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Hematology and Oncology, Inside Pediatrics

Children’s Pediatric Oncologists Spearhead Registry of Children with Cancer, COVID 

Left, Julie Wolfson, M.D., and right, Emily Johnston, M.D., are pediatric oncologists at Children’s of Alabama and assistant professors in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics. Left, Julie Wolfson, M.D., and right, Emily Johnston, M.D., are pediatric oncologists at Children’s of Alabama and assistant professors in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

Left, Julie Wolfson, M.D., and right, Emily Johnston, M.D., are pediatric oncologists at Children’s of Alabama and assistant professors in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

What started as a conversation among a Facebook group of pediatric oncologists at the pandemic’s start has now grown into the largest registry of children with cancer and COVID-19 in the country, providing invaluable information for healthcare providers grappling with the effects of the virus on their patients. 

“People started posting in the Facebook group about caring for children with cancer and COVID-19, asking what they should do,” said Children’s of Alabama pediatric oncologist Emily Johnston, M.D., who, with her colleagues Julie Wolfson, M.D., and Jenn Levine, M.D., of Cornell Medical Center in New York, helped found the Pediatric COVID-19 Cancer Case (POCC) Report. “There were no data, no guidelines, nothing,” Dr. Johnston said. The registry, which is now housed at the University of Alabama at Birmingham, is led by Drs. Johnston and Wolfson.  

The growth has been “miraculous,” Dr. Johnston said. “We started these conversations in March 2020 and had our first patients entered by the end of April, representing an incredible pace.” Today, the registry has data on more than 1,400 children from more than 100 sites. “The other hospitals are participating in the registry because it’s the right thing to do for our community and our patients,” she said. “The national collaboration has been really impressive.” 

One goal of the registry is to provide real-time information to pediatric oncologists. The team sends regular data briefs to every pediatric cancer site in the country with updated summaries. 

In December 2021, the group published its findings on 917 children from 94 U.S. hospitals in the prestigious Journal of Clinical OncologyThey found these children had a high risk of severe infection, with one-third admitted to the hospital and 9 percent to the ICU. They also found nearly half (45 percent) had their cancer therapy changed because of the infection. Fourteen (1.5 percent) died from COVID-19.  

The children most likely to develop severe disease with COVID-19 infections were age 11 or older; those with health conditions in addition to their cancer; and those with neutropenia (low white blood cell count) or hematologic cancers. Hispanic children were most likely to be infected and to have their cancer therapy modified, even though they didn’t have more severe illness. This, Dr. Johnston said, mirrors the racial and ethnic disparities seen in the wider population with COVID-19.  

She and her colleagues are working on understanding why Hispanic children were more likely to have their treatment changed. “This may reflect a combination of systemic issues, biological issues, and even our innate biases. It’s probably a combination of all these, and definitely something we need to tease apart to figure out why this is happening.” 

Dr. Johnston and her team are now collecting data on the vaccination status of all patients, including those in the registry, and the impact of vaccination on infection. They also have a small grant to delve deeper into the data, including to assess how COVID-19 in children with cancer has changed over the course of the pandemic and determine the impact of the virus on long-term health. 

An important area they hope to research focuses on the impact of treatment changes. “We’ve had such incredible improvements in survival in the last several decades in part because we’ve gotten more treatments and escalated treatment, including giving more intense, frequent chemotherapy,” Dr. Johnston said. “That’s led to improved survival. We get very nervous when we have to hold or modify chemotherapy.” 

The two Drs. Johnston and Wolfson said they feel a calling for the work. “We felt it was our duty to use our research infrastructure for this public health purpose,” said Dr. Wolfson. “Hopefully, we’ll be able to help patients and clinicians as much as possible.” 

Hematology and Oncology, Inside Pediatrics

Hematology/Oncology Fellowship Programs on a Growth Spurt  

Left to right, Katie Metrock, M.D., Hilary Haines, M.D., and Kimberly Whelan, M.D. All are pediatric oncologists at Children’s of Alabama and faculty members in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

Left to right, Katie Metrock, M.D., Hilary Haines, M.D., and Kimberly Whelan, M.D. All are pediatric oncologists at Children’s of Alabama and faculty members in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

Every year, two pediatric residents are accepted to Children’s of Alabama’s three-year, ACGME-accredited program. Their first year is a whirlwind of rotations through the inpatient, stem cell transplant, and outpatient clinics, said Kimberly F. Whelan, M.D., who completed the fellowship herself and now directs the program. “I think of it as being a very rewarding but steep learning curve year,” she said. In the second and third years, the fellows develop an area of research or scholarly focus that serves as the foundation for their first faculty position.  

“We send our fellows out to institutions all across the country,” Dr. Whelan said. “And as that number has grown, it’s been wonderful to see the opportunities for networking and collaboration and the impact our fellows are having on the field — not only here in Birmingham, but across the country.” 

The program typically gets about 40 applicants a year and interviews between 20 and 25. With COVID, of course, interviews have gone virtual, which has pros and cons, Dr. Whelan said. “The upside is it’s more convenient for the applicants since they don’t have to take as much time off to travel. And in the virtual interview you’re able to talk with them and get a good sense of what their interest is, where their passion lies, what they’re looking for in the program.” 

The downside, however, “is that we don’t get to show off Birmingham and the beautiful Children’s of Alabama, which is such a wonderful institution.” 

Recently, the Hematology/Oncology Program added two additional fellowships for hematology/oncology fellowship graduates who want additional training: one in bone marrow transplantation and one in neuro-oncology.  

Bone Marrow Transplant Fellowship 

While hematology/oncology fellows receive training in bone marrow transplant, the field has become very subspecialized, requiring specialized education, said Hilary Haines, M.D., who directs the bone marrow transplant fellowship. “The field as a whole is moving away from general hematology/oncology [and] into subspecialities, so the need to have dedicated training in these fields is definitely evolving,” she said. 

That’s why the division created the one-year fellowship program focused entirely on bone marrow transplantation. It’s one that interests many hematology/oncology fellows, said Dr. Haines, given the complexity of the field. “You get to care for a variety of patients and be involved with cutting-edge technology and new therapies.”  

Indeed, bone marrow transplants are not just for blood cancers. Today they are an option — even a cure — for other blood disorders like sickle cell anemia and severe combined immunodeficiency, bone marrow failure, and some neurological diseases. “We’ve identified more diseases that are curable via bone marrow transplant, and our outcomes have improved for the procedure, so we’re more willing to pursue transplant for diseases that we may not have in the past,” Dr. Haines said. 

Several large children’s hospitals already offer bone marrow transplant fellowships, she said, so having the option at Children’s of Alabama serves as a good recruitment tool for hematology/oncology fellows who may eventually want to focus on bone marrow transplantation.  

The first participant, who completed her hematology/oncology fellowship at Children’s, should finish her training in May. 

Neuro-oncology Fellowship 

Like Dr. Haines, Children’s neuro-oncologist Katie Metrock, M.D., points to the continued subspecialization in hematology/oncology as the reason for the new, one-year neuro-oncology fellowship she just launched. “The year is meant to submerge you into the field of neuro-oncology,” she said, which is vastly different from hematology/oncology overall. “Fellows get significant exposure to leukemia and lymphoma and other solid tumors during the general hematology/oncology fellowship, but not as much in-depth experience with neuro-oncology because the program operates slightly differently,” she said.  

Since patients often require comprehensive care from multiple medical specialties, the extra year is designed to enhance a fellow’s knowledge of pediatric brain tumors, including diagnosis, biology, clinical course, treatment options, outcomes, and areas of research. 

“In addition,” Dr. Metrock said, “the field is rapidly evolving as we learn more and more information about these tumors. This gives the fellow extra time to learn the details of the complex care required to help these children succeed.” 

Brain tumors are the most common pediatric tumors and the one with the highest mortality rate. In brain tumors, the neuro-oncologist coordinates the team of specialists required to care for these children, including neurosurgeons, neuropathologists, radiation-oncologists, neurologists, ophthalmologists, and others. The fellow will start by watching the neurosurgeon operate, then follow the tissue sample in the pathology lab, learn to discuss a neuro-ophthalmology exam with the ophthalmologist, understand the dosage and design behind radiation-oncology plans, and meet with palliative care, among other rotations — a deep dive they don’t get during their hematology/oncology fellowship.  

That experience is different from just meeting the patient and family after the surgery and diagnosis. “We feel we can better understand what’s going on with them — to the extent that’s possible — by following them from the beginning,” Dr. Metrock said. 

“My favorite year in all my training was my neuro-oncology fellowship,” she said. “It was a year when I was able to do what I loved most and ask every question I wanted to ask. I’m excited to offer that to other people.” 

The first neuro-oncology fellow starts in July 2022. 

Hematology and Oncology, Inside Pediatrics

Children’s of Alabama Welcomes Pediatric Neuropsychologist Specializing in Neuro-Oncology 

Emily A. H. Warren, Ph.D., is a pediatric neuropsychologist at Children’s of Alabama and an assistant professor in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

Emily A. H. Warren, Ph.D., is a pediatric neuropsychologist at Children’s of Alabama and an assistant professor in the Division of Pediatric Hematology/Oncology in the University of Alabama at Birmingham Department of Pediatrics.

With or without cancer, childhood is a very important time for brain development. Yet the experience of cancer itself, as well as the cognitive effects of many cancer treatments, can derail that development, leaving kids at risk for long-lasting social, psychological, and cognitive challenges.  

“The great thing is that with the wonderful advancements in medical treatments and the comprehensive care these children receive, most will survive,” said Emily A.H. Warren, Ph.D., who came to Children’s of Alabama in the fall of 2021 as its first neuropsychologist dedicated specifically to caring for pediatric brain tumor patients. “Now there can be much more attention focused on quality of life, neurocognitive development, and long-term outcomes like educational attainment.” 

Children’s diagnoses and treats more than 60 new central nervous system tumors a year. Dr. Warren uses her expertise in brain development and neuroanatomy to evaluate cognitive development in children with brain tumors. “My main goal is to provide families with a high-quality neuropsychological evaluation, so I can help them understand the potential impact of their child’s brain tumor diagnosis and treatments on cognitive and psychosocial outcomes and support their child in pursuing their goals,” she said. 

Her work begins with a comprehensive neuropsychological assessment covering everything from intellectual functioning to learning, memory, attention, executive functioning, processing speed, visual motor skills, and psychosocial adjustment. 

“With that data, I can help families understand how a diagnosis like a brain tumor and treatments like surgical resection, radiation, and chemotherapy can affect brain development and cognitive abilities,” she said. The goal of the assessment is to carefully evaluate a child’s cognitive strengths and weaknesses to promote the development of age-appropriate skills. Once she knows each child’s unique cognitive profile, Dr. Warren helps families identify ways to support their child. Supports could include developing an individualized education program (IEP) and other school-based or community interventions such as physical therapy, social skills training, or psychological therapies. 

“These children are going through so many complex challenges,” she said. “There are the social and emotional aspects of the diagnosis and treatment, which can be very hard on families. We also need to support their school reintegration because some of these children have been out of school for a while.” Additionally, children may have new functional deficits. They might be in a wheelchair, have visual or hearing impairment, “or just feel that their thinking is slower than it used to be, or they are having trouble getting their words out,” Dr. Warren added. 

“I like to spend a lot of time helping families understand the relationship between their child’s cognitive abilities and their academic achievements and social interactions. It is also important to help families understand the social and emotional impact of being a cancer survivor.”  

Dr. Warren’s research focuses on cognitive and social outcomes following radiation therapies for brain tumor survivors. “With advances in radiation technology, such as proton radiation, children tend to have better neurocognitive and developmental outcomes than we saw in the past,” she said.  “Even so, we still routinely see challenges with skills such as attention, executive functions, and processing speed. Children who receive more intensive therapies might be at greater risk for cognitive challenges. This is why it’s important to individually tailor each neuropsychological evaluation to meet the needs of each child.” 

Dr. Warren hopes to collaborate with her colleagues in pediatric oncology and radiation oncology to continue this research and is currently a co-investigator for a clinical trial exploring whether memantine, a drug used in Alzheimer’s disease, is neuroprotective in children receiving brain radiation.  

Hematology and Oncology, Inside Pediatrics

Bench-to-Bedside: Translational Focus Moves Sickle Cell Research into Clinic Faster 

Lebensburger_WEBSITE

Jeffrey Lebensburger, D.O., is a pediatric hematologist at Children’s of Alabama and an associate professor in the Division of Hematology/Oncology in the Department of Pediatrics at the University of Alabama at Birmingham.

Basic research is conducted in labs and on animal models, and clinical research is conducted in humans. Traditionally, the two don’t mix, with the basic happening before the clinical. Translational research, a mix of the two, is designed to get new discoveries and treatments to patients faster. “Translational research is a vital component to making breakthroughs in clinical care,” said Jeffrey D. Lebensburger, D.O., who directs the pediatric hematology section of Children’s of Alabama’s Department of Hematology and Oncology. 

Dr. Lebensburger and his research partner, University of Alabama at Birmingham assistant professor Malgorzata Kasztan, Ph.D., are using this approach to find better ways to prevent early kidney disease in children with sickle cell disease. Between 20 percent and 30 percent of children with the disease already demonstrate kidney injury before they hit their teens, and up to 70 percent will develop chronic kidney disease by the time they’re middle-aged. Many will require dialysis or transplantation, often beginning in their 20s. However, the most commonly used test for kidney problems rarely identifies early signs. 

“While we may think that the kidneys are doing okay in childhood based on the tests, there may be severe damage that leads to this early dialysis, which is why we greatly need this bench-to-bedside approach to prevent progression early in adulthood,” Dr. Lebensburger said.  

“We are particularly interested in looking at which patients are at risk for kidney disease and if there is a way to identify those patients early in the process, so they can get better care,” said Dr. Kasztan. 

Tracking the progression from childhood through adulthood, however, would take too long and cost too much. Yet mice genetically engineered to have sickle cell disease fully mature in just a few months, making them a perfect model for exploring kidney disease progression. 

Using these mice, coupled with a biobank of patient blood and urine samples and a sophisticated assay for kidney damage available only in the research setting, Drs. Lebensburger and Kasztan identified high levels of the protein endothelin-1 (ET), which binds to two receptors, ETA and ETB, as a key contributor to early kidney damage. Blocking the ETA receptors with an already-FDA-approved drug, however, protected the mouse kidneys. 

“That allows us to bring back to the patient what we’re seeing in the mouse model and understand if it will continue into adulthood,” Dr. Kasztan said. “Then we could potentially intervene earlier.” 

At the same time, biomarkers of early damage they find in the human blood and urine samples can be “mirrored” in the mouse model to confirm the results, she said. Then interventions that work in the animal model can be tested in patients.  

This type of bidirectional work provides the foundation for clinical trials in humans, said Dr. Lebensburger. “That’s an example of this bench-to-bedside approach: It works in the mouse model of sickle cell, so we can lobby the FDA to start a clinical trial in humans.” 

Inside Pediatrics, Pulmonology

New Pulmonary Faculty Join Children’s of Alabama

Spencer Poore, M.D., Ryne Simpson, M.D., and Christopher Fowler, M.D.

Left to right, Spencer Poore, M.D., Ryne Simpson, M.D., and Christopher Fowler, M.D. All three are assistant professors in the Division of Pediatric Pulmonary & Sleep Medicine, University of Alabama at Birmingham Department of Pediatrics.

The Division of Pulmonary and Sleep Medicine at Children’s of Alabama has added three physicians to its team.

Christopher Fowler, M.D.

Christopher Fowler, M.D., is used to the South, having completed medical school at the Medical College of Georgia, his pediatric residency in South Carolina, and his pediatric pulmonary fellowship at the University of Alabama at Birmingham. So leaving simply wasn’t on the table. “I enjoyed being here so much as a fellow that I really wanted to stay and keep working with this awesome team,” he said.

Dr. Fowler entered pediatrics because, as his wife put it, when he was on the pediatrics rotation in medical school, he was happiest and most excited to come home and tell her about his day.

The pulmonology specialty came after caring for his first cystic fibrosis (CF) patients, all of whom were hospitalized with pneumonia. “These kids had a lot going on. And they were very smart. They taught me all about their disease and how they take care of themselves when they’re at home and then how I should take care of them while they were in the hospital. I enjoyed getting to know them and learn from them so much that I decided pulmonology was the thing for me.”

His research focuses on investigating adrenal complications from steroids CF patients take. Chronic use leads to adrenal insufficiency, with symptoms mimicking a respiratory disease. Studies in adults with CF show that about 8 percent develop adrenal problems over a 10-year period, but there are no studies in children, he said. “I don’t know if it’s going to be as big a problem in children as it is in the adults. But I think it’s a good question to answer.”

When he’s not trying to answer complex research questions, Dr. Fowler can be found corralling his own children and playing the drums.

T. Spencer Poore, M.D.

Spencer Poore, M.D., is quite familiar with Children’s of Alabama, having completed his pediatric internship and residency in Birmingham. Now, after three years in Colorado for his pulmonology fellowship, he’s back as one of the pulmonology division’s newest faculty.

He chose Children’s for his first academic position because it provides the opportunity to treat a wide variety of patients, from urban to rural, with common conditions like asthma to extremely rare pulmonary conditions. “I wanted a big program that could expose me to anything and everything,” he said, “as well as springboard me into any direction I wanted to go given its world-renowned experts.”

He brought with him his research on fungal infections and lung inflammation in children with cystic fibrosis. “Fungus is an interesting organism in that in some people it causes infection and in some an allergic reaction,” he said. “And there’s probably some degree of overlap, but we don’t know the pathways. So it feels like chipping away at an iceberg.”

Whatever they find, he said, the recognition should go to the patients. “If it weren’t for the patients willing to help people they’ll never even meet, we couldn’t do this,” he said.

Outside of work, Dr. Poore enjoys cycling, both mountain biking and road biking.

Ryne Simpson, M.D.

Having grown up in Chattanooga, Tennessee, and attended medical school at the University of Tennessee in Memphis, Ryne Simpson, M.D., was not quite prepared for the weather when he completed his residency in Kansas City, Missouri, and his fellowship in Cincinnati, Ohio. So Children’s of Alabama — with its warm climate and proximity to his family — was a perfect fit. “I was tired of the cold Midwestern winters that never ended,” he said.

His focus on pediatric pulmonology comes from the “complex nature of the patients,” he said. “I enjoy that we get to do procedures like bronchoscopy, and also the continuity of working with the patients.”

Dr. Simpson’s prior research focused on identifying best practices for flexible bronchoscopy and chronic ventilation in children based on outcomes and readmission rates. He enjoys such quality improvement and systems process studies, he said, given their more immediate impact on clinical outcomes compared to basic or clinical research. “I don’t always have the mindset for multi-year longitudinal studies,” he said.

Since coming to Birmingham, he’s enjoyed trying new restaurants. Now that he has his own house, he said, he’s looking forward to getting a set of drums “and playing when I want.”

Cardiology, Inside Pediatrics

Harmony Device Saves Children from Open-Heart Surgery

Harmony transcatheter pulmonary valve

In July 2021, interventional cardiologist William McMahon, M.D., Mark Law, M.D., and the Pediatric Cardiac Catheterization Lab team at Children’s of Alabama, snaked a catheter device through a vein in a 16-year-old girl’s leg up to her heart and replaced the valve. She went home the next day with just a small scar on her leg that will eventually become invisible. The U.S. Food and Drug Administration approved the device, called the Harmony transcatheter pulmonary valve, in March. Drs. McMahon and Law were the first cardiology specialists in a 10-state region to use it.

Fewer than 20,000 children are born each year with Tetralogy of Fallot, a condition marked by four major heart defects: ventricular septal defect, or a hole in the two lower chambers of the heart; a narrowing of the pulmonary valve and main pulmonary artery; malaligned aortic valve; and ventricular hypertrophy, or thickening, of the right ventricle. These children often need surgery soon after birth and a pulmonary valve replacement by the time they’re adolescents or young adults.

In the past, that meant another open-heart surgery and time spent on cardiopulmonary bypass, which carries significant risks of complications; a week or more in the hospital; scarring; weeks of recovery at home; and a low but real risk of death. In addition, because the children have already had major heart surgery, scar tissue from the previous procedure makes the valve replacement even more difficult.

In July 2021, however, interventional cardiologist William McMahon, M.D., and his colleague Mark Law, M.D., together with the Pediatric Cardiac Catheterization Lab team at Children’s of Alabama, snaked a catheter device through a vein in a 16-year-old girl’s leg up to her heart and replaced the valve. She went home the next day with just a small scar on her leg that will eventually become invisible.

The U.S. Food and Drug Administration had just approved the device, called the Harmony transcatheter pulmonary valve, in March. Drs. McMahon and Law were the first cardiology specialists in a 10-state region to use it. While similar devices have been available for pulmonary valve replacement, few children with Tetralogy of Fallot qualified because of their previous surgeries. Now, Dr. McMahon estimates that four out of five children with the condition will qualify.

The new procedure is a game-changer, he said. “We have many patients who live in fear of that surgery because they’ve been told they need another open-heart surgery since they were 8 or 10. We certainly have some patients who reasonably don’t want to do it and some who put it off. That becomes a problem because it means their heart is working harder.”

Dr. McMahon says the advantages to the Harmony device are obvious: “There’s a quicker recovery; lower risk of major complications and death; and they’re able to get on with their lives sooner.” The team has completed 10 procedures so far with no complications other than some arrhythmia that resolved with treatment.

Some patients returned to work or school three days after the procedure. And while the valve won’t last forever, Dr. McMahon expects a new valve could be inserted within the old one in the same manner. “That’s the overall goal of these valves,” he said. “To reduce the total number of heart surgeries that our patients need during their lifetime.”

William McMahon, M.D.

William McMahon, M.D., is an interventional cardiologist at Children’s of Alabama and a professor in the Division of Pediatric Cardiology, University of Alabama at Birmingham Department of Pediatrics.

Inside Pediatrics, Neonatology

Quality Improvement Significantly Improves Outcomes for the Tiniest Babies

Left, Colm Travers, M.D., and right, C. Vivek Lal, M.D., are neonatologists at Children's of Alabama and faculty in the Division of Neonatology in the University of Alabama at Birmingham Department of Pediatrics.

Left, Colm Travers, M.D., and right, C. Vivek Lal, M.D., are neonatologists at Children’s of Alabama and faculty in the Division of Neonatology in the University of Alabama at Birmingham Department of Pediatrics.

In 2014, when neonatologists C. Vivek Lal, M.D., and Colm Travers, M.D., began digging into the data on extremely preterm infants (those born before 28 weeks), they found that Children’s of Alabama and the University of Alabama at Birmingham had some of the best outcomes in the country. But there was still room for improvement.

Infants born so early are at high risk of death and intracranial hemorrhage, or brain bleeds, the most devastating outcomes in the first week after birth.

“We saw a tremendous opportunity to improve mortality and other outcomes,” said Dr. Lal. “We saw this as a chance to fine-tune our practices, and not only be the best in outcomes, but also create a narrative for others to follow.”

“Our goal was to reduce the rates of brain bleeds or deaths in the first week,” said Dr. Travers. “There’s some evidence that non-adherence to certain practices and a lack of standardization can lead to worse outcomes in the smallest babies. We felt that by standardizing care to the best available evidence we could improve those outcomes.”

That’s exactly what they did with the Golden Week™ program, a multidisciplinary, evidence-based, standardized quality-improvement plan to improve the care and outcomes of the micro-preemies. It incorporates a variety of changes in how care is provided, with detailed protocols for the first hour of life, the first 72 hours, and days four to seven.

When the initiative began in 2016, the rate of severe brain bleeds or death was 27.4 percent. Today it’s less than 10 percent and continuing to fall.

The team involves neonatologists and neonatal fellows, as well as respiratory therapists, nurses, residents, and other stakeholders who care for the tiny babies at the bedside.

The initiative began with a comprehensive literature search of every clinical trial or observational study related to mortality or brain bleeds in these babies, identifying successful interventions and then integrating them into the care pathway.

These include ensuring that the mother receives corticosteroids before delivery to help the fetus mature; delayed cord clamping after delivery; putting the baby into a certain position once they’re admitted; initiating evidence-based order sets; and limiting fluid and bicarbonate boluses and the use of inotrope drugs as well as blood transfusions.

Some of the changes were tiny, but with big payoffs, including how the nurses change the babies’ diapers. “We make sure they don’t move the head too much or lift the body too much. Anything that might cause a change in the blood flow going to the brain,” Dr. Travers said. Overall, the team made 24 changes in the care provided during the first week.

The key was not one change, but the changes as a whole, said Dr. Travers. “It was when we put all of these small changes together that we saw the impact,” he said.

The results are being published in the journal Pediatrics this spring.

Inside Pediatrics, Nephrology

Neonatal Kidney Collaborative Advances Understanding of Acute Kidney Injury

David Askenazi, M.D., is a pediatric nephrologist at Children’s of Alabama and a professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

David Askenazi, M.D., is a pediatric nephrologist at Children’s of Alabama and a professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

A bunch of pediatric nephrologists and neonatologists walk into a National Institutes of Health meeting on neonatal acute kidney injury (AKI) in 2013. The punchline? They are inspired to form the Neonatal Kidney Collaborative (NKC) with the clever website address of babykidney.org.

“At that NIH meeting, we recognized that bringing people to work together on multicenter studies was a critical step in moving the field forward,” said Children’s of Alabama pediatric nephrologist David J. Askenazi, M.D., one of the founding members and current NKC Board chair.

Today, the collaborative boasts 77 participating institutions with 168 members and 19 published manuscripts. Several of those publications come from the group’s inaugural study called AWAKEN (Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates), the first multinational, multicenter study on neonatal AKI.

The study involved a retrospective review of three months of data on 2,162 infants in Level 2 or 3 neonatal intensive care units in four countries, a third of whom had AKI. The investigators found those with AKI were 4.6 times more likely to die and stayed in the hospital an average of 8.8 days longer than those without. Other results from AWAKEN include risk factors for mortality and the development of AKI (such as low albumin and hemoglobin levels) and hypo- and hypernatremia, as well as a link between intraventricular hemorrhage (bleeding in the brain) and AKI.

“We chose the name AWAKEN because we felt like the field needed to be awakened,” Dr. Askenazi said. And it’s worked, he said, with the number of studies, initiatives and young people interested in neonatal nephrology growing exponentially.

The collaborative, he said, “not only provides opportunities to study neonatal kidney disease, but we also have committees to address the educational, advocacy, and research needs of this evolving field.”

The group recently received a significant research grant from Nuwellis, a global company focused on fluid management solutions for pediatric and adult patients, to perform the ALMOND (Assessing Longitudinal Micropreemie Outcomes in Neonates at Risk for Renal Disease) study. “This research effort will expand our understanding of neonatal kidney disease in extremely premature neonates who were enrolled in a multicenter trial called PENUT (Preterm Erythropoietin Neuroprotection Trial),” he said.

The study will use the PENUT database, which contains thousands of clinical data points and hundreds of thousands of urine biomarker data points from more than 900 babies. “It’s a goldmine,” said Dr. Askenazi. “It will allow the NKC to pose and answers questions about kidney disease in extremely premature neonates, including whether caffeine, commonly prescribed to these infants, can prevent AKI; determine the fluid provision to improve clinical outcomes; and identify additional risk factors for neonatal AKI, among other questions.”

“The work of this collaborative is contagious, and it drives me,” he said. “It makes me want to continue to help move the field forward and support young doctors who are filled with energy and excitement.”

Inside Pediatrics, Nephrology

Tracking Kidney Transplant Rejection in the Blood and Urine 

Michael Seifert, M.D., is a pediatric nephrologist at Children’s of Alabama and an associate professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

Michael Seifert, M.D., is a pediatric nephrologist at Children’s of Alabama and an associate professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

Children who receive kidney transplants at Children’s of Alabama undergo a routine biopsy six months after the procedure to look for signs of rejection. In about 20 percent of patients, those signs are there, even if their blood and urine tests look normal. “On the flip side,” said Children’s pediatric nephrologist Michael E. Seifert, M.D., “that means about 80 percent of our patients are getting biopsies that are normal.” 

The holy grail, then, would be a non-invasive biomarker test using blood or urine that can identify kidney transplant injury without needing a biopsy — which is exactly what Dr. Seifert and his lab are working on. Their research relies on a biorepository of patients’ blood, urine, and kidney biopsy tissue collected throughout and after the transplant process. 

One of the blood tests they’re working on uses technology originally developed to screen maternal blood for signs of fetal abnormalities. The test looks for cell-free DNA, or cfDNA, which comes from the fetus and differs from maternal DNA. Since transplanted kidneys also have DNA different from the patient’s own kidney, “you can look in the bloodstream for the proportion of the DNA coming from the transplant versus the normal background from the recipient’s non-transplant cells,” Dr. Seifert said. High levels of cfDNA is a sign of acute kidney injury that could be due to rejection.  

Studies in adults validate this as a good method to detect rejection. “But the problem is, those are done in adults whose native kidneys would be roughly similar in size to the transplant they’re carrying,” Dr. Seifert said. Children often have a much larger, adult-sized transplant compared to the size of their native kidneys, so the cutoff levels used for diagnosing rejection in adults may not work in children. “We’re trying to make these existing diagnostic tests more pediatric specific,” he said. 

The story is different for urinary biomarkers. It’s been known for years that the kidney releases certain proteins when it’s injured. Tests to detect those proteins, however, can take days. But a new device called SimplePlex, currently available only in the research setting, can measure several of these proteins at one time in a single sample in less than an hour.   

“We’re looking at ways to get this technology closer to the clinic, so you’re not just profiling kidney transplant patients’ risk for injury based on their standard blood tests like creatinine, but you’re also adding these additional biomarkers that can tell you more information about what’s happening inside the organ,” Dr. Seifert said.  

Being able to determine via blood and urine tests who needs a biopsy and who doesn’t would have a huge impact for pediatrics, particularly at Children’s, where these biopsies are done on a universal basis, he said. Ideally, the tests could also provide information on the underlying cause of the rejection. For instance, the cfDNA test is good at picking up antibody-mediated rejection, but not as good at recognizing cell-mediated rejection. The urine biomarkers are good at identifying both rejection types, but not at identifying rejection related to viral infections. 

“Once we understand more about the clinical scenarios in which the biomarkers perform well,” said Dr. Seifert, “we’ll be able to design interventional trials to treat the patient based on the biomarker changes rather than just the standard clinical tests such as creatinine.”  

Inside Pediatrics, Nephrology

Childhood Household Dysfunction Predicts Hypertension, Vascular Injury in Adolescents 

Dan Feig, M.D., Ph.D., is a pediatric nephrologist at Children’s of Alabama and a professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

Dan Feig, M.D., Ph.D., is a pediatric nephrologist at Children’s of Alabama and a professor in the Division of Nephrology in the University of Alabama at Birmingham Department of Pediatrics.

Verbal and physical abuse; neglect; and household dysfunction such as divorce, domestic violence, and poverty in early childhood (called adverse childhood experiences, or ACEs) affect approximately 25 percent to 30 percent of children in the United States. They also put those children at significantly increased risk for health issues like hypertension and cardiovascular disease as adults.  

“Ideally, we would like to prevent neglect, maltreatment, abuse, and household dysfunction,” said Children’s of Alabama pediatric nephrologist Daniel Feig, M.D., Ph.D. “But until that can be achieved, we need to work on mitigating their long-term effects.” Dr. Feig’s work looks at whether experiences have already changed the vascular function of individuals exposed to ACEs and whether those changes are reversible.  

“We want to see if there’s a detectable signal, something that puts them in the risk category for future disease and identify those who would benefit from intervention or therapy,” he said. 

Dr. Feig and his team used validated questionnaires to screen 78 teens for the three types of ACEs: abuse, neglect, and household dysfunction. Nearly 70 percent had been exposed to at least one ACE. The investigators also tracked the adolescents’ blood pressure with a 24-hour continuous ambulatory blood pressure monitor; measured their pulse wave velocity (a marker of blood vessel elasticity and reactivity); and looked for markers of inflammation and increased vascular tone in their bloodwork. 

They found that compared to teens with no exposure or with exposure to abuse and neglect, individuals exposed to household dysfunction had a significantly higher 24-hour diastolic blood pressure without the normal drop that occurs at night. They also found a significantly increased baseline inflammatory state. Those who experienced sexual abuse had substantially altered pulse wave velocity, which meant their blood vessels were stiffer. Despite these changes, the children had normal blood pressure. 

“This tells us that even as early as 10 to 12 years after exposure there are detectable alterations in vascular biology associated with the ACEs,” Dr. Feig said. “These individuals might benefit from interventions to reverse or slow those changes to prevent the progression of hypertension and the later risk of cardiovascular disease.” 

The team expected to see more changes in children with a history of exposure to abuse. Dr. Feig hypothesizes that the chronic nature of household dysfunction may be behind the vascular changes. “Things that reset the biology of the vessels are slow and steady effectors,” he said. “That can be dietary, that can be obesity, that can be emotional stressors, or chronic inflammation. I think that the household dysfunction category might have a greater continuous effect as opposed to episodes of horrific injury.” 

The next step is to intervene with medications to try and reduce inflammation and prevent the progression of vascular dysfunction.  

The group is currently following the study participants and hope to secure funding for larger longitudinal studies.