Session 2 - Primary Renal Dysplasia - FULL SHOW

Hi, good morning, everybody. Um, we're broadcasting from Cincinnati. Um, so, welcome back to our, uh, live webinar series. Today is, uh, session number 2, and we are focusing on, uh, renal dysplasia. We had a really successful and interactive, uh, first session back in April on, uh, obstructive neuropathy. There were a couple of uh questions that we did not. Um, have time to entertain. If we have time today, we may go back to some of those questions, um, came in, um, during the last session, but, um, this session is meant also to be, uh, interactive. Please post your, your questions, uh, on the chat section of the website and, uh, we plan to be here for the next 3.5 hours and currently, um, Again, we are in session two. So for those that um Um, not able to stay on for the entire, uh, 3 hours, um, certainly you can come back to the same, uh, platform because we do have viewable on-demand, uh, on this same link, uh, as you are logging on today, uh, or you may also share that later, uh, with your colleagues in case that they are not able to uh log on today as well. Um, we do have session number 3, in Uh, June and it's going to be on June 12th at the same time and the the session is going to focus on some new frontiers in fetal care, uh, especially when it comes to bilateral renal agenesis. So, um, the future session is also, uh, using the same link. Uh, all that you need to do is to register for, uh, session number 3, and you'll be, uh, there. So today we are going to focus on a few topics related to renal dysplasia, going from genetics to imaging, fetaltherapies available for this condition, neonatal care, surgical care, uh, including transplantation, and we'll save some time hopefully at the end also uh for question and answer. But like I said, feel free to interrupt and feel free to, uh, post your question uh as soon as you have one and we'll try to entertain that uh live. So we are very fortunate today to have um um several um Um, Really well known and well renowned uh speakers and I'm gonna share with you my, um, screen so that you can see who they are. Can you see my screen OK, everyone? OK. So, um, Today we have 66 speakers and um I also have my co-host, um, Doctor Stephanie Riddle, whom um will introduce herself, uh, shortly. And my name is Fong Lim. I'm one of the uh pediatric surgeons at Cincinnati Children and currently the surgical director for Fetal Care Center. And today, um, we are going to have 6 speakers, as I mentioned before, uh, Leandra. Marianna, Mira, Sammy, David, and Alex. Stephanie, you want to introduce yourself, um, quickly? Sure, my name is Stephanie Riddle. I'm a neonatologist here at Cincinnati Children's Hospital and I'm the neonatal director for the Cincinnati Children's Fetal Care Center. We're really happy to have everyone joining us this morning and hope we get a really nice um span of topics from fetal to neonatal to infant care for these patients. Alright, so, um, again for those that just joined, uh, this is session number 2 on renal dysplasia, uh, and the next session is gonna be in June, uh, talking about some new frontiers including bilateral renal agenesis. And these are the topics that we will go over today. And now we are going to let Leandra uh kick us off uh with genetic conditions um that can impact on the renal condition of these fetuses. Leandra is um one of our genetic counselors who have been with the fetal Care Center, um, for some time, and her focus is prenatal diagnosis and genetic, uh, abnormality, uh, affecting, you know, the fetuses and as well as in the perinatal period. Uh, Leandra, I will let you take over. OK, thanks so much. Let me get my screen sharing up. All right. So hopefully everybody can see my slides OK there and can hear me OK, but if not, please do let me know. Um, thanks everyone for joining us this morning to talk about this really interesting topic. And as Doctor Lim mentioned, I'm gonna be taking the 1st 30 or so minutes to talk about genetic diagnosis, um, in fetuses who have congenital anomalies of the kidney and urinary tract. So as I'm sure many of you know, um, there's many different types of examples of congenital anomalies of the kidney and urinary tract, and I certainly don't have time today to go into all of these specific examples and talk about their very specific genetic differential diagnosis. But there's also a lot of different genetic testing options out there, and they can all detect certain things and have their own utility. Um, so today, my goal really is to review with everybody, when you have a fetus who has KIT, when is genetic testing recommended, what genetic testing should be considered, and what are ways that genetic testing can help in the pregnancy, in the neonate, in the pediatric patient, um, and going forward from there. So to start off with some very basic and general guidelines for genetic testing. It can get very confusing and we're gonna get into the details of some of the tests that are out there. So to begin with some very just general guidelines that you can keep in mind, um, babies who have bilateral renal anomalies are More likely to have a genetic diagnosis than babies who have unilateral renal anomalies. And babies with non-isolated anomalies, meaning they have other organ systems affected, are also more likely to have genetic diagnoses than those with isolated renal anomalies. And when looking at all of the babies with cake, it's estimated currently that about 30% of them will have a pathogenic copy number variant or a monogenic disease, and on top another 15 or so% who will have a karyotype abnormality. That's a pretty significant portion of babies with cakiT who will have a genetic etiology. Um, I anticipate that this number is just gonna keep going up. So if you start quoting 30% as your risk of a genetic condition, um, I'm sure we'll be updating that in the near future as more and more genes and genetic conditions are discovered that are linked to CIT. And certainly, depending on the specific type of renal or bladder anomaly, um, the genetic diagnosis, differential diagnosis changes, and it's highest usually the chance of the highest of a genetic condition is highest usually in babies who have, um, cystic kidney disease. So that's, uh, babies who have two or more renal cysts and or increased cortical epigenicity are more likely to have a genetic etiology, with estimates that up to 70% of them may have a genetic condition. And again, when considering the general basics of genetics of the kidney and urinary tract, it is extremely important to remember that genetics is inherently a family business, and family history of cake is very, very common in babies and fetuses who have a congenital anomaly. Um, it's estimated that up to 50% of babies who have KIT will have a family member who also has, um, a congenital anomaly of the kidney or urinary tract, and that's kind of sometimes complicated because it's not always recognized, especially in parents. siblings, if they have a unilateral renal anomaly or something that's very mild, they might not have already been recognized to have that anomaly. And so it is strongly recommended that um renal ultrasounds are performed for first-degree relatives after a fetus is diagnosed with KIP. It's also really important to look beyond the kidney and urinary tract when you're talking about family history. There could be other clues in the family history that could give you a specific direction as far as what genetic conditions to consider. So for example, a baby who has a, um, or a family history of heart defects could be indicative of 22Q deletion syndrome. If there's a family history of hearing loss, particularly sensory neural hearing loss, that could be suggestive of brachiodor renal or BOR syndrome. Um, a family history of diabetes, especially early onset diabetes, could suggest a 17Q deletion, uh, that causes renal cysts and diabetes syndrome. This is certainly not a comprehensive list of everything you might see in a family history, but I hope that it helps illuminate how there are other non-kidney and urinary tract, um, anomalies or health problems that should be considered in family histories. So I'm sure everybody is wondering or wants to discuss, you know, what are the conditions that we're talking about here. When we're thinking about babies with kidney and urinary tract anomalies, what specific genetic conditions should we be considering? And this is obviously not a comprehensive list. There are Hundreds of them, um, but there are some general categories that are important to consider. So certainly, as with many babies who have any kind of congenital anomaly, aniploidy, duplications, deletions, and chromosomal etiologies are common. Um, but specifically to cake it, there are a number of monogenic diseases that are important. I know a lot of us often think about the polycystic kidney diseases, autosomal dominant and autosomal recessive polycystic kidney disease, but we should also be considering the nephronathesis disorders and ciliopathies, uh, multiple congenital. Anomaly syndromes, and finally this kind of emerging area incakiT genetics, which is genes that are associated with isolated caki. The list for this gene is just continually growing and growing and growing, um, and I anticipate we're just gonna find out more and more as the years go on. So hopefully that helps to start to answer the question, when is genetic testing recommended? The answer there is, in most babies with CAT, especially bilateral or non-isolated. And now we can move into the question of what genetic testing should we be discussing. And here on this slide, I've shown you an overview of the genetic testing options that are just really generally available in pregnancy, but they all really apply here to CIT Genetics, and we'll go in deeper detail to um all of these options. But first, I wanna put a plug in that it can get overwhelming, it can get confusing. Things don't always present straightforward, genetic, there's so many genetic testing options out there that you might not know where to start. So it's always a good idea to reach out to your friendly genetic counselors, geneticists, and lab representatives. Um, they're here to help. They have lots of good knowledge around these topics and can certainly help you, uh, with any questions or to talk through a challenging case. So to start out, I think it makes sense to begin with the consideration about whether all patients are really gonna be interested in diagnostic testing or not, and I think a lot of us know the answer to that is no. Some patients are gonna decline diagnostic testing, and so for those patients, what should we be considering? Um, generally, we should consider different types of parental testing options and self-free DNA screening options, both of which would be non-invasive. When considering parental screening, I kind of think of two general categories in this space. So there's carrier screening, that is certainly appropriate if you suspect a recessive condition in the fetus, typically autosomal recessive, but sometimes X-linked recessive, um, and ideally you'd have access to sample. from both biological parents from this testing. So for example, you might consider carrier screening in the parents of a fetus who has cystic kidneys and cerebellar anomalies, as these are suggestive of a pilliopathy, and you could do carrier screening for the ciliopathy conditions. The other broad category is diagnostic testing, but on the parents. So you may suspect a dominant condition in the fetus, and the parent has either suggestive features themselves or has a family history of features, and you would consider testing mom or dad, um, or one of the biological parents, in order to see if you can kind of elucidate what the fetus might also have. So for example, in a fetus who has kidney cysts, and for a parent who has maybe personal history of kidney cysts or a family history, you might consider autosomal dominant PKD testing on that parent, and if you find that variant, it's not diagnostic for the fetus, but you might be able to have a good assumption that that could be what's going on. Just diving into carrier screening a little bit more, um, there are lots of different carrier screening options that are available, especially with expanded carrier screening out there, and this slide is sort of meant to show you that it's a Good option, but it's not always a great option. So I compared a very large comprehensive carrier screen that had almost 300 genes on it to a large comprehensive kidney disease panel that has over 300 genes, and they only overlapped by 33 genes. Um, most of those genes are Genes that we would expect to present with pediatric or adult onset kidney disease. Um, and the genes that I would expect could present with congenital anomalies, there was only about 13 of them as they're listed here. So some of the celiopathy genes, um, Uh, multiple congenital anomalies syndrome, Smithloliopits, and some others. So carrier screening is certainly a valid consideration and choice for a family who's not interested in diagnostic testing, but it is really important to keep in mind the limitations of this testing and know that if it comes back negative and the parents are not carriers for the same condition, that does not rule out recessive condition because they're not all tested for, but it also certainly doesn't rule out chromosomal, um, and dominant disorders. The next non-invasive testing option to consider would be cell-free DNA screening. Uh, there are kind of generally three categories of this screening currently available, um, anniploidy screening, microdeletion and duplication screening, and single-gen screening. The annuploidy screening is currently what's broadly accepted by obstetrics and genetics professional societies. Um, whereas the others aren't quite there yet, but they do have their place, um, in consideration. So for the iploidy screening, really the main things, of course, you'd be looking at are trisomies 1318, and 21. Trisomy 18 is most strongly associated with renal anomalies, um, and, and bladder anomalies, but the other ones also have very high associations as well. Uh, the microdeletion and duplication screening could be useful, I think, especially for 2211.2 deletion syndrome, which has a high association with congenital anomalies of the kidney and urinary tract. Um, and there are a few other conditions that may be screened for on these microdeletion panels like 5P deletion syndrome, which is also known as Criduchas. Uh, 1P36 and deletion syndrome and 11Q deletion syndrome, which is known as Jacobson syndrome. These are less commonly associated with renal anomalies or um urinary tract anomalies, but they can be, so they could be potentially helpful. Um, it's also important to remember that they have a low prevalence in the general population, so when you do the math for positive predictive value, there's a higher chance of a false positive for these conditions compared to anyiploidy. And finally, there are some commercially available single gene cell-free DNA screens available, um, and when looking at the genes that are typically available on those, there are a few that can be associated with congenital anomalies of the kidney and urinary tract like CHD 7, which is associated with CHARGE syndrome, or JAG-1, which is associated with alligel syndrome, um, and the others listed here. So similar to carrier screening, um, could be helpful in a patient who is not considering invasive diagnostic testing, but also again, significantly limited in that they're only screening for a small number of conditions. So a negative result really doesn't rule anything out, but also a positive result needs to be confirmed because there is the possibility of a false positive. So moving on from there, we've considered the non-invasive options. So what should we be considering in parents who do want invasive diagnostic testing? Where should our starting point be? And I think in general, for most cases, your starting point will be chromosome level testing either through a karyotype or chromosomal microarray. In some cases, a targeted single gene, um, targeted familial testing or a small panel might actually be the best place to start, um, and we can go into these details in the next slides. But before we get there, um, I'm sure most of you have run into this problem. You have a patient who wants invasive diagnostic testing, but has, uh, anhydramnios related to their kidney or urinary tract anomaly. And so what do you do? You want, how do you get a diagnostic sample? Um, you do have a number of options. So if there is amniotic fluid, that is often but not always the easiest and best option to do diagnostic testing for. If there is no amniotic fluid or it's very low and you won't be able to obtain sufficient sample, um, you might consider sampling the chorionic villi. Uh, sometimes people refer to that as placental biopsy later in gestation instead of just calling it a CVS. Um, you might consider sampling fetal blood through a procedure like a pubs. Um, if there's a lower urinary tract obstruction, you might consider a bladder tap to obtain fetal urine. And if the baby has fluid accumulations elsewhere in the body like a large cystic fibroma, ascites, a pleural effusion, or a large cyst, um, you might be able to obtain fluid from those areas as well. But if there really is no fluid buildup either around the baby or in the baby, something to consider is an amnio infusion where fluid is infused around the baby and then subsequently taken out, um, when it has fetal cells in it to be used for genetic testing. Um, sometimes we also refer to this as an amnio wash. And so going back to one of my first tips in talking about genetic testing, which was reach out to your friendly lab representatives and staff when you have questions. That's exactly what I did here. I reached out to our prenatal cytogenetic techs in our own laboratory and asked them what their experience are with AUwash, what they wish that healthcare providers were obtaining these samples and ordering testing on these samples knew. Um, and their first request was to make sure you really clearly mark the sample type. If it is an amnio wash, an amnio infusion, put that on the tube, put that on the requisition form. They said they can usually tell by the appearance of the sample, but it's important because it changes how they set up the cells in culture, and so if they set it up incorrectly for the sample type, you might further delay your results, so that's really important. Um, the other thing was I always kind of anecdotally thought that we had a much higher failure rate for cell culture on these samples, so I asked them to pull our data, and I was actually surprised to see that by far most of the samples are successful in culture. There was a slightly higher risk compared to amniotic fluid, but it was not nearly as high as what I thought it was. Um, and so usually they're successful. The main difference really is that the culturing can take a lot longer, so you should expect a delayed turnaround time for your genetic tests. Regardless of what the lab's website says about turnaround time, it's probably gonna take longer for these samples cause we have to wait for them to culture, um, and you should counsel your patients accordingly to set their expectations correctly. On a similar note, the reason the cultures take longer is sometimes because there's not enough cells in the sample and they take longer to grow. Um, so for that reason, direct testing methods, which is where DNA is extracted directly from the fluid sample rather than being cultured, are usually not possible on these, um, tests. So again, that further delays the turnaround time. And finally, they mentioned to me that most of the samples they receive tend to either be tinged with maternal blood in the fluid or when they spin them down the cell pellets seem to have red cells in them. Um, so most of the samples seem to be contaminated by maternal blood, so it would be good practice to send maternal blood with all of your amnio wash samples, so that maternal cell contamination studies could be done. So now that you have your sample and you sent it to the lab and you need to order testing, where should you consider starting? Like I said, for most cases, you're gonna want to start at the chromosomal level. Um, it's estimated that about 13% of babies with KKT will have an abnormal karyotype, and that microwave can add about 4% to that diagnostic yield. Most common things we're looking at in the chromosomal space are things like, again, trisomy 1318, and 21, 22Q deletion and duplication syndrome, and 17Q deletion syndrome, which causes uh renal cysts and diabetes syndrome. But there are plenty of publications out there, plenty of case reports, plenty of reviews that talk about lots of other um copy number variants that can be seen in these babies. So this is not a comprehensive list, but these are kind of the big top 5 or 6, syndromes. And then like I said, sometimes you might actually be better off skipping the chromosome testing for the start and starting with either a targeted test, like a single gene, a variant, or a small panel. Certainly, if you have a known variant in the family, um, that's where you should start. This testing again, the cultures take longer, turnaround times are longer, and you have less sample usually to work with, so you should start where you know, and if you know that there's a family variant, that's the best place to start. Um, but otherwise, you might have a, a strong suspicion based on the fetus's presentation and or the family history that you should be looking for autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, or some other conditions. For example, again, a baby who presents with cystic kidneys and maybe polydactyle and a brain anomaly, you might actually be more concerned about a celiopathy, and it might make sense to start with a small celiopathy targeted panel rather than spending time on the microa at first. Again, this is where your geneticists and genetic counselors can be particularly helpful too, when it comes to interpreting the clinical data. Um, and I wanted to, before we move on from talking about single genes, throw in a couple of statistics about these genes, HNF1B and PAX2. Um, if you're like me, um, when I see a baby who has academic kidneys or cystic kidneys, often the very first thing I think of is autosomal recessive polycystic kidney disease. I order PKD PKHD1 testing, as well as PKD1 and 2 tests. Testing, um, but that actually might be missing a lot of our diagnoses. And so it's estimated that up to 15% of babies, especially with echogenic kidneys and cystic kidneys, could have pathogenic variants in HFF1B or PAC-2, which is a huge proportion. Um, and so we really would be doing a disservice to patients on the diagnostic odyssey if we weren't looking at these genes. All right. So we've talked about a number of options so far. And I think the last question we might have here at this point is, I've done diagnostic testing. We did the chromosomes, we did the microarray, maybe we did a targeted gene or two, and everything has come back non-diagnostic. What do we do next? And hopefully, you're not surprised by this since it's the last thing on the slide, but the next thing to think about would be a broad panel or exome sequencing. These are things that are not targeted to one very specific phenotype, but are really looking broadly at genes involved in the kidney and urinary tract. And when thinking about these panels, I think there's a few kind of reflections that we can have to think about why they can be useful. So first, is it really realistic that you're going to know all of the cakeki genes and all of their features? Remember I said there's hundreds of them, and be able to recognize them and say, hey, we should be testing for this one or 2 genes? Probably not, and I think that's OK. Is it really realistic that a fetus is gonna know the features of those conditions and present in a way that fits nicely in the box of one or two specific genes? Again, probably not. And even moving beyond panels, is it really realistic that the commercially available panels are always going to be up to date and contain all of the genes of interest? Um, usually not. The panels are updated frequently and regularly at labs, but not every day, and so if a new gene is discovered, it's likely it's not going to make it onto a panel for a little while. And even beyond these questions, if you do a micro exome, And we still don't find an answer. Do we expect that that's sufficient and that we've ruled out enough genetic conditions? I'd argue no, and that there's gonna be a space for genome sequencing probably in the very near future, um, regards to these things, the genome sequencing is already rolling out in the pediatric world, and I think it'll come to the prenatal world, not so distant future, so I think we'll be adding that to these slides very soon, um, but I won't be going into detail specifically on genome sequencing, although a lot of the exome-based considerations apply. So when talking about broad panels, what I mean there are, again, panels that are not targeted to cellulopathy or nephrosthesis or A very specific genetic condition, the BOR panel, for example. The broad panels are really looking at a number of genes that are involved in many different types of KCIT, so there's KIT panels out there, or even larger panels that are associated with all types of inherited kidney disorders. Um, these panels can be on the order of a couple 100 genes, and so there really are a broad approach to that testing. Exon sequencing obviously is even broader than that. We're not limiting ourselves to a specific panel. We're doing sequencing of all of the exons in a baby, and then our analysis on the lab side is targeted based on phenotype, inheritance pattern, familial data, all that kind of stuff. Um, and in preparing for this presentation, I pulled some of the larger cohorts of prenatal exome sequencing specifically to see what the yield is for fetuses who present with KIT, and of these, um, 6 papers that I reviewed, there was about a 15% diagnostic yield overall. Um, and similar to what I mentioned at the very beginning, the babies who had non-isolated renal and, um, urinary tract anomalies had higher diagnostic yields than those with isolated anomalies. And exon sequencing is really interesting in many ways because for many reasons, but two that I'll highlight here is that it allows us to have a better understanding of the phenotype of known monogenic disorders. So it's not uncommon that you order a prenatal exome and you get a result back of a known genetic condition that maybe didn't have a strong association with caut before, and your case might be the start of understanding what that prenatal onset renal phenotype could be or severe prenatal onset phenotype could be. Um, it also can help facilitate novel gene discovery again, because we're not limiting ourselves to a specific set of well-known genes. And so to wrap up this conversation about genetic testing, um, I will leave you on a note of caution. You should be aware of the limitations of the genetic tests you're ordering. There is no perfect genetic test. There is no genetic test that can rule out every genetic condition, and there's no genetic test that can diagnose every single type of genetic condition in one test. Maybe one day we'll get there with genome, but um we're not there yet, so it is important to know that whatever you ordered, it has limitations, and you should be aware of what those are. For example, does the test you order report variants of uncertain significance or not? This is particularly important for carrier screening and exome sequencing, since some of the labs who do that testing only report pathogenic and likely pathogenic variants, and so you Might be missing a VUS that's a key to your understanding for a fetus if um you order those tests. They, they certainly have their reasons for doing that, but it's important to know that that's the case so that you know if um you need to request VUSs from the lab, for example. They often will provide those upon request. Um, the other kind of area that I think is important to know about is deletion and duplication, not chromosomal deletions and duplications, but introgenic deletions and duplications, which I think are often forgotten. Um, not all tests evaluate for deletions and duplications, and even those that do are not all made equally. So a chromosomal microarray is really good at seeing copy number variants on a chromosomal level, and it may be able to detect deletions and duplications within a specific gene, but it really depends on the specific microarray you ordered and the specific resolution over that specific gene of interest. So if you have questions about that, reach out to the lab. Um, and even next-gen sequencing panels that market themselves as doing deletion duplication analysis, they do, um, but they're really best for changes that involve 4 or more axons. So a single exon up to 3 axon deletion or duplication may not be detected on those panels, and that's really important for some genes, especially things like H and F1B, where deletions are common. All right, and to wrap up all of this, hopefully to bring it all together before we take your questions, I wanna answer the final question, which is, why does all of this matter? How is genetic testing gonna be helpful? Um, I could probably have spent my entire time on this one slide alone, talking about all the ways that genetic testing can be helpful. We certainly don't have time for that. The point here is that, as you can see, there are numerous opportunities for clinical utility of genetic results, not just positive diagnostic results, but negative results also have their place in clinical utility. Um, and these span from the prenatal period to the neonatal period and beyond. They're informational, they have familial implications, all these are very important. Um, one specific note when considering this is not all of the genes that we know in KIT have um specific genotype phenotype correlations, meaning when you get a genetic diagnosis, it may not allow you to predict the severity of kidney disease that a baby is going to face. But it could give you a guideline as to other non-renal manifestations that you should be looking for. Um, for example, again, a baby with VOR syndrome, you should be doing hearing screening more frequently than a baby who does not have VOR syndrome because sensory neural hearing loss is associated with that. And to bring it all together and show you some of these in practice, I've put together a case example to end this presentation. Um, this isn't a prenatal case, so bear with me, but I think it's a very important case because it can highlight sort of in hindsight, what could have been different had we had an earlier diagnosis. But I think with some of our prenatal cases, we don't know what their outcome is gonna be, and so it can be hard to think forward to that clinical utility. Um, so this was a little girl who presented to the genetics clinic here at 4 years old, um, and she was seeing us because she had a prior genetic diagnosis of ARPKD, but the pathology was not consistent. All over her chart, it said genetic diagnosis of ARPKD, autosomal recessive polycystic kidney disease. But when she had a nephrectomy and they did pathology on the kidney, it was not suggestive of ARPKD. It lacked the classic cystic changes of ARPKD and instead the dominant lesion was um marked pathological changes in the vasculature. So they referred her over to us in our pediatric genetics clinic. Um, a little bit more about her history that we collected. prenatally, everything appeared fine until about 30 weeks when she was noted to have small and echogenic kidneys, and then at 32 weeks developed oligohydramias. In the neonatal period, she spent 2.5 months in the NICU. She was discharged and then the next day she was readmitted to the PICU and stayed there for 2 months. And then, um, she had been started on dialysis at 2 weeks of age and continued on dialysis until she received her renal transplant at 3 years and 10 months of age. Um, until then, she had multiple hospital admissions related to dialysis, blood pressure management, peritonitis, and otherwise she was relatively healthy, happy, developing on track. Her previous genetic test results are listed here, so she had a chromosomal microa that had a result that's normal for a typical female chromosomally female individual. Um, and then she had testing for PKHD1, that's the gene that causes ARPKD that showed a single heterozygous pathogenic variant, so more consistent with carrier status. A second allele, a second variant was not identified on the paternal allele, so she does not have a genetic diagnosis of ARPKD. Um, and she also had testing for the autosomal dominant genes, PKKD1 and PKD2, which identified two variants that were inherited, one from mom and one from dad, um, but they also didn't explain the phenotype. Dad's was just a straight-up variant of uncertain significance. Mom's was a modifier allele that can make the phenotype more severe in people who have other PKD variants, but isn't expected to cause disease on its own. Um, and both mom and dad had pretty large families with a number of siblings, and nobody in the family had any kind of kidney disease. The parents also were interested in this genetic testing and counseling discussion because they were thinking about having another baby and very concerned about recurrence risk, and they had been considering doing preimplantation, genetic diagnosis, and IVF, um, to conceive a baby without any of these variants. So we ordered a broad kidney panel. Lo and behold, we diagnosed a very different condition. So she had a heterozygous variant in the WT1 gene, um, that was pathogenic and had been previously described in multiple people with Denise-Drash syndrome. Denise Drash syndrome is a condition that causes a steroid-resistant nephrotic syndrome that leads to end-stage renal failure, so that explains her clinical course, but it also has a super, super, super high risk for Wilms tumor, up to 90% risk, and the median age of onset of Wilms tumor in these individuals is 15 to 19 months. Thankfully, this patient had already had a bilateral nephrectomy by this time. Um, but certainly had we known about this diagnosis in advance, she would have had aggressive bone tumor screening up until then, and who knows, potentially. Um, I'm not sure, you know, I'm not a nephrologist, not a urologist, but I'm not sure what her kidney management would have been different as far as transplant timing, for example. Um, also, Denise Drash is associated with a 46 XY disorder of sexual development, meaning that individuals with Denise Drash with 46 XY chromosomes can have a spectrum of disorder of sexual development, a difference in sexual development, including having completely normal female-appearing external genitalia. Um, these individuals also have a higher risk for gonadal cancers, so this kind of spurred a moment of anxiety for me because I was worried that we were gonna have to have a conversation with the parents about testing for chromosomal sex to make sure that if she had a risk for these gonadal cancers, that we would be identifying that. And then certainly, you know, if she had 46 XY chromosomes, we all know that chromosomes don't determine your gender. Necessarily, but that can then get into complicated social, emotional, and medical conversations as well. Um, fortunately, then I remembered she already had that microa that had XX chromosomes, so again, this wasn't an issue, but I hope that this sort of illuminates that there were some risks there that we were missing. What if she had developed bones tumor before we knew that this was a concern? What if she had 46 XY chromosomes and at 4 years old, we're having this conversation. What if her parents had done pre-implantation genetic testing for those other variants that we know now are not associated with her disease and have wasted all those time and money and all their resources into that testing that wasn't necessary. Um, this is typically a de novo disorder and so we weren't concerned about recurrence risk. Um. So again, I know it's not a prenatal case, but I hope that with some of that clinical course, we can highlight some of the things that could have been done differently had we known of that diagnosis earlier. And with that, um, I thank you all for listening and hope that this is helpful in considering the genetic diagnostic workup for these patients, and I am happy to take any questions that anybody might have. Actually, um, sorry, um, I just saw Alex posted your response. Uh, Alex, instead of, um, just posting that, you want to say what you just, uh, put in a chat box? Sure. Um, to your point, Leandra, as far as a prenatal diagnosis of Dennis Drash, if we've, in, in the past, we've had it both ways where we've had postnatal diagnosis of Dennis Drash, unfortunately, in the setting of the diagnosis of Wilm's tumor. And we've also had Dennis Drash diagnosed um prior to the development of a frank malignancy. And so in those scenarios that you're describing, um, once that baby reaches, you know, pretty, reaches end-stage kidney disease or stage 4 chronic kidney disease and, and dialysis is a renal replacement therapy is impending, um, at the time of peritoneal dialysis catheter placement, we typically will remove both kidneys prophylactically. Because the flip side of it is that, um, the flip side is that if you develop Wilms tumor, and you have to do um bilateral nephrectomies, then the patient has to demonstrate a period of time, usually at least 18 months of oncologic um stability before you can even be considered for transplantation. So there's an inherent delay, um, if you don't, if you have to deal with Wilm's tumor in infancy and then wait. Great, thanks for that. Yeah, so I think that just shows how lucky we got with this little girl. Um, she didn't have her nephrectomies until she was almost 4 years old. Um, so good, that all worked out. The results call the family was like, OK, there's some scary things, but luckily we're past all of that. We don't have to worry about those things. Now, but that could have been a really bad situation that was potentially avoidable had somebody, she had that ARPKD testing like in the neonatal period at a different hospital. Um, if somebody had said like, hey, this doesn't, this doesn't make any sense, we don't have the answer yet, let's order something more. Thanks, Leander, you always do such a beautiful job of providing clarity that it to a topic that in my opinion, has not always very much clarity, so that was wonderful. There was a question from the chat that I know is near and dear to your heart, um, about the topic of whether in Insurance and specifically Medicaid cover um kinds of genetic testing and also if you have an opinion about um which companies provide some of um these good genetic tests. Sure, yeah, um, so insurance. It's complicated. I'm sure you all know cause you're asking the question. Um, typically, the testing would be better covered in the pediatric period, although in my experience, um, It is generally well covered in the prenatal period as well, depending on what you're considering. So microA testing is widely accepted by insurance companies. The only times I've ever had that kind of testing be denied really is people who have insurance policies that just don't cover genetic testing of any kind, which are not common, but they come up. Um, targeted single gene testing is also or small, very small panels like ARPKD or PK, um, ADPKD testing is also generally pretty well covered. It's when you start getting into the broader panels and especially exome sequencing right now that um the insurance. Coverage is different, and there really is no hard and fast rule. I mean, I've had insurance companies who just outright deny those kinds of tests. I've had them who just outright approve them without any second question, and then I've had them where we've had to write letters and do peer to peers and all that kind of thing. So, um. My advice there is don't make any assumptions based on whatever insurance company your patient has listed on their card. There's a lot of nuances to their actual policy, so don't make any assumptions that it's just not gonna be covered, so you're not even gonna try. Do the pre-authorization if they have a commercial insurance. Um, provide letters, provide peer to calls, provide references, um, and when possible, really focus on specifics about medical management considerations that you might change. For example, if we've been doing, um, prenatal testing on this baby, if we had been psychic and had a magic eight ball, we could have said a baby presenting at 32 weeks with oligohydramnia. Small and ecogenic kidneys. We're worried this could be something like Dennis-Drash syndrome, in which case we would recommend a bilateral nephrectomy early in life to prevent the risk of Wilms tumor. I feel like an insurance company would listen to that kind of, I'm not saying that they definitely will approve it, but that is more compelling than just saying like, because we want to. Um, exome sequencing. It also hit or miss, um, less commonly covered, and hopefully that will change in the future, but I don't know how optimistic I am about the near future, so we'll see on that. Um, the Medicaid question. It is also complicated. So even if Medicaid does cover this kind of testing, a lot of the time they don't reimburse the full amounts. So it really is gonna depend on your hospital's specific policy about balance billing patients who have Medicaid or some hospitals who don't offer um. Institutional billing for their Medicaid patients and it has to be self-pay or some who just can't order this kind of testing on Medicaid patients. It's really hospital-specific, you know, our hospital, we can order the testing and we don't balance bill the patients and so we get all the testing that we want on these Medicaid patients, but like our institution ends up being the one who fits the bill for most of that. That's great Leandra, thank you again for a rather comprehensive, you know, um, presentation there and um we certainly learned a lot. uh I hope um that did answer some of the important questions for the audience as well. So I'm going to, uh, introduce the next speaker, um, Doctor Marianna Meyers, and, uh, let's see if you can See my slide show here. Um, again, for those that just joined us, um, this is, uh, recorded and it's going to be made uh viewable on demand, uh, in this same link, uh, should you have missed that wonderful talk that Leandra just gave in genetics related to renal uh dysplasia. The future, um, um. Session session number 3 in June is also going to be on the same link and I want to introduce, uh, my good friend Mary Anna Meyers next, uh, who will be, uh, sharing with us her, um, Experiences in prenatal diagnosis of renal conditions, especially when it comes to renal dysplasia. She's currently the director of fetal imaging at Children's Hospital Colorado. And um let me stop sharing here so she can bring up her slide shortly. Good morning, everybody. Thank you, um, Vong, for having me. It's an honor. And I'm gonna share my screen. Hopefully, you can see it. Is that correct? Good. All right. Um, so this is kind of my favorite topic. I am really passionate about GU pathology. Um, I have no disclosures, and I literally have one objective for this talk. Um, I wanna show that not all cystic kidneys are MCDK. And as a radiologist, I received a ton of clinical um indications when ordering renal ultrasounds that says MCDK and then you change the diagnosis and that can have a huge impact on the family and the physicians in their treatment to the patient. So briefly we're gonna talk a little bit about embryology. We're gonna do a review of MCDK or multicystic dysplastic kidney. Then we're gonna move on to talk about renal cystic dysplasias and I'm gonna show you some cases in between and mainly I'm gonna concentrate on prenatal imaging. So, embryologically, in the 1st 4 weeks of life from the cloica arises the mesonephric duct, which is gonna function as a temporary kidney until week 4 of life. Then in week 5, the metanephric duct arises, which is gonna be leading to the final kidney. The metanephric duct is gonna give origin to the ureteric bud and the renal mesenchy. And as you see here in red, the ureteric bud is gonna grow cephalide until it touches the renoblastoma, and it's very important to know that these two structures, they need to touch, they need to connect in order for some signals, some substances with signaling functions such as these that I have listed here to be released, which are going to um stimulate the development and the branching of the collecting system at the renal pelvis and in the intrarenal level. So in MCDK what happens is there is no touching, no connection of the ureteric bud and the renal mesenchyme of some sort, can be a complete atricia, a partial attricia, or some sort of disconnect. Therefore, these substances are not released. These bud branching, branching signaling factors cannot be released. Therefore, the nephrons fail to develop. And leads to a dysplastic tubular system and failure and ramification of the ureteric butt. By imaging, the MCDK is gonna be seeing um a cysts all over the kidneys involving the cortex and the medullary region. There's gonna be an absence of normal renal parenchyma, and that's mainly gonna be a histologic diagnosis, of course. And by imaging, we may see a scant amount of very ecogenic renal parenchyma without corticomedullary differentiation. The renal size will decrease over time as the cyst becomes smaller. Typically, there's no renal pelvis, and that's actually a good hint to figure out if this is MCDK or it's something else. And the normal renal parenchyma, as I said, is not formed, although, again, that's a histologic diagnosis. So why is this important? Because MCDK has low to no risk of hypertension. The risk of cancer originally thought is now uh very low, as you can see here and there are some citations at the bottom. It is associated with contralateral UPJ obstruction, therefore, you have to work up the other side as well. And there are different appearances in the ultrasound and cross-sectional imaging compared to renal cystic disease entities, and I will show you a little bit, although it's not so straightforward. There is some overlap and it can be confusing. And in general, MCDK is not associated with genetic syndromes because as I showed you, it's an embryologic problem, not genetically associated. So, in the fetal imaging, we're gonna see, for example, this is a 22 week fetus that had a very um large left kidney with multiple cysts that didn't communicate with each other. And when we say they didn't communicate with each other, we imply that this is not hydronephrosis. This is not a renal collection system uh misleading us to think that these are um hydronephrosis rather than cysts. So in the fetal MRI we can see that there is a decent amount of amniotic fluid. There is a very large amount of uh cyst with enlargement of the abdomen on the left, and in the sagittal view, you can see how the anteroposterior diameter of the baby seems to be enlarged by all these cysts. The good thing is that there is normal amniotic fluid and there's a normal bladder and the contralateral kidney was normal. So the baby was born and this is how the kidney looked and as you can see, there is very abnormal appearance of some parenchyma in the liver um sorry, the kidney with lack of corticometillary differentiation and all these cysts which don't communicate with each other. So this was indeed MCDK. The patient later on, at 3 months of age, had a MAC 3 which confirmed that there is no function within that left kidney. As we can see here, there is no radio tracer uptake and the renographic curve shows only activity on the right kidney. So, this was very straightforward MCDK. What happens when you have bilateral affection? Well, this is lethal, um, although I know that with amnio infusion and the rough trial, that could be questionable, but we'll leave that for a different talk. So, on the left, we have ultrasound images from a 21 week fetus and you can see how these images are, are actually kind of ugly because there's no amniotic fluid and ultrasound depends on having the amniotic fluid to be able to visualize the fetal structures properly. So here we have the echogenicity of the fetal ribs, so we have the chest over here, the belly of the baby over here. And at the level of the kidneys, we have a bunch of cysts in both sides. The MRI is really not dependent on amniotic fluid. We get to see a lot more and you can see all these cysts of different sizes occupying the cortex and the medullary region of the fetal kidneys as we can also see in this axial view of the baby. These babies sadly died in utero, although I'm sure we're not surprised to hear that. So let's move on to renal cystic dysplasia. If you Google renal cystic dysplasia definition, you get an MCDK definition. And if you go to OMI, which is one of my favorite, uh, web pages, and you type renal cystic dysplasia, you get over 3600 entries. So it's obviously not a very straightforward topic. I'd like to divide the pathophysiology of renal cystic dysplasia into multifactorial, syndromic, genetic, and obstructions of the lower urinary tract, although I know that was discussed in the prior session, so I'm, I'm not gonna address that topic. So, by imaging, renal cystic dysplasia may or may not have a normal parenchymal formation. It's gonna have diffuse cysts all over the parenchyma or it could have a rim, um, like appearance of cysts as we can see here in this diagram, or the cyst may have different sizes and be anywhere. The renal parenchyma is typically abnormally hyperechoic and may or may not have a visible renal pelvis and calluses. It is associated with syndromic or genetic abnormalities, as we heard from Leandra as well. It can be associated with hypertension and other GU and non-GU anomalies, therefore, we need to image the entire fetus. We may have some renal function in contrast to MCDK which has no function, however, some of these entities can progress to have no renal function at all. The risk of malignancy is not the same as was thought originally for MCDKs. However, if the syndrome it is associated with has a risk of malignancy, of course, then you will encounter that. And in general, my imaging has a different appearance, but as I mentioned, it's not too straightforward. So, I like to uh divide the renal cystic dysplasias into two broad categories, genetic etiologies and developmental or obstructive. So within the genetics, we have the HNF1 beta or the celiopathies. So, let's start with the HNF1 beta, and it's a hepatocyte nuclear factor 1 beta with transcription of a factor 2, and it's an autosomal dominant um disease important for family counseling and recurrence. It can present with diabetes, renal cyst, or renal cell carcinoma, and it may affect also the liver, pancreas, thymus, genitalia, and other organs. This is an example of a twenty-week pregnant uh patient with a proven mutation of an um HNF1 beta where we could see in the ultrasound multiple cysts, particularly at the, at the border of the kidney, at the cortex bilaterally, and there was some echogenic parenchyma in between, but the cysts were also um going into the pituary region. By fetal MRI we can see how large and um hyperintense these kidneys are. There's no amniotic fluid, therefore, the lungs didn't really develop. There is um small appearance and dark appearance of the lungs which is characteristic for pulmonary hypoplasia and the cysts are all over, but again, there seems to have more of a predisposition in the cortex of the kidneys. Um, this baby, uh, this family opted for termination of pregnancy, and while we did the fetal MRI, we got to see the mom's kidneys, and she only had a tiny cyst at the right lower pole, but mom was unaffected, although she did express the same mutation. All right, let's move on to celiopathies, and this is a very large category. So celiopathies can be divided into single-gene or multi-gene celiopathy. So, what are celiopathies is a group of clinical and genetically overlapping disorders with a common problem which is the, the problem in the primary celia or centrosomal complex. There's a wide variation of presentation, um, but mainly what happens in the kidney is celial dysfunction is associated with renal cysts and, um, can lead to renal failure. So for single gene, we have the typical ARPKD or ADPKD while for multi-gene we have the nephronopticsis which are cyst restricted to the corticomedullary border and is due to a mutation in this specific gene. In some entities. And if it is associated with renal, retinal issues, liver fibrosis, or cerebellar vermis hypoplasia can lead to Scher syndrome. If it is associated with retinitis pigmentosa, polydactyly, developmental delay, hypogenitalism can lead to Barrett-Betle syndrome. You can also find Meckel-Gruber and glomerulo cystic kidney disease. And I graded that out because there is this misconception that glomerulocystic kidney disease is a celiopathy and reality it's not. It's a mutation in one specific gene which is a UMOD that can be familiar or sporadic, but it tends to be associated with other celiopathies. They come along, that's why sometimes it's, it's um thought to be a celiopathy. So what happens in glomerulocystic kidney disease, there is an enlargement of the Bowman space and as you can see in this dichromic um stain at moderate power, you can see the glomeruli here, so that's the bundle of the capillaries with enlargement of the Bowman space which is this white appearance. So, if you look in the top part of this slide, you can see that there's dilatation of tubules, which is characteristic of sometimes a DPKD with cyst formation. So this is a patient that has ADPKD with terminal cystic kidney disease. All right, let's go to the single gene. So ARPKD is an autosomal recessive transmission um with mutation of the gene PKHD1. It has a variable presentation. It can go from decreased renal function to complete end-stage renal disease. The kidneys are gonna be large, hyperintensive MRI or hyper-echoic in ultrasound. The borders of the cyst are gonna be very um poorly defined because they're very, very small. So that's what's gonna explain the echogenic or the bright appearance of the kidneys by imaging. If this is diagnosed in utero, we're gonna have oligo or inhadremnius, smaller absent bladder, which will lead to pulmonary hypoplasia, and it may or may not be associated with hepatic disease and there are many uh publications talking about Crohli's Disease Association. So this is an example of a 33 week gestational age fetus with anhydremmius and you can see the kidneys are really large, there is no amniotic fluid and the kidneys are ecogenic but they have these kind of dots of hypoechogenicity with, which represent fluid. By MRI imaging, there's this homogeneous hyperintensity and it's really hard to pinpoint where the cysts are, but this is very typical for ARPKD. This patient did not have, at least in utero, any um dilatation of the biliary ducts. Postnatal images can show all this detail of the tiny, tiny cysts throughout the kidneys and uh the enlargement, of course. This is another example of a fetus at 29 weeks that had ADPK ARPKD sorry, and had abnormality of the kidney in utero. So the kidneys are very large, echogenic, and you can see here all these white areas in the liver, that is dilatation of the biliary system. And in this movie, you can see the branching pattern of the biliary ducts, um, particularly in the posterior aspect and the very, very large kidney. So this was a fetus that already in utero, we could see that there was, um, involvement of the liver aside from the fact that it was tested positive for ARPKD. All right, let's move on to multigens. So it's, it's very broad and sometimes it's not so straightforward to make a diagnosis. So this was a case of a neonatal one day of life, um, that was IUGR in utero, had a normal prenatal ultrasound up to 20 weeks. Then develop oligohydremias and pulmonary hypoplasia. And in these images, what I want to highlight is the presence of these cysts um that are primarily located at the cortex of the kidneys. They have different sizes, but the um medullary region seems to be somewhat spared. The baby also had abnormal um head ultrasound that showed midline abnormalities, abnormalities of the formation of a vermis and some, um, cystic formations with CSF in the posterior fossa. So this baby was, uh, showed a mutation in this specific gene and apparently it wasn't that straightforward because it could be associated with all these syndromes. So we may find a celiopathy but not particularly associated to one single gene. And sadly, this baby died at 2 days of life due to respiratory insufficiency. Schubert syndrome is an autosomal recessive celiopathy, uh, with mutation in multiple different genes, but characterizes by vermian hypoplasia, has the typical molar tooth sign shape of a brain stem as we can see right here in this MRI could have retinal dystrophy and renal cysts. This is a movie of a baby that has Schubert's syndrome. There is anhydramus and you can see something really bright on only one side of the abdomen, so we couldn't find the, the baby's um original ultrasound and they couldn't find the right kidney and when we did the MRI we noticed that this was actually a cross fsectopia with abnormal appearance of the kidneys, so the kidneys were in this distribution. Um, and they were obviously hyper intense, but if you notice, they are not as large as the ones I showed you for ARPKD so that is helpful also in the diagnosis. This baby had abnormal brain, um, appearance with the molar tooth configuration and the abnormal vermis, and it was diagnosed indeed with Schubert syndrome. Mecker-Gruber is an autosomal recessive lithoceliopathy, as a mutation in the TMEM231 gene, and I think I practiced all night to say that. Um, it can be characterized by uh renal cyst, um, cystic dysplasia, particularly with nephronopticis type, CNS abnormalities, um, specifically a posterior, more, uh, occipital parietal encephalocele, postaxial polydactyli and hepatic abnormalities. So here we have a case of a baby at 20 weeks that had 7 toes, had very large kidneys with the renal pelvis identified and a tiny appearance of cysts all over the kidneys. And indeed it was found to have this specific mutation. On top of that, had an occipital encephalocele, as we can see, here's the forehead, the top of the head, the encephalocele and also had micrognathathia and you can see here perhaps, although it looks a little bit pixelated, um, the tiny cysts that are all over the kidneys. Um, this is very lethal, so it's hard to find postnatal images of Michael Gruber. That's the only patient that I was able to find in my, um, files. All right, tuberosclerosis, um, is an autosomal dominant mutation in specific chains, the TSC1 or TSC2. It characterizes by hamartoma in multiple organs, and that's what we mostly see by imaging. And it can also be associated with angiomyolipomas, cysts, renal cell carcinoma, or ADPKD, and that is because the mutation of this TSC1 or 2 gene is right next to the mutation for the PKD1 gene in chromosome 16. So, therefore, we have two types of presentations. We have those who only have angiomyolipomas and maybe a couple of cysts, but um nothing major to that, or you may have the florid spectrum of an ADPKD pattern of tu. Atherosclerosis. So, in utero, I only have this case where you could see there's bilateral involvement of the kidneys with large and small cysts, and there is abnormally echogenic parenchyma in between. And the MRI shows the differences in the size of the kidneys. One side seems to be more affected than the other. This baby had subependyal nodules, as we can see these black dots over here in the axial brain MRI and also had a rhabdomyoma in the heart which was proven by the fetal echocardiogram. Um, lastly, I want to talk about, well, I'm gonna very briefly talk about the obstructive pathology. So the only thing that I want to highlight is that Um, the bladder outlet obstruction that creates the backup of urine into the proximal GU system can lead to renal damage, and that renal damage can be presented as cyst. So that's why I included this in the renal cystic dysplasia because it's not, um, that the cysts are originally formed, these kidneys may form originally but because of an insult later on, developed this cyst as a response to that. So this is a 20 week uh fetus that had the typical keyhole appearance of a bladder outlet obstruction in posterior urethral valves, but if you see in the ultrasound, you see multiple cysts at the periphery of the kidney with abnormally echogenic renal parenchyma. There's no amniotic fluid as you can. see surrounding the baby and the fetal MRI highlights the rim uh appearance of the cyst in the um fetal MRU sequences and also you can see it in the axial Two weighted images and again you see partially the dilated bladder over there. Um, this is an interesting case of poster urethral valves in twins, both of which had posterior urethral valves, although one was more affected than the other. And by imaging, we had an echogenic appearance of the kidney with hydronephrosis, and the MRI highlights the thinning of the cortex of this twin, which is more pronounced than on the other. And the bladder was enlarged, however, it didn't have the massive um dilatation as we are used to seeing. But in the postnatal imagings, we can see that this baby developed this peripheral cysts with a very abnormal hypeechoic appearance of the kidneys. So keep in mind that we may not see the renal cyst. Dysplasia in utero, but this takes time to develop and we may end up seeing this later on. And if we start seeing this, at least in my, uh, fetal care center, people counsel the families that if you start seeing renal cysto dysplasia in utero, that tends to lead to, um, sooner rather than later renal failure in the postnatal state. And this is a VCUG of the same baby after the ablation of the, uh, valves, although it still shows some dilatation. So in conclusion, I think the only thing that I would like for you to remember from my talk, uh, is that not all cystic kidneys are MCDK. Think about something else. Imaging can help by showing if there is or not a collecting system. Um, if there is, typically it's not MCDK, so take a look for something else and particularly look for other GU or non-GU abnormalities since this can lead you to a specific syndrome and proper uh counseling of the patient. And I think the correct diagnosis, as Leandra um talked about, is really important for parental counseling, recurrence risk in other pregnancies, and to make sure we treat these patients properly. Thank you. Thank you, Marianna. I um I don't know, um, what to say except that, you know, this is, uh, one of those conditions that really, um, Impacted the spirit of the team sometime because of how difficult, um, you know, specific diagnosis, uh, can, can be made, uh, especially in places that, you know, you don't have the, the capability of a comprehensive evaluation, uh, and you only have uh access to, say, ultrasound and nothing else. Um, how, how would you, um, counsel, you know, or at least share with us, uh, what's your opinion about, you know, uh. Centers that um not able to um have the access to other imaging modality or genetic uh um uh evaluation. That's a great question. Um, I think that if you only rely on the ultrasound, I think that it's very important to make sure you educate your providers and your team that The appearance of the cyst and where they are located is very important because you may be locked yourself into a diagnosis that may not be the accurate one, so have an open mind and think about other renal cystic diseases. So once you start into the renal cystic disease category, um, I think most OBGYNs and MFMs know that it may not be just MCDK, but I have seen that happen. Many times we get patients referred to our center for MCDK and we end up changing the whole diagnosis. So, I think it's, it's about educating um team, your team and providers that um not every renal cyst may fall under the category of MCDK. Um, I think that educating is perhaps my only advice. Uh, and it, it, honestly, ultrasound is great. Ultrasound can, can be the main sole screening tool and many centers only rely on that. So as long as you know what you're looking for, you will find it, you know, uh, uh, but I think again, education will come first, um. In my thought Doctor Meyers, this is Stephanie Riddle. Um, I have a question for you about sort of an unrelated but related topic. You've done a lot of work looking at fetal lung volumes. Um, and can you comment about utilizing fetal lung volumes for patients like this, so other models of pulmonary hyperplasia other than things like CDH or space occupying lesions? Yeah, that's a great question. So, I'm always skeptical to do fetal lung volumes in patients that have anhydramus because you're gonna underestimate. It's like the lungs are sponges that are full of amniotic fluid. So if the sponge is dry, then the sponge itself is there, but you're just not distending it, right? So we might underestimate the fetal lung volume. I think that in cases where there is oligohydramus or severe oligohydramus near and hydrammias. We do it and perhaps it's just to add one more item in the checklist that parents may use to say, OK, I'm leaning towards comfort care or termination of pregnancy. Um, but we are very careful about counseling these patients regarding pulmonary hypoplasia and the risk, you know, the, the, the kind of like the PPLV and total lung volume, uh, cutoffs that we use for CDH because they don't apply to this. Um, so I think that it's, it's wise to call pulmonary hypoplasia based on the appearance of the anhydramus, but I wouldn't quantify it. I, I think that that can be very misleading. So I would say, don't do low volumes in these cases and don't quantify it. Just describe it if it is pulmonary hypoplasia of anhydramus or not. That's it. Arianna, um, that's a question from, um, your colleague, your old-time colleague, Maria Calvo. How can you tell apart TCF-2 mutation from cystic renal dysplasia? Uh, she commented that as not all stages of obstruction will show collecting system dilatation by the time you were doing the imaging. So that's a great question, Maria. Um, it's good to see you there. Um, so, I think that that is first of all, a genetic diagnosis. I don't think that by imaging we can distinguish and also because some of these patients early on may present with a pattern and then they will evolve into something else. Like at the beginning, you may see them just as a tuberculosis with a couple of scattered cysts, um, but then later on in life, it may evolve to have the florid appearance of let's say ADPKD associated. So, um, Again, when you first see these cases, it's hard to be locked into one diagnosis. I think that we can say this is, this looks like renal cystic dysplasia rather than MCDK and then from there, your genetic counselor could help guide the testing so you can be more um specific. About what this is and also look at the rest of the fetus. If you already see, you know, neurologic abnormalities, cardiac abnormalities, that can also help you think in your mind what it is. But again with the TS, uh, wait, I think I misunderstood tuber sclerosis by the TCF2 mutation. Um, so, wait, yes, so the TC, uh, the HNF1 beta, which I think that's what you, uh, are talking about, Maria, is that right? If you wanna type, yes. Um, so, uh, it's hard. Again, you see cysts, um, if it doesn't look like MCDK, it needs a genetic testing because you need to figure out what else it is. And again, the rest of the other body abnormalities may lead you into one category or not, um, but if you don't see anything else, it definitely requires genetic testing. Yes, sorry, I misunderstood at the beginning, I was thinking about tuber sclerosis. All right, moving on, um, I hope that all of the speakers can stay on till the end, uh, in case, you know, there were questions for you later on, um, but we want to move on to my, uh, long, long time partner next, uh, Dr. Muira Habli. I'm going to, um, See if I can share my screen with you here. So, um, again for those that just joined, um. We, we are having a good time so far, um, with Genetic testing as well as uh fetal imaging for renal condition and uh Doctor Hab Lee is going to share with us um from maternal fetal medicine perspective about this condition and uh potential uh fetal intervention uh for these conditions and um Mira had been with Cincinnati uh for a long time and she had been my, uh, partner in crime for many years. Uh, she's currently the director of TriHealth Fetal Care Center as well as the chair of Perinatal Research Committee at Gumton Hospital, uh, in Cincinnati. Neera, um, are you ready to share your talk? Yes. Good morning, everybody. Good afternoon, depending on which uh time zone you are. Thank you for the organizing committee for inviting me and thank you for our attendee for their time in the weekend here. I'm gonna share my slides and we'll go from there. Perfect. You're in presenter mode, Moira. OK. Is it good mood now? Perfect, perfect. Today I'm going to speak mainly about fetal intervention in the setting of in utero renal failure. I have no disclosure except some of the images I got from Dr. Jose Perro, my partner. The outline or the objective of my talk mainly to speak about the renal functional embryology, diagnosis of fetal renal failure radiographically and chemical. What are fetal intervention we offer either am infusion via amnio port or percutaneous amnio infusion, and Dr. Taba, my partner, will present some of the cases. fetal anomalies in general are detected in 2% of all fetuses, and the GU abnormalities are the most common one. They constitute about 50 to 30% of structural anomaly that are present at birth or at the time of prenatal ultrasound. The kidney usually or the glomeruli develop between 8 to 9 weeks, and they start by 10 weeks make urine. By 12 weeks, the kidneys are completely functional. By 14 weeks, major contributor to amniotic fluid, and after 20 weeks, more than 19. 10% of the amniotic fluid is kidney related and not placenta. That's why most of the diagnosis usually of renal anomalies occurs between 15 to 20 weeks of gestation at the anatomy scan when we do a 20 weeks of gestation. As for the nephron, they continue to develop until birth, but at birth, the number of nephrons, they remain static, but there is increase in size to in order to be compatible with the changes in the babies. Now the placenta acts as an in vivo dialysis unit in the fetal life where the fetal electrolyte and fluid are usually regulated by the placental correlation with the mom and the maternal blood, as seen in this graph, there is an inverse relationship between the fetal electrolyte and gestational age. If you look at the y axis, it's sodium concentration, and the x axis is gestational age. With increasing gestational age, there is a decrease in the sodium concentration, and this is really important because it is secondary to increase in maturity of the renal tubular system. If we have renal failure, then you will see the sodium electrolyte increase because we have dysfunctional renal tubular system regardless of the etiology. Now how we diagnose renal disease, as Dr. Marianne has mentioned, either by ultrasound, our primary diagnosis for me as the maternal fetal medicine, and the MRI is always complementary to our diagnosis. The checklist that we use in general first look at the amniotic fluid. The presence and the size and the appearance of the kidney, the location of the kidney if it's pelvic or abdominal. Look at do Doppler arteries to check for renal arteries, and look at the bladder shape, volume, and wall thickness, the sex of the baby, because this helps us and also diagnosis and umbilical cord abnormalities if it's present. Now it is hard. When I was looking at the literature to find what is the definition of in utero renal failure, I honestly did not find a single paper that tells me this is the definition of in utero renal failure. However, what we use in general in most of the literature and in our workup is whenever we have amniotic fluid, oligohydremnius, anhydramnia. defined by deepest vertical pocket less than 2 centimeters plus or minus the total AFI less than 5 centimeters based on gestational age or less than the 5th percentile. In addition to a renal pathology, this constitutes about a sensitivity of 0.6 and specificity of 0.7 for the diagnosis of in utero renal failure. That means anhydremnias or oligohydremnius associated with abnormal renal function or structure, then this is considered in uterrenal failure. What are the radiologic signs of in uteroo renal failure? If you look at this image, it is mainly hypoechogenic kidney and enlarged or atrophic or abscess. In the setting of anhydremnius, we can define it as a uter renal failure. In the setting of anhydremnius or oligohydremnius, if there's no other etiology or. etiology and we look at the renal cortex appearance where you could see those cystic changes as Dr. Marianne Meyers in the previous lecture has mentioned. This has a sensitivity of 0.5 and the specificity of 0.84 that this represents in utero renal failure. Other things we look at, looking at renal Dopplers originating from the aorta, as you can see in this image, there is no renal arteries that indicate bilateral renal agenesis. In this image there is a unilateral renal artery abscess which is indicates unilateral renal agenesis. Other findings we look at. Ultrasound, the cortex, the renal pelvis dilation in this star as it's been seen, thinning of the cortex, if there's any ureter dilation, and also renal caliceal dilatation as seen by those errors, these are all in the setting of anhydremnius could be indicating different etiologies of in utero renal failure. Now, the other also definition of in uter renal failure is in addition to the geographic, we have to have some objective, objective findings. Two things we use either chemical or what's known, one of the proposed definition is using the percentage of bread bladder refilling if you have an obstruction, bla etiology. And this is defined as fetal bladder volume 48 hours after a vesicocentesis, that means a bladder tap minus the original fetal bladder volume before the bladder tap is done, divided by the fetal bladder volume before the tap multiplied by 100. A cut of 27% could predict a poor residual renal function, and there is an 80% sensitivity or a 75% specificity that this will progress into in utero renal failure. Other findings that could help us. It's like a puzzle. You get the radiographic findings, you do the bladder filling, you look at the chemical and you put all these together to say this is a fetal in uterrenal failure. The other things that help us or prognostically help us in the definition, chemical definition of in uterrenal failure is serial assessment by vesicocentesis every 48 hours. In general, or bladder tap and other words, the first urine sample is mainly when you do a bladder tap, is usually represents urinary stasis for a prolonged period of time. That means the numbers and the values of the urine electrolytes are not good yet a presentation of renal function. Then you do after 48 hours another secondary urinary sample. This also still represents the chronic renal collection from the upper urinary tract. All these electrolyte numbers. The third sample, the electrolyte represents the fresh urine excreted by the. Fetal kidney and it truly can reflect if there is the function of the kidney. Keep in mind with all of these radiographic and all of these chemical definitions that we use to help us in diagnosis, still the function of any organ is determined at the time of birth of the baby, but the literature supports that the fetus could have salvageable renal function if they demonstrate decreasing urine value defined by the following. If sodium is less than 100 mg per deciL, chloride less than 90, osmolarity less than 20, calcium less than 8, total protein less than 20, and the beta 2 microglobulin less than 6 mg per liter. All of, still we have a lot of research in the field of diagnosis of in uteroo renal failure, but these are the premium findings that we use now in our clinical practices. What are the consequences of having oligohydramus and hydramnius and renal failure? Whenever we have, regardless of the etiology, decreased in urine and fetal urine excretion, whether it's renal agenesis, cystic kidney disease, obstructive disease, this will lead to fetal compression and will lead to an acute umbilical cord compression and increased risk of asphyxia and stillbirth. In addition to the facial appearance of Potter's syndrome, defined as low set ears. Peaked nose, prominent epicanic folds, and downward slant to the eyes. Pulmonary hyperplasia is the main cause of respiratory failure and neonatal demise in these patients who have renal disease with oligo and anhydremnias. Limb deformities and contraction is also one of the consequences of anhydremnias and setting of renal failure. What are the causes of in utero renal failure? In my mind, I always do it as we do it in adults. There is prerenal. There is renal etiology, and there is post renal etiology. Prerenal etiology of in uterofenal failure that has been reported in the youth literature is mainly in some of the diseases such as in utero growth restriction. In twin twin transfusion syndrome or if there is maternal drug intake and non-steroidal anti-inflammatory. However, those prerenal, prerenal etiology, they are usually correctable or reversible etiology either in utero or immediately postnatal period. The renal etiologies include renal agenesis, multicystic dysplastic kidney disease, polycystic dysplastic kidney disease. Other postrenal include vesicourethric reflux and lower urinary tract obstruction. Those that we offer in general fetal intervention defined by amnio infusion to restore amniotic fluid are mainly the renal and the postrenal group in the fetal life. What are the types of fetal amnio fetal intervention we offer for in utero renal failure? The aim for any intervention that we do during the fetal life, we cannot correct what has happened as damage in general, but we try to restore amniotic fluid, the cushion for the baby, and this is important for lung development, especially during the critical period between 16 and 26 weeks of gestation. Renal decompression also in some cases such as in bladder outlet obstruction is one of the causes of intervention. There are two types of amnio infusion that we do in relation to in utero renal failure either percutaneous amnio infusion or amnio infusion through an amnio port, which I will describe in detail in the coming slides. What are is the inclusion criteria that we use in order to confirm before we do or offer fetal infant intervention? First, we confirm diagnosis of renal failure using radiographic and the renal functional assessment either through bladder taps if it is based on the disease or through chemical. Findings age more than 18 years of age, no genetic or any other major anomalies. It's an isolated finding. Cervical lens more than 2 centimeters, single term pregnancy, no history of preterm delivery, and there is no technical contraindications such as abnormal presentation, accreta percreta, and definitely a motivated patient. Workup we do before we do any fetal intervention, a detailed anatomy scan and MRI to complement to make sure we have completely an isolated finding that is related to renal disease. We do a diagnostic amnia fusion first in the test setting of oligoanhydremnias to confirm intact membranes. There is no rupture or any other obstetric indication, and to do genetic testing. We usually include patients that are diagnosed and the first am infusion before 26 weeks, and each of these patients go through multiple subspecialty meetings including pediatric surgery, nephrology, neonatology, MFM, transplant team, palliative care, social worker, and more and more, and they go through several meetings like that to make sure these patients are motivated and they fit the criteria for such intervention. The amni infusion protocol we use, we use a solution that is used mainly lactated ringer. The volume calculated in order to amni infuse those patients is gestational age in weeks, multiplied by 10, and the aim mainly is to achieve the deepest vertical pocket between 5 to 7 centimeters or an AFI total amniotic fluid index between 16 to 20. Frequency to maintain a DVP between 5 to 7 centimeters. In general once per week amnio infusion less than 26 weeks. If it is more than 26 weeks, we usually do it 2 times or 3 times per week based on the amniotic fluid measurement. We continue to do that till 37 weeks and gestation and the aim to do continue to do that to 37 weeks. Gestational age of delivery between 37 and 39 weeks unless indicated earlier. The amnio infusion is not indication for C-section in general. It's a spontaneous vaginal delivery unless C-section is for obstetric indications. We use lactated ringle because it's similar to what is the constituent of the amniotic fluid, and we use a warm LR as seen on this table in regarding sodium, potassium, calcium, all are compatible lactated ringer with what is in the natural amniotic fluid. For percutaneous needle or abdominal amnio fusion, we use usually a 20 or 22 gauge Eco-tip needle from Cook Company. We introduce it in a safer space than the amniotic fluid, and we infuse a sterile, warm, lactated ringer. As I said, the aim is to restore amniotic fluid and help in lung development in these patients with in utero renal failure. Complications of direct amnio infusion is mainly reported from cases that they have done in the literature and the Cochrane reviews and mainly from those that have done PPRM. We are working and now we are collecting our data to present MN port and MN fusion complications soon. The risk of choreoamunitis in those patients is 10 to 20%. As I said, this is the misleading complications in utero renal failure because most of the complications of amnio fusion is in the setting of premature rupture of membrane. 12% reported literature of ruptured membrane in these patients after the first one of amn infusion, and some report 0 to 1% comparable to the estimated risk from amniocentesis. 2.6% risk of placental abruption preterm delivery is about 8% of patients. The second type of amnio infusion is MN port. The Mio, these are the instruments we use in amnio port. This is the needle where we introduce in order to do amniotic fluid, and I will show a video of that. This is the catheter guide. This is the transducer, and this is the mediport that we use to infuse here using the power lock safety power lock needle in order to infuse amniotic fluid. This is some nice presentation I took from Dr. Jose Peru where the amnio port, medi port is put at the lower part of the ribs, and then we infuse it through this the amniotic fluid on this baby to maintain and restore this amniotic fluid, and I will share with the team a video. Show us the place to be. Mm And that's it, how we usually, that's it how we usually use the amnio port. You could see here minimal amount of amniotic fluid, and this is after the infusion, how we have no restoring a normal amniotic fluid. In Cincinnati Fetal Care Center, we have evaluated in the last almost 10 years about 439 patients with a genitourinary abnormality, 210 is bladder outlet obstruction, and 22, 20, 225 is other. renal disease, including MCKD and other disease. 67 of these have done amnio direct amnio percutaneous infusion, 40 due to a renal failure in the setting of bladder outlet obstruction. That means about 20% of bladder outlet obstruction that we see ended up with in utero renal failure. That means anhydremus, oligohydramus, with nonfunctioning or bladder capacity that is less than 27%. 27 of these in utero renal failure. The other 27 were secondary to other renal abnormality, about 12% of what we see. 25 patients have done MN port, and as I mentioned, we are reviewing all of these patients to report the complications from direct percutaneous amnio fusion versus MN port in the setting of renal failure, not premature rupture of membrane as mentioned in the literature. Our first paper that I'm just going to mention, 8 patients that we reported their outcome, and this paper is published under the title of use of an amnio port to maintain amniotic fluid in fetuses with oligohydramnia secondary to either. Lower urinary tract obstruction or other fetal renal anomaly. We reported this is our first experienced serious cases. We had 8 patients that we did MU port. There were no fetal deaths on those 8 patients. We were able to successfully restore. And maintain amniotic fluid. There was one patient who died at birth with secondary to unrecognized laryngeal warp, despite an MRI was done, and another one died from pulmonary hyperplasia after the patient has ruptured ruptured membrane after a few of the amnio infusion. None of the remaining 6 had pulmonary hypoplasia at birth. And these are the 8 patients that have been published in the literature. Most of them have infusion or diagnosis that started less than 26 weeks. You could see the 1st 3 patients were our first experience, and then we stick to our criteria. To start the infusion less than 26 weeks. Duration between infusion was about 4.3 days, and the gestational age at delivery was 34 weeks. The average gestational age with a range 31 to 37 weeks of gestation. 88% of these patients were surviving at birth and 70% in the neonatal period. There was no cases of infection. There was one catheter dislodgement, which was our first case actually that we have done because we did it at the pelvis, not at the chest as we do, and there was one malfunction of the port, and the patient at that point did not want to replace it or do another surgery, and there was one case of premature rupture of membrane. As I mentioned at the beginning, there still remains a lot for us to do in this area of fetal urology from diagnosis, from therapy, from functional imaging, be creative in order to have an assessment of that biomarkers of renal function, and we, we are, you know, should be start doing randomized clinical trial in this aspect, which there are still, where there are few are already existing. I would like to thank our team and open for any discussion. Probably I'm actually gonna hold questions until after Taba, uh, Doctor Taba presents the cases and then pose the questions to you guys together if that's OK since we're staying on the same topic. Absolutely, I'm gonna stop sharing so that Doctor Taba can present his cases. Perfect. And I apologize for the video did not have the voice. I tried to correct it during presentation, but Dr. Lim will send a link, our fetal care center link in order for to be seen. It's on the chat box now, that link. I appreciate it. Thank you. All right, it's my uh pleasure to introduce our next speaker who's gonna present sort of a follow-up to uh the information we just heard from Doctor Hubli about amnio infusions and present some cases and highlight some of the important uh factors to consider when doing these procedures. Um, Doctor Taba, our partner here at the Cincinnati Children's Fetal Care Center. He serves as the director for Fetal diagnosis and therapy, um, at the University of Cincinnati, he, where he's an associate professor in maternal fetal medicine. Um, Doctor Taba, I will turn this over to you. Thank you very much, Doctor Riddle, and uh thank you everyone for uh joining us today. Uh we really appreciate your time. Um, I'm gonna share my screen here. All right, so everyone can see my screen OK. All right, very good. Um, so, I'm gonna present a series of, uh, three patients, each with their own, um, flavor of a presentation, um, uh, that we have seen at our, at our fetal care center. And so, um, our first patient is a, uh, 22-year-old Primagravida, um, who, uh, presented at 22 weeks and 2 days with suspected, uh, lower urinary tract obstruction. In her past medical history was, uh, was only significant for uh morbid obesity with a BMI of 42 kg per meter squared. Um, this is the, uh, fetal, um, some of the fetal MRI images that were obtained, um, of this patient, and you can see these are all coronal views through the fetus. Um, and, uh, it's immediately apparent, uh, that the, um, the bladder is significantly enlarged here on the image on the left, um, and we can see the classic appearance of a dilated posterior urethra, um, um, indicative most likely of posterior urethral bowels. Now, um, looking through the imaging, um, uh, there are some concerning features, um, uh, of the urinary tract on this fetus, namely here in the image in the middle. You can see despite having bladder distention, um, you can see that there is, is quite the irregular contour of the bladder wall, um, which is suggestive of a lack of, uh, of increased intravascular pressure. Um, and perhaps a, um, a finding consistent with, uh, in utero renal failure. Uh, and this is further supported by the image here on the right-hand side, um, where you can see that the, the kidneys, um, virtually have, uh, no normal renal architecture. They're quite enlarged, and there are cystic dysplastic changes that are very apparent. Um, and so, um, these are certainly concerning, um, for in utero renal failure as mentioned previously. Um, and so, this patient, uh, underwent a multidisciplinary counseling, um, with the team members as highlighted with Doctor Hubley's talk, and, uh, she was, uh, counseled regarding the, the poor renal prognosis associated with these findings. Uh, nevertheless, um, to complete her evaluation, uh, we did recommend a vesicocentesis, uh, to look at urine electrolytes and to also establish the bladder refilling capacity. As arguably the, the bladder refilling capacity after vesicocentesis, um, is, is the, um, the best, uh, uh predictor as to how a fetus will, uh, respond, uh, to in utero decompression with vesicoamniotic shunting. Um, however, we did upfront discuss with the patient the low likelihood for shunt candidacy, um, given the imaging findings that we presented earlier. Um, so she had, uh, one vesicocentesis, um, and, uh, the, the results were fairly concerning, um, and she had poor bladder refilling after that vesicocentesis. And so we didn't see, um, a need for a serial vasocentesis under, under this circumstance, uh, given that the, the outlook was fairly apparent from the get-go. Um, so, the patient was counseled in this regard that the likelihood of, um, of dialysis, uh, shortly after birth, um, was fairly high. Um, and so she was counseled regarding the range of her options, um, including, um, expectant management with, uh, with comfort care measures after birth, uh, pregnancy termination, Um, as well as, um, uh, aggressive measures such as serial amnio infusions, um, with, um, intent for neonatal dialysis and eventual transplantation. Um, and so, after, uh, after extensive counseling, uh, the patient did desire to proceed with serial amnio infusions. Um, at the time of her initial amnio infusion, she did have, uh, demonstrated a normal fetal microarray. So, she was counseled regarding her options of amnio port versus uh percutaneous amnio infusions. And, uh, with this patient in particular, especially given her, um, her high BMI of 42, um, uh, uh, an amnio port could certainly be a, uh, an easier approach, um, for serial amnio infusions as, uh, it can be difficult to perform them, um, percutaneously, um, uh, with, uh, just with the the traditional needle approach. However, we, um, we offered both, um, uh, interventions or both modalities on equal footing, um, and we do counsel our patients that as of yet, we don't have data comparing the two head to head. Um, but ultimately, she elected to have an amnio port, which was placed at 24 weeks of gestation. She did have a total of 9 amnio infusions, um, and, uh, the port, however, did get dislodged at 30 weeks. Um, so during the amnio infusion, we did not see, um, uh, an adequate, uh, intra amniotic refilling, um, and so, um, thought was that the port became, um, extra amniotic. Um, so, she was offered at this point, uh, ongoing amnio infusions via the percutaneous approach. Um, we discussed the fact that there was amniotic fluid during a, um, a significant portion of the canollicular phase of lung development. Um, and so it is relatively unknown, uh, how much amnio infusions would be beneficial, uh, beyond the gestational age. Uh, however, we do counsel them that in the setting of oligor and hydramnios, um, having amnio infusions, uh, can reduce the risk of cord compression and, uh, uh, stillbirth related to that. The patient declined further amnio infusions, um, and she was managed as an outpatient until 32 weeks, which is the gestational age where our, our, um, patients usually meet, um, our dialysis, uh, threshold of 1.8 kg. Um, once she reached 32 weeks, um, the patient was counseled regarding inpatient versus, um, outpatient, uh, surveillance. Um, uh, and, uh, this type of surveillance, uh, is mainly geared towards trying to prevent stillbirth and the setting of anhydramose, um, and the patient did opt for, um, inpatient fetal monitoring. Um, so here is a, um, a short video, uh, on a one of the amnio infusions that was performed with the amnio port in place. And so hopefully you can see my arrow, but you can see here the fluid signal um coming out of the port. Out of the port catheter and you can actually see the port catheter. Um, uh, here on my arrow, and you can see the, um, the fluid signal increasing around the fetus. And this is at the conclusion of the amnio infusion, where you see much more fluid um around the fetus, and you can see um the length of the port catheter uh here in the amniotic space. The patient then um had a follow-up fetal MRI uh at around 32 weeks gestation, um, and we do utilize fetal MRI to um look at, uh, interval of fetal lung development, um, and to calculate and and observed to expected total lung, uh, volume. And in this case, uh, the observed to expected was around, um, 60%, and you can see Um, that, uh, uh, using special software, um, our radiologists, uh, perform digital sub subtraction, and they isolate the lungs, um, and you can see the, um, the image here on the right, uh, calculating the total lung volume. Now, I will say, um, uh, part of the discussion that we had earlier regarding performing fetal MRIs in this patient population, we are very careful to counsel our patients regarding the limitations, um, of fetal MRI and predicting pulmonary outcome. Um, while they are good at predicting, uh, the amount of volume present, it does not always perfectly correlate with function. Um, and, uh, and so we're very careful to, um, to inform our patients of this caveat. Uh, so, ultimately, the patient did have a, uh, a live birth at 37 weeks gestation, um, required about 2 weeks of mechanical ventilation, and there was a confirmed posterior urethral valves postnatally, and, uh, currently, this, uh, individual is on peritoneal dialysis and is awaiting transplantation. Um, our second patient is a, uh, 32-year-old Primagravida at 21 weeks, 5 days, who was referred to our center, um, for suspected multicystic dysplastic kidneys, which were first suspected at around 16 weeks gestation, um, and, and at the time, the, the kidneys, the kidneys appeared multicystic, and there was, um, oligohydrammio. These are our MRI, uh, images. Um, you can see there is, um, virtually no amniotic fluid, um, around the fetus. In here on the image on the right hand side, um, you can see the multicystic dysplastic changes of both the right and the left kidney. And there was also some, um, some concern of either a crossed uh fused ectopia of some kind or a horseshoe kidney, as you can see, it, it appears that the, the right and left kidney, kidneys are, are fused in the midline, I mean their location was, um, was lower in the pelvis. So this patient also underwent multidisciplinary counseling, um, regarding the natural history and life limiting outcomes of this uh of this disease state, um especially in the absence of ongoing amniotic fluid. Um, she was again offered, um, expectant management versus pregnancy termination versus serial amnio infusions for promotion of pulmonary development, and she, um, ultimately elected to have amnio infusions. Um, microwave was normal, um, off the first amnio infusion that was performed, um, and she ultimately desired serial infusions via the percutaneous, uh, approach, and she had a total of 10 of these. And so I did want to highlight our, our center's approach to um these AU infusions, and I do have a series of videos to share with you. Um, so, whenever we're performing amnio infusions, as you can, as you can see, um, they can be quite difficult in that, uh, there is no amniotic space. Um, and so, um, we do have to choose a proper target, um, uh, and where do we insert our needle in the ante amniotic space to, um, avoid the, um, creation of a corn and amnion separation. Um, and so, the, the best targets that we use, um, are parts of the fetal extremities. So, preferably the joints, so knees, elbows, um, and, uh, perhaps most effective are fingers and toes. Um, and, uh, when we approach those areas, uh, the, the joints or the, or the hands or toes simply just move, um, and, uh, allows for insertion of the, of the needle. Um, so here you can see, um, the needle approaching, um, the subcutaneous space in the fascia. And here we use color. Uh, to help us identify any significant maternal vessels or umbilical cord, um, vasculature to avoid as replacing the needle, and you can see here the needle tip is outlined by my arrow. And we are advancing um into the uterine cavity, and here is the foot. Right here. In this image, you can see I'm advancing the needle, and here is the fetal foot, and simply the, the, the foot moves, and the needle is advanced. Into the amniotic space. Hopefully you can see my, my needle tip here outlined by my arrow. And then once we are confident that we're in the amniotic space, we do a test infusion, um, and we do utilize color very often here, and the, the color allows us to see the, the fluid distribution, how how broad the fluid distribution is, and this is showing us a pretty broad distribution, which um is indicative of um uh being directly intra amniotic, um, with low concern for a cornea amnion separation. And here as well, you can see the fluid signal distributing evenly around the fetus. With the expansion of the amniotic space. Now, if we were to see a localized expansion of an anechoic area, um, distal to the needle, um, that would be indicative of an evolving chlorion amnion separation, um, and we quickly, we quickly abandon and reposition of the, uh, the needle when we do see that. And uh this is the conclusion of the amnio infusion. You can see the um the amniotic fluid is restored, um, and there's no evidence of coron and amnion separation at around the needle insertion site. So, um, this patient's last amnio infusion, um, was at 32 weeks gestation. Now, once we get to around 32 to 34 weeks, we do have a conversation with our families regarding the utility of ongoing amnio infusions. And it's, it's really a discussion of ongoing procedure-related risk, risk of prematurity, um, and the risk of oligoanhydramnios. Um, and, uh, it is, it is our thought that at around 32 to 34 weeks, there, um, has been Um, a, an adequate amount of lung development, um, where ongoing immune infusions likely don't, um, confer benefit from the pulmonary perspective. Um, and so, we do, um, have the conversation with our families at around that time to determine whether or not we continue until an, an, an attempt to get to term, or whether we just start more intensive fetal monitoring, um, once anhydrogenos ensues at this gestational age. Um, and so this patient opted to, um, forego additional immune infusions beyond that point in time. Um, she did have a fetal MRI at 32 weeks, um, which showed an observed to expected total lung volume of 72%. Um, and this particular patient elected for outpatient fetal surveillance, and our protocol is 3 times weekly non-stress test, uh, along with weekly ultrasound with biophysical profile. She ultimately underwent an induction of labor at 37 weeks. Um, during her induction, she did develop chorioamnionitis, um, with, uh, late decelerations, and she only had a cervical dilation of 4 centimeters, and so she ultimately had a cesarean delivery and had a live birth, um, with the, um, following weight and Apgars. Um, this, uh, baby only required mechanical ventilation for 5 days. And, uh, and had an immediate peritoneal dialysis catheter placed. Um, and while that dialysis catheter reached maturity, um, the, the, the baby underwent, uh, modified aquaphoresis, and this baby is also currently awaiting transplantation. Um, and finally, um, our third patient, um, is a 31-year-old prubagravida at 24 weeks, who was referred to our institution, uh, again for suspected lower urinary tract obstruction. Um, and this was first noted at 18 weeks gestation, um, with low normal amniotic fluid volume. Um, and it remained this way up until around 23 weeks, um, where, um, suddenly the, um, the fetus had developed massive abdominal ascites and anhydrammias, at which time she was referred to our center. And you can see, um, these are the fetal MRI images here. Here's a sagittal view through the Uh, through the fetal abdomen, um, and you can see, um, the significant abdominal ascites. You can see the liver free floating, the bowel free floating, and you can see the bladder is enlarged, uh, but it, it does look smaller than expected, um, with a complete obstruction, and you can see that there's a dilated posterior urethra indicative of, uh, posterior urethral valves. And here on the image on the right, it's a coronal view through the chest and abdomen. You can see that the chest is significantly compressed by the amount of abdominal ascites present, and you can also see here um that the kidneys do show significant uh uh hydronephrosis with thinning of the renal parenchyma. Here's an axial view, um, uh, through the pelvis at the level of the bladder. And I just wanted to highlight this image cause you can actually see the contour um of the fetal bladder. Um, and here it appears that there's a defect. Um, so this most likely represents, um, a urinary tract rupture at the level of the bladder, um, which explains the presence of the abdominal ascites. Um, so the patient was counseled as such. Um, we discussed the natural history and the options for management. Um, she did desire, um, full intervention measures. Um, and so we did recommend as a start, uh, to have, uh, to place a peritoneal amniotic shunt. Um, and, uh, the, the purpose of this is several fold. Uh, you know, for one, it allows for adequate decompression of the peritoneal cavity and, and hence relieves the pressure on the thorax. Uh, to allow for ongoing lung development. Um, it, uh, allows for ongoing drainage of the urinary tract, um, and, uh, and in some cases, you do see interval healing of the urinary tract rupture, and then you see subsequent, uh, bladder refilling, and these patients are sometimes then candidates for vesicoamniotic shunting. Uh, and, uh, and also, of course, restoring amniotic fluid volume, um, does confer pulmonary benefit. So, um, first, this patient underwent an amnio infusion. And once the amnio infusion was completed, um, we placed the, um, peritoneal amniotic shunt, and our preferred, uh, shunt under these circumstances is the rocket catheter. Um, cause anytime you're performing a peritoneal amniotic shunt, um, the concern is that the abdominal muscle vasculature is not robust enough to keep the shunt in place. And so if you try to use a Harrison shunt, they often do migrate, um, either outside the, uh, the abdominal cavity into the amniotic space or within the abdominal cavity. Rocket shunts have much better, um, memory and are larger, um, and tend to be retained better within the, uh, within the peritoneal space. Um, and so, um, here's the introduction of the, of the rocket introducer, um, into the peritoneal cavity. And then once the um the shunt is deployed, you can actually see the intraperineal portion of the shunt. In the um intra amniotic uh portion of the shunt. And finally, at the conclusion of the shunt placement, we can tell that it's working effectively as the peritoneal cavity appears significantly um decompressed as compared to prior to the shunt placement. Uh, so, this, uh, procedure resulted in normalization of the amniotic fluid, um, for the, for the, um, for the next 2 weeks. Um, she did have normal, uh, a microarray. Then at 26 weeks, uh, anhydramnios, uh, with a small bladder, um, did occur. Um, and, uh, at this time, it was thought that, uh, unfortunately, this, uh, you know, fetus was experiencing in utero renal failure, um, and she was counseled regarding her options at this point in time. Um, to have ongoing, uh, amnio infusions, um, versus expectant management, and she, uh, opted to have, uh, serial amnio infusions via the direct percutaneous approach. Um, these lasted until 32 weeks where this, where the same discussion was had, and she elected to um stop am the infusions at that time. Had an overall reassuring fetal MRI at 32 weeks, and she was managed inpatient for the remainder of her pregnancy and delivered via cesarean at 37 weeks for fetal malpresentation. So this was the follow-up uh fetal MRI, um, that this patient had. You can see the abdominal ascites is completely resolved. The kidneys still, um, demonstrate hydronephrosis, and you can see here the bladder, um, is, is, is still somewhat enlarged, but, uh, has an irregular contour, um, suggesting an adequate bladder filling. Postnatally, this baby did again have confirmed posterior urethral valves, did end up having a valve ablation, um, required about 9 days of mechanical ventilation. Surprisingly, this baby actually was producing urine, um, throughout the hospital stay and at the time of discharge, and so this baby is not currently on dialysis. So thank you very much um for your attention, and I'm happy to take um any questions that um the audience may have. Thank you, Doctor Taba and Doctor Hubley. One of the questions from the chat, um, was asking if there's currently any intrauterine medical treatments um that the mother may employ to try to decrease the development of pulmonary hyperplasia. Not to my knowledge that there is any medical treatment that has been used for such disease. Also there was a question about if there is any prenatal predictor of transplant uh later in pregnancy. Unfortunately, we don't have that's where we need to work more on fetal imaging and chemical diagnosis, uh, because yes, we could say that baby looks have a uterrenal failure, but once the baby is born, that is the true function of the kidney and that is the predictors which I'm sure Doctor Borak will talk about uh that. Yeah, Doctor Hubley, um, you're exactly correct. It's almost a proof of life concept where if you've made it, if the baby's made it all the way through, um, the prenatal in utero treatment and is born, that is when, as you were alluding to, that the whole point of the serial amnio infusions is not the kidney, it's the lungs. And so those children, those infants have to prove themselves to Doctor Riddle and I. That they will be pulmonary, what we call pulmonary survivors. I will say though, Doctor Riddle has some data that she's presented at some of our societal meetings and is working on with Doctor Taba at this point that the etiology um of the babies in utero kidney failure is somewhat predictive in our data. And as Doctor uh Mariana was saying that bilateral renal agenesis is not the same as bladder outlet obstruction is not the same as um um cystic dysplasia, because traditionally the in our in our series, the survive, there's only been one survivor of bilateral renal agenesis, at least in the historical cohort from 2014 to 2017, Steph, I think, was or 2010 to 2017. Um, um, whereas for boo bladder outlet obstruction babies and cystic dysplasia babies, they have a 30 day survival closer to 30 to 40% after amnio infusion. So if you would just look traditionally of those who've made it past 30 day survival, those patients with little to no detectable renal tissue on ultrasound or imaging, they do routinely quite poorly. Actually, um, We, um, are writing a paper right now. We did an analysis on this and we found that those fetuses that had anhydramus and had renal cyst, renal cysts and primarily renal cystic dysplasia, which means more than just two little cysts, those, um, had an association with dialysis needed at 24 hours of life. Um, granted, these were not patients that received chronic. amnio infusion, so on top of that, they have the pulmonary hypoplasia risk. Um, so, just to, hopefully we're gonna get that published, um, but that was what we found. And then, um, I wanted to clarify something regarding the Obtaining phenolone volumes in this population, so we don't do the phenolon volume. If we don't do the amnio infusions. So if we do the amnio infusions, then we obtain a later 2nd trimester, early 3rd trimester fetal MRI to then do the fetal volumes. Once the amniotic fluid has been restored for quite a while and has given the chance for the volumes to. Grow. Um, so I, I didn't wanna be confusing on that, um, so we do that. However, in our center, we have not had a lot of patients with this, so, uh, our practice currently is we don't do fetal lung volumes at the initial evaluation if the patients get some sort of frustration of amniotic fluid, uh, then we obtain that follow-up, the same thing as Cincinnati does. And, and in that aspect, I think it is helpful but not if it is constant antihydramnios. Doctor Eskenazi, um, what about your thoughts related to all of these? Um, thank you. Um, yeah, I'm gonna talk a little bit about that in my presentation. I think that, you know, from my perspective, um, you know, whether someone needs dialysis and makes it, um, you know, on dialysis, I think has a lot to do with, um, you know, the, the care that's involved, and that care is changing. Um, and so, um, I'll, I'll present a couple of cases that, uh, has surprised us as it relates to Um, can babies grow and be, um, uh, and survive even if they are born with very little lung, uh, function and severe pulmonary hyperplasia? And I think Doctor Taba's 3rd case really emphasizes a lot of that point. Sometimes we surmise that absence of fluid prenatally means automatic dialysis in the first week after delivery, and that is not always the case. So there is some amount of counseling that we have to do. The families that ultimately we have to meet your baby and while these are the things we're worried about, we have to sort of be willing to change our expectations either for the worst or for the better, once the baby is delivered, there's still so much that we can't predict prenatally at this point. A quick question, um, also for the panel, um, I know we talked about how important genetic testings are in some of these cases combining with imaging. So in, in pregnancies that there was no fluid around the baby, what's the approach and how reliable is that approach in terms of obtaining reliable genetic um uh information? That's, that's a good question. Um, and, uh, is, is oftentimes difficult, uh, because since there's no amniotic fluid, um, we, we have to actually rely on the, um, amnio washing, uh, from the, from the, from the initial amnio infusion. Um, and so when we, when we perform our initial infusion towards the tail end, we take a sample and, uh, and send it for, um, for genetic studies. Um, and, uh, and so things like a, like a direct microarray aren't necessarily, um, possible under those circumstances, and so we have to rely on cell culture. Um, and it can, if it's successful, it can take, um, significantly longer period of time, um, before you have, um, a result. Um. So that's, that's one consideration. The other consideration is, is performing genetic evaluation off of the vesicocentesis, but that also demonstrates a, a fairly poor yield um in cell culture as well. Um, and so sometimes it takes multiple procedures in order to have an adequate sample, uh, to actually have a, uh, a meaningful, um, uh, chromosomal evaluation. Yeah, I agree. Um, like I talked about in my presentation too, when looking back at the data, at least in our cytogenetics lab, most of these cases are successful in cell cul cell culture eventually, but some of them were significantly delayed, and so it's not always a question of can we get a genetic result, but the question really is, can we get a genetic result in a meaningful time frame? And so it sort of depends on the reason why we're pursuing. All of this diagnostic testing. We're significantly concerned for an underlying genetic etiology that would impact the patient and or the team's decisions to continue with amnio infusions. It can be really complicated if you have to wait weeks for a cell culture and cause what do you do in the meantime? Do you continue doing these procedures with the risks that they might be associated with and then discontinue them later, or do you wait? That's where it really gets challenging. There was a chat question that I just, so what is the outcome of complex anomaly in the setting of renal dysplasia? I think it's all dependent on what's the diagnosis, including genetics. I work up the history that we take with the mom, then the outcome will be based on that. I don't think we can have a general outcome. We have more outcomes of isolated renal disease, as Dr. Bombeck has mentioned. That renal agenesis, our survival is from our series which we published actually the recent bilateral renal agenesis, we had one survival. And from a multicystic dysplastic kidney or renal dysplasia in general, about our survival is 40%, which was zero before we have the infusion intervention. Thus for multiple anomalies it's very hard for us to have outcome. It's going to be based on what is our diagnosis and differential. Then we can report the outcome of these patients. And if the question is about sort of unilateral dysplasia with contralateral agenesis or something along those lines, we find that those patients fall into sort of that middle dysplasia category where those with obstructive disease do best, those in the dysplastic sort of general bucket do, um, sort of in the middle, and then those with true BRA do the worst. Um, if your question is About extra GU and extra renal um anomalies, those are actually, um, disqualifications for, um, amnio infusion at our center. So, um, that is not a category that I can speak to as typically those patients either terminate the pregnancy or uh pursue comfort care. Um, and so that's not a, a population that we follow at this point. All right, in the interest of time, I'm gonna keep us moving. Thank you everyone for your um great input and um contributions to, to this. Let me share really quick. So it's my distinct pleasure to introduce our next speaker. Dr. Askenazi, um, is the W. Charles Mayer Endowed Chair of Pediatric Nephrology, um, and the Director for the Pediatric and Infant Center for Acute Nephrology at the University of Alabama in Birmingham and Children's Hospital of Alabama. Um, he has been an amazing resource for our center, um, as we have started using modified aquaphoresis as an option for, um, early dialysis and, uh, some of our neonates with in utero renal failure. So Doctor Askenazy, we're really excited to hear your perspective, um, on the care of these infants. Great. Thank you so much for the really wonderful kind introduction and uh for really allowing me to participate in the, what is an incredible uh session that you guys are doing. So thank you for helping me be, uh, allowing me to be a part of this. Um, can you guys see my slides here? Let's see. You guys see my slides, OK? Yes, thank you. Great. So, um, so my perspective that I'm gonna share with you today is to recognize that things are changing and that, um, the way we look at outcomes in, uh, in patients who have kidney failure in utero. Um, probably needs to change because the, the way we're helping these babies are changing. And so the, what we can do outside of the uterus is changing and so our outcomes, uh, are gonna change not only based on what happens, uh, in utero with these amnio ports. It's an amniocentesis and the care that we provide them in utero, but also what happens after. So, hopefully, this will help you, um, rethink um how kidney support therapy, this, uh, I use that synonymously with dialysis, um, can help, uh, these babies with congenital kidney failure. A couple of disclosures I have to, to tell you about is that I do consult and receive funding from companies that make machines that we're using. Uh, some of these are not FDA indicated, uh, as they're, uh, uh, for, for small children. Um, I do have a couple of inventions, and I'm going to be showing some pictures, um, stories of real patients, um, their families, uh, not only give me permission, but encourage me to talk about this, um, them in these types of settings. So, um, in the next 20 minutes or so, I hope to review some of the registry data on, um, the survival of infants requiring congenital, uh, requiring dialysis for congenital kidney failure. Um, I will, um, tell you that those are, uh, a little bit old registries, so we'll put those in context. Um, talk a little bit about what kidney support therapy is and how that has evolved over the last 5 years at our institution. And with those, I think it, uh hopefully, Help you guys, um, think about why our approach to clinical decision making, family counseling, and, uh, our collaborations, uh, must continue to evolve with these advancements because things are, uh, moving quickly. So, I'm gonna present you with a case. Uh, this is a, um, a, a, a neonate that had a bladder outlet obstruction, uh, diagnosed in utero, uh, was born at around 3 kg, and, um, on day one, the patient was intubated, placed on a high frequency oscillator ventilation, and, um, the lungs were small and had pulmonary hypertension. Um, and so, uh, that was not able to support the baby with just a ventilator, so they put the baby on ECM. At that point, they called nephrology. I was not on. It was one of my colleagues. Uh, and our nephrologist basically was shocked, said, we can't do this. No one's ever done this. Uh, what do you mean we're gonna try to save this baby who's on ECMO? Their lungs are too tiny. It's not gonna work. Are you sure you wanna do this? Um, and so, after a long discussion with the family, Um, the family wanted to proceed. The neonatologists were, um, very, um, uh, optimistic that we could do this, and so we started dialysis via the ECMO circuit. When the ECMO was no longer needed, we switched over to the Aquadex, um, with a seven French temporary catheter. Um, at day 10, the patient was able to come off pressors. On day 14, was able to come off the ventilator. Still required a lot of medications for pulmonary hypertension. Uh, we were able to wean those off by around 4, 4.5 months, came off CPAP. Um, and, uh, more of the story is that this baby ended up going home, and after, um, 10 months, came off dialysis, surprising to us, uh, had enough kidney function to sustain himself. And, uh, he's now, you know, 2 years old, and he's waiting on the kidney transplant list with severe kidney disease, but not needing dialysis. Uh, he's a beautiful baby. His lungs are As far as we can tell, uh, doing very well. He does not need oxygen. He's had a couple of respiratory infections, and, uh, he's doing great. So, We said, OK, well, that was one case. Maybe that's just kind of an anomaly. So, a couple of months after this baby was born, I was on service and we were called because there was a baby who's being transferred to our hospital, who had um, um, a similar story, 2700 g birth weight, 36 weeks gestational length, had severe kidney dysplasia with oligohydramnios. Um, and the baby was intubated, was put on ECMO, and, um, and they called us after this baby was on ECMO with severe kidney failure, not making any urine at all. So they called us and I, and I said, you know, listen, are you guys sure this is what you want to do? Um, after a conversation with the family and with the neonatology team, uh, the family really wanted to do this because they've had, you know, very difficult time having a, a child. So they were, they were in it to win it. And so, This baby was on ECMO on Day of Life 2, was able to come off ECMO after about a week, um, had a gastric perforation, so it made, uh, the possibility of peritoneal dialysis impossible for a while, and we, uh, went ahead and started, um, dialysis with the ECMOs, I mean, with the Aqueduct circuit. Um, this is how she evolved. At 4 months of age, she was extubated, uh, to CPAP. At 5 months, we stopped CPAP. Um, she came off oxygen after a few months after that. Um, we, you know, discharged her home on hemodialysis because PD was not possible. Um, at around 10 months of age, we, we, we did d peritoneal dialysis, and she, she was able to, to grow and do well. And I got a kidney transplant at 2 months, 2 years of age. Um, this is a 3rd case, uh, kiddo, very similar story, started life on ECMO, extubated at 1 month of age, um, and is doing great at home on peritoneal dialysis, requiring just a tiny whiff of oxygen, uh, at night. So, These 3 cases, and we've had 1 more of a patient that started life on ECMO have really um shocked us, uh, because the idea was, look, if their lungs are too little, there's nothing you could do about it. And I think the, the message to, to me is that if you can support them and get them bigger and provide them nutrition and get their lungs to grow, um, and, um, and avoid, uh, uh, problems during the NICU, these babies do have a chance to live. So, I'm gonna step back and uh talk a little bit about some of the registry data. This is registry data from uh Europe, um, that looked at patients from 1991 to 2013, 1000 patients who were in this registry from uh multiple countries across the world. And what you can see is, um, that 80% of them at 5 years survived. These are babies that were put on dialysis within the first year of life. Um, so their survival is actually pretty good, uh, around 80%. Uh, 5 year survival. Um, this is, um, similar data from 264 patients from Australia and New Zealand, um, that, uh, again shows similar And you could see the mortality rate um in black of about 20%. Uh, you could see that most of these patients are transplanted by 5 years of age, um, and about 20% continued in the white, continued to be on dialysis, um, at 5 years of age. And then a US data registry uh from compared outcomes between uh the 1990 to 1999 decade versus the 2000 to 2014 time point. And what I want to point to is that the survival rate has improved. And so, as opposed to the prior era of babies starting dialysis below 1 year of age, um, about 60% of them, um, uh, survived. And now in the red line here, these are kids less than 1 year, um, about 80% survived in this registry. So, over the last decades, I think we've, we've gotten better, um, as, uh, this, this, this has shown us. If you put these studies together, um, I wanna just kind of show you here on the right side that, um, some of these registries, again, that are, that are prior to, you know, the, the new era, uh, but they're looking at, you know, about 80% survival in these patients who make it at, um, uh, to the registries and end up, uh, looking at, you know, long-term 5 year survival. But I think it's important to recognize the limitations of these registries, uh, because I don't think they really tell the full story. Uh, many patients, uh, and parents are told that their fetus can't survive with kidney anomalies, and so they terminate their pregnancies. Uh, maybe babies are born with kidney anomalies, uh, aren't given a chance at life. They're born and they're, they're basically, um, told that they can't live, um, especially, uh, if their lungs don't work so well. Again, um, as I've showed you with those prior cases, I think that story is evolving. And, um, and I think as we're learning about how to do kidney support therapy, I will argue that many babies are not given the optimal care and support, uh, but that is going to change as, um, nephrology is getting better, and there's a, a big focus and emphasis on, uh, learning how to do, uh, dialysis for babies better. And, um, and then lastly, I'll mention that in these registries, um, many of the patients who are born and are trying to, to have, um, um, survival, um, don't make it to the registry. So you have to essentially leave the hospital to make it onto those registries. And so, um, again, something to consider as you kind of, uh, look and think about those registries. So clearly we need some, some newer registries that are gonna allow us to understand uh what this current era, uh, what their outcomes are. Um, should all babies with end-stage kidney disease be dialyzed? Um, I don't know. Uh, certainly, there's people that, that would argue back and forth, uh, of when and how. Uh, certainly, it deserves, uh, um, a major conversation with all the stakeholders, especially the families, to recognize what they're, what they're in for. Um, and best case scenario, they'll have, you know, 6 months or a year of, of really difficult hospitalization. Um, and, and therapies and dialysis and long-term, uh, the need for, for transplant. But once you've made a decision to, to support the baby, um, let's talk about what we can do to make, make the likelihood of a good outcome best. OK? So, once you've made a decision, don't look back. Let's make it work. And, and so, when we talk about, uh, kidney support therapy, um, Dialysis, renal replacement therapy, whatever you wanna call it, um, there's certain principles that are important for you to understand. There's two types of dialysis. One is through the blood, and one is through the peritoneal dialysis cavity. Um, and there's different sequences. So you can do it 24 hours a day, you could do it prolonged, which usually means 8 to 12 or 16 hours a day, and then intermittent hemodialysis, which is, you know, 3 to 4 hours a day, um, Generally performed in babies daily or every other day. Each of these has advantages and disadvantages, and the choices um of what to use are guided by the patient, the goals, and what you have available at your um at your institution. Um, I think of them as tools, um, and so if you have a, a, a nail that You need to push through a board, you could certainly do that with a paintbrush. But if you have a hammer, uh, pull out the hammer and, and accomplish the goals that you have in front of you that day with the, with the options that seems to, uh, be less likely to lead to problems, and more likely to get you to accomplish your goals. And so what are the goals? What are we, what are we supposed to be doing when we take care of a patient with dialysis? Well, we have to, you know, be the homeostatic function because the kidneys aren't functioning. So we have to make sure that the electrolytes, the water, the uremic toxins are really kind of where we want them to be. Um, and we also have to make sure that we allow plenty of opportunity for provision of the things they need, the calories, the medications, the drugs, the blood products, uh, that they're gonna need, um, to, to, to do well. And what it shouldn't do is shouldn't cause problems, it shouldn't cause hemodynamic instability, it shouldn't cause bleeding, shouldn't mess up your vessels. So, ideally, you have, um, you provide a therapy that doesn't cause these problems. And probably as important is that, you know, your therapy can't freak people out, OK? If, if people are walking, you know, dialysis machine into a patient's room, And the mom starts crying and the parents, you know, and, and the, and the nurses are nervous, and the neonatologists are, don't understand what's going on, um, then, you know, that, that's, that's limiting our ability to really uh provide the best care. So, Let's talk a little bit about peritoneal dialysis. Peritoneal dialysis is great. Uh, we use it all the time for different situations. Um, most of the babies in the registries receive peritoneal dialysis. It's simpler, and it's really a goal that we need to get. You to go home because um most of the time, um, in the outpatient arena, peritoneal dialysis is much simpler, uh, to do than having in-center hemodialysis. Um, um, and so, generally, we have to get the kids to be around 6 kg before they can go home. And, and certainly in most of these kids, the goal is to have them on peritoneal dialysis, um, you know, uh, to, to be able to, to sustain life through, uh, through home peritoneal dialysis. But the problem is that ideally, um, we should not be using peritoneal dialysis for the first week or 3. after we place the catheter, we can, uh, but it's just less likely to work well. There's, there's more likelihood to be malfunctions or complications, leaking, infections. Uh, so ideally a peritoneal dialysis should be held for a couple of weeks, uh, for it to be healed before we use it. And it's not necessarily appropriate in all cases. Um, if you need to have very, very tight precision on fluid balance, where you're making changes from hour to hour, um, it's not as ideal as, um, as continuous renal replacement therapy with, through the blood. Um, certainly, it's not ideal when the PD is not working. If it's leaking, if it's infection, if it's malfunctioning, we could try to kind of, you know, work around those problems, but it's really not ideal. Um, and certainly, there's situations where you have an abdominal process, for example, the baby we had with the gastric perforation or if you have someone who's got, you know, uh, needs a colostomy, uh, where you can't really, uh, use peritoneal dialysis. Intermittent hemodialysis, I mentioned, um, is the most efficient approach, but it comes with certain problems. Uh, the hemodynamics can go off when the machine is initiated, and really, um, it's, it's great when you can accomplish everything you need to in 3 or 4 hours of time. Sometimes that's not possible in these kids, and so you may need 6 hours or 24 hours to really accomplish the goals in a steady, um, and, um, um, systematic, um, gentle way. So why not traditional CRT? This is something that we've been using for a long time, uh, but these machines that have traditionally been used, um, are too big. Um, I'm gonna talk about the HF 20, which is a new filter available in the United States. It's 60 mLs extra corporal volume. That is about half of what it used to be. So up until now, we had circuits that were double, but even this circuit, I just wanna walk you through kind of the thought process behind it. So, if you have a patient who's 3 kg and they, um, the blood volume is about 80 per kilo, that means a baby, a term baby will have about 240 mL of blood inside their body. And so if you're taking 60 mL out to get the machine started, that represents about 25% of their total blood volume to get the machine started. So, that's great, and we can do that, and we can do blood primes, and we can kinda make it kind of uh less likely to have hemodynamics instability. But if you have smaller and smaller babies, so if you have a 1.5 kg baby, you can see that that then represents about half of their blood volume. Um, and if you have patients who are sick, who are on, you know, pressors and have pulmonary hypoplasia and pulmonary hypertension, Um, little changes in these human dynamics can really tip them over. And so it's not ideal for these babies when they're sick and when they're small. To give you an idea of what this would look like if you did it for me, I weigh about 70 kg on a good day, which means I have about 5 L of blood in my body. So you're, you'd have really high blood flows. Um, and essentially, if you compare this 25%, you know, extra corporal volume, It's about 1250 mL. So imagine if to get me started on a, on a machine, you have to take 1.25 L of blood out of my body to get me going. You could, you could see how possibly I may not like that very much, especially if I'm critically ill in the ICU. So, back in 2013, we, um we used to have these conflicting conversations with our neonatologist because I was frustrated that they would call me uh when the patient was already very swollen, when the patient was already, you know, had a very significant problems, when they were, you know, really already started to be malnourished. Um, and so there was a frustration and I would come back and say, look, you know, you gotta call me sooner. And, and one of the doctors that I work with, uh, we'll call him Doctor Diaper today, um, you know, he basically pulled me aside and said, listen, we like you, but your machines don't work. They're a pain in the butt. Uh, my nurses are not very comfortable. My patients are crashing when you start the machines. Um, and it doesn't work so well. Um, they have all these complications. They call me at night all the time and I just don't like them. So The question that, that came to me was to say, well, what if we had a smaller circuit? Um, a clever person solves a problem, a problem, a wise person avoids it. So if we had a smaller circuit, maybe we can avoid all these issues that we're having, and, uh, and maybe that would change things. So, in theory, it would improve the hemodynamic stability. We would be a lot uh able to use smaller access, um, smaller catheters for these babies with that have smaller vessels, have less blood exposure. And essentially, potentially this could be a game changer. If it could decrease or change that risk benefit ratio, maybe they would call me sooner when I thought it was more appropriate. And so, we found this machine that was uh uh FDA approved for adults, for ultrafiltration. Um, it's small, it has an extra corporal volume of about 33 mLs. So it gets the uh 4 kilokedo down to about 10 10% extra corporal volume. So now we have this circuit that we, is, is small, and potentially would be useful. Um, it does not have the ability to do dialysis. But we came up with this idea to say, well, what if we do what we call replacement with CVH where we infuse some, some fluid through the circuit, um, and we do some Y connectors to kind of make it all kind of rigged up correctly, and do what, um, what we sometimes do, um, with continuous, um, renal replacement therapy, uh, by, by clearing with convection as opposed to dialysis. Well, it worked. And uh we have now done um um 91 babies in our NICU since 2013 with this therapy. Um, I will tell you that, um, if you look at this chart, um, this is back in 2003. We did very little dialysis in our NICUs, uh, with the, the, uh, Prismaflex, the machine that I showed you earlier. And, um, and you could see the number of patient days that we do. In our hospital over the last several years. Um, and, uh, we now do more days of CRT in our NICCU than we do in our PICCUU and cardiac ICU combined, partly because we're using the, this, this modality on these babies who have end-stage kidney failure. So, in 2008, we had several kids with end-stage kidney disease that were on circuit for, for months and months. Um, and so that's why you saw this, this big blip here. Um, this is the survival across our cir uh, our hospital, um, NICU, uh, both kidney with patients who have acute kidney injury as well as those with end-stage kidney failure. So you could see that the mortality rates, um, um, are decreasing in our survivals, um, are getting better over time. You can see here that um very few times during our initiation of the therapy, we need to do anything to these babies. Uh, we don't need to give them blood, we don't need to give them volume, we don't need to give them calcium repressors, we don't need to make any adjustments. And the, and the 2% of the time that we've had these interventions needed during initiation, they were pretty mild, a little bit of calcium or a bolus of saline, uh, adjustments in their dopamine. And over here on the right, you could see that year over year, um, most of our circuits are lasting plenty long. And so the, the benchmark that we have is that our circuits should last for at least 60 hours, and you could see that, um, about 60% or 70% of years of our circuits last for, you know, 2.5 days or longer. We, uh, published our data, um, um, with our friends at Cincinnati Children's and Seattle Children's Hospital, um, and, um, it was a three-center retrospective cohort from 2012 to 2018, and, uh, and we describe our experience, um, mainly to point, point out that not all the babies survived the hospitalization, but most of them survived their initial, um, CRT procedure, and we had very little, um, Um, need for cardiorespiratory support at the time of initiation. So So now we're in a situation that we can look back on what we're supposed to be doing, and I could tell you with uh um confidence that we can do it. Um, we can make your electrolytes, sodium, potassium, phosphorus, whatever number you want it to be. Uh, we can clear as much or as little as you think is necessary. Um, and, uh, we can allow for provision of calories and anything else you need, because when they're on these circuits, you can give them 200 per kilo, 400 per kilo, and I'll take that off, uh, without having any, um, uh, problems with, uh, fluid balance. And perhaps more importantly, is that now we can do this without hemodynamic, uh, problems, without bleeding, without vessel damage, um, and people don't freak out. Everybody seems very comfortable in our institution to do it. Our nurses at the bedside are trained. In a simple um machine compared to some of our other things. And our neonatologists, you know, understand this therapy and they recognize that it's not such a big deal anymore. I'll tell you that there's another machine out there that has recently been FDA approved. Um, it's called the Carpodium. It was designed from the ground up to really be a machine for, for small children and babies. It's got all the bells and whistles, and, uh, and it's also a machine that, that institutions are starting to get, and, uh, and it's also gonna be kind of a game changer in how we take care of babies, uh, who need, uh, kidney support therapy. So our current approach is, number one is these babies gotta grow. If we can't grow them, then we're really just spinning our wheels. Um, we don't withhold nutrition to avoid dialysis. I think it's a really bad idea. Um, And as I mentioned, if you're on CRT you can give him as much fluid as you want, because we're, we're gonna be right there taking it off. And it's really about finding that balance. You're deciding what our goals are for fluid for that day, and we can, we can make adjustments in our machine to achieve the goals that we want. Um, so, the second is we start dialysis when the babies need it, so we don't wait until the baby is starting to be malnourished, or a fluid overloaded, or uremic before we start. We look at the baby and say, well, is the baby able to, to maintain homeostasis of fluid and electrolytes, and, um, and uremic toxins. Uh, if they can, wonderful. Uh, if they can't, if we can't get them big, if we can't give them nutrition, uh, we go ahead and start. Again, avoiding complications is not just about uh the technology, although it's super important, uh, but really it's also about educating our team, uh, developing the right processes and procedures to, um, to develop safety nets, because these patients are fragile and, um, and small changes can happen that could tip them over. Um, we've learned that, um, Preventing and treating pulmonary hypertension is very important in these patients. Um, so, the things that neonatologists know well about pulmonary hypertension, Um, need to happen in these patients, otherwise, we end up getting into, into problems and, and, uh, really can't get them off of ventilators and nitric oxide, etc. But if we can do that, um, as well as to get these kids' lungs bigger, uh, we, we can have success and get them off these therapies, and, uh, and get them off, um, uh, ventilator and oxygen support. Um, and then finally, you know, options are really good. Devices, uh, and these approaches that we have are complementary. Those babies that I mentioned to you at the start of the talk, um, all of them received CRT, intermittent hemo, peritoneal dialysis, and it's really about what makes sense for that patient at that particular moment, uh, to help them kind of get to where we want them to be. And lastly, um, having a surgical team and having the right catheter placed at the right time by the right person and the right vessel is essential, uh, for us to be able to do this work. This is a study that we recently published in Pediatric Journal of Pediatric Surgery. Uh, we'd like the 6 French power honed double lumen catheter that is, um, able to be cut to the desired length, um, so that we could put it in the, the perfect little window, um, where these patients need them to be. So, um, to put this all in context, then, um, again, it's hard to compare to other registries, uh, but, again, for the reasons that I mentioned, but I will just mention that, for example, in that USRDS database, there was 372 patients in the, in the entire United States over a 14-year period of time. Um, in those other studies, 5 countries, 264 patients, um, we're doing a lot more than that if you think about one state doing, um, in 5 years, doing 27, uh, patients. And so, we're doing, you know, a lot more patients than, than previously. Um, and these patients are much Thicker, uh, many times. Um, I'm presenting patients that needed, uh, CRT. Uh, so the patients who ended up needing peritoneal dialysis aren't really, uh, these 27. These are really the 27 patients that, uh, were the most, um, dependent on dialysis, if you can, if you can, uh, state it that way. And, um, and again, uh, not all of the babies survived. These are, again, end-stage kidney failure patients at our institution over the last 5 years, and we have about a 50% survival rate. Um, and, and again, but these patients were super, super sick. I hope that our numbers are getting better over time. Certainly, in 2019 and 2020, um, those patients born then, um, had an 80% survival rate, but again, small numbers to, to know if it's a real trend. Um, I do wanna mention that if anybody is out there who wants to learn more about, uh, neonatal kidney support therapy, we have a course that we put on where we go through the machines, the, the, the different types of therapies, um, our approach to access, education, the prescription medications, nursing, uh, the PT and OT, uh, challenges that these patients have. Uh, so if anybody's interested, we have this course quarterly, um, and we spend a day and a half talking just about neonatal kidney support therapy. So, in summary, the decision to support a baby with dialysis, um, when they're dependent and have congenital kidney disease is not easy. And, um, and the care is not easy, uh, but I think the benefit rat ratio is changing. So, our conversations with families need to change in our approach to, um, registries and our approach To the outcomes that we're looking at when we do things like amniocentesis, I think need to change, um, because the, the evolution of kidney support therapy and neonates are, are going to continue to get better as more and more institutions, um, have these therapies available and develop programs to support their babies. Uh, kidney support therapy can be performed safely, safely in even really small and really sick babies, um, without Having them develop complications without freaking people out. Um, I tell folks, and I probably need to be careful how I say that, but if you bring me a really sick kid who's 1.2 kg, um, I feel pretty confident that our team can put him on circuit safely and could, um, again, support them, um, so that, uh, we can take care of him with all the other medical needs that we need. Um, it certainly takes time, education to build programs, to build collaborations. Um, you need dedicated families, um, really to give these babies a chance at life. And, um, I really thank you guys for your time, um, to, um, and, and for the opportunity to share our experiences, and, um, and I'm happy to answer any questions that you may have. David, is excellent talk. Um, I certainly enjoyed that a lot and learned a lot. Um, are there patients that you would not consider placing them on ACO? If, if they are, what are some of the criteria? Besides severe genetic abnormality, obviously. So that's a, a great question. I think that the The patients that we've had, we we didn't make the decision to put them on ECMO, um, in the sense that our neonatology and surgery colleagues, um, spoke to the families and they were placed on ECMO. So, so we weren't involved with that decision. We kind of were told later, hey, I have a patient on ECMO that we need your help with. Um, If it was me kind of providing people guidance, um, I think that Giving a, a, a child an opportunity on ECMO is potentially a reasonable thing to do if you have um a family who really understands what they're getting themselves into, recognizing that the likelihood of a, of a good outcome is not 100%, recognizing that even if they, um, even if they, the, the baby's gonna survive, it's gonna require multiple surgeries, multiple therapies, um, months and months in the hospital. Um, So, I think it, it, it's an individual conversation that, that you have to have with families. Um, I think the classic indications for ECMO or the contraindications, um, pre, really severe prematurity or, you know, um, has multiple congenital anomalies, I think, you know, still kind of, um, um, apply. Uh, but our institution is, is, you know, become confident that we can support these babies with Nutrition and fluid balance and electrolyte balance, and so they're, they're, they're offering it to their patients a little bit more. So what about bilateral renogenesis patient? Yeah, I think it's really It's a hard question. Um, I think it, it comes down to, do they have lungs that potentially could grow, and can you, as an institution, as a program, Provide them and grow them in context of them needing ECMO and needing, you know, such severe respiratory support for a while. Um, my job is to allow you to take care of the baby without concern for uremia, without concern for electrolyte problems, and without concern that you're gonna make them fluid overloaded. Um, and so, if you have a, a patient who, um, meets other criteria to, that you think that you could grow them by giving them nutrition, even without kidney function, um, then I think that, that at this point, it's It's possible to, to, to have a good outcome. Uh, we don't have enough data to be able to say, you know, the, the probabilities for different diseases, as you mentioned, or for, um, different severities of pulmonary hypo hypoplasia, hyper hypertension at, at birth. Um, but we're learning that what was possible, uh, five years ago is different than what's possible now for us. Thank you, David. That was great. I just, one quick thing, it's always great to hear the nutrition, um, idea be thrown out. We talked about this in our first, uh, session, but as a neonatologist, it's always a challenge when you're fluid restricting these patients so severely. Um, sometimes I think that contributes a little bit to the hypotension situation we can find ourselves in, but not being. Able to give these kids good nutrition is not giving them a good neurodevelopmental outcome, even if they survive to go home from the NICU. So I think the advent of a lot of these new therapies like modified aquaphoresis and like CP ADM is really gonna help us, even if they are survivors, improve ultimately their outcomes because we can give them better early nutrition. Yeah, I, I totally agree. I mean, the, the, we had a patient that was transferred from another institution. Yeah, the kid is, you know, a month old. By the time we got to him, he lost weight from birth. Uh, they were giving him, you know, very, very little nutrition because of those reasons. The PD catheter wasn't working and the kid was just starving to death and, and it wasn't surprising that they couldn't heal their PD catheter, that they were getting infections. Um, So, I think, you know, the approach of saying, OK, well, let's, let's do the things we know how to do well by giving them nutrition and supporting them. Um, let, let's, let's put the kidneys out of the picture. We can, we can do the job of the kidney well. Um, and so if we can do that, we, we, we work together with you and say, well, how can we get these kids big? Awesome. Thank you so much, Doctor Ashkenazi. I'm gonna move on to the next, uh, speaker, um, and this will finish our panel for the morning, um, but again, we'll stay on for questions after we're done. Um, so our final speaker this morning, um, is Doctor Alex Bondock. He is the surgical Director of kidney transplantation. and assistant professor of Surgery and pediatrics um at the University of Cincinnati and here at Cincinnati Children's Hospital Medical Center. And Doctor Boondock is gonna talk to us about some of the surgical considerations for these patients who require early dialysis, um, as well as an eye towards eventual renal transplantation and some of the outcomes that we've seen, um, here locally. So Doctor Bondo, take the floor. Thank you, Steph, and thanks to Doctor Askenazi. It's an, that was an awesome talk really highlighting some of the challenges in um caring for these patients, um, because truly one of the things that, you know, I can talk to you guys about is the multidisciplinary nature and the way that we succeed is through that is exactly what um he was describing, and I'll touch on all those aspects here. But from a with an eye towards the surgical considerations that Doctor Askenazi was uh alluding to, because thoughtful consideration of um how do you dialyze these patients via which catheters, um, enteral access, um, kids with stomas, things like that all have has evolved very significantly in the last even, let's say year or two for us. So, the title of my talk today is the surgical Considerations for in utero kidney failure. The objectives of today's talk are just to discuss the perioperative and physiologic considerations that are unique to this patient population that Doctor Askenazi alluded to already. Um, reviewing options for renal replacement therapy and types of catheters, which has also been touched on, um, and considering the other surgical needs of these patients and specific, um, anomalies that these patients face. And then finally, as uh Steph alluded to, I'll, I'll touch base on um uh our experience with renal transplantation of bladder outlet obstruction patients uh here at Children's in Cincinnati. And so, um, the first, I, I started out as a case per Doctor Lim's request, and this is an ex-thirty-seven week old, uh, male child who was born to a G2P1 mother, whose 20-week anatomy scan revealed a massively, uh, dilated bladder with a urachal pop-off there, you can see. So as red as megacystis, there was anhydramnios, um, a severely echogenic left kidney with peripheral small cysts, and no normal right renal tissue or left renal tissue was noted for that matter. And so the prenatal diagnosis was made of bladder outlet obstruction. And as a result, the um um mother infant died underwent an MRI at 21 weeks, uh, which, which demonstrated the very distended bladder you see there, as well as um bilateral severe cystic renal dysplasia. Um, the patient, uh, as described by Doctor Habli and Doctor Tabal underwent 9 amnio infusions over 9 weeks. And as we discussed, the baby ended up undergoing a repeat MRI at 33 weeks gestation, um, where the bilateral cystic dysplasia of the kidneys was reinforced and pulmonary hypoplasia was, um, the diagnosis of pulmonary hypoplasia was also made with Uh, the total lung volume estimated here was 37 mLs, where the normal range at 33 weeks to 35 weeks is anywhere in the neighborhood of about 50 to 130 mLs. Um, so, certainly, uh, um, a cause for concern for us and also giving us a, um, thoughts on how to prepare for this child when, uh, he was delivered. So, unfortunately, the baby was aneuric at birth. Uh, there was no urine via the urethra, and this was the ultrasound that was demonstrated at the time of birth. Um, hemodynamically, he required, uh, initiation of epinephrine and vasopressin. He was also started in on inhaled nitric oxide and hydrocortisone. So shortly thereafter, the urologists were consulted. Um, and they went ahead and placed a percutaneous angiocah to try and decompress the, uh, bladder system, a percutaneous vesicostomy, as demonstrated by the star there, you can see the catheter. So a lot of the sort of, um, hypoechoic fluid was was drained, but the hypeechoic debris, uh, was still trapped in the bladder. And so what next? Um, as we've already talked about, it's not just a balancing act between, you know, it's not a binary balancing act. We have to consider, as Doctor Askenazi mentioned, the renal replacement therapy, but then you're balancing all the other things, specifically in my, in my case, the fitness for surgery and the risk of general anesthetic. Which is then a balancing act between cardiovascular status, pulmonary status, other congenital anomalies, and how are we going to handle the genitourinary tract and, uh, especially in the outlet obstruction patients, but all KCU um patients. And so, I don't have to belabor this. I, you don't want to hear a surgeon talk about the renal considerations of these patients, especially after Doctor Askenazi. But the other thing I would add is how are we gonna manage the bladder? What is the urinary system drainage, and what is the bladder status? Um, as we mentioned already briefly, the cardiovascular status of the patient is the patient hemodynamically stable or on vasopressors. Uh, we usually echo these babies in their first week of life to look for evidence of pulmonary hypertension, as if it wasn't, uh, abundantly clear by their ventilatory needs, uh, as well as congenital heart defects. We also look at their pulmonary status, which goes hand in hand with their cardiovascular status. Because some of these children need escalation to invasive positive pressure, uh, ventilation as even the oscillator, you already heard Doctor Eskenazi talk about his experience with patients who are placed on VA ECMO for the same reasons. Um, some of our patients come out and surprise us and they're extubated in the 1st 24 hours after having been intubated and they're, um, Uh, immediately postnatally in the resuscitation room. And then again, as we discussed the the ongoing assessment of pulmonary hypertension. And so, in these first few days um of life, we have to consider what kind of renal replacement therapy options. Um, uh, are we gonna consider? And again, same things that Doctor Askenazi already touched on, but it sort of, as we think about that, it informs how the types of catheters I'm gonna place at the initial operation. So not only are we thinking about how stable is the patient, what kind of anesthetic considerations are we gonna have, but also what kinds of catheters will the baby be stable enough to have? What kind of urologic procedure should uh um he or she have at that time. And so typically, um, for our the way we initially proceed once baby is stable enough, Um, in this case, uh, the case that I described to you, we went to the operating room on day of life 5. the baby was still on vasopressin, which was weaning, the epinephrine had been weaned off, the steroids were still on, the baby was still on inhaled nitric oxide. So, again, we have a very short window of when the baby can be under general anesthetic. And so what we typically do here is we place a temporary right internal jugular 7 French hemodialysis catheter. Um, as well as a laparoscopic or open assisted peritoneal dialysis catheter. Exactly for the reasons that, uh, Doctor Askenazi said is that we like to have the option to do blood blood renal replacement therapy either via aqua continuous CRRT or by eventually hemodialysis as we allow for about 2 weeks, typically, the peritoneum to heal, uh, it's incisions where we placed the PD catheter. And so, In this scenario, just some tips and tricks we've picked up over the, over time. We never place catheters in the subclavian for future reference, for future hemodialysis or fistula-based dialysis as the patient hopefully will, you know, grow older, um, and eventually likely outlast any kidney transplant they would have as an infant. We also sort of tunnel this percutaneous catheter. Uh, we make a counter incision in the neck near the mastoid process, almost like an emo cannula, so that this percutaneous catheter is actually somewhat tunneled because these polyurethane catheters have the tendency to kink because of the weight of the lines that go to the aquaphoresis machine or even the dialysis machine eventually. Um, You know, aquaphoresis for the short term is sufficient, but over time, and it certainly in this scenario, the baby doesn't make any urine and will need formal dialysis. And again, as I mentioned to you, this time on the hemodialysis, usually a couple weeks, will allow for adequate peritoneal healing in anticipation of uh peritoneal dialysis initiation. And so, from a tunnel peritoneal dialysis catheter placement, um, as Doctor Eskenazi made it clear, it's the long-term pre uh preference for physiologic and social reasons and ease reasons. Um, from a technical consideration that we typically like to do them with a laparoscopic approach. You can do it open with fluoroscopy if the baby is is particularly hemodynamically unstable. Um, this is specifically in regard to our patients who have undergone cardiac, um, procedures or have structural heart disease and have high right-sided heart pressures. Oftentimes they will not, um, tolerate laparoscopic insufflation of their abdomens. So we do that with we do that from an open approach. Uh, typically we will place the catheter and the and the cuff through the right rectus sheath with an exit site. Um, on the left lower quadrant with a downward facing course, there's, um, a, a, a reasonable amount of retrospective data suggesting that a downward facing course for a peritoneal dialysis catheter decreases its risk of, um, uh, peritonitis and catheter site infection. We also do a concurrent omentectomy, and I'll show you some data on that later. And so this is essentially what it looks like. The X marks where um uh subcutaneously or intro uh inside the fascia is where the catheter is actually going in, and then we make a gentle curved tunnel to the contralateral side of the abdomen, so that it's a downward facing um exit site. And so for this patient clinically, um, 5 weeks later, the baby was, uh, working up on peritoneal dialysis, uh, with a functional catheter to fill volumes of 30 mLs per kilo. Uh, but more recently, we're having some, uh, intermittently inadequate return volumes, uh, which is either a peritoneal issue or more likely a catheter-based issue. Um, with peritoneal dialysis, as is not uncommon, we noted a right inguinal hernia, uh, with a hydrocele, uh, that fills up with peritoneal fluid or peritoneal dialysate, and then the patient is also nasogastric feed dependent. So once we get out here and we have reasonable peritoneal dialysis is when we start to think about other surgical procedures. Now, what I would tell you for a lot of these babies with in utero kidney failure, whether or not they have a true cause, such as Eagle-Barrett. Um, of their in utero kidney failure, um, what our urologists have termed this, termed what a lot of these babies have is pseudo prune belly. And the reason they say that is typically because of how distended the bladder was in utero, um, with little, uh, um, um, Amniotic fluid surrounding them, that bladder ends up distending and distorting the development of the abdominal wall. And I would tell you that the vast majority of these patients, the boy patients and the female patients for that matter, have inguinal hernias, and a lot of the babies also have undescended testes. And so when you think about surgery in these children, sort of distant from birth, distant being weeks, um, what we're trying to do is prevent disruption of peritoneal dialysis with minimally invasive approaches, laparoscopy, tiny. Incisions, incisions that are higher up on the abdominal wall, and then all the procedures where we will locate G tubes, where we will locate stomas, things like that, all are done with an eye towards future transplantation. And so in this same baby, we show you the ectopic testes. And so I talked to you about omentectomy. Um, because this is a very common reason why peritoneal dialysis catheters fail in young children, and this is a, um, a, uh, data that has been published or has been presented at meetings and is now currently in revision from Meredith Shi and, uh, a consortium of, uh, pediatric. Nephrology groups in the Midwest. Uh, the senior author is Donna Clayes, who's also on staff here in Cincinnati. And what they found was that, um, when you look at the adjusted, uh, multifactor multivariate analysis of reasons why peritoneal dialysis catheters fail in children, is usually age at the time of peritoneal dialysis catheter insertion. In this case, it's 4 times more likely to fail if the patient's over the age of 6, and that When you have omentectomy, that dramatically decreases the risk of this happening, of, of PD catheter failure or infection. And so you could see here in one of these patients, um, omentum was clogging up the catheter, and it can wrap up and and distort the catheter, the pigtail catheter. You can also get fibrin, protein proteinaceous deposits inside the catheter, and so here, we just use a blunt wire to um sort of roto root that tissue out of there. So the other surgical considerations I told you about were the inguinal hernias. Um, and so, here, what we've started doing, one of my partners who's particularly facile, even in small children with laparoscopy, uh, is started to fix these hernias laparoscopically. Um, other things to consider are enteral access, um, such as G tube placements, um, undescended testes, and more recently, um, We started after some um data came out at, at a meeting that Doctor Stu Goldstein, uh, who's one of, who's our head of pheresis here, um, saw was that traditionally, our center had not offered peritoneal dialysis at all for patients who needed stomas for other congenital anomalies such as um anorectal malformations, uh, or even Hirschprung's. But more recently, because of, um, intraabdominal catastrophe for one patient who had Hirschsprung's disease, Um, we were able to sustain her on, um, on peritoneal dialysis for a period of time with an ileostomy, and that's shown in the top panels. And then, um, also recently we've, we had a patient with an, uh, um, anorectal malformation who had his stomas made at one day of life and had developed subsequently worsening chronic kidney disease to the point where he needed Um, renal replacement therapy. And because he already had stomas and we already had to go back in for surgery, we went ahead and tried peritoneal dialysis based on our experience with the first patient, and he's been sustained on peritoneal dialysis and at the same time, we put a gastrostomy, uh, tube in his stomach. And so here's the picture of that patient's abdomen, stoma in the left lower quadrant, gastrostomy in the left upper quadrant is peritoneal dialysis catheter. We exit site we flipped uh for for hygiene to the right side. And so what happens long term? This was a paper, uh, or this was a poster that we presented at uh PAS just, uh, last, a couple weeks ago, uh, done by one of my research fellows, Carrissa Lake, and Braxton Ford, who's one of the maternal fetal medicine fellows, uh, working with Doctor Taba at the university. And this covers um our experience from 2010 to 2018 on patients with bladder outlet obstruction who've survived uh to renal transplantation and their outcomes. And um what you see here is we tried to break it down, each panel to the multidisciplinary to reflect the multidisciplinary nature of the care of these patients. And so, um, you can see that 80% of the patients required ventilator support at some point in their, in their nursery stay. Um, but luckily, only um 2 patients required minimal oxygen support out of the 18 we've presented here. Um, Postnatally, uh, I'm sorry, post-nursery, um, we had an average of 6 hospitalizations, uh, with 8 operations. And sorry, I should have hit that earlier. And from a dialysis standpoint, 9 89% of the patients or 16% of the 18 patients required dialysis at some point, and the duration of pre-transplant renal replacement therapy was 1.7 years. And to speak to Doctor Riddle and Doctor Askenazi's um um points about how important nutrition was. Um, was that we were able to supplement these patients, um, 80% of whom needed gastrostomy tubes, um, where they were able to get these babies to a similar Z score to their peers, uh, by weight, but interestingly enough, height was, we could never achieve, um, uh, similar height by weight, uh, growth parameters. And so from a transplant perspective, uh, the median age of transplant was 2.3 years. Um, a lot of these patients had complex genitourinary needs that the urology service helped us with, um, or, you know, they're, they're critical collaborators in this whole thing. Um, and then long term, the median, the mean follow-up, um, Uh, it was 6 years for these patients with a median follow-up of almost 7 years, and we report a, you know, a survival over that time period of 94%, which I think is relatively good. Unfortunately, we had one patient, um, experience graft loss from chronic rejection and then one death, um, uh, in a patient who was unrelated to their renal disease. So that's about it, and I'm happy to take any questions or make any comments um uh on the data we presented. That was great, Alex, thanks so much. Um, I think it was great that you mentioned the experience that we've had with the patients with ostomy and you know, you alluded to the data from the North American, um, registry that was presented a few years ago that sort of led to this shift, but any sort of, um, learnings that you guys have had. Out of those few patients that we've done so far, um, and things that, that we need to consider for the future as we expand, um, the option for postnatal therapy. Yeah, no, I think it, I mean, it's interesting because both of those patients, as you might surmise, have not had simple postnatal courses. The first patient perforated her colon. Um, after initial PD catheter placement, which because of her Hirschprung's, that was her initial presentation of Hirschprung's. So we had to biopsy her rectum and make her ileostomy, and she was able to sustain on PD after she, we sanitized her peritoneum for a period, but then it failed, more than likely because of uh peritoneal failure, and then the second patient actually um had a complication with his colostomy. So, at that point, we, because of our experience with that first patient, we elected to revise that surgery, um, and then place a PD catheter. Luckily, there was no peritoneal contamination. So I think it really ends up being, you know, those were our feasibility patients, and then what we've learned in that regard is keeping the peritoneum sterile, but also meticulous, um, technique when you're building the stomas. So that you are completely isolating the outside from the inside that you're not gonna, you know, contaminate the peritoneum. But from a sur purely surgical perspective, you know, when we make stomas for anything else in a patient who does, in a neonate who doesn't have renal failure or in utero kidney disease, it's not like we're contaminating their peritoneums. So I think it stands to reason that if you, if you make stomas in a, in a Durable, meticulous way, those patients can be sustained on peritoneal dialysis. Yeah, it's certainly shifted the way we talk to families prenatally. Not all of these things are able to be diagnosed like with your patient with um Hirschsprung's and we've seen them with imperforated anus and things. So, um, it has shifted the way we've counseled these patients. So, um, it'll be interesting to see their experience moving forward. And, uh, one last thing to add is sort of from a, from a system standpoint, as has been alluded to, the, the people who take care of these patients and their surgical problems, uh, are, it's a specialized team, just like it is with you guys and with Doctor Lim and the nephrologists, but, um, the transplant surgeons, the pediatric transplant surgeons here in Cincinnati, and essentially take care of these patients' surgical needs from birth to transplant and beyond. So, I have, just as a matter of course, I have two other partners. We're both trained in pediatric surgery. We're also board certified in abdominal transplant surgery, and so that allows us What Doctor Askenazi was referring to, building that experience, building that comfort level, where to put the catheters, how to handle these surgical problems, and that's really the way we've, we've learned is, you know, we try to be as specialized as possible, but it also gives the, the, the families and the teams familiar faces to, to help put with, um, you know, from birth to transplant. So, um, there was a question from the audience, obviously, um, you know, not all centers are like, um. Some of our, um, presenters here. Especially, you know, what we can offer, um, comprehensively from the get-go. Um, there are, there are plenty of places that, uh, resources are low, uh, and inadequate. Um, how would you approach those patients in those areas? I mean, it's not just, you know, uh, in third world countries, certainly we see that pockets also in United States, right? And also some of the um The advanced, um, uh, and developed countries. Anyone from the panel. Yeah, I'm happy to, to answer that. I think that, you know, like anything else, I mean, as physicians, we're, we need to know what we can do and what we can't. And we need to reach out to our colleagues for, for help. And so, You know, we, if there's things that we can't do at our institution, you know, we should be sending them, you know, do the right thing for the patient and, and finding those resources that are out there. Uh, at the same time, um, you know, institutions should be looking at how to enhance their programs, enhance their ability to take care of patients. But in the meantime, uh, don't, don't hesitate to reach out. And I think too, Fong, um this is where the importance of the fetal, the prenatal fetal counseling, um, portion of things comes as you sort of go over what you think is the severity of the disease process with the parents or the family of that, um, unborn child that You know, you're looking at, we can cite you data of how long your baby will be living in the nursery, and how long your baby will be living in the hospital, and what it looks like on the back end, and the problems that can happen, how many hospitalizations, what transplantation looks like. And so I think if, you know, depending on the resources of the persons of the institution in general and plus how involved that care can be, then you can at least the parents can make the most um Informed decision possible. And I think one of the things that we've learned, maybe one of the upsides to the pandemic has been the availability of, uh, virtual consultation and the ability to counsel patients that are not physically present with us. Um, and I think that could be a resource, um, certainly, we've had referring Physicians join some of these um sessions, as well as the family itself to um try to understand the resources from, from where they're coming from, and I think that could be, you know, a benefit that comes out of the pandemic as these, uh, virtual resources have improved. Well, we definitely have had a wonderful, uh, panel this morning or this evening to some of you. And um I really hope that, um, You know, you all, uh, find this um type of live webinar, um. Not just interesting but also um Benefiting, you know, Your center and also your patients and we, we would love to hear back from you if you have any feedback on how to make something like this um more useful uh and also more interesting. Um, we, we have session number 3 coming up in June and certainly hope a lot of you and your colleagues, um, as well as your, your friends. Uh, can join us. Uh, I apologize that some, uh, countries, uh, were not able to view this live webinar, uh, smoothly because of the platform, um, in those areas, uh, but hope that, um, you are able to log on to the recorded, um, series. And able to view that, you know, hopefully, uh, in a, in a easier fashion or hopefully smoother um when you come back and view the recorded session. And I want to take this opportunity to thank all of the um the speakers um in the panel as well as uh people that help us to make this successful from our global cast crew, um, Jay, John, you know, especially, uh, and all of those that help us to put, you know, this webinar together, um, and More importantly, I'd like to thank all of the um the audience uh from around the world to, to make this uh successful without, without the audience, we will just be talking with each other on uh on this Zoom meeting. Um, so thanks all of you again for taking your time joining us, uh, even, you know, I know some of you had to get up at 4 a.m., 5 a.m. to join us and others, um. You know, uh, uh, putting away your, your important Saturday night, uh, agenda, uh, to join us. So thank you again. If we don't have any um additional questions for the panel here, we will conclude here a few minutes early. And remember, so remember that David, you, you wanna say one more time about your um your quarterly um course. Yeah, thank you. So, um, our next course is May 23rd and 24th. Uh, we have just like two or three spots available, so just email me if you wanna do it. Um, and then, uh, again, it's, it's a full day of, uh, didactics, and then it's a half a day of simulations. Um, and, uh, again, we have, uh, neonatologist speak and surgery speak, and, uh, nutrition and pharmacist to really try to be comprehensive about The care that, that, uh, is needed to support these, these children. So, just send me an email and I'm happy to, to, to, to get you guys hooked in. I think the, the next one is middle of June. Middle of July, sorry. Um, Alex, actually there's a question just posted. Uh, by Doctor Kaskas. About tricks you would recommend for insertion of PD catheter by open method? Yeah, I responded um for the first part of it, but typically when you do any PD catheter, um, our, the, the ones we have are pigtail catheters, and they measure the distance from the cuff, um, to the tip of the catheter, and usually it's by infant, pediatric, adolescent. Usually the way I estimate that is the distance between the bottom of the belly button to the pubic bone. So I would tell you for most neonates, it's actually a child's catheter, a 6.5 centimeter catheter. Um, you can go through the same incision I described in the slides, but in this way, if you don't have fluoroscopy, you, you have to insert the catheter over a metal stylette. And you aim, you use your hand and you feel the anterior superior iliac spine, you touch that and then you walk it down the pubic bone and try just by blind feel, try to get behind the bladder and then deploy the catheter. You can also, before you, you know, push your, push, place your catheter, you can pull the baby's omentum up through that incision, and you can just do a, a sort of blind omentectomy, not obviously not getting too close to the colon. So that's, I, and if you have fluoroscopy, that's the best way to confirm where the tip of your catheter is. So those are sort of the my thoughts on open um PD catheter placement. Stephanie, you want to take the honor to conclude. Just thank all of our speakers again for joining us today and taking time out of their busy Saturday mornings and Saturday evenings for those around the world, um, and hope you guys have a great rest of your day. Thank you very much. Thank you. Thank you.