Episode 33: ARPKD

Welcome to the Kidney Chronicles of Pediatric Nephrology Podcast. I'm one of your hosts, Emily Zangla, and I'm an attending pediatric nephrologist at Sanford in Sioux Falls, South Dakota. I am delighted to have three rotating co-hosts joining me. Vivian Chi, a third-year medicine pediatric fellow at Sanford University. I'm a health-heli-garrity assistant professor of pediatric nephrology at MUSC. Jason Mizorak, associate professor of pediatric nephrology, University of Iowa's stead family children's hospital. A disclaimer, this podcast is not intended to provide medical advice for patients. Our views are our own and do not reflect that of the institutions we work for. Any patient scenarios that come up are fictional. We are not providing any real patient information. Hello, this is Kelly. Emily and I had the opportunity of interviewing Dr. Lisa Gay Woodford, who is a professor of pediatric nephrology at the Children's Hospital of Philadelphia. She is a world-renowned expert on both AR-PKD and AD-PKD, and we were able to talk to her about her knowledge of AR-PKD. We sincerely enjoyed interviewing her, and I hope that you enjoy this episode as much as we enjoyed making it. I want to start by asking what prompted your interest in AR-PKD? So I think like a lot of physicians who choose a physician's scientist route, their origin story begins with a patient and a patient experience. And for me, going into residency, I already had experiences as a medical student that had pointed me towards an aprology. In fact, when I was an intern, the fellow at the time had been one of my residents when I was a medical student, and he was the renal fellow. A baby was born with AR-PKD from relatively modest means, didn't have a pediatrician, but the time she was ready to be discharged home. And so he asked if I would be willing to take her on in my resident clinic, and I said, "Oh, it's a great idea." And she had relatively reasonable kidney function. Her major issue was that her blood pressure was very tricky to control, so I worked very closely with him over series of months, seeing her pretty frequently, either in my primary care clinic or with him in the renal clinic. And then when she was about a year of age, I got a call from him, an urgent call to come to the emergency room. And that just didn't happen. It was very unusual. And so I went down and it turns out that this little girl, for reasons that we've never been able to sort out, had been with her mother shopping and had what we can best describe as a hypertensive crisis, with significant CNS injury, and was brought to the emergency room and ultimately died. And as a pediatric intern, having a patient die is a very traumatic event. This was a little girl who died with a disease that we knew so little about. And so when her mother asked what happened, I thought we were out of the woods, because she'd survived the newborn period. I was giving her all her medications, et cetera, et cetera. We had so little to offer in terms of understanding what her course had been. We didn't even know the gene that was involved. And that was a very sobering moment for me, dealing with these children who have these very severe clinical problems and not really having any insight into what is going on and what would be the best therapies for them. And so I asked forward to when I was a senior fellow, there was a little girl who had transferred her care from another institution and she became my patient. With that little girl, she had done very well for a year or so. And then she had an episode of Colanjitis. And it just started a downward spiral that impacted both her liver and her kidney, and she too died. And I remember very clearly being in the ICU with the family and the mom saying, "What happened? How could she have been doing so well for several years? And now both her kidneys and her liver have become very problematic." Again, the sort of the memory of the first child. And at that time, it was just at the sort of the early phases of gene cloning and gene identification. And we thought at that time that maybe as many as 50% of these children died in the newborn period. So there wasn't, it's a rare disease and there wasn't a lot, at least as we understood it at the time, a large cohort of children that we could apply these genetic tools to try to understand the gene. This was right about the time the cystic fibrosis gene was identified. And yet there was a very good mouse model that for all the world looked like the human disease. And the same guy that had been my fellow said to me, "You should think about using this mouse to identify the gene." And then you can use a series of strategies to then say, "The counterpart in human, maybe this is what's going on in this disease." And that's what sold me on what has been my professional career. That's really fascinating. And it also draws on so many of the questions I have for you today. It is just such a sobering experience when you see patients have really poor outcomes. And you realize there's so much we don't know. And just to do them justice, you want to be able to get answers so other families get to have better outcomes. And these families feel like something was done about their child's life. On that note, you'd mention genetic testing and initially not knowing the genes. Obviously at this point we do. Well, genetic testing is the gold standard for diagnosis. Not all patients do test positive on current testing. Can you help us understand why that? So I think the first point is that ARPKD has a number of look-alike disorders. We call them phenocopies. And they really, at least from the perspective of the kidney, look very much like ARPKD. And they also have variable degrees of liver involvement. And some of these genes like NPHP2 and NPHP3 are in a family of genes that cause nephronophysis. But these specific genes along with NPHP13 don't cause the classic form of nephronophysis. It actually causes an early form of disease where the cystic disease looks very much like ARPKD. And in particular with NPHP13, it can be very severe liver disease. But there are other mimics as well. And so for a child who is suspected in prenatal life of having ARPKD where the genetic testing is for, particularly for PKHD1 is not revealing, my interest is what other genes were looked at. So for example, there are children with mutations or variants in PKHD1 that can look like ARPKD. There are a very small number of children that can have two abnormal copies of PKHD1 and very much look like ARPKD. So what other genes were looked at would be my first approach. But in a study that we did almost 20 years ago where we had a cohort of children who had pathologic confirmation of their diagnosis of ARPKD, even then we only had a detection rate of about 82%. So I think there are other aspects of this disorder. You could say, well maybe there are other genes that cause ARPKD. And we have over the past several years identified two genes, DZIP1L and CYS1. CYS1 interestingly is the human counterpart of that mouse gene for that mouse model that I talked about. But they only account for a handful of patients. So what about the other 18%? One thing that we know from more recent genetic work is when we do genetic testing to a certain extent, it's like we're looking for keys at night under a street light. We look where we know to look. We look in the coding region. We look at the adjacent base pairs that are upstream or downstream that can affect splicing. We don't take a deep dive into the intronic sequence. We don't look extensively at the promoter region. There may be some cases that can be explained in PKHD1 related disease that are in those regions. That's the subject of of continued research. So the bottom line is there may be complexities in PKHD1 that we're just haven't sorted out yet, but even more importantly, I think it's these other genes that can cause disease that so closely mimics ARPKD. Did you help to find that gene in your mouse model, the PKHD1 gene? The PKHD1 gene actually was found by three groups. Two of the principal groups were the group at the Mayo Clinic led by Peter Harris and our collaborative group that included great Chimino, Steve, Somal, Clouc series and my group. Interestingly, the Mayo Clinic recognized that a rat model, the PCK rat, had a disease that looked like it was somewhere between ADPKD and ARPKD and they identified the region in the rat and they knew from comparative genomics that region in the rat corresponded to where we had linked the human PKHD1 gene. So they used a comparative genomics approach. We used a straight positional cloning approach. My group did clone the gene in the C.P.K. mouse and we actually have recently shown a couple of families that have children with an ARPKD-like disease that have mutations in the human counterpartal. I use the term mutation and variant interchangeably because most people recognize a disease causing change as a mutation but the current preferred descriptor is a variant, a pathogenic variant. Well, that's pretty cool that you took it from bedside to bench, kind of back to bedside. That is one of the things that I think is a unique experience for physician scientists. There are lots of fabulous PhD scientists but they are that much removed. There are lots of fantastic clinicians but they are that much removed from the lab. Living in the space between the two has the possibility of that kind of reward. Yeah, definitely. Some other questions based on the story you told us to start. I wanted to ask historically the infant mortality rates of ARPKD as a result of pulmonary complications have been pretty high. Do you feel like this rate has been improving this time? I think that first of all, what is the percentage of children who die in the newborn period and all sorts of numbers get floated around? And so, several years ago, we decided to take an EHR based approach to try to estimate the true incidence and prevalence of ARPKD. I was a children's national. We use CERNOR as our electronic health record. And so we use the CERNOR database and the U.S. National Statistics to estimate that the incidence of ARPKD is 1 in 26,500 live births. That corresponds really nicely to the estimate of 1 in 20,000 live births that cloud series put forward. And I start with the mortality because the understanding where that number is sort of gets to your question. I'm not sure that we accurately understood the mortality partly because we didn't have large numbers of patients. We had case series or small studies and people extrapolated from that. But when we did this EHR study, we determined that the mortality rate in our cohort was about 21%. Now, this was a study that really focused on patients between 2010 and 2014. Neonatology had gone through an incredible revolution prior to 2010. The development of all kinds of ventilatory mechanisms, ECMO, the development of surfactant, all of these different sorts of strategies. And I'm sure that if we're able to do the same study 20 years before the perinatal mortality might be higher. But the real bugaboo about ARPKD is there are some of these children who are born with critical pulmonary hypoplasia. We make a link between how much amniotic fluid they have and their chance for having critical pulmonary hypoplasia or reasonable lung development. But it is a very crude link. And we've published, others have published. There are children who have four weeks, no amniotic fluid. And they come out and need a little bit of oxygen. There are other kids who have moderate oligohydramneos who are impossible to ventilate. And so I think that there are a number of factors that go into lung development. There was that very famous study that was run out of Hopkins, where particularly families that had children with no kidneys were given serial infusions of saline. And I think from that study what we've learned, which we sort of knew at least hypothetically, is that the interplay between the kidney, which makes, in the latter part, a pregnancy, a majority of the amniotic fluid, the interplay between the kidney and the placenta and the lung in terms of the lung development is very complex, involves more than fluid, more than physical forces. And that's an area that I would really hope there would be more research down the road. And particularly in thinking about are there things that we could do for these cherbs prenatally that could help accelerate their lung development, because once they're born with critical pulmonary hypoplasia, our tools just are not, they're not effective enough to rescue them from this critical lack of development. I think a lot of us run into that issue with so many neonatal conditions. So hopefully whatever research continues to come out of that can help children with all sorts of cacket. Another thing you'd brought up in your initial stories is what led you into the field was some of the severe hypertension that can come with some of these patients. And I was just curious, what is the risk of hypertension as a whole with ARP Katie, what percentage are classically sought to develop hypertension? And can you discuss the pacifiziology behind hypertension and just how severe it can be in some ARP Katie patients? Because I think a lot of us see some of our ARP Katie patients that have their kidneys remain just very difficult to control hypertension. So the hypertension is fascinating. These children have a collecting ductulation. They don't have a glomerular lesion. To the best of our knowledge, they don't have a substantial vascular lesion. They have a collecting ductulation. And so one central player, and I think it's a multifaceted problem, but one central player in the hypertension is I think collecting that dysfunction. In fact, I think now there's pretty good evidence to support a hypothesis that was originally put forward by Bernard Kaplan when he was still working in the UK, that these children have hyponitremia and hypertension. And what links the two of them is that they cannot get rid of free water. So they dilute out their sodium and their total body fluid overload it. And his proposal, which we still use today, I'm sure Emily, you use it in your patient that you've just recently seen, is when we think about diuretics, we think about diuretics that are going to cause you to put out more water than salt, right? So we use lesics. I mean, the other diuretics are just not as effective. But I think that obviously it is more than just free water retention. And in the absence of understanding mechanisms, what we do understand are drugs that affect vascular tone. And so we use a whole variety of them. We use the ACE inhibitors, we use calcium channel blockers, we use direct vasodilators. And you're absolutely right. It can be very difficult to manage these children. Interestingly, it's difficult to manage these children when they have good or normal kidney function. As they lose their kidney function, the blood pressure becomes easier to control. Again, pointing to a central role to this collecting ductileism. Is it the hyponetremia? Can you think of it like an S.I.D.H.? Well, I think that the pathophysiology is different, but the consequence is the same. Kids with S.I.D.H. hold on to too much water. And they are sodium's plummet because sodium is a concentration. And I think in the immediate newborn period, when you see sodium's falling into the mid-20s, yes, to prevent the neurologic consequences that we do supplement these children with sodium. But I think it is something we got to keep in mind about, again, complex pathophysiology, but a central player is an inability to excrete, dilute urine, free water retention. And so as you're going through weeks and months of managing these children, because you may have seen this in your fellowship, I've certainly seen this in my practice. Kids coming to for consultation or various other kinds of referrals, they're on five or six anti-hypertensives and three millipuplets per kilo per day of sodium chloride. You're like, "No, wait a minute. Wait a minute." And I'm so very tempting. I think we just it's a good lesson for medicine and When we start an agent, we have to understand what mechanism are we trying to impact. And as we go down the course of time, is that mechanism still in play? And to just iteratively reconsider our medication regimens. I mean, in academic hospitals, this is part of the reason, I think, that we're required to, for kids that have prolonged hospitalizations, to rewrite orders from soup to nuts periodically. It's like, are you really sure that this is what you want? I'll give you a personal example. My mother had pancreatic cancer and spent a lot of time in the hospital. And this was ultimately for a variety of reasons in a community hospital. Worders were never rewritten. And she was on a number of, of thrombolytic or antithrombotic agents and getting vitamin K. And at different points, those agents made sense. But at a snapshot in time, it didn't. And so I use this as an example to say, with these kids in particular, we should be really asking ourselves, what mechanisms are we trying to address? Right? So if it's hyponatryming that is critical, we just want to get the serum sodium concentration up. If it is, we're trying to promote the excretion of a dilute urine, all that, the lasex makes sense. If we're trying to raise a dilate, because we don't really understand the mechanism, that this drug in combination, with this drug in combination, with this drug makes sense. And so really thinking through what we know and what we don't know, and iteratively reviewing our medication regimen, I think it's important in a lot of disorders. It's very important in controlling blood pressure in ARPIDI. I can definitely think of a number of different conditions where I've seen a lot of salt being given and just really high amounts of normal saline in just the other medications like the antibiotics, the patients being given and then people are so worried about why the blood pressures are so high. Right. Right. Right. Right. Right. And I think that's why as nephrologists, we tend to think mechanistically. And I think it's part of the fun of managing patients to think mechanistically, because when they move with how the mechanistic scenario is playing out, and you see a result. That is, that's gratifying for you. It's gratifying for the patient. It's gratifying for the family. Yeah. Um, what is your approach to neonatal hypertension because I know the RAS system plays a large part right in hypertension in these kids. But I know it's maybe not the best drug to use right away at birth just because of some nephrologist, maybe still going on. Yeah. So I'm not sure the RAS system plays a big role. I don't think there's a lot of evidence to say that's the case, right. We use ACE inhibitors because they are very effective vasodilators, right. And so let's just think about nephrologists for a minute. So nephrologist finishes at about 34 weeks or so. Most ARPKD babies, here's another conundrum we don't understand. Most ARPKD babies, uh, their pregnancy is going to spontaneous labor at about 34 weeks. So there's not a lot more nephrologist that's going to happen. Now, if an ARPKD baby is born prematurely, that's a different story. And I think that obviously this is very severe hypertension and partly what we use are agents that we can effectively and safely deliver intravenously to these babies, these very little babies, right. So let's pick on on beta blockers. People use propryndylol. They're always thinking it will help with the portal hypertension. For a newborn baby, propryndylol is an IV drug, right. But it's not the best in that class of drugs, not the most effective. And the portal hypertension is, if it's going to happen, is years down the road, right. So why wouldn't you think about agents like libatalol, for example, right, that give you more vasodilitation, a more sort of more powerful agent than propryndylol. And you can deal with those issues. That's kind of a problem for the doctor in the future, right, the patient in the future. So I think again, if you're confronted with severe hypertension, that's the challenge for you to address, not the other associated things that might happen down the road. Yeah, that makes sense. And I'm specifically avoiding Emily, you know, well, I start with it. We all start with ACE inhibitors, right. And then I add this and what you want to do is your, the mission is to control their blood pressure because blood pressure out of control has very untowards effects. I will reference the story I started with. And so you want to try to hit all the different receptors and mechanisms that we as nephrologists know how to do. Right. And that's in the absence of really understanding a mechanism aside from that collecting duct lesion. And that's what I do use, Lasix. Sure. Okay. That makes sense. I had some other questions about you earlier mentioning hepatic failure and some of the complications that go along with that as well as diagnosing it. And some of the steps that can occur is a result of biliary complications. Some patients with ARPKD experience renal failure before hepatic failure. And for others, it's the opposite. What is sought to be responsible for the significant variation and presentations, because I think as we all see it can vary quite a bit from one. So, so we don't have a precise answer. I think that what we do know is severe biliary complications is not a neonatal challenge. It's said down the road challenge, maybe in the first or second year of life, it can start to be a challenge, but it's a down the road challenge. So that's the first point. The second point is that the older literature said that there was an inverse correlation between severe renal disease. You had very mild hepatic disease and you could have hepatic disease and that usually was associated with various mild renal disease. That's much too simplistic a structure. We've all seen that clinically. I think perhaps one of the most revealing studies and exciting studies came out of the A-Rage PKD database effort that is European database based in Cologne, Germany. The preponderance of the patients, I think they're now about 800 patients in the cohort are from Germany or from Turkey, but they are other nationalities represented. And what they demonstrated, it's not the type of mutation in PK HD1, which we always think about, right? What's a miscensitum change? It'll get milder. Oh, it's a frame shift mutation. Oh, it's going to be very severe. Oh, it's a spicy mutation. Well, it kind of depends on what the spice product is. It's nothing to do with those types of variants. It has to do with the position of the variant. And what I want to bring up in this moment is PK HD1 encodes an enormous protein that passes once through the membrane and has a relatively short intracellular tail and a really exuberant end terminus that is extracellular. That end terminus undergoes regulated cleavage at the membrane. So can it act as a receptor, but the cleavage product also is ligand? We don't know the answers to that, but some clues may come from this genotype phenotype correlation. What Max Libo and his colleagues were able to demonstrate is that if a patient had two miscens variants in sort of the first third, not the initial, but sort of amino acids 700 to 1800. Remember, this is a 4000 amino acid protein. So in that kind of first third. So that's well into the extracellular domain. They tended to have a much more severe renal course. So what the obvious question is, what does that stretch of the genome encode in the protein and what do those domains in the protein do? There's work on that. We don't have an answer yet. Similarly, in the liver, it's different as you might imagine. There, it's if patients have miscenspiruses, I'm only talking about miscenspiruses here, right? Because that's what the analysis showed. Miscenspiruses in the last 40% of the gene, then those tended to have a higher rate of developing portal hypertension. So again, there is the transmembrane region and the intracellular region. How does that figure into the pathways that are operative in the collagia sites leading to portal hypertension, that are operative in the collecting duct leading to the secondary processes of inflammation and scarring that claim these kids kidneys. We don't know the answers to that. But these now are initial clues. And because they're different against to your question, Kelly, we see kids that have really bad. We see kids that have really bad renal complications and sometimes we see kids with both. And sometimes we see kids who skate by and relatively unscathed. They have kidney disease, they have liver disease, but it's not, you know, a sort of clinically dire. And some of the genetic information may provide part of the answer. I feel like I had always heard what you've described is just the kind of misconception that a lot of people have that the more severe renal presentation are going to have less severe liver and then deliver less severe renal, but I will say that I've seen patients where that didn't quite seem to play out. And here's another kicker. There are a small cohort of patients with PK HD one pathogenic variance in trains one from the mother one from the father who have virtually no kidney disease and only liver disease. That is so hard right to counsel parents when they come to see you for a prenatal evaluation, they want to know, okay, I, it looks like the baby may have this, the parents both have the gene on the carrier screen. And you're just like, I don't know and they're like, well, I have a good amount of amniotic fluid is and it's just so hard, right. Very hard. I think that what is really hard is to dance that fine line between giving information that you know is evidence based so you don't go overboard, you don't overstate the data. But you don't just throw up your hands and say we have no idea the weight of the evidence suggests that children with reasonable amniotic fluid levels tend to do better. There are exceptions, absolutely there are exceptions. Similarly, children who have no amniotic fluid appear to be at higher risk for critical pulmonary hypoplasia. But as I described to you before, there are kids that are the exception to the rule so you can give them the sort of statistical parameters. I think one of the things about prenatal counseling is if someone's coming to you for prenatal counseling, probably the kidneys on fetal ultrasound are abnormal. So these children who show up with biliary only disease, that's a presentation later in life. So I don't think that should confound what is going on. And the other thing to think about is that again, because the pace of kidney disease isn't, it seems to be faster than the pace of the congenital hepatic fibrosis and its evolution. And our children on particularly mid gestational ultrasounds and even at birth, who by ultrasound, now it's not the most sensitive test, but it is clinically the most available to us, have what look to be normal livers. And here is where it's important to counsel parents, ARPKD is a disease of the kidney and liver. The liver is a further down the road issue that we will have to set up a monitoring mechanism for. And so you could say, because I, you're smart women and I assume you're going to ask this question, well, how do we monitor? Remember, the lesion and ARPKD involves the colangia sites, the colangia sites are the only silia siliated epithelial cells in the liver have patocytes don't have a silia. And with a little bit we know about this protein, it localizes at least in part to the primary silly. So it must have some function there, right. So if we think about the colangia sites, they only make up about 5% of the liver mass. The best enzyme we have, it's not perfect, but the best enzymes that we have are elk floss, if you fractionate elk floss remember there are five fractions of elk floss only one comes from the biliary system. Yeah, that's not clinically available to most of us. The other reasonable marker is GGT, but the classic LFTs that we follow those are transaminases that are released by damaged hepatocytes and unless children have severe colangitis with subsequent bridging fibrosis that they're damaging the hepatocytes between the portal triad. Transaminases are usually very normal. Merl A. Anganan did a study at the NIH 78 patients with ARPKD exquisite deep phenotyping and she came up with a profile to monitor patients for liver disease that involved GGT and then markers of splenic dysfunction. So platelets and when she did her study PT now we use I and R. And so that's what I monitor in terms of laboratory tests. I also for children who are just about to begin school, I will either I'm now in a fortunate situation. I have a fantastic hepatologist as my partner, but in previous institutions where I did more of this myself before referring to hepatology. I would not only get an abdominal ultrasound to look at the liver, but I would get a Doppler flow studying to just establish the baseline. That's really helpful because I think a lot of people do just get LFTs and they keep coming back normal and the kid is just repeatedly getting these infections and they're like, no, can't be related to the bio ducts of LFTs are normal. You bring a really important point up so these bio ducts are normal for the visual that I give people is think about a bush in your yard. It has the seeds of branches right very close to the ground. That could be the ramifications of the portal venous system through the liver and then for those of us who like gardening, they are very often these weeds that are these beautiful vines that wind themselves around. The branches of the shrubbery in our yards, thousands of the bio ducts that beautiful elegant branch surrounded by this lattice work of bio ducts that will developmental program is disrupted in ARP KD. The branching of the portal vein is not as exuberant and the associated bio ducts of ARP KD and sometimes they're so chaotic that you can see them grossly dilated. The more dilated they are, the higher the risk for ascending collagenesis. It's a clearance issue in part, right? One of the things that is also interesting, we've seen this in our mouse models, we've seen this in human patients, is that sometimes children will get one episode of colonitis and they won't have the dilated bio ducts. Then you'll follow them up and you'll see this on subsequent scans. That's called corollic syndrome. Corollic syndrome is the association of hepatic fibrosis and dilation of the bio duct tools. And so now they're at even more risk because you asked the question, why do they get recurrent disease. I think in part it's because there is some change in these chaotic bio ducts that leads them to be dilated and thus more susceptible to ascending infection. That's helpful to hear because I definitely have had a patient that was coming in for repeated infections and I don't think I ever fully understood what about the bio ducts was leading to it. Another question I have is what would be an indication or if you ever do this, a unilateral nephrectomy. Yeah, so the nephrectomy story is very complex. So children with ARPKD, as I said, typically a board of 34 to 36 weeks. Many of us have experienced and none of us have gotten around to writing about it in a thoughtful, comprehensive way, which shame on us. These children somewhere around the first few weeks of life can undergo an explosive growth in their kidneys. And that can have all kinds of consequences. When clinicians see that their concern is we're not going to be able to ventilate this child, we're not going to be able to feed this child. So we'll take the kidneys out. We've got great dialysis, right? So again, this same group, ARPKD in Europe, did a very thoughtful analysis and it was very well controlled. Essentially what they came out as their assessment was that removing both kidneys in the first three months of life, these children had a much higher frequency of really severe neural eye complications. And of course, for us as nephrologists, we see that data, it makes perfect sense because they're hemodynamically unstable. Right? So I think there is not a sort of clear, so it's very clear to me when I get calls from an antitologist and we have this kid, we've seen this explosive growth. We want to take out the kidneys. You know, we just want to discuss it. I point them to this study because there is no good study that is of substantial size beyond a case series, small case series. Most of my case reports that say that you really improve ventilation by removing both kidneys. Now it's more complicated in terms of a single kidney because which one do you choose? If it's a nutrition issue, if it's a respiratory issue, what I say to folks when they ask about these situations is what I said about bilateral nephrectomy, certainly less than three months of age. In terms of unilateral nephrectomy, I hold myself in these conversations to the highest stringency. Are you absolutely sure there is nothing further that you can do for ventilatory support and you're going in the wrong direction? Are you absolutely sure there's nothing that you can do to feed this child more effectively in terms of the chloridensity of what you're trying to feed them, etc. You never in a clinical situation want to foreclose an option in an authoritative way when there are no data. But I ask people to think very carefully about what they're doing because the data that are there don't strongly suggest there's a benefit and there's clearly a downside. Yeah, definitely given the risk of end stage renal disease in these patients, it's just pushing them further along there. You know, I mean, but if someone makes the case to me, they are on high frequency ventilation and we don't have anything further to do in terms of our management. And we're afraid that we're going to lose this patient because of our inability to ventilate the properly and scaling up our ventilatory support, we're causing all kinds of damage, etc, etc. I mean, again, you don't want to foreclose their options in terms of what they may be able to do. Yeah, definitely that makes perfect sense. I know sometimes our neonatal colleagues have to focus on the lungs though. So it's nice to point them in a direction. And I think neonatologists are very experienced about pulmonary hypoplasia, right? And thinking about all the tricks and strategies to optimize lung function. And so I think that where we can help is to come with a really strong evidence base to say totally. We cannot find a substantial cohort where nephrectomy has been done and showed benefits. It's in the realm of case studies or case small case series small. I mean less than 10 less than five. And here is a study that looks at the issue of early nephrectomy and they did look at you and allow to affect me. It just wasn't as clear, but it's very clear if you take out both kidneys in children less than three months of age, they suffer severe neurologic complications. And as nephrologists, we don't even have to ask why we know it's because they're hemodynamically very unstable. And I think that's interesting to you or in the realm of the NICU how often is air PKD able to be detected on anatomy skins prenatally. Is it almost always seen or not. Yeah, so it's a great question. So AR PKD has, you know, that if you think about it, it is a very skewed distribution. But there's a long tail, right? And I personally have patients that were diagnosed at five years of age or even in adolescence. And I'm sure they're a hepatologist that have patients who were diagnosed in adolescence because they come with their primary clinical issue being their liver disease. And I think that it is hard to put a number in terms of the anatomic scans. So if anatomic scans are typically done at 20 weeks and with some practices, as I understand it, they follow it up like a 24 or 25 weeks. You would expect by that later date that you probably would pick up something that looked abnormal, whether it was kidney size or ecogenicity. But I think that there are kids that even to this day who are born with AR PKD and it is a surprise. There, I'm just a set of twins that I was recently consulted about that were born at 30 weeks gestation had respiratory issues, but 30 week twins, particularly if there's other issues in the pregnancy can have respiratory issues. And it was a physical exam done after birth that suggested, hmm, maybe the kidney seemed, I mean, I can really feel that led to an ultrasound that led to the diagnosis. Wow, and I mean, I'm sure with the twin pregnancy, they were getting more frequent ultrasound and the average pregnancy to so we got them 24 weeks as well. So I don't know the details of the prenatal monitoring, but I use this to illustrate that as smart as we've become with genetics and better fetal imaging. There are times we can be surprised so we should never be, you know, dismissive. Oh, if it wasn't picked up in the newborn period, it can't be a RPKD. I mean, as I'm in the fetal period, it can't be a RPKD. It can be. It can be at a year of age. It can be at five years of age. That's really helpful to now. So say you're seeing a patient and you suspect ARPKD, what kind of genetic testing should you send? I know you mentioned nephronopheosis can look similar to ARPKD. What other diseases should we? So a panel that includes PKHD1, PKD1, P2 and PHP3 and PHP13, HNF1B is a great mimicker, can look like ARPKD. And then there are some of the disorders that are typically associated with syndromes like Jubeir that can present looking like ARPKD. So I think so many of us as nephrologists, if we do genetic testing as an outpatient, use the NETERA panel, which is a very highly annotated panel. It's great. And it includes all the genes that I just mentioned. Okay. The issue that comes up in clinical practice for us as nephrologists is it is an annotated set of genes that are the most common single gene disorders in nephrology. So atypical HUS genes are on that panel and numbers of those genes are dominantly acting. So I have had the situation where you get the TARIS panel back, all the sister genes have been exonerated. And now I have a likely pathogenic variant in one of the HUS genes. I have a likely pathogenic variant in one of the system area genes. And you're like, well, I can follow that up, right? And so there's the genetic cons. There are targeted panels that assist to gene panels done by a number of different companies. You know, partly your practice is going to be dictated by insurance and approval, right? And so if you're interested in these disorders, I would cozy up to your local medical geneticist and sort of say, okay, when these kids come along, I want us to partner in how we're going to do this. I'm going to send the NETARA panel and NETARA makes it unbelievably easy for clinicians, right? Which is the beauty. And it's a set of 384, I believe, genes that are highly annotated. It's a great panel until you don't get the answer you're looking for and you get these unexpected variants that you got to track down. So maybe you and your geneticists say, listen, we only have two nephrologists. We have one medical geneticist. We don't have manpower. I will send the NETARA test and then we'll discuss what comes back and we'll decide on the follow. That might be a reasonable approach. If you are in a big medical center that has lots of medical geneticists, one thing to think about then is would targeted panels make more sense to -- and it's not just cutting down the cost, which is an important consideration, right? And if you don't care about the US, it's extremely expensive. It's the cost to the families. You know, we're going to do genetic testing. Most people don't understand doing a genetic test is not doing a BUN in creatinine. Right? So you do the genetic test and everybody's very hopeful, this is going to give us our answer. We'll just wait. And then you have to call them and say, the good news is, your child doesn't have defects in any of the cystic disease genes that we're thinking about. The not so good news is the child doesn't have any defects in the genes that we know about. And the really not so good news is we found these variants in other -- genes that we need to think about to be sure that these aren't disease causing in your channel. What a triple whammy for a family. Yeah. Yeah, definitely. I think partnering with a geneticist that deal with that a lot. Right. And you may know that the genetic counselors are, I mean, high demand and not every medical center has access to lots of genetic counselors. But medical genetic counselors, these people in this space can be very helpful. Yeah, totally. Well, you answered all my questions on my list. Kelly, what else do you have? I just have one last question and it's not related to any of the other prior topics. But I'd heard that these patients with air pkd often have high rates of UTIs and I was curious what would predispose them to the high risk? Is it just assists like urine gets caught in there and doesn't exit the kidney normally? Well, so, so let's think about it. The pathology is dilutation of the collecting duct. They're not true cysts, they're not cis like adp kd. Okay. So in that dilated space to get infected, you'd need stasis. But more importantly, you'd need bacteria to find a way from the bladder to the kidney. Now, we don't know that there's a higher risk of reflex, which would be the delivering the bacteria from the bladder to the kidney. It is really unclear what the mechanism is. But we actually reported this in our initial North American database study for ARP KD that 25% of the kids with ARP KD had experienced urinary tract infections. And I think when this has been looked at over the last 20 years, that maybe not exactly the percentage, but that higher frequency has continued to be observed. And the answer to your question is like a lot of questions with ARP KD. We don't understand the mechanism. Gotcha. So more research to be done for sounds like a number of years on ARP KD, but still good to get the answers we do currently have from someone that's was knowledgeable is you on the topic. Yes, thank you for your work. I always just reading a text box your name under this section or the cystic or genetic diseases. So thank you for your work because you clearly have led the path to make our jobs a little bit easier. I know again, we still don't have a lot of answers, but we do have a good amount now.