Dr. Nancy Rodig - Pediatric Kidney Transplantation: Challenges, Advances, and Future Directions

Uh, well, I think we're gonna get started just so we can keep everybody on time, but, um, good morning, and it is my great honor to introduce, uh, one of Boston Children's very own, Doctor Nancy Roedig, as today's grands round speaker. Doctor Rohdig pursued her pre-medical studies at the College of the Holy Cross, followed subsequently by medical school at Washington University School of Medicine in Saint Louis. This was followed by residency training in pediatrics at Saint Louis Children's Hospital. And fellowship in pediatric nephrology here at Boston Children's Hospital. Following graduate uh graduation, we were fortunate enough to have Doctor Rodick stay on his faculty, where she has been a truly amazing clinical partner, researcher, collaborator, leader, and friend. So, without further ado, Doctor Rodig. All right, Eliza, thank you so much for the invitation. Um, it's really a pleasure to be here and clearly as being surgeons, it's not surprising you start your grand rounds early, earlier than most. I almost like slept in my office overnight just to make sure I'd be here on time. I was a little nervous last night going to bed. So this is wonderful. I have one disclosure, uh, I serve on a, a safety review committee for drug, uh, for the treatment of primary hyperoxyuria type one. so that's my one disclosure. Um, in terms of goals, I wanna review the outcomes of pediatric kidney transplant in general, uh, update recent advances in a couple of specific diseases that actually very much impact surgical planning, uh, review the challenges of current care. I do this a lot. I wanna emphasize the, the, the, um, benefit of kidney transplant in pediatrics compared to dialysis cause it's the much preferred and optimal therapy, but we certainly have a lot of challenges. Uh, and detailed pediatric clinical trial of a normal immunosuppression regimen that's actually centered here at Boston Children's Hospital. And at the very end, a single slide, uh, just looking at a couple of therapeutics currently under investigation. Uh, clearly, before I do any of this, I have to acknowledge the great work of Doctor Joseph Murray, who performed the first successful long-term kidney transplantation at the Peter Bent Brigham Hospital, AKA the Brigham, AKA MGB, uh, in December of 1954. This is between two identical twin brothers. Um, the recipient, Richard lived for an additional 8 years and actually died of causes not related to kidney disease. Um, and the fact that they were identical twins really did promote, uh, the acceptance of that, that kidney from his identical brother. Uh, Doctor, uh, Murray also pioneered the use of total body irradiation and first chemical, you know, immunotherapy, which include azathioprine. He performed the first successful transplant between non-identical twins in 1959, and the first successful deceased donor kidney transplant in 1962. And for his great body of work, he shared the prize, the Nobel Prize in Physiology or Medicine in 1990. And I believe it was the chief of pediatric sur uh plastic surgery here at Children's uh from I think 1972 or before 1972 to 272, but was here as well being at the Brigham. In terms of transplant outcomes. Currently transplant, as I said, the preferred option for children with chronic kidney disease or end-stage kidney disease. The other option is dialysis, and dialysis is a difficult therapy for any child. Uh, it certainly doesn't promote a good normal milieu. Uh, the survival benefit of being transplanted far exceeds that for the treatment of dialysis. They have a better quality of life and better outcomes in terms of function. Patient survival is exceptionally high, so the 5 year patients survival is greater than 94% for kidney transplantation. In terms of graft survival, this has improved dramatically over years. So the 10 year graft survival for a living donor kidney transplant is about 78%, and the 10 year survival for a deceased donor kidney transplant is about 57%. And to us, that sounds good, but if you, you know, there's a lot that's, you know, that, that says is that if you're a child, if you're an infant or a toddler, you're not gonna have one kidney transplant throughout your life, but you're gonna have multiple transplants throughout your life. And that's certainly when we meet families who are suddenly, you know, uh, presented with this diagnosis of end-stage kidney disease, to also get them to wrap their head around the future of not a single transplant, but multiple transplants with intervening dialysis. It's certainly a difficult path. And clearly, you know, the goal of extending the longevity of any kidney transplant, uh, to go beyond these 10 year survival rates is the goal. We've had dramatic gains in outcome, improved, improved outcomes for the youngest children, children less than 5, right? And I have to say here at Boston Children's Hospital, we are a referral center for many, you know, the region for these small children. Many centers feel comfortable performing transplants on their older children or adolescents. When you start getting to these really young children, uh, we look to the, I actually I have to admit this, the expertise of our surgeons who can do these surgeries, uh, with great success. We also lend a fair bit of medical support because to Grow a child, uh, to be an appropriate size, uh, for a kidney transplant is not without challenge if they have renal failure. And if you are an infant, a neonate who develops end-stage kidney disease supported with dialysis, the, uh, likelihood of you getting to transplant is probably somewhere around the 60%, 60%, you know, so 40% will pass due to complications of dialysis. Um, so, we have to say that, you know, as a partnering team between the nephrology group and the surgical group, I think we do offer, uh, a great service to the entire region. This is just looking at the outcomes based upon age, um, and just at living donor transplants, outcomes at 3 months, 1 year, 5 years, and 10 years. And what you can certainly see is that at the 1 to 5-year group, they do the best actually of everybody, right up to 10 years. And people may identify a pediatric, and actually the 6 to 11 years, they do really well too. But you can really see the group of pediatric patients that don't do so well, right? And it's not a shocking, but it's that 12 to 17 year old. So the kids who are transplanted as adolescents, their outcomes are relatively poor, and in fact, they're only better than those who get transplanted at greater than 65 years of age. These are people with great comorbidities who also get kidney transplants of lower quality. So, our children either get living donor kidney transplants. Or deceased donors that have the best donors, right? So, we get the top 3, quality donors for our kids and they do worse than the 65-year-olds, or sorry, only better than the 65-year-olds at the 5-year and 10-year mark and certainly reflects, I think the challenge that many of us who take care of chronic kids, kid, you know, any kind of chronic disease, you know, how those adolescents uh fare over time. But I really want to emphasize is the incredible um improvements in uh the incidence of rejection in the first year over time. So, in the late 80s, more than 50% of patients would have rejection within the first year of transplant. And if you look at over time, right down to 2007, 2010, that is a dramatic improvement, about 10%. So you've gone from 55% to approximately 10%. But I have to admit, if you look at the current data, that's kind of flat. It still remains somewhere between 10 to 15% getting acute rejection within the first year. Where do I have, oh, there we go, I'm just gonna use this guy's show. But, so you can see a great improvement in the slope in the first half, right? Going up to 12 months, that's absolutely amazing. But if you look at the rest of the slope, the slope beyond a year, I think you would all agree with me that that is a continuous slope that goes up, and those slopes basically parallel over time. We have really made no gains in late rejection in our patients, and this severely impacts the long-term allograft function, I think, overall, and this is the problem. Acute rejection upfront, great. Long-term rejection, we really have not made sufficient gains. So look at allograft survival trends. This is not just pediatric, this is pediatric and adult survival in both living donor and deceased donors. And again, good improvements over time, right? But I think you'd have to agree with me, again, these trends also kind of look at this kind of slope. The slope is just not significantly improved. We really would like things to flatten out, to say that our living donors will have a 20-year survival of 78%, not a 10-year survival of 28%, 78%. So this just speaks to great improvements, but the fact that there's still a lot that needs to be improved. So, what I want to do now, I'm gonna talk about that, what we need to do and improve later in the talk, but what I really wanted to talk about is a couple of disease states. So, two disease states that have changed dramatically with respect to surgical planning and what we ask of our surgeons. Uh, this includes, you know, so when, when you, when you, what we previously needed both a liver and kidney transplant, and now we only ask for a kidney transplant. Um, because we combine this with targeted therapy. And the tooth disease states are complement mediated hemolytic uremic syndrome and primary hyperoxyuria. So, the improvements in HUS have really been kind of for a while now. We've had these agents for in excess of 10 years, and primary hyperoxyuria is something that we're really, uh, just started, um, uh, having these incredible therapeutics that have completely revolutionized the care of this disease. But in terms of complement mediated HUS this is distinguished from the more common diarrhea associated or sugar toxin associated that you learn about. So that's expected, you got exposed to something. That set off this cascade of endothelial injury in your glomeruli and you get HUS. You know, it's, you could fully recover your kidneys, maybe about 10 to 15% of the patients don't and they need transplant, but that's not gonna come back. It was an insult. It was an infectious trigger that insulted you and you lost your kidney function, but we can transplant you and you won't, and it won't return. This complement mediated HUS is basically the underpinning of this is a dysregulation of the complement cascade, right? So, the complement cascade is always slowly ticking over in all of us, kind of getting ready to attack pathogens, right? And, but we have this regulation system that prevents this trick over on our healthy cells. So these inhibitors of the complement cascade, right? And in this disorder, it's dysregulated. So about up to 30 to 50% of patients will have mutations identified that identify um uh a mutation in um in, in this regulation process. Um, and if we think about the mutations that we find, the vast majority of those, uh, which is important for the surgeons, are those that basically, um, loss of functions that kinda dampen the system, right? Dampen the C3 convertase, and they're produced in the liver, right? So if you're identified to have this mutation before these therapeutics, you got a liver, kidney transplant. The other mutations which are less common are what's called gain of function mutations. So, if the C3 commatase requires two proteins to come together to churn out the complement system, one of them is mutated and doesn't want to dissociate, does not want to dampen. So it's just rev, going, going, going, going, going. And kids who have this will have episodes of HUS recurrent. They get an infection, uh, these little triggers that just keep happening and, and ding them, ding them, ding them, and it keeps happening till they go into end fail, you know, to end-stage renal disease. And the final common pathways in the complement system is something called a membrane attack, um, complex, and basically, it's the formation of a pore that is supposed to go into a pathogen, like a bacterium to cause it to lice, but it's a pore that goes into the child's cell, particularly in the kidney, and causes a cell to lice. So, there's a pore, there's an osmotic stress, the cell gets disrupted and, and churns out this, uh, kind of terrible process in the kidney. So, the renal pathology is thrombotic microangiopathy, and not to torture, but I have to look at a nice picture. That's a beautiful normal glomeruli. And I go, I know you might look at it and say, that's gorgeous, right? That's what Steve thinks, it's a gorgeous glomeruli. But it's got nice open capillary loops, right? Nice number of cells. This is a very unhappy, you know, um, thrombotic microangiopathy. You don't see any open capillary loops, and actually where that arrow is, is a capillary thrombi. So this is the pathology of, of HUS in the kidney. And prior to the availability of current therapeutics, kidney-only transplant, which is what we used to do. So when I was a fellow and a junior attending, you'd get HUS if you didn't know what the genetics was, which we didn't know the genetics early on, you kind of said, we're going to go for a kidney transplant, and you had to say to the family, this may recur. And I'll be honest, pretty much all those early cases when I was a fellow or a junior attending recurred. And if you recurred and we didn't know what was going on, you went back on dialysis and that's where you stayed. When we started learning about the genetics of it and the underlying pathophysiology, if we learned that we thought it was a complement factor H or I which comes from the liver, we recognize, OK, well, now maybe you need a liver kidney transplant and certainly not being a surgeon, recognizing the technical, um, the, the technical need for that is, is pretty significant. Um, and, you know, the, the outcomes are certainly, I imagine, much more challenging in terms of a liver transplant than a kidney kidney-only transplant. No, I just mentioned, so certain mutations are gonna go for both. So we have now is complement hitters. And I think, you know, many people who work in the oncology ward are used to hearing about ecalizumab, and that is something that inhibits this complement cascade. It binds to C5. I'm sure I have like a pointer, but I'm gonna just keep using my little mouse here. C5, if it binds to C5, it prevents its cleavage. So, the cleavage of C5 turns into C5A, which is a pro-inflammatory cytokine, kind of stirs things up. When it also prevents the cleavage of C5B, which is part of the C5 convertase, this enzyme that churns out the complement cascade and forms the membrane attack complex, this pore that causes cell lysis. So these inhibitors, ecalizumab, which you give every 2 weeks, and more recently ravalizumab, which you can give every 8 weeks, has been an absolute game changer for this disease. When initiated early, it prevents the development of end-stage renal disease. And when the end-stage renal disease has developed, it permits a kidney-only transplant without the risk of, of recurrent disease. And this has been an absolute game changer. HUS was, you know, we currently have two diseases that I, I hated the most then, HUS and FSGS. This, this therapeutic has taken away the challenges of HUS in the most amazing way, right? So, now we're preventing kids from going into renal failure, and the poor kids that show up in renal failure, we can basically give them a kidney and, you know, stop the risk of recurrence, which is absolutely amazing, and don't have to ask our surgeons for a combined liver, kidney transplant. This issue, you know, I mentioned the complement system, the intent is to protect us, is to protect us against pathogens, and when you block the um this complement cascade, you are increasing their risk for encapsulated bacterium and in particular, meningococcus. So the big issue with these drugs is that they have to be vaccinated. They have to be on prophylaxis indefinite, um, and they can still get bacteremia. So there's this big deal. If someone calls us who's on ecolizumab and has a fever, it's an automatic, you go to the ER now, your local ER so they can get you on some ceftriaxone should this actually be, um, um, bacteremia. So the next disease, which is a much newer, you know, change in care is a primary hyperoxyuria, which is, you know, not to torture everybody, but it's basically a group of rare inborn metabolism issues of glycoxylate, uh, resulting in hepatic, so liver overproduction of oxalate, and that's the issue. It's autosomal recessive inheritance, and PH type 1 is the most common, it's about 80%, and it's due to pathologic variants of the hepatic enzyme. Here I'm gonna alanine, glyoxylate, amino transferase, I'm just gonna call AGT, right? So it's a liver enzyme, um, results in this crazy overturning of oxalate, and oxalate's a problem because it's poorly soluble and deposits as calcium oxalate in various organs, and as you can imagine, where I'm heading is to the kidney. So, oxalate is excreted in the urine, and increased urine excretion leads to deposition resulting in nephrocalcinosis and kidney stones. And clearly this is just a flat plate. For some kid who has oxalosis, you can actually see their kidneys by a flat plate. So if you can see a child's kidney by flat plate, that might be an indication that this is potentially this, the disorder, and there's a CT scan of um primary hyperroxyuria. Um, and I have to remember, you know, not to, to embarrass or to, um, compliment HB, uh, but I remember once I was coming on to service and Bill Harmon was in, you know, with the old, you know, 10 South, I think is where we were, and I was kind of half paying attention cause he's about to sign out to me. And they were talking about an outside referral, a referral from Rochester, and they were just talking about her coming and surgical planning. And I think, you know, HB kind of brought up some of the images and he was looking over, you know, the ultrasound and the local team had just thought it was kidney dysplasia. It was a little baby, dysplasia on dialysis now. And what he noticed from the ultrasound, it did, you know, it certainly looked echogenic, but it was a little bit brighter than, you know, he was like, gee, this is awfully bright. And I'll never forget that cause I was looking down at some paperwork. I wasn't even paying. Attention. Then he was like, this is rather bright. What does this mean? This doesn't seem right. Which then brought up this whole question of, what is the diagnosis? We almost proceeded for this child, a kidney-only transplant in a disorder that was liver-based. Had we done that, it just would have come right back into the kidney. So, I'll never forget that moment of H being like, mm, what, what is that all about? That doesn't quite look so right. So the issue with uh primary hyperoxyuria is clearly, so the, the, you know, the calcium oxalates depositing in the kidney that causes nephrocalcinosis, kidney stones, obstruction. The calcium itself sets off an inflammatory cascade and fibrosis, which results in like kidney damage over time, right? Um, and this is the way you're getting oxalate out of your body. So when the kidney function falls below roughly 30 to 40 mL per min, then the oxalate kind of starts building up in the blood. Right? And it then kind of starts hitting, it's like exceeding this supersaturation threshold of 30, 50 micromoles per liter. If we tested our oxalate in our blood in a normal population, it's somewhere between 1 to 3. So the minute it gets up to 30 to 35, you're gonna be at risk for this stuff depositing elsewhere, not just in the kidney. But in the bones, in the heart, causing dysrhythmia, in the retina, in the skin, right? So this is kind of a systemic oxalosis. This is again, another reason why you really want to identify this because now you're kind of depositing the stuff everywhere. So clearly, it's critical diagnosis early to provide intensive supportive care. So if a child shows up and has still maintained kidney function, intense supportive care is a pain in the neck. It's hyperhydration. You're just trying to keep the, the, the, the calcium oxalate in a dilute form to go out the kidney, so it doesn't stick to the kidney, reduce the damage, and get it out. Um, for the kids, uh, it's also, you know, uh, alkalizing their urine. You often have to put a G tube to hyper hydrate them. When their GFR is too low, you're gonna put them on dialysis. And if you think about dialysis, I think most people are used to our patients coming in for hemodialysis 3 days a week, right? When they're on peritoneal dialysis, they do this every night at home. If you have primary hyperoxyuria, peritoneal dialysis is simply not enough clearance because the 7 day a week peritoneal dialysis basically equals the 3 day weeks of intermittent hemodialysis. You need to get this out of the child's body. They have to come for intermittent hemodialysis 6 days per week. We give them off Sundays for everyone's sanity. We have kids that were coming to our, our unit 6 days a week from Connecticut. Um, until we could get it down low enough and proceed with, with, uh, therapies and transplant. This is a major, uh, burden to the family and to the child, as you imagine. They're traveling back and forth. They're on dialysis for 3 to 4 hours and have to travel back home. It's a full-time job for the family and a terrible life, uh, for the child. Um, and also what I should say is that when we start dialysis for our patients, we typically start dialysis when GFR is roughly less than 10. We have to start this earlier, somewhere between 30 and 40, because if we don't, then you're gonna start hitting the supersaturation uh issues and having systemic um Uh, oxalosis. And I said, if not diagnosed, um, and kidney-only transplant is performed, renal failure will, will occur. And if you look at the literature, approximately 4 to 10% of this uh uh this, this disease is diagnosed after transplant. So they put the kidney in and they said, oops, what is this? What is, why is this kid getting stones? Why is there nephrocalcinosis? So, it's been a diagnosis after kidney transplant in 4 to 10% of the cases. That may change over time, you know, we're doing more genetic testing on our patients. There's these kind of available gene panels, but you have to have the thought that you need to do the gene panel for that first child that I mentioned, for dysplasia, not everyone does a gene panel for dysplasia, and so that still could get missed. And this is the, uh, you know, this therapy that again, I'm on a, uh, the safety review committee for the, that top one. This one here. But what these are is, uh, what's called small, there you go. Goodness. Yeah. All right. So what I'm gonna say is basically the small interfering RNA. So if you've heard about these therapeutics, they are absolutely amazing, right? So these are basically therapeutics that are basically targeting the hepatocytes. So in these two specific drugs, they go only to the hepatocyte. Right? And what they eventually do is they affect in a gene-specific way, the, the transcription of specific mRNA. So, you're basically halting, you're silencing genes, um, and what they're doing is they're silencing genes upstream to the, to the mutated. Sorry, mutated gene. I'm gonna go over here. AGT. I can't, I can't go over there cause you won't be able to hear me. But basically, if you have AGT and the obstruction there is leading to oxalosis, if you are stopping the genes before it, you don't build up the precursor to oxalate, and they're actually building up the precursors that get out of the kidney without any problem. So these therapeutics are absolutely amazing, go right to the hepatocyte and basically dramatically reduce the the production of oxalate, an absolute game changer for this disorder. So in terms of treatment strategy, strategies for PH1, you've got choices and I'll be honest, uh, you know, we talked about, I was gave a talk on the genetic basis of kidney disease at the PAS, um, this past year, so pediatrics, um, uh, you know, meeting and, you know, we, we talked about our options, right? So, the options for PH one, if you have an intact kidney function, you still have a good GFR, you can do a liver-only transplant. Right? Before you actually lose all your kidney function with the hope that once you put your new liver in, your kidney function will stabilize. Simultaneous combined liver, kidney. And then sequential liver and then kidney transplant. And what I should say, as a, you know, for the surgical team, any kidney transplant and a primary hyperoxyuria is gonna entail native nephrectomies. If you remember the pictures of the flat plate and the CT scan, those are kidney rocks of calcium oxalate. So, even once you put a new kidney in, that stuff eventually is gonna have to come out and it's gonna come out through your new kidney. So, all the surgical planning, I should say, entails native nephrectomies. So you've got preemptive isolated liver, simultaneous combined liver, kidney, sequential and then a kidney transplant. So you put the liver in first, you let things normalize, you let the, you continue to dialysis to get the oxalate out, and then you put your new kidney in. And then isolated kidney transplant after treatment with uh the small interfering RNA um prepared with intensive, you know, hemodialysis. And as a surgeon, Eliza, which, which one would you pick? What would be your favorite? Absolutely. So I'm gonna quote, because you made out Hershey's, I do love a combined liver, kidney, right? And this is why we have surgeons cause that's an insane statement to me, but I'm so happy that she does like combined liver, kidneys. But absolutely right. So what we would choose is an isolated kidney transplant after treatment with these therapeutics. So for this kid that shows up, it's already in renal fib. In a dialysis unit, we start using these therapeutics, and the purpose of that is basically, you're going to now stop the hepatic production of continuing oxalate going out into your system, right? You're going to start dampening or reducing the systemic burden. Once you get their blood level down to a safe level, then you proceed with kidney transplant and maintain this therapy. Um, I'll be perfectly honest, I was shocked because at the PAS, uh, people were still talking about combined liver, kidney, and I thought, you know, you know, this seems crazy, um, to me, to be honest, with these therapeutics, and then sure enough, in 2023, there was a report of an isolated kidney transplant under this therapy, and this was reported in 2023, and actually in February of 2023, we took care of one of our own patients under this therapy. So he went through dialysis, we put him on this drug, we dropped his level, and he went to kidney and he's doing great. His levels in his blood are still below detected. And I'll be honest, so I've just started using open evidence, right? So I'm not sure who in this room uses open evidence, like this is amazing. And when I looked at this at open evidence, they actually recommended combined liver, kidney. So I'm shocked by that and I think it gives me like pause for open evidence cause I don't think that is true. I think that, you know, again, it's still may be early days for this, but I, AI, right? So I would, but I would, I really do think that ultimately, it, this will be the therapeutics. It'll be this drug with kidney only. This makes sense to me. Absolutely. So challenges. So what I have to say, you know, PDF kidney transplant, like I said, is the therapy of choice, right? We want transplant for our patients who are on dialysis or heading into, we prefer a preemptive transplant to avoid dialysis. Well, we certainly have, I, I mentioned, suboptimal long-term allograft survival and what is the basis for it. We have complex immunosuppression regimens, right? So there's, uh, these can falter. Kids may not take them. Their levels may fall below detection when, when we don't intend them to. Um, even when we, they take it perfectly, there's insufficient control of this allergenic response. You saw those curves. There's a chronic rejection. There's a chronic graft loss in transplant recipients. Clearly, some can do well for decades and decades, but the majority do not. And as I mentioned, rejection. The other problem is we have terrible bio biomarkers to monitor, right? So people think about monitoring kidney health. Sure, you have serum creatinine, but you can have a lot of damage before your serum creatinine goes up. And you can imagine if you have a baby with an adult kidney transplant, you know, their creatinine is gonna be 0.2. If they're Creatinine goes to 0.4. There's been like 50% reduction of their GFR, potentially a lot of damage to the kidney, and this can fluctuate, but particularly in little children, creatinine is just a really, um, challenging biomarker. You know, clearly, it's the one that's the cheapest. We look at it all the time. We look for trends, but it's just insufficient. Uh, I'm gonna talk a little bit about donor-specific antibody. This is when the immune system, um, basically makes an antibody response specifically to the HLA antigens of the donor. This is a major problem in transplantation for kidneys, particularly in children. We'll look at that data. And then there's something called donor-derived cell-free DNA. This is a really neat, you know, um, test that we now have, and it basically looks at Uh, we have, uh, kind of, um, you know, fragments of DNA floating on us all the time, you know, for all of us who don't have a transplant, it's just our DNA. For kidney transplant recipients, they have some of the donor DA and the rest of this is their own, and it, it's, it's presented as a fraction. So, when that fraction of the donor-derived cell-free DNA is going up, it suggests allograft injury and cell breakage, right? So, it's a nice test, but I'll be honest, it's expensive and you can't run it every 5 seconds. These, both these tests, the DSA test and the cell-free donor-derived DNA, uh, they're in the thousands of dollars, so recognizing the cost. And I'll also say they're late, right? So if you've got DSA, if you've got donor-specific antibody, and you've got allograft injury, it's almost too late. You're just recognizing injury. You don't have that anything that's leading you towards something's about to happen, and that is certainly something we would love to have. So in terms of suboptimal long-term real graphs, looking at immunosuppression, I have to say the advances of immunosuppression uh for kidney transplantation have been overall slow. And if you look at the great, like the revolution of care in oncology, uh, immunotherapy, all these other therapies that have really come to, um, to, uh, patient care have been remarkable. And a lot of it, it's almost like targeted therapy of the cancer, right? So harnessing the immune system to say kill that. It's almost like transplant needs the opposite. We need to, we need to divine a cocktail that basically says ignore that and keep everything else intact, so they're not getting infections and cancer, but they also don't, uh, you know, destroy their allograft. In 2000, a common immunosuppression at children's was, you know, this triple cyclosporine, azathioprine, and steroids. And everyone was on steroids. In 2006, 2009, it was a random randomized controlled trial, and we were one of the participants that proved that steroid protocol was steroid-free protocol was safe in low immunologic risks. And what low immunologic risk means a kid who's coming to their first transplant, you screen their blood, they don't have a lot of anti-HLA that can suggest a high risk for rejection. Um, so really, and this is the majority of our patients, the majority of our patients for transplant are, are first-time kidneys, though we certainly get repeat kidney transplants for kids who have either lost their graft because they've had it for a long time or lost it to rejection. And I want, this is again one of those things that just shows you how little things have changed. So, this is data from the SRTR registry for basically allographs across the country. And this is just looking at pediatric immunosuppression at the time of discharge from their transplant hospitalization. And that top line, the dark blue is basically uh triple immunosuppression, TA, MMF steroid. The lighter blue is those who are on steroid-free, and then less than 10, 10% are on other therapies. But that is a completely flat curve. Nothing has changed really in terms of the most common regimens, you know, provided to our patients, and I think speaks to a need to change. And when we look at our current immunosuppression packages uh for our patients at Boston Children's, um, we think about them, you know, I have to say we have packages, we have options, but they're relatively limited. So for those kids who we call a low immunologic risk, those who are first transplant, not sensitized, we offer steroid-free under the, under, um, induction with Capa oralamtuzumab. So this is lympho-depleting. So we'll offer steroid-free if we lymphodeplete you upfront. And then you end up on tacrolimus, MMF if you're deceased on a kidney transplant. Um, for those who have a living donor that comes from a parent, so they're a haplotype match, lower risk for rejection, you'll actually, your steroid-free basis will be rapamycin and MMF. Now you might say, well, what's up with rapamycin? So the benefit of rapamycin is clearly a softer immunosuppression. And so if you apply to everybody, you're gonna have higher rejection rates, and that's been certainly, you know, proven true in, in the, in the literature. Um, but if you can tolerate it, it's less immunosuppressing, um, lower risk for viremias, lower risk for cancers, right, down the road, and our patients have a god awful risk of cancer throughout their lifetime, not even just PTLD as children, but other cancer risks, particularly skin cancer, is just through the roof. Um, so we rapamycin. Echo. There we go. Um, so that's why. For the high logic risk, second transplant rejected in the past, a lot of antibodies, you are now gonna be on alumtumab and triple. Um, and then we have a couple of disease-specific packages, FSGS, um, with the recurrence, we have these specific packages. But what I wanna say is if you look at the lion's share of our population, this low immunologic risk, we basically have one package, we apply it to everybody. This does not at all meet the biologic variability of our patients, the recipient, the donor dyad, it just simply doesn't. So when we apply this to everybody, some people will do beautifully, some people will have god awful rejection, and some people will have horrible infections and cancer, right? So we're doing the same thing for everybody with huge variation in outcome. A good number of kids will do just fine, but we have the kids on the ends, rejection and then over immunosuppression with infection and cancer. So it just really, it just shows you that, you know, we need, things just need to change. Um, and when we look at rejection, the high risks for donor-specific antibody, like I said, this is directed at the recipient HLA, sorry, the donor HLA, and it's a really a critical biomarker for the risk of rejection, in particular antibody media rejection. And the biggest problems, HLA come in class 1 and class 2. It's the class 2 donor-specific antibody that's the biggest issue. In terms of early and late rejection, as I mentioned, I showed that graph, right? So a lot of, you know, kids will get early rejection within the first year, but I'll be honest, it's more often T-cell mediated rejection. That is a rejection type that we can treat well, right? You can usually just turn around and stop cellul rejection, and that's the most common in the first year. After the first year, the most common type is antibody media rejection, and that is an absolute beast, right? I have to say, very rarely do we make that go away. And if we think we made it go away, it's just because we happen to biopsy on that day when things were quiet. They, to make people stop making antibodies is really challenging, and we throw everything at them. Rituximab, IVIG, we used to use um bortizumab, tocilizumab, uh, now we're gonna use daratumumab. I mean, this is really kind of people just trying to, to control this, right? But once the, I hate to say it, once the cat's out of the bag, it's out. So when we think about immunosuppression protocols, what we're really hopeful is that we can optimize the care upfront to reduce the development of donor-specific antibody cause once it's out, it's a pain. And what I have to say, those slow curves of kind of like rejection and allograft loss, it's, it's primarily allograft, um, AMR one, right? So, chronic antibody mean rejection events, and I hate to say it, we're on cyclosporin or tacrolimus, right, which are nephrotoxic, but these have been the cornerstone of our care because that's why acute rejection rates went down so well over time, was the introduction of, of calcineurin inhibitor therapy. So TA is a great med, reduces rejection, butt certainly causes kidney damage. This is just looking at donor-specific antibody in an adult cohort of about 1000 adults in uh in Paris and looking at allograft outcome just based upon whether you have DSA or you don't have DSA. And you can look at allograft survival at 7 years. It's quite high for the DSA negative cohort, but for the DSA positive cohort, you know, much different. And some people with DSA will not get rejection. Some people with DSA, you biopsy them, their kitty looks completely bland. Those people are probably going to look like DSA negative patients for the long term. But for the kids that are DSA positive and you biopsy them, you have rejection, you're in big trouble. DSA positive, but you don't meet criteria for rejection cause there's all this criteria you have to meet. Um, but even if you have a little bit of microinflammation, a little bit of glomerulitis, a little bit of pertubular capillariti, you are likely not to have a great outcome. You are gonna have an effect on your kidney from this DSA. And then they did a study looking at these DSA positive rejection negative patients, and they certainly had transcripts of rejection active. So there's, there's ongoing damage despite having overt rejection. So among pediatric patients, this looked at the European cohort of about 340 recipients in Europe who are on standard, standard triple immunosuppressions. They're on steroids. Um, and you can look at this formation of donor-specific antibody over time. There's no way you can look at that, but the red line is the development of class 1/5 years, and the blue line is the development of class two, the more problematic one. And basically, DSA developed at greater than 10% at 1 year and greater than 30% at 5 years and probably to the tune of 40% cause many kids will have both. This cohort had 12.5% developed AMR within the five-year cohort. They found that class 1 was not associated with AMR, but if you had class 2 DSA, this was a 4 times increased risk or nearly 4 times increased risk for AMR. If you had class 1 and class 2, it's nearly a 5 times risk for AMR. And as I mentioned, AMR is a complete problem with respect to long-term allograft function. For the kids that lose their kidneys to AMR and rejection and antibodies. If you look at them, if they're what they're called highly sensitized. So, unfortunately, when kids have a kidney transplant and they make antibodies, you kind of wish they would just make it to that specific donor, right? They would just do that person. Unfortunately, they do not. They do general sensitizations. They make antibodies to the community. Community at large. And we'll have some kids that after a single transplant, will be greater than 99% sensitized, meaning that if they go on the deceased donor list, less than 1% of people will be a reasonable immunologic match for them. And you can imagine how long they will wait. And so the system has for donation has give recognition to those highly sensitized patients, giving them priority across the country, because they're a really hard group to, um, transplant. Furthermore, You're that highly sensitized, we're gonna hit you hard for your second transplant. You're gonna get aamtuzumab, triple immunosuppression, now you're gonna be at higher risk for infection and down the road cancer. So really this like donor-specific antibody, HLA is a real, real problem for the current graft and for your future grafts and future life. Like I said, we need something better, right? So I'm not sure what I'm gonna talk right now is actually better, but it looks promising. But I'll also admit that this isn't the only thing we need. We need other things down the road as well. So Belata, I'm not sure if anyone's, you know, familiar with Belata, but just to say, if you think about um the way that, you know, um, your immune system would recognize an allograft or a donor kidney, it's basically this, this, you know, communication between what's called angiogen-presenting cells and the T cell to act. Activated, right? And so when we think about, um, this activation, the classics is signal one. So basically, you've got your allo antigen sitting on a, a, um, what's called an MHC molecule. It communicates with the T cell and says, T cell, go, start proliferating, make cytokines, you know, make antibodies, right? But there's other signals, signals that will, will enhance that proliferation, enhance that T cell response, and other signals that will dampen it. And what belatacept is, is basically a co-stimulatory blockade. It is gonna block this positive signal that says go, proliferate, make cytokines, make antibodies. Um, so it inhibits T cell activation, proliferation, and cytokine production. Without the nephrotoxic effect of calcineurin inhibitors. And the way belade is used, kind of in transplant biology, it really is to replace CNI, to replace tacrolimus. And in adult studies, um, it lowers DSA rates and better maintain GFR, which is really exciting. So this is just to touch base on this landmark adult study. It was called the Benefits trial. It was um maintenance belato versus maintenance cyclosporin. And so, these adults randomized nearly 700, they got basilixumab induction, which is not lymphodepleting. Everyone got, you know, CellCept and steroids, and you either got cyclosporine or belato. And the Blato dosing was basically two regimens, a more intensive regimen and a lower intensive regimen. Uh, and what I meant by more intensive, you just got a higher dose, more frequently than the lower intensive regimen, cause they weren't, they were trying to figure out what is the ideal Belata regimen. Really great study. And so from this study, you know, there was a 43% reduction in the risk of death or graft loss at 7 years favoring Belata over cyclosporine, right? So that was, and this is again, adults. And I'd say it's adults kind of prime adults. So they had living donors, kind of younger adults, typically less than 55 with high-quality deceased donor um grafts. This is actually, you know, what this, this graph is incredibly important. So, though, you know, you saw the 43% reduction in graph loss and death, um, but this looked at the EGFR between the two groups. And that top line, the orange and the blue is the outcome of the two Belataros, the high intensity and the lower intensity. And the GFR actually didn't decline over those seven years. It actually maybe went up a little bit, like by 0.2 mLs per year, right? And the lower graph reflects the cyclosporin EGFR outcome, so a reduction in kidney function over time to the tune of about 2 mL per year. So that was an incredibly important thing. And again, I'm mostly obsessed with donor-specific antibody cause I hate them so much, de novo donor-specific antibody. And you'd look, this is the, um, the development of uh de novo donor-specific antibody at 7 years was 11.8% in the cyclosporin group and 3% in the low-intensity group, a remarkable reduction in donor-specific antibody. Production. And also, this slide, when I saw the study, it made me so angry. So, if you may not remember, when I first discussed the donor-specific antibody in children, we get about like 4, 10 to 14% at one year. They're getting 11% at 7 years. We get like 30 to 50% at 5 years, truly. Adults make donor-specific antibody less, and I think it's because kids' immune systems are Just ready to go. We have, they have much, you know, more competent immune system. And for older people in transplant adult medicine, they soften their immunosuppression because they are easily over immunosuppressed. I think adults just simply make donor-specific antibody less than pediatrics do. So, it's a real pediatric problem, donor-specific antibody with respect to graft longevity, sensitization, and kind of damning them for their future, future course. So, the problem with the benefit study though was, it was a great study, right? So a lot of good stuff. You have to say, well, what's the bad stuff? So they, it's certainly, Belatacept in the context of MMF and steroids had a higher incidence of acute rejection within the first year, in the tune of 22%, 17% versus 7% in cyclosporine. Between the low intensity and cyclosporine, it was not deemed, um, it didn't meet uh non-inferiority. So, you know, that seemed to be OK, but still higher risk of rejection. But if you looked at the group, um, they actually had maintained. The Bella kids who got rejection, like the Bella adults who got rejection still had better GFR than the cyclosporin group, and that was really important, and that's well recognized. Higher risk for acute rejection under this protocol, but you still have better renal function when it was down the road. Another very important thing in the study because people didn't know, is, uh, there was a high risk for, for PTLD and unfortunately, CNS PTLD restricted to those who are EBB naive going into transplant. So for this drug, you have to be EBB um serum positive. You have to have had EBV in your life and made an immune response to control it after you're transplanted. Now, in pediatrics, that is a challenge for us because a good number of our children, particularly our young children, remain EBV naive, so they can't use this drug, basically, many, and that's now a black box warning. The adults, they were also looking at conversion. So this, this, the benefit trial was looking at um Belata at the time of transplant. Um, they then started looking at conversion, right? So, what if you were on cyclosporin tacrolimus, but they did a biopsy and you look like you had a lot of nephrotoxicity from your tacrolimus or other reasons you're not tolerating it, they would convert them to belitas. CellCep steroids. So, there's a lot of success doing that. Um, and this, again, it's hard for you to read, but the, the red line is basically the converted to belitaep. The blue line is, uh, maintained on calcineurin inhibitors in their GFRs over time, favoring Belatacept. And again, belata conversion had lower DSA though did have higher proteinuria. So in terms of pediatric experience, you say, well, who would want to use Belatai, right? Um, one, you can't use it unless you're EBV positive. But there's a lot of kids who could benefit. So the kids who do a biopsy and their graft looks terrible, there's no, in fact, no rejection. It just looks like they could see an eye toxicity. Um, what about the kids who don't take their meds or come into clinic and their levels are always low. They haven't developed rejection yet, but you know they will. So Belatacept is a monthly infusion. I didn't say that. So, you know, Belata, you give eye. IV monthly. So, there's a downside of that. You have to come to the hospital monthly, but you are not required to take pills, right? And so, you can couple Belata with, with lower pill burden. It'll improve their, their compliance and improve their long-term outcomes. That's why people are really interested, and we're hoping less DSA, which really, uh, impairs our kids' long-term outcome. So the PI experience really just started with conversion, like the adult conversion, and the studies look actually quite good. Again, some acute rejection, cellular rejection early on, but again, not much for AMR, the antibody rejection. And then there was another study looking at the tailored use of beta adolescent kidney transplant out of Duke with uh Eileen Chambers. And this is actually a de novo use in pediatrics. It was only reported of 3 kids, right? Um, aletuzumab, Bella, and ultimately rapamycin. For two of them. Another one was a lupus patient, so she got a different protocol. But this was, uh, Eileen Chambers is at um Duke and works closely with um Alan Kirk, who's a very well-known, um, transplant surgeon, does a lot of immunobiology, uh, pretty active guy in research, um, pretty amazing. And so, Looking at options otherwise. So Bella, the Benets trial was one, but Alan Kirk, uh, looked at a new CNI-free and steroid-free protocol. Um, it was aamtuzumab, which is again a lymphodepletion, Belatas, and ultimately rapamycin. And again, you might say, Why rapamycin. Again, it's not nephrotoxic. Rappamycin may also be somewhat proallergenic. And what I mean by that is if you, if you lymphodeplete them and let the cells come back under rapamycin, they may develop a tolerant profile, meaning the immune system is kind of OK with the kidney, which is pretty amazing. Not perfectly amazing, but you still have to take immunosuppression, but it favors it. CNIs really don't have that tolergenic, uh, effect. And so we looked at renal transplantation using Bella without steroids or calcin inhibitors. Outcomes were quite good. And those early rejections, uh, under the benefit trial with CellCept and steroids is because they had this population of effector cells that were co-stimulatory blockade resistant and under rapamycin, these didn't expand, which is really exciting. And then the outcomes for this trial were long-term outcomes for 106 adults. Graft survival in the adults was 97% at 5 years. They had a well-maintained GFR. Their GFR didn't decline, kind of like in the benefit trial. Acute rejection rate in the first year was 6.6%. That compares that 17 to 22%. I talked about that, 1st, 1st benefit trial. Belatapa was well-tolerated, but I have to say the downside is errolimus is a great drug, but not always super well-tolerated. Oral ulcers, you know, in about 30% of the patients and protein are in about 10% of the patients. So again, this is not the, the, the package that can fit all, um, but for those that they tolerate it, it's a, it's a really great package. Um, so, Eileen Chambers, who's at Duke, who works with Alan, um, Kirk, basically, um, With David Briscoe. So people here probably know David Briscoe, who's basically uh immunobiology researcher here at Children's. Um, he's a PTC, uh, research director, um, came up with a protocol kind of matching Alan Kirk's protocol for adults. So basically, lympho depletion, RAPPA, and bell belatassa. So, um, so this is actually the Advancing Transplantation Outcomes in Children Advantage Study. It's an NIH sponsored study. Uh, David Briscoe is the principal investigator. Eileen Chair, uh, sorry, Eileen Chambers is the protocol chair and I'm one of the clinical co-chairs. And so we're the main site here at Boston, uh, at Boston Children's Hospital. There's 20 other sites. So it's, uh, uh, including trying to get one site in Canada. And not to belabor the protocol cause I think just to say we're hoping to get 100 patients in each arm. So it's gonna be a randomized, uh, controlled trial. It is a randomized controlled trial. Um, we're unlikely to get, I say, I hate to say it, 100 in each arm cause enrolling children in trials is challenging, I have to say. Um, the standard of care arm is kind of like a, a typical thymoglobin induction, ultimately be on MMF and CellCept and steroid-free. These are low immunologic risk patients. The trial arm is gonna be ultimately be on Belatas and rapamycin for the long-term. And again, these patients have to be EBV positive coming in and can't have diseases that are gonna recur. In terms of the primary endpoints, we're looking to see if de novo use of Bella, so Bella at the beginning, not conversion, Bella at the outset, um, versus the standard of care of tacrolimus and MMF will prevent the development of de novo DSA which we all, uh, really would like. Or maintain uh optimum graft function. It's a combined endpoint. So, we're looking at the incident of de novo DSA at 1 year, and who has a, who has a greater incidence of decline in GFR by greater than 7.5 mills per million for 1.73 years is 2 years. We're looking at outcomes of DSA production and GFR. How do they compare? Secondary objectives to make sure this is safe, right? You know, just look, you have to look at PTLD rates, infection rates, rejection rates. So, this is gonna be extremely important. Um, and what I'd have to say, which is exciting to maybe help fill in some of the gaps of our monitoring, there's a ton of exploratory objectives. So, the study has basically two parts. It has a clinical outcome part, all the stuff that I see in clinic, your function, your numbers, your biopsies, your creatinines, how do you do over time. This is paired with an enormous number of mechanistic studies, so partnering with labs across the country to look at these exploratory, um, outcomes, looking at urinary biomarkers and do they predict how well a graft is doing, um, in relation to, these are potentially urinary biomarkers that could give us a signal before someone gets a rejection, before someone. gets, um, a donor-specific antibody. And I'll be honest, it's probably more likely they just may provide really good, what's called negative predictive value, meaning that your graft is OK, and that those are the people that maybe over time we can pull back their immunosuppression, reducing their risk for future, uh, cancer and infection, but maintaining graft integrity. Um, they're also looking at, you know, in, in the, our biopsy samples, you know, intrograph transcriptomes to get the kind of like the phenotype and to phenotype the cells. Are the, are the cells leaning towards more of a regulatory pattern or a tolerance pattern in the bella, Bella arm? So there's gonna be a lot of really great signs that's gonna be associated with the clinical outcomes. The study is currently enrolling. Um, so what I wanted to take like 2 seconds for cause it's 7:150, I have to stop talking soon is, and I won't spend too much time because I talk about one protocol and I have to say, it's been kind of discouraging over the years that things weren't changing so much, but I have to, when you go to the, the the ATC or the WTC really feel like there's kind of this groundswell now. A lot of people are using these biologics to see if we can um kind of tilt the immune system to a more tolerant protocol, like I, sorry, tolerant kind of phenotype. And not to belabor this, you know, the Beltasi uh co-stimulant pathway is one co-stimulant pathway. There are others and people are looking at other antibodies to block that to see if, um, that will have a favorable outcome. There's other things that will, will basically promote kind of regulatory cells, so T cells that say, hey, don't touch that graph. That's adoptive regulatory cell therapy. That's still pretty early, but that would be great and I think there's gonna be CAR T cell for regulatory therapy, which would be amazing. And then over time, people have been trying for quite a while looking at mixed chimerism protocols, which basically you take, you're gonna have your living donor, right? You take some of their stem cells or bone, bone marrow cells to see if you can, you know, promote tolerance of this graft. The problem with that is the, the, you know, the preparatory reg. is kind of a little bit hard on the recipient, so they're trying to refine that protocol to see if you can really uh basically get someone who has a little bit of bone marrow, treated a certain way, can get the kidney from the same person and be tolerant to that kidney and have really minimized immunosuppression without rejection. So you're gonna have a long-standing graft function without all the risks of um rejection medicines. So in summary, pediatric kidney transplant is highly successful and it's a therapy of choice for NCH kidney disease. I talked about all this negative stuff, but I want to say this is what we want for our kids cause dialysis is, is really difficult. Outcomes have improved substantially, particularly with respect to early rejection. Rejection in the first year, cellular rejection, right? But we can treat cellular rejection pretty well. Improving long-term function remains a central goal. De novo DSA and antibody media rejection remain a significant barrier to improving the longer-term outcomes, to move that, that slope, to push it up, which is particularly relevant, I think, for children who get donor-specific antibody far more frequently than our adult recipients. And CNI-free protocols which spare nephrotoxicity and regimens that promote tolerance are under investigation. And I don't want to say, here's the crew. Some of you are actually in this picture, I believe. So this is, um, I have to say, you know, working in this division has been absolutely amazing. Uh, it is, I think, uh, uh, uh, an incredible example of multidisciplinary care. Uh, so this includes people, our floor nurses, floor staff. We have our surgical team that's there, um, and if you. Look at the surgeons. I want to say this, there's the good Doctor Lilihi, HB, and Eliz in bright green. And yes, there was an email telling us what to wear on this day, and I did not send that email, but we all paid attention to the email because people were threatening us for this picture. This is actually a picture that was taken at the time. We did 1000 transplants at Boston Childrens, 1000 kidney transplants at Boston Children's. But if you notice there's one surgeon missing, who's missing? Alex Wenker, where are you? He was in the OR. He was working. He was doing operations, so he couldn't be in the picture, but there he is with a funny hat that says, is there any imaging I have to look at now or something like that for the liver team. Um, but truly, this, this team is basically, you know, social workers, dietitians, the nurse practitioner team from our outpatient team, they keep our program going, right? I hate to say it, when, before a kid goes to the end-stage program, if they're my primary clinic, I'm their doctor, they love me. I send them to this clinic, they almost forget me immediately. It's the nurse practitioners, uh, Joanne, Courtney, Fahima. They, they, they are the ones who are just amazing and supportive of this team, and I, we would just die without them. Um, our social workers and I died to, it's just the whole team. Not everyone's in this picture, but it's just an absolute, it's like a dream team, and clearly our surgeons are so talented, um, and responsive and, um, approachable. It's just absolutely insane. And then clearly there's no way I could do this presentation without acknowledging Bill Harmon, who is an absolute like giant of pediatric nephrology. He pushed forward the care of end-stage, kids died of, of end-stage renal disease when he first came along. And through his career, he optimized dialysis therapies for children. He optimized, you know, kidney transplant outcomes for children, and absolute beast for pediatric nephrology. So, thank you all. Nancy, that was terrific. Thank you for that, uh, whirlwind review and For um, Dumbing down a little bit for those of us who are immunologically challenged, or at least intellectually immunologically challenged, uh, uh, and, and, and for honoring Bill. Um, uh, our new, we moved our office suite and my desk is exactly where Bill's used to be, and I'm feeling adequate sitting there. Um, uh, and, uh, this is a webinar-style Zoom. There's lots of people on, and so, um, put questions in the chat. We actually don't have much time and I got one already by text. Um, There was so much excitement, which some of us saw about that curve dropping for acute rejection. And you express so much frustration with the slope of the curve and thereafter not changing in decades, uh, and you've hinted at some of the newer things coming along and mutations and, um, um, avoiding a second organ transplant, etc. um. I'm gonna ask you to speculate Um Do you think that with all of the genomic revolution, gene therapy, specific targeted therapy, prenatal diagnosis, Do you think that will improve immunosuppression, uh, in this new era, um. To, to flatten that curve. Before or after we prevent these diseases in the first place and put you out of business, uh, by prenatal diagnosis therapy. Absolutely. So what I'd love to be is put out of business. I'd love to have less to do, um, and I think what you mentioned is the gene therapies to affect diseases so people don't get to renal failure. Like we said, eccolizumab and, you know, the SIIRNA inhibitors. So basically, they're going to prevent disease. When you talk about genetics, you're absolutely correct because understanding the genetic underpinning of any disease is potentially going to promote therapeutics that will reduce or retard progression of chronic kidney disease. And even the study and the advantage study is going to be the look at genomics between recipient and donor, right? Can you learn something between the dyad that says, look, this, this, this couple specifically needs a lot more, this couple needs a lot less. So, that also will promote, I think, graph, you know, longevity as well as reducing risk. In terms of other stuff, I mean, you look at GLP-1, you know, agonists, SGL-2 inhibitors, these are things that we can provide to our kids upfront to have fewer people get across the line for needing a kidney transplant, um, and delay it for as long as they can because you want to delay it for as long as you can. But I certainly think the gene the genetic underpinning disease and the genetic, um, Underpinning of the immune response of the recipient, which may not really depend upon whomever they get. It might be more dependent on them, or the immunologic interaction between the recipient and the donor. When we understand that better, I think that certainly will promote long-term graft function, hopefully with less toxicity, because that's the problem. Again, it's a one size fits all package that get a lot of kids in trouble. Yeah, our goal should be to persons out of business. I wanna be out of business soon enough, uh, um, and then questions in the room, um, and while we're doing that, there is a question, um, I think the person who asked this question who was hungbe knows the answer to this, but, uh, thought it might be important for this crowd. I think I know the answer to this. Uh, why is it that the teens do worse than everybody else? All right, so, um, I have a bias. Because they tend to not take their medications as well, I, I think. Um, and I think that's a pretty, you know, it's a time with which they're, you know, they're developing their own autonomy. Um, they're being provided more personal independence and more personal responsibility. And you can imagine when there's a conflict between parent and child, it becomes a, a problem in terms of people being on their kid all the time and fighting about it all the time, and things can, you know, it's a, it's a, I think the primary underpinning truly is um um under immunosuppression. A quick question. Uh, first of all, a fantastic, uh, lecture. I learned a ton. Uh, we often see patients with hemolytic uremic syndrome as surgeons. Uh, should we send each of those to genetic testing and to whom should we send them? So you should, if, if it's a kidney, I, I would send them to us and then we will help facilitate that. But I think, you know, I, I'm embarrassed to admit, um, because you're, you might be more involved in the oncology. And more, more in the intestinal, you know, they can get, uh, uh, various complications, whose intestine we operate on them. Yeah, no, I think if someone has, you know, a concern for hemolytic uremic syndrome, you should send him to the nephrology group like Truly, like GN like true hemolytic uremic syndrome. Yeah, I think you should send them to us. So you can certainly send them to a geneticist, um, but we have in our, within our program in the last couple of years, we now have a renal genetics clinic. So it's a, a nephrologist who does genetic disease, genetic research, um, and if he thinks there needs to be written that kind of shuttled to a more broader genetic evaluation, they will, but I would really do that, um, to understand like the underpinning. And do they get compliment blockade or what do they do? Who knows? Well, you, you're way beyond, uh, our pay level here. No, no, no, please. All I can say is you guys could do what I do. I could never actually do what you do, right, in terms of, you know, the hand thing, whole hand stuff. I don't know. I, I walked once in with cash into an OR and I think I contaminated the, the, the entire scene within about 2 minutes of my arrival. He was very kindly and asked me to leave. I was like bumping into everything. It was just all bad, so. Yeah, I wanted to, um, thank you, um, follow up on that other question I think of Doctor Kim's like, have we, I mean, we know that teenagers don't take their medicines as well, but I suspect that just from anecdotally, I feel like we're probably also transplanting for slightly different indications at that time and have we delved into sort of the, the subgroup analysis of like outcomes for each specific and is it medication non-adherence? Do we think there's something a little bit different in the way that their immune system is? You know, I just think that's like a super, it's worse than I actually thought it was. So one thing I would say that clearly there's certain diseases that have a higher risk for recurrence, OK? So, um, FSGS recurs in kidney transplant. If it recurs in kidney transplant, those outcomes are, are more poor and that probably does locate into this kind of 12 to 17 year old group more commonly, OK? Um, recurrent disease like primary glomerular disease, probably, you know, kind of, kind of spans the whole age group. Um, in terms of them being immunologic different, the reason I brought this up is that if you look at the outcomes of, you know, I hate numbers on the screen, but, you know, this group, the 18 and 34 year olds, unfortunately also includes our guest. Includes some young adults, so young adults as well. So it's like young adults up until like 21, 22, 23, just screw up, right? I, and I shouldn't say that there's other things that are going on, but that's the only thing that makes sense for this curve that suddenly goes up when people mature and know what they're doing. So this, this kind of dip and up, I mean, I do think it does suggest a good deal of this has to do with executive function, acceptance, timing, um, but there certainly are, are diseases that are probably more often. In the, in the adult, sorry, in the adolescent cohort, right? But, um, so I, I, I shouldn't be so simplistic, but I do think one of the major factors which has been well studied is adherence. Adherence is challenging, and that's why Belatacept, a monthly infusion is, is kind of desirable for some. What are your thoughts on it? No, I mean, I think it's, I think it's like an interesting area for improvement. I'm like wondering if some of these studies that use Bella, where it's less onerous to have to take it every day or even like in varsis where you take it once a day instead of twice a day, may, may help. So, um, Eileen Chambers at Duke, who she's been using Bella for a while, and what she'll even say is some of her kids on Bella who screw up their single dose daily dose of RAPA, they'll have very low levels of RAPA, and they still maintain their graft, and then she'll yell at them and start taking a RAPA again. But it's not perfect, that's not gonna be true for everybody. Monotherapy for A Bella is probably only good for some and not all. Again, it's this biologic curve that we don't know who needs what, but it's, it's that hopefully will improve. And then the whole thing with Bella, there's been studied at WTC, can you go every 2 months, which would help things, but then again, you might want to check their labs. There's ultimately maybe a subcutaneous version of something like Bellatacci, right, which would be helpful for people not to come to infusions, but the nice thing about coming to infusions, we get to see you and say, what are you up to, you know, how's everything going, you know, that kind of stuff. So it'd be interesting to um. Uh, it's probably been done to know if that, uh, curve comes up faster for one, for males versus females and the other way around, um, just because executive function is not to faster than one thing, but I'm not gonna go there, um, but we've all had teens, um, I wanna thank you. We're, we're out of time. I, I particularly wanna make note of something that you sort of just glossed over. Um, Boston Children's is known for the greatest discovery science and pediatrics in the world. Uh, and known for the greatest innovative care. And care delivery, we haven't been known for doing clinical trials, uh, in the last decade or two people have jumped on and become a site for other people's clinical trials. There are not that many clinical trials that are initiated where the primary site is Boston Children's. That's a huge amount of work. Congrats for doing that. Uh, and more, more of us need to be looking towards that. Uh, I, on behalf of everybody, I wanna thank you for not only this presentation, but. Uh, the incredible leadership that you have given personally over decades to the end-stage renal program, to dialysis, and to the transplant program, uh, it has made a difference for so many hundreds of kids and, and, and, uh, their families, and us. So thank you very much.