Neonatal Care and Growth in Infants Requiring Dialysis

And it's my pleasure to introduce our next speaker, my partner and collaborator, Doctor Kara Slagold. Doctor Slagle completed pediatric residency at Medical University of South Carolina and neonatology Fellowship at Cincinnati Children's Hospital. She has a great interest in the neonatal kidney, especially acute kidney injury and congenital renal failure. She's the first neonatologist to serve as the co-director. Director for the Center for Acute Care Nephrology at Cincinnati Children's really reflecting the importance of this partnership and care for neonates with severe renal disease. Um, today she'll be discussing the nuances of fluid and nutrition management in these infants. So thank you, Doctor Schlegel. Thank you. Thank you for that kind introduction and for allowing me to come and chat with you all today. I'm gonna share my screen here and then we'll just get started. So as a neonatologist, I'd like to provide you with a little more background on the history of the movement away from strictly palliative care being offered following birth for severe obstructive neuropathies. Um, renal development and amniotic fluid, as you heard earlier, play a critical role in pulmonary development and thus. Infants preterm with any pulmonary compromise were very limited in resuscitation efforts prior to 35 to 40 years ago. It doesn't seem like 1980 was that long ago, but it was. So in 1980, the use of surfactant played a critical role for improving neonatal mortality and really changed the landscape of what we consider viability. In the last 20 years, which was the 2000s, there's been an intense clinical shift in fetal intervention and resuscitation in this population, which you've heard about. Additionally, during that time, we've continued to push the envelope on the ability to provide kidney replacement therapies to smaller infants, and thus odds of survival continue to improve postnatally. As you've heard, the Cincinnati Children's Fetal Care Center offers these interventions, and over the last 6 years, we had 108 mothers with abnormal amniotic fluid receive their primary obstetric care with the Cincinnati Children's Fetal Care Center. The median gestation age at time of referral was 20 weeks, and there was a 17% survival for those that did not pursue any fetal interventions, which improved to a 49% survival to at least stay of life 7 with aggressive interventions that you've heard spoken about. Additionally, if you remove neonates who had bilateral renal agenesis, survival improves to 54%, and those that survived a day of life 7, 80% survived to discharge. As these short-term outcomes continue to improve, we must also focus though on the long-term outcomes. As a neonatologist, we know that growth and early nutrition is linked to poor neurodevelopmental outcomes, but this population offers a unique challenge because increasing nutrition comes at the cost of fluid balance, and fluid balance in this patient population is critical for survival because these infants have minimal ways to remove excess fluid. Additionally, because of the severity of illness, nutritional status in the first week of life alone is often pararal. Thus, the caloric intake is limited by the amount of nutrition you can fit into their total fluid volume, in addition to the type of line, central versus peripheral, as it impacts the osmolarity you can provide through that line. So let's just take a case. Let's take Patient A. The mom was a 20-year-old G1P0 referred um at 19 weeks for concerns of UPJ obstruction. Her amniotic fluid index, actually at the time of referral was 6 centimeters with a deep vertical pocket of 2.5. However, that later reduced to anhydramnios. She had abnormal findings on fetal MRI, oligohydramnios, a right multicystic kidney with no normal renal tissue, dilated right collecting system, left kidney with pelvic dilation, and no definite hydroureter, and no visualized bladder. The fetal echo showed mild biventricular hypertrophy and a small pericardial effusion, and fetal-free DNA demonstrated a low-risk female. She underwent serial amnio infusions performed typically for an AFI of 0 to 2, and then she also had 3 vesico amniotic shunts placed, and I had trouble going back through to her chart because that's at a separate hospital, but I believe that was, um, specifically in a urinoma that was quite large. Infant was born via cesarean section at 34 weeks with apgars of 5 and 8, for preterm labor and premature rupture of membranes. Birth weight, length and head circumference are demonstrated in the tra, um, and those use the Fenton growth curve, which we'll talk a lot, a little bit about the differences in a minute here, um. But the fit and growth term is typically for preterm infants or infants less than 37 weeks. And so you can see her percentiles there, and then the Z scores plotted at the end of that table. And as a general rule of thumb, if you're thinking about preterm infants, for those of you who are not neonatologists, for every 2 weeks an infant is born early. There's about a 1 Z score difference below the World Health Organization, which is what you use for term infants. So if we plotted this infant on the World Health Organization growth chart, she would fall at about a Z score of -1.5 for weight, minus 2.5 for head circumference, and -2.5 for length, and that'll be important here in a minute. She also had respiratory distress syndrome, which required intubation in the delivery room, followed by high frequency oscillator ventilation. She was dependent on vasopressors, specifically vasopressin and epinephrine for poor LV function and pulmonary hypertension, and she received antibiotics in the 1st 48 hours of, um, life, which also, you know, is, is needed for that fluid volume, and she did not pee at all. She underwent peritoneal dialysis catheter placement shortly after birth and began dialysis on day of life 6. we restricted her to 60 mLs per kilo per day of fluids until about 1 month of life, and for this population, per our protocols, we really attempt to restrict them as much as possible while still being able to maintain enough nutrition to keep them in an anabolic state rather than a catabolic state until either urine output picks up or we're able to. Remove the fluid through dialysis and so for normal reference, infants typically reach a goal total fluid volume of about 140 to 160 mLs per kilo per day by about day of life 5, and that mimics intake patterns and accounts for normal physiologic changes as renal function adjusts the extrauterine environment, but for these infants we restrict, we continue to restrict them because they don't have urine normal urine output. She received a total of 48 days of perenteral nutrition and reached full interal feeds by day of life 50 of maternal breast milk, which is significantly delayed. So even in our micro preemies, they typically reach full enteral nutrition by 1 to 2 weeks of life without um any issues, and otherwise we're starting enteral nutrition immediately following birth and then increasing the volumes to those total fluid goals. She was fed through a nasogastric tube. Which is not surprising as many of these patients have feeding intolerance secondary to oral aversions from breathing tubes, um, noxious stimuli in their mouth, or what we presume is GI discomfort with the initiation of peritoneal dialysis and abnormal taste from renal failure. However, at 34 weeks, we would expect her to have the oral skills to take by mouth, and then she was transferred to a different hospital closer to the family's home at day of life 61. A primary role of the kidneys is to maintain homeostasis. So if the kidneys lose the ability to produce urine, this job becomes the primarily. Primary responsibility of the providers with the goal of ends equaling outs. However, when there's no urine output, this becomes a major challenge. So we can use dialysis to assist in this, but peritoneal dialysis catheters require time to heal, especially since they'll be used long term as kind of a bridge to transplantation. Currently, we also use a modified adult machine to assist with this, but the ability to remove fluid in those first few days of life is limited by the neonate's ability to tolerate large fluid shifts, as well as a, a, a catheter placement. And this significantly impacts the ability of what we can give to the neonate. Um, in addition, nutrition is just a piece of this. It must be balanced with the need for other medications, so like in outpatient antibiotics, suppressors, um, and potentially even bulk products. So if you think about you're restricting to 40 to 60, if you're giving 15 mL per kilo of bulk products and 5 mLs per kilo of antibiotics and another 5 oppressors, you've, you've used a lot of that total fluid volume just for those. So as we try and maintain homeostasis at the compromise of nutrition early on, we still don't know though the cost of the long term on growth and neurodevelopment, and there's really a paucity of literature related to long-term follow-up in this population. The association with infants with end-stage renal disease and growth failure is well described, as is growth in preterm infants. However, the combination of these two is largely unknown, and what we do know is that the 1st 2 years of life account for greater than 1/3 of a person's adult height. Multiple studies have also demonstrated that short stature has a significant impact on quality of life, physical, emotional, social, and school functioning, especially in children with chronic kidney disease. In addition to quality of life, though, the North American Pediatric Renal Trials and collaborative studies in 2008 found that children initiating dialysis with a height less than the 1st percentile for age-sex comparison had a two-fold increase in mortality risk. For this reason, we aim to create a pilot study to better characterize and describe current practices and somatic growth patterns, thus to understand potential signals, the hypothesis that growth failure is there and present, and thus to find a potential for targeted interventions. So we use a single center retrospective review of maternal infant dyads that were followed by the Cincinnati Children's Fetal Care Center over a period of 4 years, and these dyads were referred for fetal kidney dysfunction, which is defined as an abnormal or reduced amniotic fluid index in addition to kidney abnormalities on fetal imaging. Our inclusion criteria were those admitted to the NICU with the dialysis access catheter or line placed at less than 30 days of life, and we excluded subjects with bilateral renal agenesis, um, and those that then had a death prior to 30 days of life or had insufficient clinical data for analysis. Our main outcome of interest was somatic growth, specifically anthropometric Z scores, and although preterm infants. are smaller than term infants to be consistent with measurements across that first year of life and to look at the overall growth pattern, we did use the World Health Organization growth curve. So remember what we talked about earlier with the differences. Um, this also adjusts the Z score for variations in growth for sex, and then we recorded weight, height, and head circumference measurements in addition to demographic, perinatal, and clinical data. We had a record of 150 mother infant dyads referred over those four years, with 68 pairs ultimately receiving their obstetric care elsewhere. Of the 86 pairs with complete data, 8 went on to have an intrauterine fetal demise prior to delivery. 78 infants survived to delivery. Um, first bilateral renal agenesis was excluded, then those who did not survive to 30 days of life, and then ultimately those, um, infants that didn't require dialysis catheter placement either. Um, and this yielded us 17 infants with data over the course of the 4-year period. 9 of those subjects had posterior urethral valves, 4 subjects had bilateral multicystic kidney disease. Some had only 1 kidney with a multicystic kidney, and then 1 subject had, um, a UPJ obstruction. So a little bit broader than just, um, obstructive neuropathy, but it gives you an idea of growth patterns for this cohort. All subjects required peritoneal dialysis, and 10 subjects received prolonged intermittent kidney replacement therapy, um, also known as PIKRT, and it uses the Aqueex SmartFlow Ultrafiltration device in the NICU, um, so you might also hear it referred to as modified Aqua. Um, the median duration of PIKRT was 23 days, and other modalities of extracorporeal kidney replacement therapy in the first year of life included hemodialysis and CRRT. Subjects were primarily male, um, and also white, and the median birth gestational age was slightly preterm at 35 weeks. Infants all had respiratory compromise, with all but one infant requiring mechanical ventilation, um, in the 1st 30 days of life, and the majority having pulmonary hypertension and vasopressor dependency early on. There was also a high level of postnatal hydrocortisone exposure and inflammatory states, sepsis and neck, which are known influencers of growth. Um, and just for your knowledge, hospital length of stay was around 4 months, and 3 infants did die prior to NICU discharge. When we break down the intake of this cohort, as you can see, the daily fluid allowance is very restricted at birth, and per our protocols, this continues into the first week of life, but then is liberalized by the second, and for those reasons of increasing urine output or the initiation of dialysis. Um, enteral nutrition is significantly delayed until about 1 month of life, and it should be noted that because of the combination of para-enteral and enteral nutrition and the difficulties of the retrospective study, we did not pull average kilocalories during these times, but it is an area we plan to look at in the future. Oral routes were primarily via nasogastric tubes, despite our cohort being at a gestational age where we would expect them to be able to take feeds by mouth, and this likely reflects the severity of their illness. These infants also commonly receive tube feeds run over a long period of time, if not continuance, for feeding intolerance. And it is well known to neonatologists that milk fat, which accounts for some of the caloric content, binds to that plastic tubing. That the longer the duration of feeds are running over, the less milk fat the patient sees, and thus the less calories. And as subjects become more stable and closer to home, we advance them to what we refer as bolus intake over 30 minutes if we can every 3 hours. In addition, we were surprised that our infants had a large amount of not only human milk, but actually maternal milk, um, and caloric content and macronutrients can vary in mother's milk with mothers of preterm infants making higher calorie, high fat. Milk in the 1st 2 weeks of life and then they transition to a low calorie high water proportion, um, closer to term um or past that 2 weeks and donor milk is known to be closer to that, um, higher proportion of water and lower calorie and only 1 infant in our cohort received donor milk and that was just at 2 weeks, which was then transitioned to the maternal milk by 1 month of age, um, contributing so donor milk really didn't contribute to growth failure in this population at least. All infants who survived a full and oral feeds received fortification with a median maximum fortification of 28 cacals. Um, and initiation of the first fortification occurred at about 21 days of life. A normal term formula is 19 to 20 cacals per ounce, and preterm infants typically take anywhere from 24 to 28 cacals depending on their gestational age and their, um, needs. So getting to the meat, these are the Z scores plotted over time, um, with weight being in the first group, followed by length and then head circumference. So it should be noted again that these are based off the World Health Organizational, um, growth curves, which has measurements for infants 37 weeks and above, and our cohort was, um, median gestational age of 35 weeks. So it does contribute to some of the shift below zero, especially in those 1st 1 to 2 months of life. However, we really wanted to be consistent so that we could see a comparison over time. Um, so even if you shift those 1st 2 months, there's still a profound lag in all parameters with the most notable being at 1 to 2 months of age. And this occurs about the same time that you see us start to shift children to primarily inner or infants to primarily internal nutrition and roughly about 1 month after they begin fortification. And then, as you can see, normalization of parameters begin to occur after that, um, with the median time of discharge actually being about 4 months, which is this gray bar here. Although we had a small end, we also wanted to compare the growth tre trends between infants receiving the PIKRT or modified Aqua, um. And those that did not. So this is the plot of those that did not receive um modified Aqua or PIKRT. And, and what you can see when you overlay the two, the two groups, there was no statistical difference between gestational ages if you're looking at this. There's really not a big difference. There's maybe a little bit of variability at each bar, um, but there was no statistical significance. However, it should be noted that further analysis is needed with a larger sample size. In conclusion, our cohort demonstrates profoundly impaired growth with a lag in all parameters by 2 months, and this supports existing literature on poor growth in infants with end-stage kidney disease. Early weight trends in this population likely reflect fluid balance and not nutrition, so you have to remember that linear growth is very important, and it supports the need to follow that linear growth velocity and evaluate, um, caloric density of perenteral nutrition early on. Poor growth additionally reflects illness severity or can reflect illness severity, and so energy expenditures from respiratory distress and inflammatory states likely further impact growth. Excuse me. Advancement of enteral nutrition, excuse me, was delayed and a large proportion of infants received human milk. And opportunities for personalized fortification strategies via breast milk analysis are attractive for future interventional studies. And catchup growth is very velocity is impressive, however, linear growth fails to normalize. Excuse me. Thus, exploring signals related to acceleration and length recovery may further drive future protocols. So overall, as survival becomes more favorable for more severe cases, more research is greatly needed to impact long-term outcomes and really guide parental counseling. A special thanks to Doctor Riddle, Doctor McNeilli, and Doctor Clays who really helped me with this talk and this data, as well as the Cincinnati Children's Fetal Care Center, the Perinatal Institute, the Center of Acute Care Nephrology, um, and the Division of Pediatric and General and Thoracic Surgery. Thank you so much and I'm happy to take questions. I apologize. My mouth's a little dry. Thank you so much for that. Um, I think one interesting thing from, you know, the neonatologist's perspective, we're always taught that breast is best, but as you showed, these patients require a really high level of fortification that they really require a lot of support, and we're very nervous about fortifying patients and who require peritoneal dialysis So it's a very delicate balance, um, and trying to protect, protect their neurodevelopment, their linear growth, which can affect transplant timing and outcomes, um, and so what are the opportunities with breast milk that we may have moving forward? Yeah, so we're really cautious to increase, um, fortification of calories early on because. If we have any sort of catastrophic um abdominal event it really limits our our opportunities for dialysis in the future, um, but there is things such as milk fat so just like you would do for a Kylothorax where you skim the milk fat off the top and then give like a low, low fat content milk you can actually use that fat and supplement it, um. To the breast milk and hopes to increase the fat content of the milk, um, and thus provide extra calories that way without providing a higher osmolarity, um, and then there's also opportunities for specific breast milk analysis, so truly seeing what that patient is receiving on the other end and then adjusting our fortification strategies to there. Their needs, expenditure needs, I should say. Yeah, I think those are really exciting opportunities as we are extending these therapies to more and more patients, so. Thank you all.