh uh liver rejection at kings. We tend to kind of uh do uh uh we, we, we are a little bit in, in, in between. In that we uh uh we, we, we, we follow some of the kind of a guidelines from, from the kidney transplant in that we adjust immunosuppression on the basis of the immunological risk, but we tend to immunosuppress patients uh less than a typical kind of a kidney alone uh transplant uh would be receiving. Thank you. And then there's been a few questions about um monitoring D SAS and um you know, when do we check? And um yeah, and sort of um yeah. So indications for checking um in both liver and kidney and sort of just kind of the general reasoning behind, behind doing this and how best to manage it. Yeah. Uh II mean I can, I can take that quickly and so on the kidney side. Uh And that guys, we, we don't check it on a regular basis. Um It's done, you know, if the patient has a protective rejection increase in creatinine increase in protein. Yeah, of course, you will, you will do, you will do a DSA, checking, um, other units do it. The problem is when, when you have a developed DSA, you don't know what to do with it. Um, the, there is a lot of literature showing that, you know, some people have DSA and don't develop rejection. Um, so basically we don't know, uh, if, if, if you want to have a look, there is the ultimate study. I don't know if, if, if people are familiar with that, which was a study uh convicted by uh uh pro at K. But they, they, they tried to um basically, there were two groups, one group who, who was uh randomized with uh DSA checks and of immunosuppression which was like higher t level, higher. Mm F do et cetera. And, and basically, I mean, the outcome of the study is uh that uh people who have the assay s do a bit more rejection, but in terms of allograft loss in the long term, there is no difference between doing it or not. So, um the study doesn't show that there is uh you know, uh in terms of allo graft loss, uh uh a benefit of, of doing so. So, yeah, so we don't do, we don't do it on a, on a regular basis uh in, in, in liver transplantation. The truth is that most units never check the assays. Uh uh Unless the pathologies suggest uh in the case of allograph uh dysfunction and the biopsy have been performed that there are histological features of antibody rejection. Uh We, we don't, most units not even check uh whether there are performed antibodies at the time of transplantation. Which is probably quite unfortunate because as I said, acute A MR is rare, but it happens, we see one or two cases a year. In our, in our experience, this is mostly uh very, very high titer, perform antibodies, both anti class one and anti class two. And I say it's unfortunate because it's better easy to check this uh uh before transplantation, it is very easy to identify the patients who are at risk of having antibodies. Uh uh those uh at high risk of being sensitized. And because we tend to lose the grafts or, and the patients in those individuals who develop acute A R because it's difficult to diagnose and make the diagnosis kind of um late. So I think that something that we should implement but, but it, it, it still hasn't gained traction would be to um to, to, to monitor DSA in patients who are likely to be sensitized at the time of transplantation. Just basically females with history of pregnancy or retransplantation and then check because this would be so easy check whether those antibodies disappear three days after transplantation. If the heart disappear, I think it's extremely unlikely that this patient uh will develop. Uh and a Mr however, if these antibodies, particular anti class one are still, there are high titer then I think these are individuals who uh should be monitored more closely. But again, this is kind of uh this is my personal recommendation. This is not necessarily what most of the units are doing. Thank you. Um I suppose maybe the final question, I guess I wrap it up nicely or just a question to say really. Um what was the outcome in the patient from the case he presented? And um what was it called? Yeah, as, as I said, she's still, she's still on treatment at the moment. Um Her, her creatinine hasn't improved that much. So she will probably need another, another biopsy. I think it's quite an interesting case because even if she had CRF of zero, no DSA, uh she had the back in the background of C uh CRF of 45% which means that she may have some sort of, you know, immunological response when we check for D SAS. Of course, we check for A B and DR we don't check for the other type of DSA. So she could have basically other anti HL antibodies or uh antibodies again, you know, minor antigens. So all these things um are not really captured with uh what we've just described today. Um So yes, we'll see. I II will, I will update you. That's great. Thank you. Um So I suppose they say to say um thank you for uh to both speakers for fantastic talks. Um Really enjoyed it. Um so we can answer all the questions, but obviously, we just conscious of time. Um And with that, I'll just hand over to um kit quickly just to introduce the um next talk. Yeah, thanks very much. And just to say as all we've got nearly as many Chinese online as we did at the start for webinar, which I think is amazing. You've managed to keep a bunch of largely nephrology engaged through hepatology talk too. So, and that was beautifully done and really helpful. I think for us to hear the differences and the similarities both between kidney and liver transplantation. So um just a yeah, echo victims. Thanks for two really excellent talks in our next session continues nicely along a similar theme. It's on the last Wednesday of the month in May Wednesday the 29th, I am focusing on immunosuppression and again, a similar format, we'll have two speakers and one from a clinical perspective. And then we also hope to have a pharmacist speaker which I think could be a really useful insight and come along and ask and if you difficult questions, whether that's tli dosing or whatever else, you want to pick a transplant pharmacist brain on. So I'm sure that will also be a really useful session. And we really love to hear your feedback. It will really help to inform the content of these education sessions going forward. So you can do that through me at the end of the session um and certificate should also be issued automatically um if you join this webinar, so get those uploaded to your E portfolio. Um So just a final. Thank you um very much again for attending and we'll leave it there. Good evening. Bye.