Chapters Transcript Video Neonatal Nephrology And so now I would like to introduce dr brakeman. Dr paul brakeman is a pediatric nephrologist and the medical director of the UCSF pediatric kidney transplant program. He specializes in evaluating and treating pediatric dialysis and kidney transplant patients. He has research that focused on the engineering of renal epithelial cells for bio artificial kidney and also on developing three dimensional culture systems to study kidney toxicology injury in the lab. He enters medical degree and doctorate degree through a combined program at the johns Hopkins School of Medicine at UCSF. He completed his pediatrics residency, serving as chief resident, followed by a fellowship in pediatric nephrology. He has numerous publications and awards, including the highly t da boss Academy of Medical educators and is a well known and respected teacher to trainees in our program. So without further ado I'll hand it over to you Dr Braitman. Thank you. Hi, good morning everybody, I can't see you but you can see me. So I encourage people to put questions in the chat and shallow is gonna be tracking the chat and we'll feed those questions forward to me. Um I'm going to talk today about neonatal nephrology and I've chosen to take kind of a broad view of nephrology and touch on a variety of different topics. Have one disclosure which is like that. I had a consulting relationship with Alan lamb incorporated and this is the outline of my talk. So I actually am choosing to touch on a variety of different topics I want to start with the embryology of kidney development because in the neonatal period we many times encounter patients who are still developing their kidneys. Their kidney development isn't mature and that affects what happens to them clinically and long term in terms of their renal outcome that I'm gonna touch a little bit on neonatal G. F. R. And maturation of G. F. R. A few slides on tubular physiology and handling of electrolytes for neonatal. And then I've got a little section on neonatal hypertension, neonatal A. K. I. And then finally I want to take some time to talk about infant dialysis and specifically end stage kidney disease care for the patients who are neonatal and on dialysis um and kind of lay out what that looks like in terms of current state of um outcomes as well as what it's like to take care of an infant on dialysis long term for the parents and families because I think many times that comes up in our in our clinical work where we have a patient who we know has bad kidneys and is only a few weeks old and is looking at a lifetime of dialysis and hopefully kidney transplants. I want to go through what that looks like. So let's start with some early kidney embryology um in the developing fetus there is a structure called the estrogenic core that forms. And then the net freak duct is a little tube that forms from that and grows cada lee and the net frick duct then sprouts other tubes and specifically there's sort of two um phases of that so early on in fetal development. In the first sort of 6 to 10 weeks there's a primitive committee called the miso nephritis that develops and it regresses actually most mammals, aside from a few tubular structures that persist in males to give rise to the testing, these epidemics vast difference and seminal vesicles, tubular structure um in lower animals that efforts persists and is actually a functioning kidney after birth. And in mammals like I said, it regresses and then farther Cogley there along the network duck. There's a co induction event where the Euro Terek bud sprouts from the netflix ducked into what's called the miso network missing kind, which is a specialized medicine kind and that actually begins the malian kidney development. And I'm going to have another picture of that specifically. So this is what that looks like here. The network duct is in pink. The metric tubules are shown sort of roster early and then there's a green patch which is the meta metric missing time. And that's a specific medicine kind that actually can be identified by markers. Typically RNA markers can identify it before, you know, in a in a fetus even before the Euro Terek bud hits it. And then there's this co induction event where the ureter eric bud sprouts out of network doctor. There's no sprouting, There's no kidney. Um and then specifically inside the median epic music. I'm a specific group of cells called the captains and kind forms. This is occurring at about 5 to 6 weeks in humans. You can identify the metal music. I mean you get the very first year it eric but sprout and by week 7 to 8 you can see the captains and kind. So this is relatively early on. Um, if you look closer at the mechanisms behind the sprouting, there's a variety of genes that have been identified uh that can lead to, you know, the disruption of the genes means to know spotting. So G D N F G F A pax two, there's a list here. But basically in mouse models, if you delete these genes and the proteins that are made by them, then you don't get sprouting and get no kidney. And when we, when we see a patient antonin Italy who has sort of renal a genesis from an early stage, it seems most likely that it's a sprouting problem. They don't necessarily have one of these genetic defects. So a single missing kidney actually doesn't mean that there's automatically a genetic issue with one of these proteins or genes. And In fact actually, if you do whole genome sequencing on patients with one kidney only about 17% of them will have an identified single gene um, abnormality. And so usually we think of this as a stochastic um, situation where most of the time you get a good sprout in the kidney forms, but sometimes it just doesn't happen. Um and so that's something that we describe the families when we meet them and aunt in Italy for counseling around having renal a genesis. The other thing that can happen is you can get too many sprouts. So there's a variety of genes that have been identified to be associated with too many sprouts. And what happens when you get too many sprouts If you get say two, then you end up with a duplex system, which I think many, most of us probably at this point, I've seen on some ultrasound because we're getting a lot of ultrasounds these days and we see ultrasound reports that say that there's a duplex system which is basically to your orders coming from two sprouts. Now, typically that's not a significant problem because the two sprouts tend to both go into the magnetic missing time and you just essentially form two kidneys that are fused and will oftentimes look even completely normal. There are issues associated with having to to your order. So it's not uncommon to see one year to be obstructed in one year to have reflex and that has to do with how the network duct grows down to join the bladder. I'm not really going to discuss too much about that, but this initial sprouting event um is you know, obviously critical for kidney development and then also over sprouting can also lead to phenotype that we routinely see in clinical practice once that sprout forms the sprout, then braque branches. So the ureter eric but branches into a complex tree. There's genes that control this branching process that have been well described. Um And this branching process is critical because at the tip of each of the branches is where the primary life form. Um and so if you don't have enough tips, you won't end up with enough memory lie and you'll and you'll end up with less overall kidney volume and function. So this is just a graph showing in mouse days over time as the urinary, but branches and forms a more complex tree that the kidney volume increases and this increase in kidney kidney volume correlates directly with a number of glimmering light being formed so that, you know, a concept here is that each sprout forms at least one Effron. So when the curative branches, each new sprout has a tip. Each tip has at least one ephron associated with it. And it's interesting right at the end of development there's actually a burst of multiple net franz forming around a single tip that kind of ends kidney development. So that This this development tends to end between 32 and 36 weeks, but usually between 32 and 34 weeks. So um infants that are born before 32 weeks are definitely at risk for having an abnormal burst of Saffron formation at the end and can definitely end up with fewer Franz. This is what that looks like in mouse days. So The from left to right as it goes up, there's sort of a plateau going for a few days and then right at the end in 22 or 23 days of life of fetal life. For a mouse, there's a burst of new new New Franz formed. This is just a picture of what the different formation looks like. So the pink hair is the Euro Terek bud and then right next to the ural Terek. But there's a specific missing time cell group that differentiates called cap. Amazing time. And then that cap, amazing time actually undergoes a mesenchymal epithelial transition informs a little epithelial sac called a renal vesicles. All and then that reno vesicles all. Here's a picture of it in a mouse. So the RV. In this picture is the renal vesicles and it's actually a sack structure. It has liquid in the middle and it sits right next to the tip of the ural Terek bud, that little renal vesicles expands and grows longer and becomes a longer tube and that tube connects to the ural Terek bud. And eventually what you get is a full ephron where the distal third of the ephron, the distal tibia and collecting ducts have come from the the urinary, but tissue and then the proximal two thirds of the reference. So the the glomeruli list, the proximal tibial, the ascending limb. Henley's loop are all derivatives of the renal vesicles of the captains and kind. So there's actually two different cell groups. This actually becomes kind of very relevant if you try to grow kidneys or try to assemble kidneys, which people are doing these days, because kidneys are actually made out of multiple kinds of cells. So there's both these two different kinds of epithelial cells that are required as well as obviously the nerves and the blood vessels. Um, so it becomes a little bit complex to grow kidneys and nobody's really succeeded in growing a functioning kidney yet. This is a time course of development now laid on a on a human weak scale. So it goes zero to basically 40 weeks and a few weeks after birth. And what this shows is that um you know what I described in the beginning, the urinary but sprouts around week 5 to 6, then um there's formation of the first Neff Ron around week nine or 10, there's an increase in the renal mass. Um and then around week 20 the kidney takes over production of amniotic fluid. This is relevant for the um, antenatal um, physiology of the fetus because if there's no kidneys, there's no amniotic fluid and then the kidneys continue to grow and in general Neffa genesis is thought to be complete by about 36 weeks. One interesting question is why does not for genesis stop and the answer is that eventually the kidney runs out of those cat missing time cells. So over time, the cap cells will initially replenish themselves that they're used up and eventually that replenishment stops and there's no more capsules. This is actually very relevant clinically because you can't make any new NEh franz. We're born with our entire contingent contingent of difference for our life. And so as a nephrologist, you'll see us actually sometimes do relatively aggressive things to spare a small number of neutrons because we can't make more. This specifically is important in patients who already have chronic kidney disease where they maxed out the function of the remaining net franz. A regular human has has some cushion, right? Because you can donate a kidney, one good kidney is enough to have a basically normal life. And so people can donate a kidney. But when somebody gets to the point where they have measurable chronic kidney disease essentially lost the function of an entire kidney, they're already down at least 50% of their net franz and probably more. And so you'll see us do things to relatively aggressively protect the remaining net franz, including hospitalizing people for relatively mild dehydration to prevent a K. I if they have chronic kidney disease, you'll see us stop like ace inhibitors before surgery. There's a variety of things we do to try to preserve net because we can't make more. So just to summarize, uh, meet the men enough for us, which is going to become the final kidney first developed in about week 5-6 in humans. By week nine, you can see primarily in humans. By week 11-12, the first urine is produced. Um, and then by week 12, the fetal bladder detectable by week 18 to 20 urinary retention and mix tradition begins so the bladder can be seen emptying on antenatal ultrasounds. This is also about the time, like I said, where the amniotic fluid production is taken over by the kidneys. And if there's no kidneys, there's no amniotic fluid by week 30 for the genesis is mostly complete and by week 36 we think of the genesis has done important concept here is this idea that we have when we have a certain number of neutrons. In addition, we have patients with a number of net franz is just fewer. If you look at actually the whole population, there's a range of different number between about 500,000 and 1.5 million. So that's actually a pretty big range that's like having six legs or two legs. Um, and so the net foreign number is actually fairly broad in the population, interestingly, the lower patients with lower numbers of neutrons are absolutely associated with hypertension. Um, and also our law likely at risk for chronic kidney disease as well. This has not been studied quite as well. There's been multiple studies linking low camera light number in a variety of different populations, including very low birth weight infants. Um, in patients who have have come from in in situations of starvation of the mother. So there's a variety of things we know that can perturb different number and those are that's associated with hypertension and is likely associated with chronic kidney disease as well. I'm putting questions here in case you want to put anything into the chat if there's something urgent, I'm happy to answer now as well. I had a question real quick. Um you said the number of neutrons is not going to change. You know, you are not increased through life. Um you're kind of born with what you have. So as the kidney is growing as the child is growing, you know, there's like some growth, there is what is what exactly is growing is. Yeah. So what you're maturing there is your filtration pern Effron and and that includes lengthening the loop of Henle e. It includes changing the blood flow into the glamorous lists. And so while there is no new net franz, you get more filtration Effron. Thank you. I want to talk a little bit about glamorous filtration rate and supplies to neonatal because we measure it. Um and it's not the same as what we measure for adults. Um and I think an important thing to know is that prior to birth, the fetal filtration rate is significantly lower than after birth. So glamorous or filtration refers to the amount of fill trait formed by having pressure in the glamorous list or capillary and pushing liquid on the capillary into bowman space where it's then collected and goes down the tube. You'll, so the amount of blood cleaning that occurs is depending on the filtration and actually the miracle of the of the human kidney is actually the concentration that occurs after that. So in a regular adult sized person is about 100 and 60 liters of Phil trait that are created a day. Then that's concentrated down to about one liter. So prior to birth and infants. The actual fetal G fr scaled for size is significantly low and then it increases rapidly after birth by changing the blood flow through the through the camera list. So in the 1st 24 hours um it turns out that actually G fr correlates with the renal mass and the renal mass correlates with gestational age. So at the very beginning to you know whether you're born at 32 weeks or 30 weeks, 36 weeks or 40 weeks or 42 weeks. You generally have roughly the same G. F. R per kilo body weight. And then in the first five days after birth the G. F. R. Increases about to fold. This is by more generally by modifying the blood flow so the hormones that control the renal blood flow change. And all of a sudden primarily is getting more blood flow and there's more filtration. So for example a G. F. R. Of the term infant is about 15 to 20 mils per minute per 1.73 m squared. To put that in context, we think of normal G. F. R. As 100 to 120 mils per minute per 1.73 m squared. So for scale for size infants really aren't cleaning the blood very well by one week that's increased to about 40 mils per minute per 1.73 m squared. And by 1 to 2 years uh Children reach their sort of usual adult type G. F. R. Of 100 220 mils per minute. And then as was pointed out this then scales that the patient continues to grow. And so one thing that's key here is that the steady state serum creatinine, what we would call normal creatinine may not be reached for some instance for up to four weeks or even longer in premature infants graphically this looks like this. So this is a sort of one of the most complete studies of neonatal T. F. R. By a group led by Smeets. They took 1500 studies that were published, they screened them, they found 51 relevant studies with data on neonatal and then they combined all these studies together. So there was a total of 881 infants with 976 G. Fr measurements and then they sort of graft them out to look at what G. F. R. Looks like over the first month. And you can see that there's a sort of doubling in the first five days and there's a slow increase over the following three weeks. This just goes a little bit longer. This is actually very old data from 1975 and I haven't seen a more complete picture. Um But this just shows how in the first month there's a rapid increase in G. F. R. And then there continues to be maturation over the next. What it turns out to be about 1 to 2 years. This becomes relevant specifically in the patients who may not have normal kidneys. Um, But but the kidneys may actually end up functioning better after a year than they were at a month. So we routinely have patients with some amount of displays and maybe they have small kidneys. Maybe they have one multi cystic dis plastic kidney and one kidney. That's just this plastic. And they might leave the nursery with a creatinine of say .6 or .7, which is more than twice normal. Um and a year later they're creating might be completely normal for their age and size. Now, we don't think of those patients as having normal kidneys because they demonstrated early on that they maybe had fewer neutrons or maybe they haven't matured as quickly. So I think one should always take, you know, be a little bit cautious when somebody has abnormal creatinine in the first one or two or three months of life even when it normalizes. We still assume those patients have risk for hypertension and chronic kidney disease later in life. And we we canceled the parents about that. This is just a picture of creatinine measurements in units with different weights and sizes. So it goes from the square boxes are 1000 to 1500 g. The triangular boxes are 1,506,500. And basically what this shows is that um for smaller infants and these were earlier gestation first because either not SJ infants but just smaller, normal for gestational age but younger. So for younger gestational age grannies are higher at birth and they stay higher for longer and you know by three weeks here or four weeks they come down to close to term. But even in three weeks for what one kg infant the average creating is still higher than you would expect for a term infant. So premature infants have lower G. F. R. At birth. And um premature infants have a smaller increase in G. F. R. At the time of birth. And they have a time lag to their maximum G. F. R. So it's it's not uncommon to find a small premature infant who at nine months of age might have still elevated creatinine. So in one study looking at these preterm infants about two thirds still had slightly lower G. F. R. As demonstrated by higher creatinine at nine months of age. So are patients who are born premature have risk of chronic disease and hypertension long term. This is just a picture looking comparing um creatinine clearance across different gestational ages. Um And what's interesting here I think is on the far right for the term infants there's actually a fairly widespread this is measured in the very first day of life. Um So it probably represents that early doubling of creating. So the term infants where they doubled their creating quickly some of them had had or so they doubled their clearance quickly. Some of them had clearance was very low and some of them had higher clearance. We do have some other ways to measure kidney function than creating. So there's a a protein called system and see which is a housekeeping protein and it's now being measured in infants routinely. We don't actually have great data on how you it is compared to creatinine and we don't really have a calculator for infants which incorporates the status see with creating to kind of get an ideal measurement. But I think in the next few years going to see that um that's what we've seen in the older older Children. So there's a very well validated creating systems and see calculator that includes height and gender that measures out or the estimates G. F. R. And patients 2 to 25 years old and I think we'll see a similar thing for infants soon. So just a little break to see if people want to put in questions or have specific questions. Now I'm gonna move on to some neonatal renal physiology And these slides really don't have any graphics. So they're a little bit wordy. So I apologize for but I want to talk about water homeostasis first. As pretty much every pediatrician knows term infants undergo some weight loss after birth. This is typically about 10% weight loss to the isotonic volume contraction, the first week of life due to diary sets of extra cellular fluid. And in preterm infants this weight loss can be greater 15% is one figure I've seen quoted. And in addition the neonatal concentrating ability is reduced due to immature tubular function and relative insensitivity to a th so the ability to input put aqua pouring into the proximate to bill and resort water is reduced. So specifically if you look at what an infant can do, the maximal concentration that infant can attain is about $700 million 1200 and 1400. And that basically the maturation of the system occurs over the first year between six and 12 months. Most infants can achieve this adult concentrating ability. So obviously this affects our practice because we have to recognize that younger infants aren't really able to concentrate their urine and have that increased risk for dehydration. In addition, premature infants have a delayed ability to form a dilute era. Um So an acute water load and a premature infant can't be dealt with as quickly as in a term infant. So for sodium homeless homeostasis is a similar process of maturation. In the first week of life, sodium losses are initially high due to a high fractional excretion of sodium. Um The fractional excretion of sodium with Athena is highest in preterm infants that are less than 32 weeks and then it is actually um lower as gestation for higher gestational age. So Tina in a term infant is usually around 1%, but it can be up to 5% or more for very low birth weight infants. And over the first week in term infants, athena drops rapidly to less than one and then the infant is in positive sodium balance thereafter and positive sodium balance is required for growth. So it's actually possible that this um sodium homeostasis is not normal, which we sometimes see in patients with this plastic kidneys where they'll be sodium wasting, but the patient cannot grow purely from a lack of sodium. This will usually show up on blood tests as a low sodium, but it doesn't always show up that way. So sometimes we have patients who have just plastic kidneys or chronic kidney disease and we know their sodium wasting and um we actually will treat growth failures sometimes with extra sodium. um in the preterm infants that pena doesn't increase quite as rapidly and it may not drop below 1% until as late as two months. So there's this clinical risk of hyponatremia in the premature infants in the first 2 to 6 weeks of life. Um And in addition because they have higher sodium requirements, uh I know that the nicu doctors respond to this and have appropriate, they meet this sodium requirement almost always because I rarely walk in for a consult and find a patient where I think they're not getting adequate sodium. Um So this is just something that we clinically know as relevant and is and is sort of worked on in our nurseries, potassium homeostasis also is, has a maturation period. Um so the ability to excrete potassium is reduced to birth and the term infant and even further premature infants. For example, the average year potassium at one week for a 30-32 week old is about 6.5 versus 5.1 for a term infant and that 5.1 is higher than you would expect on average for an older child or adult. This the mechanism mechanism for this is probably relative resistance to our resistance to valdosta ronin, the distal tibial and or low activity of the sodium potassium https medicinal. Net phone or at least that's what animal studies show. And I think it's a reasonable to think that humans are the same way there's also a maturation of acid base physiology. So the renal threshold for bicarbonate loss decreases with earlier gestational age. So for term infants the C. 02 on a regular venus blood blood tests is the normal range of 19 to 23 which is lower than for Children or adults in preterm infants. The normal range is more like 18 to 22. And then for very low birth weight it's more like 14 to 18. And this is due to deficiency in the proximal tubular carbonic and hydrates. And also in decreased amounts of the like the bicarbonate co transporters. Um The carbon IQ and hydrates specifically in animal models appears later in gestational ages and then actually is up regulated rapidly after birth. So this is the likely likely critical mechanism for this physiology affect um One slide on nutrition which I think everybody knows about at this point but 30% of babies will avoid on delivery 92% by 24 hours and then 99% within 48 hours every now and then I get a call about this. And usually it's in the context of this baby had an abnormal antenatal ultrasound and we're sitting on him or her 36 hours later. They still haven't voided. But I think most of us have seen those numbers before. Short pause to answer questions. There is one question in the Q. And A. Um you mentioned height and gender. Um G. Fr what is being done about the past use of race to determine E. G. F. R. Correct. So yeah this new this new equation has no race. So it's it's race agnostic. It's uh it's called the U. 25. You can get it by googling you 25 pediatric g. f. r. You meaning under 25 but it contains height, gender, gender at birth and then creatinine and taxi. Thank you. Um So I want to talk a little bit about blood pressure. Um So blood pressure and healthy term infants increases rapidly during the first six weeks and the initial systolic blood pressure rises in term infants is about 2.5 mm of hemoglobin per per 24 hours at the beginning. So normal blood pressure is also higher for older gestational age infants. And there's a variety of factors that affect neonatal blood pressure including salt handling maternal age, maternal third trimester age. There's some evidence that salad associated inhibition of 11 beta hydroxy lives actually affects nina Blood pressure and actually maybe a driver for some of the hypertension we see in preterm infants that are exposed to a lot of plastics. So I think that's an interesting one that's kind of being worked out currently. The most recent paper I saw on that was 20 from 2022 and this is relatively recent the last few years I had this table. Not that we're going to read the entire table but just to show sort of that variation and blood pressure with gestational age. So if you look at the 99th%ile for 26 week infant, the 99th%ile for systolic blood pressure, 77 for a 40 week infant, it's 100. So there's a pretty broad range. And then as patients are out of the womb and grow, the number goes up as well. So we keep these blood pressure norms in mind as we see patients as a as a nephrologist. In addition, preterm infants have this, this is just this is actually to show the rise in blood pressure for preterm infants over the first week because it is actually fairly rapid. So if you look at sort of the high end blood pressure for this was for babies that weighed about 1400 g at day of one of life. The sort of high systolic for these infants was about 75. Um but the average was only 63 and that average increased substantially. So by seven days, that average was 74 when 11 point increase in a similar amount of increase in the diastolic pressure, interestingly, for inmates who are being ventilated, the averages were higher at the beginning, although the final average after seven days was actually similar. So clearly there's some type of stimulation or alteration in blood flow through the lungs, potentially that changes blood pressure in these patients who are ventilated, we have some common causes of neonatal hypertension. So when I'm called to the nursery to evaluate a child with high blood pressure. Um These are the things I tend to think about this is actually so there's been a couple of different studies looking at ideologies of hypertension and donate. And specifically one thing I want to raise here is that if you look at term infants who have high blood pressure, there's a significant rate of renal vascular issues in those patients. If you look at the entire population of hypertensive patients including the preterm infants who oftentimes have more medical interventions. Um renal vascular issues are not the most common cause of hypertension in most nominates that we see in the nursery. If you look at the list, chronic lung disease is actually the most common cause of neonatal hypertension. With about 50% of all neonatal hypertension being related to chronic lung disease. There's intrinsic renal disease not just reno vascular that is relevant. So 10 to 25% of of infants with hypertension will have had some intrinsic renal disease such as a. K. I. Is the most common Associated thing with hypertension. There's neurological causes of hypertension I mentioned the vascular causes which overall are only about one or 2% of the whole population then henderson and cardiovascular causes also are sort of lower on the list but more common. So how do we evaluate a neo Nate with hypertension. I think these are sort of basic recommendations taken from this review by Horton and I think it's very similar to other papers I read. But the cbC to look, the CBC is actually a screen here for clotting. So if there's a significant thrombosis somewhere they'll be low platelets and or low hemoglobin. Although interestingly sometimes this may take time to appear. So an acute promise may take 12 to 24 hours to change the platelet level. Um BMP two look obviously a kidney function with calcium hyper calcium. You can be a driver of hypertension for limb blood pressures are relevant obviously to look for a co opt your analysis to look for some intrinsic renal diseases such as chronic syndromes can be associated with hypertension and renal ultrasound with Doppler to try to look at the renal vessels. Clearly ultrasound is not the most sensitive tool for evaluating renal vessels but in in small babies and specifically very small babies. It's pretty good. So I've uh for term infants I've seen actual study comparing um ultrasound to Gold standard and applying sort of about a 70% sensitivity in the hands of experienced technician chest x ray I think is also important to look at heart size. And then additional laboratory laboratory studies may be indicated depending on what's found. So renting levels can be pretty variable in infants but there's something that we oftentimes. Secondarily thyroid studies, you know depending on presentation genetic testing may be relevant such as for patients with hyper calc mia looking for Williams. Um So these are sort of a basic evaluation and then we have to make a decision about whether to treat an infant who has had high blood pressure. So in general asymptomatic infants with systolic blood pressures or maps that are greater than 95th%ile less than 99% can be safely followed clinically. In fact actually most patients in this range their blood pressure will normalize over time. Over the first few months of life infants with systolic blood pressure mass greater than 99% tiles should have that complete evaluation I described and then if it's persistently treated with antihypertensive. the choice of antihypertensive can vary based on cause and severity. The most commonly used agents or calcium channel blockers. So I saw 11 study in um looking at a group of infants that actually were recruited for a. K. Ii but many of them also had um hypertension in that group. About 60 plus percent were on calcium channel blockers. For more acute and severe hypertension. There is data on the use of carnitine infusion in infants that shows good at safety and efficacy, efficacy. So that's a continuous um calcium channel blocker that seems to function well we do try to avoid. Um And now AC inhibitors or an allergy pill in infants less than about 44 weeks because we do think there's potentially an effect on different formation. And certainly for infants less than 36 weeks when ephron formation may still be happening. We will try to avoid unless there's an absolute reason to use it, such as wanting to affect cardiac after load and remodeling specifically. So, um I do see patients in neonatal nursing. I will say that most likely you'll see us using calcium channel blockers. And I recognize that many of these patients outgrow their hypertension. So part of my part of my counseling appearances, we're gonna start this now for your baby who's 21 x 27 week with high blood pressure. But it doesn't necessarily mean it will be there for Forever. I think the younger the baby is, the more likely they are to have persistent hypertension. I think that we see a lot of patients who are 30 or 31 weeks who have had um not completely normal lung function have been an auction potentially early on who have high blood pressure. And I tend to see those patients outgrow their hypertension if their kidneys are otherwise normal. But we're seeing more of these patients obviously long term in our clinic. I also want to I want to talk a little bit about acute kidney injury. Um I'm going to actually backtrack as I misplaced my slide. So there's just a sort of a waste basket case of neonatal ak I because it has sort of all the risk factors included. So um other developed severe preeclampsia at 26 weeks, her infant is delivered via C section at 26 37 weeks weighing 560 g. He's managed with innovation, mechanical ventilation and surfactant. He's treated at 48 hours of life within the medicine for a P. D. A. He then develops neck on day of life 15 and is treated with um Priscilla says the background for seven days is creating a five weeks is 50.85 so it's high. So if you look at a case like this, I kind of gave all the risk factors at once. But in this patient what are you what are the risk factors for a chi for this patient? What can be done to mitigate or reduce episodes of ai in situations like this? And what is the long term outcome in situations such as this? So if you look at acute kidney injury in um neonatal in general it's highly variable sort of the percentage reported in kind of all comers between one and 22% for sort of all comers. If you look at you know smaller infants. So very low birth weight infants. There specifically been a consortium running called the awakened consortium and looking at acute kidney injury in infants and in their group and they're very low birth weight infants. There's about 50% will have a k. I if you look at non cardiac ECMO neonatal it's about 26%. If you look at me in it's undergoing cooling for ischemia, it's 38%. If you look at the units undergoing cardiopulmonary bypass for cardiac repair at 64%. The most common cause appears to be pre renal failure where the perfusion is poor into the kidney. Um And the this actually may or may not be documented. So um certainly there can be hyper perfusion events that occur in the peri partum period or even before birth where babies are born with acute kidney injury that improves. And it can even be fairly severe acute kidney injury. And there's actually no documented hyper profusion that you can find in the maternal chart. Um some of these patients with severe severe a TN may have profound and persistent Algeria. They can eventually recover and end up with sort of normal creatinine. I wouldn't say necessarily complete recovery because we don't look in the kidney with biopsy to prove that the kidneys 100% normal. But it's definitely possible to have very severe 18 after birth including severe allergy area, you know, very close to dialysis or even on dialysis for a few days and then have a recovery to normal creatinine by discharge and at one year and a two year. Well I'll say I would expect that these patients will have higher rates of cKd later in life. So there's some risk factors for a. K. I have kind of run through them. So low birth weight infection or sepsis or hypertension specifically the situation of neck has been identified P. D. A. S. Are associated potentially because of the human dynamic changes. And also potentially because of the indo medicine used to close them for toxic exposures is clearly relevant. Sepsis is clearly relevant. Um And then obviously if you have a structurally abnormal kidneys that's an ak Ak I risk. And one of the treatments we have. So our primary treatment is supportive care. It's good to have you know judiciously use fluid to avoid severe fluid overload. Severe fluid overload itself is associated with mortality in the in the niCU and ICU setting. Um And so responding to fluid needs with only the smallest amount needed in the cases with Oliveria is useful. You know rarely is that something that we can control because patients who are hypertensive enough capillary week and who need intravascular volume. Um We give it as clinicians avoiding toxic medications can be important. We don't really have a pharmaceutical agent that directly targets renal recovery yet we know a lot about the sort of the molecular physiology of renal recovery. But as of yet there's not an agent to give somebody who's had acute kidney injury that helps the kidney tubules regrow and be healthier. There's actually many agents under study for this. Um So I'm hoping that in the next 5 to 10 years we'll see something like this first four older patients and then it will hopefully show communicates there's accumulating case series data that demonstrating that dennison blockade either the offline and online offline or caffeine in preterm infants. Specifically. That may reduce the risk of A. K. I. So that's another sort of pharma pharmaceutical intervention that I think that we're making more commonly in R. N. I. C. U. In our I. C. U. With infants. And then obviously we use renewable placement therapy either CRT or peritoneal dialysis um to support infants when they have severe AK I. Um And interestingly in the setting of a. K. I. At least a third or more of the patients will come off of renal replacement therapy. Obviously there's some patients who have obvious chronic disease either just plastic kidneys or small kidneys or posterior urethral valves where if they start renal replacement therapy more we're more cautious that they may never come off. But sometimes those patients who have structural issue are obvious chronic kidney disease. You also get a. K. I. And they may need um renal replacement for some period of time a week or two or three and then we'll still be able to come off and while they may have chronic kidney disease they may you know be able to leave the nursery successfully off of renal replacement therapy. And then we have our patients who um and then so one thing that was initiated the awakened um study group has really done a pretty deep dive into neonatal A. K. I. And have some uh published guidelines for mitigation and I think that um as Children's hospitals were moving through some of these some more intentionally the others. But I'm putting this up here hopefully just to sort of get people thinking about it. So one is to develop center specific A K. Ii surveillance guidelines to increase A. K. I. Monitoring. So we're not missing early ai where we could make supportive interventions that might prevent prolonged A. K. I. Another recommendation is to develop center specific guidelines aimed at necro toxin stewardship. So active creating monitoring for patients on toxic medications. Um review and document documentation of parameters related to kidney health in the chart and A K. Ii such as having in your daily progress note, you're now put fluid balance and blood pressure. I think we generally have those things auto populated but thinking about them and potentially commenting on them documenting a chi episodes in the disk. Charge somebody for neonatal I think is important because any mayonnaise that's had a significant AK I episode has a definite increased chance of having hypertension and CKD later and then working together to develop some outpatient referral guidelines so that patients who have had significant AK I end up in nephrology clinic for long term follow up. So um you know, for example, high risk babies that should have nephrology follow. We would potentially include patients with a K. I. Stage two or higher or a history of multiple AK I events during their neonatal stay severe Ak i requiring dialysis is kind of an obvious one and we rarely missed those patients. And then in addition very low birth weight babies or S. G. A babies are at higher rates of having hypertension and CKD. And I think it's um one of the things that I do is when I meet with primary care providers is to sort of make sure that they're monitoring these patients with blood pressure with actual measured blood pressure is when possible even in the first year or two of life before current recommendations for blood pressure measurement because that's one of the early indications of CKD is hypertension in these infants who are very small at birth or her S. D. A. I will say that some of these things are in process. I want to thank Vivienne Newman, I don't know that she's on today but she and I have had multiple conversations about trying to implement some center specific guidelines on aflatoxin stewardship. And I think I think we're going to make some progress in the next year on that. Um And I want to talk a little bit about the infants who don't do well that have severe renal failure and it doesn't get better and they require chronic dialysis. And this is where you know we as an apologist have um fair amount of experience some of us over multiple decades and I think that we are oftentimes called into account counsel patients or families in this situation about what it looks like to to be alive on dialysis as an infant and for a family to take care of a baby on dialysis. And these slides are pretty worried and I'm gonna go through them and then we're definitely gonna have some time for questions at the end. But this is the kind of counseling that I give to a family where the infant clearly is going to be severe chronic renal failure and likely requiring dialysis starting within the first few weeks or months of life. So the first thing I describe is that peritoneal dialysis is our target. It's strongly preferred because of better fluid removal and probably better toxin removal as well. Now this obviously isn't always possible if there's been a major abdominal event. Peritoneal dialysis may be impossible and we can maintain an infant on hemodialysis. But frankly, for a small infant in the first few weeks or a few months of life, we end up actually using continuous renal replacement therapy. So, CRT until they're big enough to where they can tolerate doing intermittent dialysis for four or five hours a day every day because fluid removal needs to be constant. An infant. Um, when we do pair tail analysis typically for at least. Um, The first few months. Um, we use manual peritoneal dialysis, which is a 24 hour procedure in the intensive care nursery. When patients actually get big enough. So when you can fit about 100 and 20 mils, 230 mils into the peritoneum. Then they can use a machine called a cycler and they can do 6 to 8 or 10 exchanges overnight for 10 to 12 hours. That's kind of our standard regimen for an older infant at home. So basically when infants leave an intensive care nursery on dialysis, we've we use we loosely there so we have a parental dialysis um nurse practitioner who does our training named Megan Finn. She's a wizard in terms of teaching parents how to run an ICU in their house. So parents are taught basically to take their 456 month old home on a parenting dialysis Eichler and do all the things that we typically do every day in an intensive care unit. Um Almost all infants who are on dialysis in the first who start within the first month require energy tubes. That's both for medications as well as calorie delivery because most of these patients will have some amount of oral aversion. So even if they're nibbling and taking some breast milk, they will routinely exhibit abnormal hunger and not be able to get all their calories in. In addition we convert these N. G. Tubes to G tubes later on when they're a little bit older. Um And there have G tubes typically for 5 to 8 years. Always through transplant because the transplant medicines there's a lot of them and they were basically require a G tube for medicines and fluids after transplant. Most infants on peritoneal dialysis vomit a lot. It can be many times a day Are you know are successful, feeding is not not vomiting, it's vomiting and still gaining weight anyway. Um In general patients on peritoneal dialysis have 5 to 6 medicines given 2 to 3 times per day. So it's a significant amount of work. Growth is slow. Most patients are in the lower quartile for growth Final I. Q. Is reduced by about 10. In addition development delay is our developmental delay is universal. So typically patients who are on dialysis won't won't walk at a at a year. They'll walk at 18 months or two years after transplant. They will not talk at a year. They will not sit up at six months. Everything is delayed and then there's some catch up after transplant. These patients spend a lot of time in the hospital. It's uh you know averages about 120 days in the hospital. In the first year of life for an infant. On peritoneal dialysis. I generally describe three or four rehospitalization events for these patients. And then pretty much all of them will have one surgery for mechanical complex complications from peritoneal dialysis, either hernia or catheter malfunction. We convert um N. G. tubes to G. tubes when they're big enough to run on a regular human dialysis machine for a month. And that's a that's almost that's a surgery that pretty much all these patients will have as well. So this is a long is a complex medical life. I basically described it as a full time job for one parent or caregiver and it is about 6-8 hours of work and that work continues until um transplant. Um in addition, many of the infants that we have in this situation actually got there by having kidney damage from bladder outlet obstruction. So for the patients that were born with posterior urethral valves or other bladder bladder outlet obstructions, they have pretty much all the complications above as well as about a 30% risk of abnormal bladder function. So if they have chronic kidney disease as well, they often will progress to end stage renal disease, interestingly, in the population of bladder outlet obstruction that have not requiring dialysis but have significant chronic kidney disease. The best predictor of their long term outcome over their entire childhood is actually what they're creating is in kidney function is in about a year of life. By that point, the kidneys are fully mature and they've gained weight so many times. We are counseling patients in the nursery who have Poster you throw valves and they may have a creating of 1.5 or maybe 1.8 leaving the nursery. So definitely not at all normal, but it may actually get better to the point where it might only be .8 or .7 in a year of life. And those patients will are, if it's less than one in a year of life, then it's those patients are are unlikely to end up on dialysis and childhood. So we have some some special things that we cancel around for poster you throw valves patients. So our target in doing dialysis on an infant is have the infant grow big enough for kidney transplantation. We generally transplant at about 80 cm of length and about 11 kg. And for patients on dialysis, infants, this generally takes between 18 and 24 months. Um, we use adult sized organs, Sometimes they're from teenagers, but they're generally adult sized teenagers and we do this because the blood vessels from the kidney that need to be sewed into the recipient. Um, if they're, if you use a child sized kidney and the blood vessels are small and much more likely to clot. Are transplants are not perfect. They last on average 13 to 14 years for a deceased donor transplant, 15 to 18 years for a living donor transplant. The transplants require 7 to 10 medications twice today for 1 to 2 years and then typically 3 to 5 medications. Long term transplant also carries with it a hospitalization burden due to infection. So for infants and small Children, I generally counsel that they're going to be hospitalized 1 to 3 times per year in the first year and typically the second year after that, they're older and the hospitalization rate goes down. So I definitely have 17 and 18 and 19 year old patients who are rarely hospitalized despite having their transplant when they were two years old and being in the hospital three or four times the first couple of years. We also have, we also use immuno suppression for a transplant. So we have long term side effects of immuno suppression, such as a 15 to 20% rate of secondary cancer. Most of this is skin cancer, but in general, solid organ transplant, solid organ cancer rates are increased 5 to 10 fold as well, Patients can get other transplants. So if you're a parent with taking care of an infant on dialysis, what we, what we basically, they quickly figure out that if there's a transplant and it wears out, then we have to get, you know, we need another transplant, right? And the answer is yes. And most patients can receive up to about three transplants. Subsequent transplants don't do quite as well because the immune system is already sensitized. So the average lifespan of a second or third transplants, about 11 or 12 years. And if you do all the math of what it looks like to have a transplant that last, say 16 years and then you do a little bit of dialysis average is about three years and you get your next transplant in the last 11 or 12 years and you do another three or four years of dialysis and you get another transplant the last 11 or 12 years. The expected survival for an infant analysis with current technologies, maybe 50 to 55 years outside maybe 60. But it's definitely a reduced lifespan. It can be a very, you know, busy, successful active life. You know, patients work, they can go to school. There's been thousands of babies born to um women who have kidney transplant. So it's a it's a it's a medical life but it can be pretty active and uh and busy and and frankly happy. I take care of these patients who have had many happy years. Um if you look at the math on the outcomes, the neonatal initiate chronic dialysis in the first month of life, one in four expire after starting dialysis, one in eight regained native kidney function. These are the ones who don't have obvious structure defects, defects. The overwhelming majority of those with regained function or A. K. I, infants or cortical necrosis. And they clearly have some risk of hypoxia. Asia long term from that injury. Um, 4-5 of these patients will require hospitalization. The overall survival to transplant of all neonatal initiating dialysis is 80% survival to three years and almost all of transition to transplant at that point, if you look at neo Nate so that our and your birth that have worst kidney function or potentially have no kidneys. The survival to transplant is less maybe 20-40%. And then specifically we're running a trial nationally called the raft trial looking at amnio infusion in infants who have an hydra Emilio's aunt in Italy. So essentially putting in amniotic fluid. So the lung skins developed to help them survive. And in that population sort of to date, we're looking at, we're seeing about a 30% survival after birth, but only about 30% of those are surviving to leave the hospital. So it looks like our long-term survival on that very severe population is going to be more like 15, probably 15-20%. And that's all my slides. Thank you so much. We do have a handful of questions. We'll try to get through them in the last five minutes here. Um, there is a question. So what happens if a family, for example, is unable to care for an infant with such high medical needs? So that a family that chooses to pursue dialysis for an infant And to be clear, not all families choose that and we support decisions not to pursue dialysis. I didn't make this an ethics conversation, but those are some fascinating ethics around that. But in a family that chooses to pursue dialysis for an infant. But it's, I mean, those patients end up in foster care and we definitely had some infants place successfully into foster care and then who've gone on to transplant. Thank you. And there's another question. So it seems like there's a common teaching that the creatinine in the 1st 24 hours of life is a reflection of the mother's creatinine. But did they understand correctly that it actually correlates more with the baby's renal mass. So, no, I was actually referring to, sorry, I should have been more clear correct if you measure the creating the it starts out at the start out equal to the maternal creating. So around say, a term infant with a normal mother might be around 1.8-1 and then it drops and it drops pretty quickly based on the function of the baby has. So usually you will see a decrease in the 1st 24 hours, but that decrease can be delayed. Um and the amount of that decrease will depend on the kidney function. Um, so I, you know, when I, when I am taking care of infants who I know has bad kidneys, I definitely counsel the parents that the creating of birth will be the maternal creating and then we'll see where it goes. And we won't really know how good or bad the kidney function is for potentially a week or two. Um, as we see what the creating does or the over time, a lot of my discussions about glamorous infiltration rate and I tried to use that term because I kind of wanted to divorce it a little bit from the creating measurement, but the dynamics of the crowning measurements are similar to what I showed Fergie fr thank you. What do you use to measure your blood pressure in young infants? In your office in primary care. It's really hard to get a good or accurate measurement in the younger kids and especially if there's developmental issues um and really bad at getting good blood pressures and older kids who are neuro diverse and fearful. Yeah, no, it's it's incredibly hard and it takes time and we recognize it as specialists were given time to do those hard measurements. So typically, so less than a year, Oslo metric measurement is the standard, ideally you want to do an arm. If you can't do an arm, you can do a cap, a normal calf. Blood pressure is pretty good indication that the blood pressure is normal. It's not 100% guarantee. But in general cap blood pressure is run higher than arm. But the standard is an arm blood pressure with Osceola metric machine for patients less than a year, recognizing that that fails all the time, right? It routinely doesn't work. So trying to do it in the primary care setting is very helpful to me as a nephrologist failing in the primary care setting is very common and I routinely fail in my own office. I have I have patients who are in the nursery and I had good blood pressures in the nursery and I've never had another blood pressure sense between the ages of like three months and two years when they finally calmed down. So it's really hard to do and in the neuro diverse population um I think trying manual blood pressures is another important task. I recognize that that you know it may not be time and you know, busy primary care clinic to do that. And there's nothing wrong with referring to nephrology to help evaluate blood pressure when you maybe have gotten high blood pressure and in your primary care office and you want to follow it. But you know that how hard hearted is we routinely see patients in the entire visit is just trying to get what I think is a real blood pressure. We're setting the parents up potentially to take blood pressures at home to monitor that way. Thank you. Last question. We just have a minute left for a healthy baby who has not avoided after the 1st 24 hours. What is your general recommendation? Well, I think that you know the I think an ultrasound at that point is sort of my starting point obviously assessing hydration status which has always been done. But I think an ultrasound is reasonable just because you don't want to miss the baby that has a bladder outlet structure that's been missed and mentally and that definitely happens. Um whether you do that at 25 hours or 39 hours or 47 hours I think depends a lot on the situation of discharging the social situation. Thank you so much. All right, well this was so informative. Thank you very much, Doctor brinkman for presenting yet again at our Grand Rounds series. We love hearing from you. Thank you everyone for attending, and we will see you next week. Created by
