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Good evening, everybody. Thanks so much for joining us tonight. Um This is our third educational event with the British Transplant Training Society or a BTP T. Um My name is Ailish. I'm a Renal Registrar in Edinburgh. Um And I'm really excited to introduce tonight's talks which are on immunosuppression. Um I'm going to just start by giving a little bit of background to BTP T and then I'm going to hand over to my colleagues who are going to introduce our speakers for tonight. Um So BTP T is a trainee society that's affiliated with the British Transplant Society. We aim to cater for doctors from all specialties who are interested in solid organ transplantation. And we have members that range from medical students to foundation trainees, core trainees and registrars. Um With our education event, we hope to provide educational content that's engaging for um individuals across all of these ranges of groups. Um And we invited speakers from across the UK and further afield to share best practice, inspire trainees and help us develop our career as future transplant physicians. Um This is our third of four planned sessions and then we're going to take a summer break and we'll aim to pick these back up again after a change over time in August. Um So again, thanks so much for joining us this evening. Um And I'm going to hand over to Simon now to introduce our first speaker. Yeah, thanks very much. Yeah. So, um our first speaker is uh Angel Grover. Um Angel is a senior transplantation and bad pharmacist at the Royal Brompton and Herfi Hospitals. Uh undertaking our initial training at King's College London. She's going to talk to us a little bit about uh immunosuppression in solid organ transplant. Thank you. Brilliant. Thank you Simon. Um And thank you for inviting me for this session today. Um I will just share my screen. Yeah. Is it true? Sorry, I will try that again. Chest cream screen and it's this one? Perfect. I think I'm sharing now. Is that OK? That's great to see you and see you now. Thank you. Brilliant. Perfect. So, thank you for inviting me and good evening everybody. So I'm I'm my name is Angel Groin. I'm one of the senior transplantation and thats pharmacist based at Hairfield Hospital. And so today's presentation is about immunosuppression, post heart and lung transplant. Um So, an overview of the um presentation is I'll be looking at the principles of immunosuppression and go through some brief PK profiles of the drugs that we commonly use as part of our immunos immunosuppression regimens. Go through some sorry, therapeutic drug monitoring Um I thought I'll talk a bit about um oral and IV conversions um a bit about starting any interacting drugs. So, look at some pharmacokinetic and pharmacodynamic interactions. Um And then I've put some slides together just at the end about what a typical post transplant protocol looks like. Happy for you to ask questions along the way or towards the end of the presentation. Um So, principles of immunosuppression. Um So I thought I'll give you this up into three stages which looks at the initial or induction uh protocols that we use post transplant, what a maintenance regimen looks like. Um And then treatment of acute rejection episodes. I did see on the website that there was another session regarding um management of rejection. So I thought I'd focus this session more on induction protocols and maintenance, immunosuppression regimens. Um So, induction protocols. Um the aim is to induce dose dependent T cell depletion in blood in blood and peripheral lymphoid tissues when the risk of cellular rejection is at its greatest. Um The advantage of using induction therapy is that it allows for a delayed initiation of um C NS. This allows for a reduction in maintenance agents and helps with renal recovery, post transplant. Uh It induces a host hyporesponsiveness to the alloantigens. The risk of um using induction therapy is that it, it puts the patient as at an increased um risk of infections especially CMV in our patient cohort. Um The other risk associated with it is PTL D. So, what agents do we have available for use as part of induction? Um So we've got polyclonal antibody preparations and the agent of choice at our center is R AD. Um And we've also got other monoclonal antibody preparations such as Basiliximab, which is usually used um in renal transplants. Um and other anti CD 52 agents such as Alimi. So, ra DG um we use it as an induction agent in our heart transplant cohort. Um And we also use it as part of acute rejection when steroids aren't enough. Um At our center, it's usually a consultant decision to start a DG post transplant. And it's usually based on, for example, how the surgery went, was the patient? Um Are there any signs of infection or sepsis, post transplant? Did they come out with their chest closed or did they, did, do they require ECMO support post transplant? So all of that sort of put together, helps them make a decision for if they are for induction therapy or not. Um So, like I mentioned, the agent that we typically use um is G um So RG is a pasteurized preparation of rabbit IgG, which is essentially collected from rabbits that were immunized with human thymocytes. It contains antibodies against a whole range of molecules present on T cells including C D3 CD four CD, eight CD 28 CD, 45 essentially wiping out um all your T cells um but it also has antibodies against non T cell antigens present on erythrocytes, monocytes, platelets and neutrophils. There's also some antibodies present in it which are directed against B lymphocytes. Um So the dose as per our transplant unit is 100 mgs IV which is given by a central line. Um for three days, we monitor T cells closely and we start tacrolimus or the CN of choice. Um at either when the T cell count is over 50 or by day seven. So, side effects associated with it are anaphylaxis, chills, rash, thrombocytopenia, leukopenia, hypertension, um nausea, vomiting, and diarrhea. So some of these side effects won't be visible because your, your patient is sedated and intubated post transplant. They're sort of more applicable when you're using RD gene in a setting of acute rejection on, on a ward based unit. Um So maintenance therapy um due to the strength of the alloimmune response, the drugs that are currently available cannot be used as single agents to prevent rejection without unacceptable toxicity. So what our current practice is is that we use this sort of multidrug therapy approach. So we use a combination of agents with complementary immunosuppressive actions but they have deferring adverse effects um to achieve synergistic immunosuppression but having the lowest toxicity possible. So, a combination usually consists of a calcium urine inhibitor. Uh the agent of choice usually now is tacrolimus, you'll see the oral transplants on cycloSPORINE and those that are stable will continue on cycloSPORINE, you've got a cell cycle inhibitor. So an anti metabolite in the form of mycophenolate or azaTHIOprine and then a corticosteroid such as prednisoLONE. Um We also now start to see a lot of patients on MTO inhibitors such as simus. Um And this would be either as uh as an adjunct therapy um for coronary allograft vasculopathy in our heart transplant patients or it would be instead of a cni so your T would be, would be stopped and you'd be added on sirolimus as a less nephrotoxic agent. So I think to understand the pharmacology of our immunosuppression agents. It's important to understand the T cell activation cascade and it looks like a complex slide, but I can talk you through um what's happening on the slide to have a better understanding of the events that lead to the activation of a helper T cell. Um So we'll start on the left essentially at this bit. Um So the early um calcium dependent phase of a uh of activation begins with the T cell receptor which binds to this complementary HMC class two molecule with an associated peptide um in its antigen presenting grove, which is essentially leading to your signal one, but to have a full activation, sorry to have a full activation. We also require the signal to um which is caused by the binding of um the complementary adhesion molecule on the surface of the antigen presenting cell and the T cell. So when these two sort of come together and are activated, it leads to signal transduction from the T cr um via the C D3 complex. Down here. Subsequent intracellular signaling involves the mobilization of uh intracellular calcium. And this leads to the activation of calcium urine. Just here. Calcineurin diphosphonates the NFA T to lead to this activated form of NFA which then uh translocate to the nucleus. And so binds to the promoter region of various genes encoding cytokines such as il two regulatory proteins and the il two receptor. The pattern of cytokine expression depends on the nature of the T cell. So it could be a th one cell or a th two cell which then lead to the recruitment of various um cytokine T cells and other effector cells. Um essentially leading to more pro proliferation. The il two comes back to attach to the il two receptor which then initiates a second sequence of intracellular signaling involving the tor, which is the um target of Rapamycin, which leads to D DNA replication. Um essentially leading to cell division cell expansion and essentially leading to uh T cell propagation. So as you can see the sites of action of various immunosuppression can be seen in this figure. So you've got your tacrolimus and cyclosporin. Um And I'll talk a bit more about their mechanism of action. You've got your sirolimus which acts on to and then you've got your uh cell cycle inhibitors such as MMF and azaTHIOprine acting on the um regulatory proteins um inhibiting cell replicate cell DNA replication. So the first CN I thought I'd talk about is tacrolimus. Um I know the slides a bit busy but it essentially runs through the pharmacokinetic profile of ta. Um I thought the thing to highlight with ta is that the oral bioavailability of TA varies. So your oral and IV conversion of TA aren't the same. The experience that we have in house at hairfield is that the conversion sets at about 15% for most people. Uh but different people have different cytokine, uh different absorption profile, which leads to a a slight variance in what that final dose looks like. Um the distribution of and protein sort of protein binding of tacrolimus is that it significantly binds uh to erythrocytes and therefore, um the blood concentration differs uh significantly depending on what that binding looks like. So, in your typical patient, if there is a variation in hematocrit and albumin, you will notice that the tac level um sort of goes into peaks and troughs depending on what the albumin looks like. Um in terms of metabolism, it is extensively metabolized by the cytochrome P 450 isoenzyme system. Uh with three a four being the main enzyme that breaks down tacrolimus. So any drugs that act as inhibitors or inducers of this isoenzyme have a significant um effect on tacrolimus levels. In terms of excretion, it's excreted. Um a very little bit of it is excreted in the urine. Most of it comes out as um in the bile complications of cni. So the most common side effect associated with tacrolimus and cyclosporin is its nephrotoxicity. Um Other bits to look out for are things like hypertension, bleeding gums, diabetes. Um It can also lead to electrolyte disturbances. So it causes a increase in potassium and a drop in magnesium. The thing that patients will most commonly talk about and tell us about is the tremors um which are usually at its worst just after transplant. Um And that's also to say because your target tacrolimus levels are at the highest for the first three ish months, post transplant. As the target levels start coming down and the levels start coming down. The tremors do do improve um high levels of tacrolimus are associated with uh um with C NS side effects such as convulsions. Um and tacrolimus is also known to cause dyslipidemia. The next one is your cell cycle inhibitors with MMF and mycophenolic uh or mycophenolic acid and azaTHIOprine. Um So, it's a pro drug that acts by inhibiting purine synthesis. Um and it blocks uh secondary antibody responses mediated by memory b cells. Um in terms of absorption, it has a great bioavailability. So it's got about a 94% bioavailability. Hence, the oral and IV doses are equivalent. Um post ingestion, the oral dose is rapidly absorbed and converted to its active metabolite, which is uh mycophenolic acid and max plasma concentrations are achieved uh approximately two hours post administration. I think what's interesting to note is that the C max um was reduced by about 40 per 40% in the presence of food. However, this didn't cause a change in the area under the curve. And I think that's important because um that's important to understand because most of the patients, uh a lot of patients actually initiated on MF the most common side effect they will tell you about is gi related side effects. We usually counsel patients to take MMF on an empty stomach along with the tacrolimus. Um But knowing this information, one of the things we can do is that we can counsel patients to take MMF with food and that uh sort of blunts the curve, um the C max um that doesn't affect the area under the curve and hence doesn't affect efficacy. So it can reduce side effects without actually affecting the efficacy of azaTHIOprine of MMF. Um So that's quite helpful. Uh So, mycophenolic acid, in terms of distribution and protein binding, it undergoes uh intrahepatic recirculation which leads to a second peak about 6 to 12 hours post administration. Um it's highly protein bound and therefore, the free plasma concentration is greatly altered based on again, what your albumin level is, halflife is at about 18 hours. Um And the inactivated compound is excreted by the kidneys, but some of it also comes out in the bile adverse effects. So the most common side effects are your gi related side effects. And in terms of blood results, we're looking at things like bone marrow suppression or white drop in white blood cells or neutrophils. Um And the other thing with azaTHIOprine is um a caution with gout. So, allopurinol inhibits metabolism of azaTHIOprine. And therefore, we have to reduce the dose to 1/4 so quarter of the max do of the tolerated dose or switch these patients to mmf So it's just something to bear in mind. I won't go into a lot of detail regarding prednisoLONE, but I just um I thought it added in there for completion. Um The way it is both uh it has an effect on the innate and the acquired immune system. Um and I've just added some details in there about the pharmacokinetics of prednisoLONE. Um most common side effect of steroids. It's something we've all come across quite frequently. Um But the big ones are uh Cushing's diabetes, hypertension osteoporosis. Um It can cause significant mood swings, especially because we end up giving our patients boluses of methylprednisolone post transplant and then high doses of steroids um till we wean down to baseline doses. So something to keep in mind um when we are giving patients such high doses of steroids. So, sirolimus, um this is an immunosuppression with a new mode of action. Um So it acts a lot later in the cell cycle to inhibit cytokine, stimulated proliferation of T cells. Um The most common side effects associated with it are thrombocytopenia and the big one is increased lipid profiles. Um And the reason actually, we don't initiate it. One of the reasons we don't initiate it straight after transplant is its effect on impaired wound healing. I'm also one to think about if patients go in for smaller surgeries whilst on croim and what the effect would be on w on wound healing. POSTOP. The great thing about it is, it's not as nephrotoxic and it's not as, it, it's, it doesn't cause diabetes as much as the other C NS. It's got a really long half life. It doesn't have an IV formulation. So it would need to consider switching to ACN if you were in a situation where you couldn't um give climus orally time to steady state is about six days. Um Anything more than twice weekly levels is a bit silly just because of the very long half life associated with it. That was a whistle stop through um the immunosuppression agents. Um I just thought I'd, I'd quickly talk a bit about IV and oral dosing in terms of switching. Um So with TAC and cus, like I was saying, with the PK profiles, the IV doses are not equivalent to the oral doses. Um with TA we do about a 15% conversion. Um when we're switching between formulations and with, with simus, it's about a third um with MMF and azaTHIOprine because of the grade bioavailability, you can do a 1 to 1 switch to IV. Um And then prednisoLONE um with, in the unit with doses over 30 mg, we end up on methylprednisolone and with doses less than 30 mg, we end up with the conversion to hydrocortisone. So, like I mentioned, um it's about 10 to 20% with tac and then about a third with cycloSPORINE. The other thing to note is we don't um we never stop the IV and start the oral, we sort of wean the IV down whilst at the same time having oral doses of tacrolimus slowly uh titrate it up. And once we've reached uh sort of minimal doses of IV, and uh oral is able to stably keep the tac within target range. At that point, we stop the IV and continue on oral. So it's almost the sort of um overlap whilst you get patients stable on, on one or the other. Um This slide inter uh sort of demonstrates um the PK related drug interactions that are associated with um RCN S with our tacrolimus because like I mentioned, it's clear through the cytochrome P 450 isoenzyme three A four system. Um our main enzyme inhibitors and inducers and uh and the ones that I wanted to highlight that are sort of part of common practice um are the antibiotics. So things like Erythromycin, um we, we do still come across patients who end up um getting clarry from their primary care for um a chest infection for five days and then get admitted with an AK with at of 50. Um So that still te tends to happen. So we, we're quite hard on counseling our patients and ensuring they understand that they can't have Erythromycin post transplant um antifungals. Um So we have drugs such as um isoconazole, boric, conazole and posaconazole on there, which we tend to use in our, for example, lung transplant cohort. Um if they have Aspergillus, um fluconazole is um is always a naughty one that creeps in when people end up taking courses for thrush. Um So again, it's one that we end up counseling our patients um uh counseling our patients on. Um the other one I thought I'd highlight is calcium channel blockers such as dilTIAZem um which also has an interaction with T and needs monitoring and dose adjustment. Um Over contraceptives, things that you wouldn't think about that are part of this sort of inhibitor profile. Um And then in an era of COVID, the one to look out for is Paxlovid, um which is usually contraindicated in our, in our cohort. And we end up using other forms of treatment rather than paxlovid enzyme inducers, includes things like Rifampicin, um Phenytoin, Phenobarbitone, carBAMazepine. Um And then herbal remedies such as Saint John's, what we normally ask our patients to inform us if they want to start any herbal remedies. Um Just so we can do an interaction check to make sure that it's safe from uh interaction perspective. I put an example there and I'll just briefly run through it just to give you an idea of how significant the interaction between posaconazole and tacrolimus is. Um So the table on the top is a dosing chart for uh uh a lung transplant patient that was transplanted about in 2022. Um So, just to give you an idea, this patient was on about 3.5 and 4 mg of ta daily. Um And then once we started the posaconazole in December at a loading dose of 300 BD and then 300 mgs once a day thereafter, the tack sort of we, we sort of with, with withhold the, we ended up withholding the tac um for uh just over 24 hours and then reintroducing it at 0.5 mg. Once a day, the patient ended up stabilizing on a dose of 0.5 PD um with levels staying in a, in their therapeutic range. So it's quite a significant interaction from the get go. Um We have a lot of experience in managing the interaction just because of the number of patients we and that end up on azole therapy. Um So we can now manage it in an outpatient setting. Um And then just to give you sort of a difference between what it looks like when we're stopping azole therapy, even though the sort of therapy was ceased in November, it takes about a month for the isoenzymes to sort of get reactivated. Um and the patient to end up on a similar dose of tacrolimus that they were on pre posaconazole. So the sort of interaction when you stop is a lot slower and the enzymes get activated in a couple of weeks rather than straight away uh as compared to the inhibition. And then more broadly, just speaking about pharmaco pharmacodynamic drug interaction. Something to be aware of when we're starting our patients on multiple drugs. Um is thinking about um the increased risk of nephrotoxicity associated with drugs such as vancomycin, amphotericin aminoglycosides, um increased risk of hyperkalemia because we know our drugs already increased potassium levels. So, initiating them on ace inhibitors, uh spirolactone uh and potassium supplements also the increased risk of myopathy when we add in lipids, uh do a heart transplant cohort um on tac and cycloSPORINE and then briefly in the next couple of minutes. I just wanted to run through what a typical uh transplant immunosuppression regimen looks like for our heart and lung cohort. So for our heart transplant patients, we start off with MMF preop. Um We don't give any tacrolimus just because we will use, we could use induction therapy, POSTOP during surgery. They get a shot of methylpred, POSTOP. We either go in with RA DG or TAC as confirmed with the consultant. Um RA DG goes at a dose of 100 mgs once a day for three days. Um We give a dose of methylpred at 1 to 5 mgs twice a day on day one with MMF initiated at 1 g BD. So the T the RA G continues um thereafter for three days, methylpred at 1 to 5 mgs once a day. Um last dose of ATG initiation of prednisoLONE and then we wean down from 70 mg uh down to a baseline dose of 0.2 make the kick, continue monitoring T cells. And then once we're either at T cells greater than 50 or at day seven, we start oral tacrolimus. The lungs are slightly different and the heart and lung transplants are slightly different in the fact that they get tak pretransplant. Um they aren't for induction therapy, post transplant. So the MMF uh starts at a dose of 500 twice a day, the same regimen with the methylpred. And the difference is that we start t at 0.05 M twice a day thereafter and dose are just based on levels. Those are my references and that was, that was the end of my presentation. Thank you. That was great Alan. Thank you very much. That was really fantastic summary of, of um immunosuppression um of Doctor from King's College Hospital. He's a consultant, hepatologist and transplant hepatology lead at KC H. He's currently chair of the Liver Advisory Group and a member of a number of National Transplant Hepatology Review Groups. Um And so without a further deal handover, thank you very much and thank you for the invite. Uh And I'm so impressed that so many people are hanging in there this time of the evening listening to talk. That's great. Um I'm sorry, I'm gonna have to say next slide please because my sharing didn't work. Thank you. Um So I'm going to start with a case and just briefly outline some of the problems we face. This was a young girl who was transplanted at the age of nine, who presented when I started at King's actually nearly 20 years ago with rejection and was clearly noncompliant and was resistant and developed chronic rejection. And I was one of the hepatologists who despite some fairly bad behavior leading up to that, we consider her a candidate for retransplantation and we retransplant her. Uh And very early on, she developed graft dysfunction and she was on a combination of Prograf. And so this next slide, please. And to my horror when I was on call in December. So, you know, seven months after her second transplant, she had undetectable t at levels presented with deep jaundice graft dysfunction and had, you know, the worst thing for us, which is steroid resistant rejection with bar duct damage and required ATG which you've just heard talk about as our kind of salvage therapy for resistant rejection. Uh And then she I sent her back to her home uh area over Christmas. She had more rejection, had more rounds of methylprednisolone. Next slide, please. And you can see on the left hand side in the various panels, her ta levels in the top panel were all over the place. Her transaminases were all over the place and her bilirubin peaked at 850. So, you know, that is really, really high end and only responded slowly to therapy and I'll come back to this case. Next slide, please. So when it comes to liver transplantation, I'm going to try to bring some general themes that may apply to other organs as well. Um Next slide, if you look at the eraser of survival, if you look at the left hand panel where I've drawn the yellow square, sorry if you go back. Thank you. If you look at the early era of transplantation, we had a significant amount of sadly grafted patient loss in the first year as you can see in the bottom two curves. But in the later era, obviously, we got a lot better at keeping people alive early on. But if you look at the right hand, uh as you look at it, the yellow square, what you can see is the curves from the early and the late era are coming together. So we're much better at keeping people alive early. But actually the rate at which patients in grafts sadly get lost after five years is actually higher now than it was uh pre 1988. And that's something we're getting wrong here. Next slide. And there's a very good study in liver transplantation uh called the N I DTK study with huge numbers in the American registry which sense a death at one year and looked at all cause mortality afterwards. And in this era, with hepatitis C recurrence, more than well, around two thirds of all deaths were deaths with a fully functioning graft. But because of cardiovascular disease, malignancies, infections, renal failure, and other causes where the liver function was normal. And we would anticipate in the era where we've got rid of essentially hepatitis C as a serious issue for recurrence, this percentage will be even higher. So probably death with a functioning graft will be somewhere in the order of 85 to 90%. Now, next slide please. And if you look at the factors that are associated with uh this uh mortality after one year, um There are some things we can't do anything about. You can't do anything about having male patients. You can't do much about the age of some of our patients because they're getting older and living longer. Um You can do things about things like smoking and better management of pretransplant diabetes. Next slide please. But you can see in the yellow squares, there are other things that kill our patients in in liver transplantation that we need to manage better. And that's post transplant diabetes, hypertension, renal insufficiency, which we've heard a little bit about with our agents and retransplant after one year. And these are all things that our immunosuppression choices can affect. Next slide, please. Um I'm just going to show you this. He's a, he's a friend and an ex colleague of mine. But I also want to remind people that the introduction of tacrolimus into transplantation really happened with liver transplantation through a Multicenter UK study which clearly showed that it was superior to cycloSPORINE all the way back in 2002. And I'm going to show you that actually it remains the mainstay of all transplant therapy. Really. Now, next slide please. So what, what are the big things we need to manage differently? And and I think this applies to heart lung transplant as much as uh liver transplantation and indeed to pancreas transplantation and intestinal transplantation. The big one of the biggest killers for us long term is renal failure. Uh Next slide, I was a trainee when this uh seminal paper came out in an England journal by Ojo et al. Uh And I think we were all shocked to see that the incidence of renal failure, post liver transplantation was the second highest of all of the solid organs. Uh And we were particularly shocked because if you look at the rest of the organs that you can see on in this figure, all of them use substantially higher immunosuppression exposure than liver transplantation. So why is this next slide, please? Well, first of all on the left in the blue squares, you can see that actually having renal failure, post liver transplantation comes with a significant risk to the patient and the graft. So it's a bad thing and we need to to make sure that we minimize its impact. But when we always think, well, this could be related to immunosuppression. The only mention of immunosuppression in this seminal paper was to show that cycloSPORINE significantly increased the incidence of post transplant renal failure in this cohort of patients. So tacrolimus actually, whilst we blame it a lot for things may not be the only answer to why this happens. Next slide, please, we always blame the drugs. But in reality, there are lots of other reasons. The very system we use to select patients for liver transplantation favors people with intrinsic renal dysfunction. And you can see on the right hand side that the introduction of meld which is a a listing and allocation system in the states that most of the world now uses in various modified forms, dramatically increase the incidence of end stage renal disease in a post transplant population because renal dysfunction is part of the selection criteria for liver transplantation. Next slide. Not only that there's this wonderful study of um French study that looked at biopsies of all all patients coming in for listing for liver transplant, very difficult to do. Uh and they were blinded and sent off renal biopsies to histopathologists to have a look at more than half of the biopsies in patients with apparently normal renal function were abnormal. So, histologically, they already had renal damage before transplant. And that fits with the slide I showed you before that we're transplanting people with unrecognized renal disease as part of our listing and allocation system. Next slide. So what can we do about this? Well, I one of the things I wanted to highlight to you as trainees is we always think that randomized controlled studies are the gold standard. They're level one evidence, but they have flaws and they have just as many flaws in reality as registry studies, but they're just different flaws. So this is a, we use a lot in studying renal dysfunction and how to minimize it. And this is the paper that introduced the use of mycophenolate in liver transplantation to protect the kidney. You can see large numbers uh standard dose ta versus low dose ta and mycophenolate in liver transplant patients. Next slide. And you can see on the right hand side in the red square that the combination of low dose ta and mycophenolate would uh led to a significant reduction in uh renal dysfunction, post transplantation. And is the main reason why we now introduce mycophenolate as a renal sparing drug. But if you look at more detail in this paper, next slide, please look at the levels that were used. These are levels that I wouldn't use in any of my liver transplant patients. The standard dose tak in the first week had levels always above 10 and something really around 12 for most of the first week and never really came down much below 10 all the way up to 4048 weeks. These are doses and exposure. We would never use the reduced dose tak I would stay still in the first, you know, um 4 to 8 weeks was using higher levels of exposure than we would use as a standard dose. So if you compare a very bad regimen with a not so bad regimen, you're gonna see a benefit but it doesn't mean this is the right thing to do. Next slide, please. We do move. Uh A as you heard in the first uh talk increasingly to using antibody induction. The initial paper in liver transplant uh that showed uh um anti L2 receptor inhibitors. Uh anti antibody inhibition was a favorable thing to do for reducing renal attrition, post liver transplantation. Uh used Daclizumab, we don't have that available anymore, but we use basiliximab with reduced and delayed tacrolimus, mycophenolate and steroids. And you can see in the right panel that the attrition in renal function with reduced and delayed introduction with daclizumab induction was better than in the other groups. However, again, the trough levels were inappropriate. They're not levels we would use in standard practice, there was poor compliance with the protocol in, in the uh cohort used. And the exclusion criteria included people with renal dysfunction who probably are the ones who benefit most from this regimen. However, next slide, uh I would say there's no question that systematic analysis has shown that antibody induction favors the minimization of renal dysfunction, post transplantation in people who have existing renal dysfunction. As I've shown you next slide, please. Um What about MTO inhibitors? Well, the, the one that really has sort of been pushed quite a lot is everolimus and the registration studies, uh it was compared to tacrolimus uh with reduced tacrolimus and overy standard tacrolimus and then an arm with tacrolimus elimination and eolus monotherapy. Uh In the in that first registration study, they had to get rid of the ta elimination arm because of significant adverse events that mainly included rejection and graft failure. Er but they did indicate that you could preserve renal function better with a a composite uh protocol of and and reduced tak compared to standard tak. However, um as I said, the reduced ta was probably around the area. We would actually use a standard and the standard TA was in the exposure range we wouldn't use. So again, this is a common theme with many of the RCT S next slide, please. And in the longer um follow up series of some of this cohort and a new cohort. Again, they showed a benefit in renal function with everolimus and in this case, with late tak elimination, but there were some serious flaws with this study as well because 33% of the patients were on cycloSPORINE. This is not something we would use as standard of liver transplantation unless they can't tolerate to chlorus. We didn't have level data which is you have to have to be able to interrogate this effect. And there was a high attrition rate in terms of drop off in the eolus limb. So if it's not used properly, it can be not very well tolerated by patients. Next slide please. Another group that we really have to get better at looking after. And this overlaps with renal dysfunction is metabolic dysfunction associated liver disease previously called NAFLD nonalcoholic fatty liver disease. It, its incidence is rising across the Western world and indeed even in Southeast Asia. Um and uh and the Middle East. Um and if you look at the left hand panel, the red bars, the incidence of recurrent uh fatty liver disease in transplant patients who were transplanted with fatty liver disease is astronomic. It's 90% at five years. Um that comes with all of the associated problems of dyslipidemia overweight, uh poorly controlled diabetes and renal dysfunction. And we really haven't established a regimen that is best suited for this population at the moment. Neuron inhibitors are still the mainstay, but of course, they exacerbate the cardiovascular risk, poor diabetic control and uh potentially uh hypertension. So it it may be that we have to come up with a better regimen for these patients, but we don't have it yet. Next slide, please. What I want to emphasize though, for any of you interested in liver transplantation and I emphasize this is different for all the other organs, including heart, lung and kidney rejection is really no longer the big issue for liver transplantation. Its incidence has dropped over the period from its first um inception in liver transplantation and it should not be the driver of how we treat patients. Next slide, please. Um I wrote a quote. Da Vinci simplicity is the ultimate sophistication. Actually, one of the things that doctors do really badly is to make the life of our patients more simple. So they adhere to medications and this is one of my biggest bug bears and I will talk a little bit about this in, in um in trying to develop a better immunosuppression strategy for all of our patients including in other organs. Next slide please. If you look at all of the solid organs, actually, er, Sabine Des did a really fantastic er, paper on the rate of non compliance across all organs, heart lung, uh uh liver and uh kidney. And it's interesting non compliance with medication or attendance to clinics is worse before listing. Uh It's always worse before listing. It gets very good in the first six months, post transplant for all organs and then it gets worse and worse and worse and continues to get worse up to three years and onwards. So if we're gonna intervene with uh with um uh adherence to immunosuppression, you have to do it early post transplant, you have to do it prior to transplant. And in the first six months when patients come to clinic and take their drug to build the confidence in the regimen, you're giving them next slide, please. And we know from lots of data, I could have picked lots but that actually uh complex regimens are associated with poorer adherence to immunosuppression. And we seem to not be registering this but this is commonly accepted in diabetes management, uh hypertension management, obesity management, hepatitis C treatment. As I show you and yet in transplant, we still add on medications to non compliant patients in the hope that they'll take the next one and not the one that they didn't take previously. Next slide, please. This is what happened to viral hepatitis. In the right hand of this patient was the regimen. We used to try to cure patients up until 2013. And in the left hand is what we know effectively cured 98% of our patients. And not only was it a much better drug but it was much better tolerated and compliance was much better. Next slide please. And we've shown at King's we were very early adopters of once daily tacrolimus that it improves adherence, particularly in a higher risk younger population. We looked at our experience of once daily tacrolimus published in liver transplantation and we had two cohorts. So once we switched early post transplant as part of a protocol and younger patients, you can see on the right hand side, the median age was 26 in this group who were switched much later and we switched them because we were concerned about their adherence and the effects on the graft function. Next slide please. And what we can show in the red square at the bottom is in that late cohort where were younger and switched much later, their rejection rate was nearly 50% before we switched from twice daily to once daily to Chromus. And it dropped to 10.8% after we switched to a once daily regimen. Er and we often only had them managed on that 11 single drug. Next slide, please. And you can see on the right hand, this is intrapatient variability, which is a good marker of adherence er was statistically significantly better in that late cohort, it was switched from twice daily to once daily. Tacrolimus, a much simpler regimen. Next slide please. This is a wonderful study in renal transplant called the Admira study where they had electronic monitoring of patients as they opened the capsules uh packet to take their drugs. And they looked at what happened to individual patients when they were on a twice daily regimen and stopped to once daily. And you can see in each, each block is one patient and you can see the top set of lines going from left to right to the evening dose. The bottom set are the morning dose and you can see how different people are in adhering to the morning and evening doses. Some patients are really bad at both, but the vast majority are much worse with the evening dose in timing or taking compared to the morning dose. So, simplifying the regimen to a once daily really makes a difference to their adherence as we showed in our paper. Next slide please. Uh And and this has been shown in registry data where there's a 8% graft benefit and a 6% patient benefit in using once daily versus twice daily in the Multicenter study. Uh You can go more quickly through these ones. I think next slide please. Uh And actually in Multivariate and univariate analysis, uh tacrolimus monotherapy once daily therapy was associated with significant improvement in graft and patient survival. And this was shown in a an extension cohort in the same registry uh following patients up to four years. Next slide, please. Um And we have shown actually that using the once daily regimen, we also reduced the risk of new onset uh d in our liver transplant population. And this is statistically significant and may well be associated with patients taking their medications more regularly. And consistently. Next slide please, we have now moved to a newer regimen with a preparation called VA, which is, which has a much more uh I think um optimal PK profile, which you can see in the kind of orange curve which the C max is actually much, much more flattened and probably performs better. We're just evaluating whether this actually gives us better outcomes and we'll have data on this soon. Next slide, please. So going back to my case, uh when she presented with this catastrophic early graft dysfunction after a second transplant, we didn't do what we we normally do, which is add on even more burdensome medication. We actually got her to see a psychologist. We got her a Dossett box. I stopped all her tablets, everything except a single once daily tacrolimus and said, please just take this every morning and don't worry about anything else. Don't worry even if you're eating, but just do the same thing every day and take it every morning. She now comes to see me every six months when I thought she probably wouldn't be alive by this date. She's now had two Children. This was an article about her in the newspaper locally, but she's now got um two young kids next slide, please. And she has completely consistent levels, completely consistent adherence. So simplifying is a much better thing than making things more complex, which is what we as doctors tend to do. Next slide, please So just as general principle, excessive immuno suppression across all organs uh is really associated with declining renal function, recurrent and atypical infections, de novo uh non transplant organ based malignancies and PTL D and and other toxicities. As we heard in the first talk, inadequate immunosuppression, of course, is injured with uh is associated with immunological graft injury and rejection and potential failure of the graft. Next slide please. But our decision making when we come to using tacrolimus is really based on some very crude uh parameters. We base it around the age of the patient. We base it around the disease etiology. Whether it's immune or not, we base it around the existing renal dysfunction or metabolic comorbidities. We, we base it around the time of transplantation. As you heard, we give uh higher basis and exposure early and then reduce it to later. We base it on some imprecise liver function tests and we base it on levels. But actually the problem is none of these are very good biomarkers to make a a robust decision. We have very poor sensitivity and specificity for the efficacy of our immunosuppression in preventing rejection and for the safety of our immunosuppression in minimizing toxicity because we use very surrogate levels and surrogate markers to determine what we do. Next slide please. We need to tailor immunosuppression much more. II put HEP HEP C because historically, it was important, it's now almost nonexistent. But for hepatocellular carcinoma and other malignancies for patients with metabolic risk. As we've already talked about uh extra transplant organ malignancies which are increasingly common in our aging population. Patients with recurrent infections and patients with de novo malignancy. We need to consider enhance stimulus suppression in patients with autoimmune diseases. Positive antibody cross match particularly non liver based transplantation and patients who've got rejection. Next slide, please. Uh This is written by a very good friend and colleague of mine from Australia. And he wrote an editorial saying there should be no such thing as protocol immunosuppression in liver transplantation, immunosuppression should be personalized to the individual patient on the basis of several factors. Um And, and do, do I think we adhere to this? No, I don't. Next slide, please. Um So II would say when I was a trainee in immunology before I came back to complete my training in transplant, I thought we would be away from tacrolimus. Now with neologic, the some of the drugs that we heard about before which specifically target certain aspects of T cell activation. But all of those have fallen by the wayside. And we're really, we're still based on tacrolimus and it's here to stay. I would say once daily, tacrolimus is much better than twice daily. And I think any of you who prescribed twice daily should try to take a drug that you have to take at the same time every day with a three hour embargo in the evening for not being able to eat and you try doing that and I will pretty much guarantee you'll find it impossible. So I think twice daily should not be used anymore. Um It's poor. Uh We are poor at delivering individualized immunosuppression. We still use protocols. I always say this to my trainees, worry less about rejection and more about over immunosuppression because it kills more of our patients and simplifying drug vision reasons is always good and you should always be trying to do that and not make things more complex when patients are struggling to take the drugs. You're already on next slide, please. Thank you. I think that's the end. Uh Great. Thank you very much for a fantastic overview though. Um So I'm just doing the slides as well. You're very welcome. Um So I just gonna hand over to my colleagues and I'm just gonna go through some questions. Yeah, so that to decide whether it stop. Yep. Brilliant. Well, thank you both so much for your time this evening and giving to excellent talks for us. They were really fantastic overviews and it's really interesting to hear about how things are done in the different organ groups as well. So that's um that was wonderful. Um I wonder if I could start with a question for an um which she was saying great talk. Thank you very much. Um I didn't realize that mycophenolate was highly albumin bound. Um Is there any practice in your center? About adjusting the dosing for patients who might be hypoalbuminemic, for example. Yeah, thank you for the question. Um I think um unfortunately, we don't that there isn't any current practice for dose adjusting mmf based on albumin count. I think we've moved, we, we do end up and II II like that point about um sort of personalizing immunosuppression based on the patient in front of you. And I think even though there is a protocol for what you sort of want to start off at or what you want to achieve based on the evidence that we do have, the dose titration happens more in line with um adverse side effects or what we tend to do in some of our patients. For example, if we're worried about absorption is to MPA levels. Um but the sort of evidence behind, I think the clinical significance of MPA levels is slightly blurred. Um So even though it is, it is something that is available, uh the clinical significance of it is questionable. So it's, it's an indicator that something that can be used but with a pinch of salt. Um so I think you'd be driven with um a a couple of things put together to drive what that final dose looks like for our patients. OK. And can I also ask a question to answer them? Uh It was really about, I suppose that the calurin inhibitors and adjustment of dosage in patients who have um graft dysfunction you know, further down the line, obviously, you mentioned about using it as a, as a agent whenever patients present with rejection. But is there a much in the way of adjusting calcium urine inhibitor dosages as well? Yeah. So I think when you end up treating for rejection, it's sort of looking at multiple factors as to what let you know it's trying to identify the cause of rejection in the first place because if you haven't identified that, that in itself, you know, you, you then have you, you're treating the effect, but you're not really treating the cause. Um So one of it, one of which will be, are you, is your maintenance immunosuppression regimen effective for uh the patient at hand. Um And that would include looking at your attack target ranges. So, for example, with uh hearts, we would normally end up on mainstay immunosuppression with the CN I and MF and your pred would be weaned off about a year, post transplant, whereas the lungs stay on all three as maintenance agents. Um So then it's looking at, do we need to adjust uh t target ranges um to make sure that they are correct? Are they in, you know, what's the time and therapeutic range over the last six months? Is there a lot of variability in terms of, are they dropping off? Are they not attending clinic and sort of identifying those um issues before changing your t your attack target ranges Um, so yes, we would look at it, I think very rarely have I seen it go up significantly. It's usually, um, the levels are running too low or, uh, they're not as compliant and it, it's then looking at how do we optimize from that perspective, um, for these patients? Ok. Thank you far. I wonder if I could ask you a question, um, which is maybe kind of deviating a little from immune suppression. But I was interested in a lot of your comments about the kind of burden of medication that we give patients and trying to simplify it. For example, by using once daily kind of preparations of tacrolimus, for example. Um I suppose from a kind of kidney perspective, so, you know, we were so aware of kind of diabetes and cardiovascular risk and so on and I often find that you're then adding in more therapy for patients, like trying to get them on, you know, statins or thinking about ace inhibitors and BP control and so on. I suppose I just wondered if you had any comments, you know, when you're trying to simplify it for patients, I suppose a lot of it is going to be individual based and timings and where they're at. And I wondered if you just had any comments on how to approach that situation. Yeah, I mean, so I would say that treatment of comorbidity should follow best practice guidelines across the piece however much you want to simplifies. I mean, they are really overburdened with medications. They come with their list of this huge pill burden and they come with a bag or a backpack with what they carry around with them. So the bit I try to simplifies is immunosuppression. You know, it is extraordinary how many times we have a non compliant patient who's got rejection and the standard response in clinic is to add a medication, they're not taking the first medication. And you think somehow magically, they're going to take the next one. And actually the best thing is to wipe out everything and start from scratch as we know in care of the elderly. This happens all the time. Actually, when you get these 80 year olds who turn up, you know, with a seven or eight medications that nobody really understands why they're on because they're legacy medications. One of the best things often to do is to stop everything and build up with. And you often find that using 30% of what they came in on. And so what I try to do is simplify the immunosuppression a lot, which obviously the liver being a bit more forgiving. I see that point. Somebody made that point. It is a much more forgiving organ. We 70% of our patients on monotherapy with once daily tacho within a year. So I think that's much harder to achieve in heart lung and kidney, particularly with a high risk kidney so I think for sure. But that bit, I really focus on the second bit you're talking about actually is actually a very complicated problem because we make GPS so scared of managing our patients, the stuff they know how to manage probably better than you. And I, we've made them so scared of touching when we say, well, you know, their BP is not adequately controlled, their diabetes is not adequately controlled. Can you do something? They don't do anything because they're slightly overburdened and utterly scared of touching a transplant patient because this moment they make a mistake, what do we do? We pile problems on them. So I think we have to be much more team oriented and join up everything so that we manage the details so that our patients live longer. We're all very good in getting people through one year for what else patients who survive in 10 years? And that's the bit we've kind of neglected a little bit. Yeah, thank you. Um And we've got another question, I suppose um kind of when patients are acutely admitted to hospital. And I suppose this will often be in the context of infection. For example, I think this question probably relates to not a specific concern relating to acute graft dysfunction, but just in terms of management of immune suppression in those settings. Um I think our kind of standard approach certainly in kidney medicine is to double steroid, withhold any anti proliferative agent and continue tacrolimus. But I wondered how that compared to liver, heart and lungs. So maybe a question for both of you. I go first. Yeah. So II I'm thank you. I think we would, we normally recommend, do you mean in terms of if they go, if they have an admission for um, an infection? Yeah. So, um, we normally, um, I think t stays on as the same and we, because we're quite strict on our target ranges um just because of the risk of uh risk of rejection associated with drop in levels. Um So we, we do continue with our tacrolimus and then monitor and dosage just based on levels. Um MF usually continues uh unless there is a gi related side effect and all a gi related um complication. Um and that's the only time that we would consider um reducing or stopping it. But again, it would depend on things like um time, post transplant. Um And if they are a third agent like prednisoLONE, I usually going up on doses of prednisoLONE during an acute phase of when they are quite unwell if needed. Um But um yeah, I would, would usually end up continuing all three unless there was potentially a gi related incident and you would consider withholding MF or if they were extremely septic. Um You would consider withholding MMF. Um But again, it would, it would, it would depend quite, um it would depend on how long um they are since post transplant, what their last biopsies look like. Um, and then, you know, make that decision based on that. Yeah, it's interesting. We do slightly the opposite. My heart sinks. We have about 6000 transplant patients out there because we're a very old unit and have a lot of young patients as well. And we get phone calls from all across the country and they say, oh, they came in, they got this pneumonia. We stopped the attack. They're carrying on, on their mycophenolate. They haven't done anything with steroids. And so mycophenolate monotherapy is terrible for graft function. You always get rejection. A A is very good. It really is one of the few drugs you can keep from people who have sepsis. We learned this during COVID, you know, the protocols across all organs for COVID stop the antiproliferative. Keep the tacrolimus unless there's a drug intra and add steroids, as you just said. And trying to get that across to people is quite hard. But that's what we recommend. We don't even do modify the tac exposure. They're above therapeutic range, we go by levels. Um You know, the thing that we always worry about is they come in from a community called pneumonia. They get on Claritin as their level double and then their kid stop working and nobody know what to do. But in general, we maintain ta stop anti proliferative and we often top up the steroids, double the dose No. Ok, great. Um And uh there was a question from Roderick as well about any preference for antihypertension therapies in patients who have uh tacrolimus induced hypertension. Um, again, probably to, to both of you, but ii appreciate obviously we've talked about the less there more a little bit in terms of the therapy. But is there any kind of rules of thumb and with the best evidence in liva, is amLODIPine to start off with it? It's well tolerated. We start off with a low dose. Um But yeah, and actually, except in the setting of renal dysfunction, when we often use ace inhibitors. But I think that would depend on different organs though. Yeah, I think we normally go with ace inhibitors unless um they're older patients in which we ended up end up on amLODIPine as the best evidence. But yeah, usually ace inhibitors as long as um they can manage it and their potassium stays all right, because that's the sort of um added sort of pharmacodynamic interaction with aces. Um But usually it's well tolerated and that's what we end up with. If I make a general observation, we we're very good at blaming every ill on tacrolimus that happens with the number of patients I've had, they have a seizure and it's tus you know, they have, there's no question, tremor and tach I completely accept. There's no question that if you have, as I've shown with the data for liver transplantation, a degree of renal sensitivity or undiagnosed, renal dysfunction attack will make it worse. But it's often not the cause of everything that we blame it on. It can be managed, it can be used better. But we, we tend to just say, oh, it's tus, this drug has saved 100s of thousands of people's lives and it's now cheap as chips and it works really well. We just need to be better at using it, but stop blaming it. Yeah. Well, thank you so much, both and that was fantastic evening. Two fantastic talks. Um And we really appreciate your time this evening. Um Thank you, everyone who joined us this evening. Um These talks will be available and catch up. Um As well as the speakers are happy with that. Our next event is going to be on the 26th of June and it's going to be on multivisceral transplantation and for our attendees, if you fill out the feedback form and you'll get a certificate that will be issued automatically to you after you have done that. Um So just like to say, thank you very much again. Um Thanks all for joining and we hope to see you all soon. Thank you. Thank you. Thank you.