Um, you know, as I sit here, uh, or sat through the initial part of the discussion and also in the Cincinnati Fetal Center when, um, I am interacting with patients who come in and have, uh, some sort of fetal genitourinary disease, I'm always, uh, you know, impressed by all the discussion about the renal aspects and transplant and dialysis. And all those things. But, but I always come back as a neonatologist to say, yeah, but, and that is, yeah, but all that's important, but it doesn't matter if the patient is not a pulmonary survivor. And Um, even though that's something that's very important, it's something that is frequently overlooked in these type of discussions and rightfully so because, uh, you know, when we, the problem originates in the kidneys and that's the or in the renal tract and that's, that's usually the focus, but you still have to address this question and that the issue of is this infant a pulmonary survivor and it's not really a simple question to answer. And so we start out in the, you know, in utero and we look at the amniotic fluid status and if the infant has normal amniotic fluid status, you know, from a pulmonary standpoint, then you're, you're just going to observe and that's fine. If the infant has low or no amniotic fluid. Then of course you have to address the question of should this be, uh, should be the amniotic fluid be replaced in some way, whether it's shunting or amnio infusion or, or what have you. And so I realized that that's a huge area and I've just simplified it down to the word replace, um, and we know from our internal experience that if you can replace the amniotic fluid to the point that the amniotic fluid levels become normal. That your likelihood of becoming a pulmonary survivor increases significantly, significantly, and our internal data suggests that that's around 80%. On the other hand, if the amniotic fluid levels are not returned to normal, then of course your outcome is poor. Um, but then once you've gone through all this and you go to the delivery room, then the question is how do you determine whether that infant is a pulmonary survivor or not? Because. Uh, just to say, oh well, if they have lungs and they work and they survive, well, that's good enough, but it's more complex than that. Obviously, if the infant doesn't make it out of the delivery room due to respiratory status, it's easy to categorize categorize that infant as a non-pulmonary survivor. However, if they survive out of delivery room, it doesn't necessarily mean that they are a pulmonary survivor. Now you might say, well, if they're on room air, then they're definitely going to be a pulmonary survivor, whereas if they require some sort of respiratory support, whether that be, uh, whether that be nasal cannula oxygen, head hood oxygen, CPAP, or mechanical ventilation, then it's debatable about whether or not that infant is going to be a respiratory survivor. Um, but, There's a lot of factors postnatally that go into whether or not an infant is going to be a pulmonary survivor, and unfortunately we don't necessarily have the answer to all those questions. So for instance, we don't know if this infant is going to sustain postnatal lung injury after delivery, such as from sepsis, and obviously all these patients are at extreme risk of sepsis and developing pulmonary lung injury from that. We don't know if this infant is going to be good or bad in the nutritional category and therefore have problems with uh lung growth in general and lung growth. We don't know if this infant is going to be placed on a ventilator for a brief period of time and require high pressures and be, uh, be re or uh subsequently rece uh be uh. The recipient of barrow trauma from lung injury from the ventilator, so there's lots of factors postnatally that go into the question of whether or not an infant is going to be a pulmonary survivor or a non-pulmonary survivor, and I think it's important here to say that just because you are a pulmonary survivor. That does not mean that you're normal from a respiratory standpoint. Many of these infants will be able to survive from a pulmonary standpoint, but their reserve lung function, just like their reserve renal function, is not normal. So if they are, you know, if they are, uh, have some sort of injury, they can rapidly change from a pulmonary survivor to a non-pulmonary survivor. And I think that, you know, as an example to that. We have had babies who have had a renal problem who have then had uh some sort of replacement, had normal amniotic fluid, but then after delivery developed chronic lung disease as a, you know, evidence to the fact that they are not normal from a respiratory standpoint. And this is something that we struggle with. The inability to determine whether or not a baby is in one of these two categories after delivery because during that time when we're trying to answer these questions, we're also trying to decide, are we going to do peritoneal dialysis? Are we going to proceed down the path of dialysis and renal transplant. And Lost my slides. Um, and we have multiple questions that we have to answer during the first few days of life that are, uh, that are competing as far as whether or not we should proceed. So bottom line is this is just a bit of a reality check to emphasize that this is an important issue, but we really don't have the answers to this issue when it comes to this patient population. Any questions for um Doctor Kingma related to uh what just he, what he just presented regarding pulmonary survivor? Well, next, we're going to have um Doctor Jan Scober, um, our director uh for the renal transplant program here to talk about managing advanced chronic kidney disease in, uh, fetal center graduates. Can I have the mouse, please? Thank you. Thank you and thanks for having me. Um, I'm gonna start out with an example. You've seen these pictures a lot already. The two important, uh, and fairly unusual features of this particular MRI are, um, obviously there's neither much amniotic fluid nor much urine anywhere here. And secondly, it's particularly late during gestation, and this is why this mother came to our center after having had several interventions elsewhere that were only partially successful, and there were both some shunts, so there must have been some urine at some point, um, but there were also some amnio infusions in her history. Not only did she come to us very late during her pregnancy, but then, um, she within a day or two of meeting us developed uh preeclampsia and some fetal deceleration, so she actually had to deliver her baby without really having had much of a chance to finalize plans and um discussions about what all these prenatal findings really meant um. And so sure enough, uh, uh, a very sick baby was born weighing 2.2 kg, uh, with very poor initial pulmonary status, multiple pneumothorosis requiring high frequency oscillatory ventilation, and, uh, completely aneuric, at least for the first several days of life, so not good. Um, we had met this family obviously shortly before birth, so we continued our involvement together with our urological colleagues, um, led by Doctor Reddy, and indeed this baby did undergo an urgent valve ablation and bilateral ureterral stenting after birth. Um, and, uh, interestingly and probably somewhat surprisingly, there actually was gradual improvement in the baby's both pulmonary status and renal status such that, uh, over the next week or two, the baby was weaned to room air and there was some urine output, and I think um. The fact that there began to be some urine output, even though there was absolutely no urine slash amniotic fluid late during the pregnancy, um, uh, brings us back to one of my salient points, and that is, uh, we're, we really like urine and we're talking about babies who have urine, if we're talking about measuring things in the urine prenatally or shunting things. Postnatally we also like urine even if it's bad urine that is just water and doesn't contain much cleared metabolites like healthy kidneys would put in there, um, but any kind of urine is much better than no urine, and that is why what we do both prenatally and postnatally. Uh, can be very different based on whether somebody is aneuric or has urine output and as was pointed out earlier, these babies with obstructive neuropathy. Actually, oftentimes have a concentrating defect and they make lots of urine. It may again be bad urine, but at least it's fluid. So after the um stenting and the valve ablation, uh, urine began to flow better and better, but the creatinine went in the wrong direction. You can see here the first several days of life, this patient's creatinine skyrocketed from 1.5 to 3.5 and then stayed there. But then, um, as we saw things improve and as we learned from those stents that the left kidney wasn't really doing anything. And all the urine came from the right side. A more permanent solution was uh right cutaneous ureterostomy and ureterrolysis at 3 weeks of age, and, um, and that was followed by a gradual decrease in serum creatinine to 1.5, which is still high, uh, of course, for a baby, but it's better than 3.5. Um, the amount of urine output and the meticulous management of things that I'll talk about in a minute, uh, allowed for avoidance of dialysis and for discharge actually after 5 weeks of NICU and hospital stay. And so far this patient has actually done reasonably well, only had one re-hospitalization. The creatinine for a baby, of course, astronomically high, but the baby is growing and is stable from a biochemical health standpoint with the appropriate, um, with the appropriate medical therapy, which I've summarized in this bullet point here and I'll get back to. And um some of that meticulous management of course requires special nutrition that is administered more often than not in these babies via some sort of feeding tube, either an NG tube or a more permanent gastrostomy, because babies with this degree of chronic kidney disease tend to not have enough of an appetite and an ability to drink and swallow enough to grow without support. And this baby's dad has passed the initial steps of his kidney donor evaluation. So once we get this baby to the size that he needs to be to safely be transplanted, he will in all likelihood receive his dad's kidney. And at our center that size is typically somewhere between 88 and 10 kg. So that puts, uh, the timeline probably somewhere into the second year of life. Um, in the meantime, of course, it is very important to continue. Uh, aggressive and, uh, regular lower urinary tract management, so you have to become friends with your pediatric urologists, which at our center thankfully is the case, and that management generally, uh, aims to reduce the risk for urinary tract infection both with antibiotic prophylaxis and with things like bladder irrigations, antibiotic bladder irrigations that could be part of a catheterization program. Um, and with bladder pressure management, we believe that bladder pressure is not only important prenatally but also postnatally, and our urologists manage bladder pressure with, um, anticholinergics and again with a catheterization program that's, uh, guided of course by. By measurements and urodynamic studies and if catheter catheterizations uh don't work, then more invasive management options may be required. And this is based on work that has been done that shows clearly, uh, that these obstructive neuropathy bladders can be very high pressure and not only that, but they can also change over time so they need to be followed regularly and the, the management may change, which was what was alluded to earlier. When we heard that at other centers, patients' bladders at 3 or 4 or 5 years of age looked like they had, uh, like they had, uh, uh, evaded, um, uh, their, their wellness and were causing more trouble again. Back to the chronic kidney disease, uh, I had summarized the management in one bullet point earlier. I want to expand a little bit. What is chronic kidney disease. Well, it turns out we don't really see that much hypertension in these babies, and we think that's because they have such high urine output, so they actually don't tend to be volume overloaded, which of course is one of the drivers of the hypertension one usually sees in chronic kidney. Disease they also tend to lose sodium because their tubules aren't working, so it's harder for them to retain sodium as another mechanism for hypertension, but typically, and in this baby perhaps as evidence for how bad his kidney disease was, um, there's some anti-hypertensive therapy that is oftentimes required in chronic kidney disease. Uh, as you know, kidneys make erythropoietin if they're healthy, if they're not healthy. You need to treat that, so we need to supplement iron and we need to, uh, teach the families how to inject erythropoiesis stimulating agents such as erythropoietin, um, so these babies don't become too anemic because anemia has all sorts of negative effects, cognitive negative effects, energy, quality of life negative effects, and of course in the old days when it required transfusions, also allo sensitization, uh, uh, problems. Um, bad chronic kidney disease will result in secondary hyperparathyroidism, which, if untreated, will impair bone health and skeletal health, which of course is especially bad in a child that needs to grow. Oftentimes if you're not on dialysis but have advanced chronic kidney disease, you develop an associated metabolic acidosis, which is also bad for growth and for well-being, so we have to figure out how to buffer that with medicines such as citrate supplementation. And then the whole feeding piece becomes very um becomes very specialized and our dietitians are extremely good at following growth and mixing together formulas and teaching families how to pre-treat formulas with things like uh potassium binding resins to prevent hyperkalemia so that's a very complex and challenging. Uh, part of chronic kidney disease management, especially in these young babies that have a lot of growth to do, uh, uh, not only but also to be healthy and especially healthy from a pulmonary standpoint like Doctor Kingma alluded to earlier, um, and then with bad chronic kidney disease, I mentioned the problems with feeding and swallowing, and that's only part of the. Uh, of the developmental challenges that come with chronic kidney disease in young children who have a lot of growing and a lot of developing to do, um, so we oftentimes get our occupational or physical therapists and our feeding teams quite involved with these patients and with these families. So that's the really summary of what we do when it comes to medical management of chronic kidney disease. Now chronic kidney disease in adults is the same thing minus a lot of the growth and development related things. And so there are actually guidelines out there how to manage chronic kidney disease, um, but they're written by and large for older children and adults. They have. Uh, as the basis, the now worldwide accepted chronic kidney disease staging that I've outlined here, there are 5 stages, with 1 being hardly any kidney disease and 5 being close to or beginning end stage kidney disease. It's staged based on GFR as shown here or creatinine clearance, um, and of course the. The more advanced your CKD stage is, the more intervention and care you require. The problem with the babies that we are talking about that exists regarding CKD is, even normal babies with normal urinary tracts and normal kidneys spend their first year of life developing normal kidney function or normal GFR or what would be. Considered a normal GFR at any age beyond 2 years all the way into adulthood, and you can see here that a normal GFR for a newborn at 1 month of age is about 50, and then it takes a whole year of evolving to the to what's accepted in older individuals as a normal GFR and that is about 100 and um. And so that's why Dr. Reddy mentioned if you apply this principle, which you certainly can, to patients who have abnormal kidney function, that's why we really can't make reasonable predictions, at least historically, based on clearance and based on creatinine until somebody has spent that first year of life establishing what their kidney function is going to be. The example Dr. Reddy used having been babies with valves, of course. And so even the writers of these guidelines accept that these GFR criteria don't apply to children less than 2 years of age and that we're really only allowed to categorize these children into normal, moderately reduced, or very severely reduced age adjusted GFR. That doesn't keep our friends in Europe from publishing guidelines about practice recommendations for care of infants with stage 5 chronic kidney disease. Um, but those guidelines exist and they do, um, they do reach all the way to initiation of long term dialysis, which of course is the most severe version of advanced chronic kidney disease therapy. Um, and they're almost at the same time a few years ago, there has been a very nice summary of the ethics of offering and providing, uh, infant dialysis which I've shown on the other side of this slide. Um, the upshot of all of these statements and editorials is that dialysis for small children remains quite challenging but has been improved as far as outcomes and feasibility is concerned and is certainly something that can and perhaps should at least be discussed with families on an individualized, uh, basis. So what if you need to go to dialysis? Well, you have to also become friends with your pediatric surgeons, especially your transplant surgeons, and make sure that they're friends with your pediatric urologists. All of that is working quite well here, um, because as I said, the surgeons need to be involved and Doctor Alonso will talk about that more. Uh, for example, when it comes to gastrostomy placement, uh, certainly for dialysis catheter placement, and then of course, eventually, uh, regarding preparations and eventual performance of a kidney transplant. How do we decide who needs dialysis? Well, really it's failed CKD management, and it's not some kind of creatinine cutoff. The creatinine itself doesn't really bother us alone. It's how the baby is doing, and a baby isn't doing with chronic medical kidney disease management. If the baby stops to grow, and we pay attention here to not just length or weight, but also head circumference. And um if we can't medically manage things like hyperkalemia or metabolic acidosis, that's also as much of an indication for dialysis as some of the more basic kidney function markers like serum creatinine. Um, the modality of choices, of course, peritoneal dialysis because that's the technically least difficult, uh, way to provide dialysis in small children like this. Um, there are. Other approaches on the horizon, for example, um, uh, in my references to this contribution, I included the recent Lancet paper that was co-authored by people in the United States, including here at our center and people in Europe, describing carpe diem, a sort of a mini CRRT hemodialysis option for babies, but that's not ready for prime time yet. So by and large we still look at peritoneal dialysis as the way to go. Um, it remains technically difficult, of course, and it introduces a major additional, uh, layer of complexity and therefore quality of life threat for, um, for the parents because eventually we try to teach them and ask them to do this, um, at home, my um. My party line when we counsel parents about this is number one I focus on the length of time this may be needed because as I said, these babies aren't transplantable until they reach a certain size after 1820, how however, however many months, um, and, uh, uh. How complex this this therapy package is, especially if it involves dialysis, and I always use the example that typically our parents will tell us that if they both held jobs prior to having to take care of a complicated, complicated, challenging baby like this, uh, when that started, one of them usually stopped working and, and the baby became his or her job. Um, Once again, urine output remains a big plus because it's very hard to manage fluid balance with just dialysis if there's not some residual um diuresis that helps us. And then it's hard to put somebody on chronic dialysis if there's not some prospect of transplantation down the road, because if, if for some reason transplantation doesn't sound like it will become an option, then one sort of enters a never ending one-way street that can become quite quite challenging. Of course the goal is uh then transplant even though life doesn't become completely normal after a transplant either. This is one of our first fetal care center graduates who traveled down that road with his family and who is now in first grade with a kidney transplant and with ongoing. Uh, lower urinary tract management and somehow his parents were able to deliver the care and the involvement and the support that that they needed to. They also delivered consent for me to show this Christmas card and they delivered not only 2 more babies, but what you can see here on this Christmas card is that mom also delivered the kidney that went into uh into this patient. So that's the success story to conclude my remarks. Thank you, Doctor Gobel. Um, any question for Doctor Gobel and for Doctor Kingma? Um, actually, on the, um, on the chat room, there's a question for Doctor Kinger. Um, Is there a common transitional course, do you think, uh, do you know of for these babies with, um, urinary tract obstruction that survives, and any telling signs in the delivery room regarding, um, which patient will do well, which would not? Yeah, I think that, uh, you know, obviously, room air in the delivery room, you know, a baby who comes out, has normal oxygen saturations and never requires oxygen, that's a, that's a great sign. Um, but, uh, it's not an absolute sign and unfortunately it's not a frequent sign either, um, in that, um, these babies will often require respiratory support of some type in the delivery room, even the ones that will go on to be a pulmonary survivor, um, and I think my approach depends on discussions with the parents, um, and if the parents want, you know, truly want completely aggressive care. Um, then I will provide whatever support is needed for at least the 1st 3 to 4 days because, uh, there are a lot of infants who will require high levels of support. One of the examples that was just given, you know, that may require oscillator or whatever, uh, pulmonary vasodilators, high levels of support in order to survive in the first few days, and then we'll begin to improve. So if the parents want aggressive care, I will do whatever is needed from a pulmonary standpoint. During really about the 1st 3 to 4 days after that, if the parent or if the baby is not showing signs of stabilizing and improving, uh, then you have to sit down with the parents and discuss the reality that this infant is likely not a pulmonary survivor and I think the other thing that you have to, um, realize is that even if you make it through the first few days you may have to come back to that issue down the road. Um, most frequently in the settings of sepsis, uh, you know, we've had babies who have been on peritoneal dialysis who have developed, uh, infection for whatever reason and then gone from room air to ventilator to never coming off the ventilator, and then, um, You know, you know, facing the reality that this infant is going to need a trach and, and chronic ventilation and, and, you know, does that really make, uh, renal transplant a possibility in that infant. So, so you kind of have 22 times when that that question becomes answered, and I usually say about the 1st 3 to 4 days of life after that you're looking for improvement. Now I'm not saying that the infant's extubated by day 3 or day 4. I'm saying you're showing signs of improvement. And then I think. You have to readdress that question anytime you have a, uh, an episode of lung injury, you know, from sepsis or something like that. So, thank you, Paul. In fact, uh, you bring up, um, one of the points that will help us to segue into, um, Doctor Alonso's, um, presentation as well. Um, the question is, in the event that the baby developed peritonitis and peritoneal dialysis is not available, what do you do? Um, I think Doctor Goldman and Doctor Alonso can, uh, speak to that. Well, short term, uh, you can try hemodialytic, um, strategies that's typically very challenging because you have to blood prime your circuits and you have to put very large catheters into relatively very small blood vessels, um. The, um, the other strategy that requires slightly smaller catheters that we've begun to utilize successfully as of late is to use a modification of what's called aquaphoresis, which is basically ultrafiltration with. A little bit of convective clearance trickery that has allowed us now to um maintain an aneury baby with um with intraperitoneal problems now chronically in somebody say who has the requirement for major abdominal surgeries, um, not being able to do PD in a small child is a very ominous situation. And Doctor Alonso, your, your point on that and technical challenges in Inserting a, a working well, a well working, uh, dialysis catheter, inserting a well working hemodialysis catheter, um. It's difficult, uh, if you want it to be a temporary catheter, um, because there's not much catheter design uh for these small kids and you end up with a lot of catheter that's not intravascular and it, it, uh, moves in and out no matter how you secure it, um, and it's an 8 French size catheter in a, in a newborn, so it's, uh. Pretty much limited to uh the jugular veins. Um, maintaining it, if it's a tunneled catheter is a little bit easier from a movement standpoint, but still, it's a very large catheter and likely to cause, uh, thrombosis locally and or, uh, stenosis in the central circulation. Any other question related to that? If not, um, we are going to have Doctor Maria Alonso to continue to give us, sorry, can I ask one more question. Yes, um, and that is, uh, the question of nutrition in these infants. I know it's a very difficult question, but any, any thoughts on that as far as, as approach to nutrition and, uh, routes of nutrition? Yeah, so, um, the Nutrition in somebody with urine output. Is a little easier in somebody who's in somebody who's oliguric or aneuric because you don't have to concentrate it that much. However, um, as I mentioned regarding sodium, the high output babies lose all sorts of things and so you have to follow them very closely what's their potassium doing? what's their phosphorus doing, and we actually find ourselves supplementing some of these electrolytes that we in our older patients preach to avoid because they tend to have problems with retaining phosphorus, for example. Um, as far as calories is concerned, our, um, so the, the density of the formula is essentially an inverse function of the amount of urine output. And um then our dietitians, as you know, work together very diligently to calculate how much calories does somebody need to grow and they track that very carefully, how much protein A is required, and B, can we afford without driving the BUN into dangerously high ranges which can lead to needing dialysis, the needing the ability to provide adequate protein. Intake may by some of these babies dialysis because you can't manage their BUN otherwise and then as I said, it's not impossible but relatively unusual to expect these babies to um drink spontaneously. In amounts that will be able to supply this um this amount of nutrition, that's not to say that mothers who are motivated to breastfeed couldn't contribute their breast milk, um, and then we usually build something. Or make something with that breast milk that meets the baby's specific needs and that incorporates mom's breast milk. It's typically pumped breast milk in that case, but it's not impossible at all, and we actually like to include breast milk if it's available. Thank you, and you're not gonna touch on route. Well, I, I mentioned, yeah, and Maria, well, the majority of these kids have an NG tube or a gastrostomy tube, and they keep that even around transplant, which is when we actually like it again a lot because they need to be on a bunch of medicines, um, but neither one of these options are without drawbacks. So, um, Maria is gonna get into that some more, all right.
