Bench to Bedside

June 2014

Gene Study Points to Novel Pathway for Diabetes Treatment


New research from The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania details how a diabetes-related gene functions on a biological pathway that affects the release of insulin. Finding drugs that act on that pathway may eventually lead to a new treatment for type 1 diabetes.

“In 2007, our genomics team found the first gene in a genome-wide search to play a major role in type 1 diabetes, but we did not know its function,” said co-study leader Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP. “Now we understand how this gene plays a critical role in regulating insulin metabolism.”

The current finding builds on a 2007 genome-wide association study by Dr. Hakonarson and colleagues at CHOP showing that variations in the KIAA0305 gene, also known as CLEC16A, correlate with higher risk of type 1 diabetes and other autoimmune diseases.

The research team subsequently developed a strain of mice in which the CLEC16A gene was deactivated. They then collaborated with endocrinology expert Doris A. Stoffers, MD, PhD, of the Institute for Diabetes, Obesity and Metabolism at UPenn to breed a subset of the knockout mice in which only the pancreatic cells were affected. Dr. Stoffers was co-senior author with Dr. Hakonarson, and is the corresponding author of the study, which appears online in the journal Cell.

The investigators show that the CLEC16A gene acts upon a pathway crucial to insulin secretion.

The gene normally helps protect mitochondria, the tiny energy-producing components of cells, but when the CLEC16A gene is knocked out, damaged mitochondria are then digested — a process called mitophagy — and the resulting loss of energy output disrupts beta cells in the pancreas in their normal job of secreting insulin.

“The ultimate result of the deletion of CLEC16A is an accumulation of unhealthy mitochondria, leading to less insulin being secreted by the beta cells,” said Dr. Stoffers.

In humans, an inability to produce insulin is the hallmark of type 1 diabetes. The study team showed that humans with single-base variants in CLEC16A have reduced beta cell function, although with less extreme effects than in the knockout mice.

The researchers showed that the CLEC16A biological pathway has downstream effects on a protein called Parkin, already known to be a master regulator of mitophagy. The current study is the first to link the CLEC16A pathway with regulation of Parkin-mediated mitophagy and to suggest how this process may affect diabetes by dysregulating insulin secretion.

If drugs can be developed to act on the CLEC16A pathway, they could provide a new, targeted therapy for patients with type 1 diabetes who harbor risk variants in the CLEC16A gene, said Hakonarson.

More information about the study is available here.

Direct link:

Using Children’s Feedback to Measure, Respond to Adversity


As any pediatrician will tell you, children are not just little adults. Assessing and treating pediatric health issues is not the same as assessing and treating adult health issues, only in miniature. Children are different from adults in myriad ways — physically, developmentally, and emotionally.

They also use language differently than adults do. For one, children have much smaller vocabularies than adults. According to the website, average native test-takers aged 8 years old know approximately 10,000 English words, while adult test-takers know between 20,000 and 35,000 English words. And per the American Speech-Language-Hearing Association, even children without language disorders may have issues with language pragmatics, i.e. using language appropriately, changing how one uses language to fit situations, and following conversational rules.

Acknowledging that children use language in unique ways, one CHOP researcher has been striving to incorporate their voices into public health measures. With the support of the Stoneleigh Foundation, The Children’s Hospital of Philadelphia’s Roy Wade, Jr., MD, PhD, MPH, has been working on a new project that seeks to add children’s voices and language feedback to tools used to assess and respond to childhood adversity. An attending physician and public health researcher, Dr. Wade’s current investigation builds on the results of a major study recently published in Pediatrics.

With Youth Feedback, Project Adds to CDC Study

Published online June 16, Dr. Wade’s Pediatrics study, which he conducted alongside Children’s Hospital’s Joanne Wood, MD, MSHP, and David Rubin, MD, MSCE, as well as the University of Pennsylvania’s Judy A. Shea, PhD, sought to add the perspectives of low-income inner-city youth to measures of adverse childhood experiences (ACEs). Dr. Wade’s study follows the CDC’s landmark Adverse Childhood Experiences Study, which was initially conducted from 1995 to 1997. Designed to assess the associations between adverse childhood experiences and “later-life health and well-being, the CDC study’s findings “suggest that certain experiences are major risk factors for the leading causes of illness and death as well as poor quality of life in the United States,” according to the CDC site.

Dr. Wade’s research seeks to build on the original ACE study (which focused on abuse, neglect, and other measures of household stress) by adding disadvantaged youth’s voices. For example, chronic ACEs experienced by inner-city youth such as pervasive community violence, economic hardship, and racial discrimination were not assessed in the CDC study. Therefore, by partnering with community organizations in Philadelphia, in the Pediatrics study Dr. Wade conducted a series of focus groups with low-income inner-city young adults aged 18 to 26 years old to get their perspectives on ACEs.

After meeting with a total of 105 participants, the researchers found that stress related to family relationships (such as domestic substance abuse and domestic violence) was the most common ACE cited. The second most commonly cited area was community stressors, including “neighborhood violence, crime, and death.” One focus group participant said, “There were shootings every night, so much so that the kids couldn’t play outside. You wake up in the morning and find that someone from your friend’s family passed away.”

Chronic exposure to violence has been associated with a number of adverse outcomes, not the least of which is the propensity to engage in or commit acts of violence. In addition, per a study led by New York University’s Patrick Sharkey, PhD, published in the American Journal of Public Health, experiencing community violence such as homicides “generates acute psychological distress among caregivers and impairs children’s self-regulatory behavior and cognitive functioning.”

Overall, Dr. Wade and his team note assessments of childhood adversity “should include experiences relevant to the target population,” and ACE research “should be broadened to include stressors experienced by youth in low-income urban settings.”

Partnering to Respond to Adversity

Which is precisely what Dr. Wade’s current project, funded both by the Stoneleigh Foundation as well as the Perelman School of Medicine’s Center of Excellence for Diversity in Health Education and Research, aims to do. Over the course of this three-year project, Dr. Wade will be working “to build a youth-informed measure of childhood adversity that informed by kids but also informed by the organizations that actually use the instrument,” he said. He has been working to partner with organizations across healthcare, social service, and youth mentoring groups to create the measure, which will eventually be adopted by the partner organizations. Dr. Wade then plans to gauge the impact of the tool and adversity assessment on each organization’s work, seeking to measure how it changes practice “in unforeseen ways,” he said.

In contrast to the Pediatrics study, with this project Dr. Wade is looking to recruit children as young as 8 years old. And because the children involved could be so young, Dr. Wade said he will be looking to use the kids’ language to reform questions and fill holes in questionnaire. For example, in Dr. Wade’s measure he might avoid using words like “incarcerated” (used in the original CDC study) in favor of simpler language.

“We’re giving these kids a voice where they didn’t have one,” he said, adding that the project will give children who have experienced adversity “an opportunity to speak about their life experiences.” After all, Dr. Wade said, it is the children who experience trauma who “are the true experts in understanding what childhood exposures were stressful and traumatic for them.”

The measure itself will be a series of questions, Dr. Wade said, as part of interviews that will be concerned with validating the framework of areas of concern established by the Pediatrics study. While conducting interviews for that study, he found that the very act of talking was cathartic for the study participants.

“Invariably when I finished the focus groups, the men and women would come to me and say thank you,” Dr. Wade said. “What I learned was that this was one of the first times in their life they were actually able to talk about their experiences in a way that was empowering, that they felt like it was going to be translated into something that had meaning and purpose, and that was transformative … it was empowering because it was actually going to help someone.”

So with the current study, Dr. Wade’s hope is that by creating an assessment tool and promoting its use, he and the organizations involved will create a dialogue between children, their families, and providers that facilitates open discussion of trauma. “My hope is that this discussion becomes cathartic for patients as it allows them to share their life experiences in much the same way that the young adults from my focus groups found the experience empowering,” Dr. Wade said.

In sum, the question this project asks is, “How does understanding the complexity of someone’s life experience change the way you provide services to them?” Dr. Wade said.

To read more, see the Stoneleigh Foundation page about Dr. Wade’s project.

Direct link:

Platelet Granule Formation Gives Insight Into Rare Disease


If you take a normal platelet and examine it under an electron microscope, you will see a bunch of black dots. The specks may not seem like much at first, but cell biologists at The Children’s Hospital of Philadelphia Research Institute speculate that these dense granules hold the key to unlocking the mechanisms behind a rare disease called Hermansky-Pudlak syndrome (HPS) and other forms of bleeding disease.

HPS is estimated to affect one in 500,000 to one in 1,000,000 individuals worldwide. In certain places, like Puerto Rico, it is much more prevalent — about one in 1,800 individuals. People with the disease have a tendency to bruise and difficulties with blood clotting, which can be deadly under certain circumstances such a pregnancy, major surgery, or dental surgery.

“Those dense granules don’t get made in a set of patients, and the consequence of that is the patients bleed too much, and they’re not able to make blood clots efficiently,” said Michael S. Marks, PhD, who received a grant in May from the National Heart, Lung, and Blood Institute to better understand how platelet dense granules form and why their creation is disrupted in HPS.

Dense granules are lysosome-related organelles (LROs) within platelets that act as a storage compartment for small molecules such as calcium, adenosine diphosphate, and serotonin. These molecules are released when platelets begin to accumulate at sites of blood vessel damage.

“We know that there are important things stored in those granules, but we have no idea how they get there,” Dr. Marks said. “This is the first time anybody’s taken an approach to try and understand how dense granules are put together and how those molecules get stored in them.”

HPS can be difficult to diagnose because it affects multiple organs, and the symptoms can be variable and nonspecific. Mutations in the genes associated with HPS prevent the formation of LROs or impair their performance in platelets, pigment cells, and lung cells. Subsequently, in addition to excessive bleeding, a main feature of the disease is oculocutaneous albinism, which causes abnormally light coloring of the skin, hair, and eyes. By the time people with HPS reach their 30s, a lung defect called pulmonary fibrosis appears that rapidly worsens, and the lung scarring often is fatal.

“Getting a good diagnosis early would be really important,” Dr. Marks said. “That would be the most immediate impact of this grant.”

The study aims to achieve a better understanding of two dense granule integral platelet membrane proteins that Dr. Marks’ team at CHOP and a collaborating group in Colorado recently identified — SLC35D3 and VMAT2 — which may act as vehicles to import dense granule contents. The investigators suspect that this delivery is impaired in HPS, and the dense granules do not form completely. Necessary machinery could be missing at a crucial time when a dense granule’s membrane coalesces from other membranes in megakaryocytes, which are platelets’ precursor cells that reside in bone marrow. It appears that this occurs during a late stage of differentiation of platelets from megakaryocytes.

In order to test this hypothesis, scientists in Dr. Marks’ lab will collaborate with another group of experts in megakaryocyte and platelet formation from the lab of Mortimer Poncz, MD, division chief of hematology at CHOP. They will take megakaryocytes from mice and then modify them by adding fluorescent proteins that hopefully will allow the investigators to visualize dense granule formation using live cell imaging. The next step will be to put the megakaryocytes back into the mice where they will produce platelets, and then take the platelets out to analyze them.

Dr. Marks also will compare the same mutations in human cells by using megakaryocytes created from stem cells of patients with HPS. Deborah L. French, PhD, a specialist in making induced pluripotent stem cells, will assist with this part of the project. Dr. French is director of the Human Stem-Cell Vector Core within the Center for Cellular and Molecular Therapeutics at CHOP.

The investigators will determine if SLC35D3 and VMAT2 live on dense granule membranes and whether or not they are expressed on platelet membranes in both the human and mouse HPS models. What they discover could guide new diagnostic approaches.

“If we’re right, then we could make antibodies to those proteins,” Dr. Marks said. “Then it should be a very simple test to look for exposure of that protein when you activate platelets.”

Such a diagnostic test would be helpful for identifying HPS as well as other forms of bleeding disease due to mutations in genes that encode proteins on these dense granules. As researchers learn more about the proteins’ structure and the jobs that they perform, this knowledge could be applied to designing drug therapies that either enhance the proteins’ activity, as would be the case in HPS, or decrease the proteins’ activity, which could potentially modulate diseases that cause too much blood clotting.

“Ultimately, maybe, we’ll be able to come up with some kind of treatment,” Dr. Marks said.

“That will depend on whether we’re right with some of our guesses about the proteins that are on dense granules and whether we can characterize them further and identify steps that would be downstream from them.”

Dr. Marks also is looking forward to working on a future study with Susan Guttentag, MD, that recently received grant funding. That investigation will focus on the formation of another LRO, the lamellar body, in lung epithelial cells. Dr. Guttentag and colleagues have shown that HPS models interfere with this process that underlies the lung fibrosis in HPS.

Direct link:

Gene Networks Could Offer Autism Treatment Targets


After analyzing the DNA from thousands of patients, investigators from Children’s Hospital have uncovered several gene networks that may play important roles in autism. These networks may offer attractive targets for developing new autism drugs or repurposing existing drugs that act on components of the networks.

Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics, and his team also found that one of the autism-related gene pathways also affects some patients with attention deficit hyperactivity disorder (ADHD) and schizophrenia, which raises the possibility that a class of drugs may treat particular subsets of all three neurological disorders.

Autism spectrum disorders (ASDs), of which autism is the best known, are a large group of heritable childhood neuropsychiatric conditions characterized by impaired social interaction and communication, as well as by restricted behaviors. Dr. Hakonarson and his team note that recent investigations suggest that up to 400 distinct ASDs exist.

The investigators conducted a genome-wide association study that drew data from CHOP’s genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organization Autism Speaks. The study compared more than 6,700 patients with ASDs to over 12,500 control subjects and represents one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.

The study focused on CNVs within defective gene family interaction networks (GFINs) — groups of disrupted genes acting on biological pathways. In patients with autism, the team found three GFINs in which gene variants perturb how genes interact with proteins. Of special interest to the study group was the metabotropic glutamate receptor (mGluR) signaling pathway, defined by the glutamate receptor metabotropic (GRM) family of genes that affects the neurotransmitter glutamate, a major chemical messenger in the brain regulating functions such as memory, learning, cognition, attention, and behavior.

In ASDs and other complex neurodevelopmental disorders, common gene variants often have very small individual effects, while very rare gene variants exert stronger effects. Many of these genes with very rare defects belong to gene families that may offer druggable targets.

Dr. Hakonarson’s team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the GRM pathway, while other teams have implicated GRM gene defects in schizophrenia.

“Even though our own study was large, it captures only about 20 percent of genes causing ASDs,” said Dr. Hakonarson, who added that larger studies are needed to further unravel the genetic landscape of autism. “However, strong animal data support an important role for the glutamate receptor pathway in socially impaired behaviors modeling ASDs. Because the GRM pathway seems to be a major driver in three diseases — autism, ADHD and schizophrenia — there is a compelling rationale for investigating treatment strategies focused on this pathway.”

Based on the results of the study, Dr. Hakonarson is planning a clinical trial in selected ADHD patients of a drug that activates the GRM pathway. “If drugs affecting this pathway prove successful in this subset of patients with ADHD, we may then test these drugs in autism patients with similar gene variants,” he said. The study appeared in the journal Nature Communications.

Additional details are available here.

Direct link:

Concussion Prevention, Care Are Key Targets for Research


Few healthcare issues reach the presidential podium and ESPN headlines, but the topic of sports-related concussions in youth scored both, therefore gaining momentum as a national priority.

President Obama hosted the first-ever White House Healthy Kids & Safe Sports Concussion Summit on May 29, where key stakeholders gathered to promote new efforts that will increase research to expand knowledge of concussions and create a culture of safety that supports children in disclosing symptoms and optimizing their recovery.

“We want our kids participating in sports,” Obama told the audience. “I’d be much more troubled if young people were shying away from sports. As parents, though, we want to keep them safe, and that means we have to have better information.”

A concussion is a mild traumatic brain injury caused by a blow or jolt to the head or body that causes the brain to shake. Annually, young people make nearly 250,000 visits to emergency rooms in the U.S. to be treated for brain injuries from sports and recreation, according to the Centers for Disease Control and Prevention. Some concussion symptoms may appear immediately after the injury, while others may not show up for several days. They can include headache, nausea, dizziness, sleep problems, difficulty concentrating, and moodiness.

Pediatric sports medicine specialist Christina Master, MD, and President and Chief Operating Officer Madeline Bell of The Children’s Hospital of Philadelphia were in attendance at the summit as it was announced that CHOP will begin development of a comprehensive pediatric and adolescent concussion registry. It will provide a database of information about concussion cases to inform scientific research to improve care.

The registry is a result of a Department of Pediatrics Chair’s Initiative project at CHOP called Minds Matter that involved a multidisciplinary team who set out to create tools to standardize and streamline concussion diagnosis and management across the CHOP Care Network so that primary care providers could handle the majority of concussion cases more efficiently and seamlessly.

“We incorporated a SmartSet feature into CHOP’s electronic medical record that gives providers standardized and evidence-based guidance on how to clinically evaluate and manage concussions,” said Kristy B. Arbogast, PhD, director of engineering for CHOP’s Center for Injury Research and Prevention, who led the Minds Matter team along with Dr. Master. “We coupled that with in-person training, and the response has been great. We believe kids are getting much better care.”

The clinical demand for concussion care throughout the CHOP system remains high, with a total of about 12,800 concussion visits in 2013 alone. Consequently, the need for pediatric research is great. Dr. Arbogast contributed to an Institute of Medicine report in 2013 that revealed many gaps in researchers’ understanding of the causes and consequences of sports-related concussions.

“A lot of what we think we know about concussion and prevention, if you pull the curtain back, the fundamental data supporting those ideas aren’t there,” Dr. Arbogast said.

In his remarks at the summit, Obama announced several public-private partnerships to support new concussion research. For example, the National College Athletics Association (NCAA) and the Department of Defense are jointly launching a $30 million effort to fund a comprehensive clinical study of concussion and head impact exposure. And the National Institutes of Health is using funding from the National Football League to begin a longitudinal research effort to detect, characterize, and measure the chronic effects of repetitive concussions.

With so many entities willing to take the ball and run to improve concussion diagnosis, management and prevention, the fundamental science is changing quickly, Dr. Arbogast said. Finding the best way to translate that research into evidence-based advocacy will be the next challenge that she hopes to tackle in her new role as a member of the National Council on Youth Sports Safety.

David Satcher, MD, former U.S. Surgeon General, and Eliot Sorel, MD, a global health expert from George Washington University School of Public Health and Health Services, convened a multidisciplinary panel of experts to form the national council. They invited Dr. Arbogast, the NCAA’s chief medical officer, Safe Kids Worldwide’s chief executive officer, and two former professional football players, among others.

“Its mission is to raise awareness and apply an integrative approach to create a culture of prevention and reduce the number of injuries that children sustain in sports,” Dr. Arbogast said. “We want to think about youth sports in a way that children can gain the benefits of physical activity, leadership, and character development while ensuring that they are as safe as possible while they play.”

During their inaugural meeting in February, the council identified several sports safety concerns — concussion, overuse injury, heat illness, and sudden cardiac death — and decided that their first goal would be to take aim at changing the culture around concussion. Workgroups hold virtual strategy meetings on a monthly basis, and they anticipate that their efforts will culminate in a best practices tour in 2015.

Council members will visit about 10 localities and host town-hall like events that will feature innovative practices and approaches to concussion prevention, diagnosis, treatment, and management. While the spotlight will be on sharing knowledge, they anticipate some sports players will lend their star power to help change society’s norms. Athletes, parents, coaches, school professionals and healthcare providers must realize that, “shake it off” is not an acceptable response to concussion; it is a brain injury that deserves serious attention.

“I like being part of an entity that is tasked with shaping the national tone on this issue,” Dr. Arbogast said. “And I am excited about the opportunities to possibly highlight some of the phenomenal clinical care CHOP sports medicine, primary care, and trauma doctors are providing for kids with concussions and to show that CHOP is a thought leader on this issue.”

Direct link:

Biomarkers for Mitochondrial Diseases Emerging


A major limitation in many therapeutic interventions is the inability to follow how they affect the early biochemical steps of chronic disease. In some cases, patients and clinicians spend months tracking symptoms to figure out if a treatment is working.

A new approach being developed at The Children’s Hospital of Philadelphia and the University of Pennsylvania could allow investigators to know within days if a chosen therapy reverses the intracellular mechanisms that go awry in Friedreich’s Ataxia (FA), a genetic mitochondrial disease, and other more common secondary mitochondrial disorders such as Parkinson’s disease and Alzheimer’s.

FA is a rare, progressive neurodegenerative disease that is heavily disabling because it affects a variety of body systems. People diagnosed with FA experience general unsteadiness, motor speech problems, increased heart wall thickness, and a higher tendency to develop diabetes over time. Most people with FA are wheelchair bound within 10 years of their symptoms’ initial presentation and die from heart disease by the age of 35.

CHOP clinicians and researchers have developed remarkable expertise in FA, and they help about 250 patients, which is approximately 5 percent of the population with this disease in the U.S.  Earlier this year, a new Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence opened to carry on this work under the direction of Robert B. Wilson, MD, PhD, professor of pathology and laboratory medicine at the Perelman School of Medicine, and David Lynch, MD, PhD, FA program director at CHOP.

“We are the center for research on FA for the world,” Dr. Lynch said.

One of the center’s first goals was to establish a biomarker development program with the expertise of Ian Blair, PhD, of the Perelman School of Medicine. This collaboration is the focus of a new National Institute of Neurological Disorders and Stroke grant awarded to Dr. Lynch.

“A unique aspect of this grant is our chance to partner on a technique that not only may be useful for understanding the mitochondrial abnormalities that are proposed in FA, but also for monitoring it and related diseases in clinical trials,” Dr. Lynch said. “So it may be crucial for developing new therapies for individuals, but it also is likely to be a key tool in defining the ability of people with FA to respond to such interventions.”

Dr. Blair has discovered a way using mass spectrometry techniques — a highly accurate, quantitative method for exploring compounds — to follow the metabolic events of live behaving mitochondria isolated from platelets of a person with FA. Mitochondria, traditionally known as the powerhouses of cells, are specialized to perform specific functions within tissues. The investigators suspect that the metabolic functions of mitochondria might be crucially compromised in FA, leading to tissue-selective metabolic dysfunction.

“We know that the disease affects the whole body, so what we see happening in platelets is likely to be a mirror of what’s happening everywhere,” Dr. Lynch said.

One of the places where his study team has seen abnormalities is in the Krebs cycle, also known as the tricarboxylic acid cycle, which produces adenosine triphosphate (ATP) that transports chemical energy within cells for metabolism. ATP feeds electrons on the electron transport chain for cells to make more ATP. The investigators suggest that insufficient bioenergetic capacity may lead to decreased metabolism through fatty acid pathways.

“We find that in FA there are specific blockages in this pathway,” Dr. Lynch explained. “This might suggest therapy because it would allow you to bypass those blockages if you gave people the right nutritional supplementation and ameliorate, if not cure, the features of the disease.”

In principle, this approach could be applicable to any mitochondrial disease, Dr. Lynch said, not only on the therapeutic side to identify which metabolic steps to circumvent, but also on the monitoring and biomarker side to measure response to a therapeutic agent. If an intervention works, scientists would expect the metabolic abnormalities that Dr. Blair identified to reverse.

“It provides a powerful way to follow the disease and an ideal biomarker of therapeutic success,” Dr. Lynch said. “This is potentially a way that we could follow many, many disorders.”

In the near future, Dr. Lynch anticipates his study team’s early successes will spin off into investigations of novel nutritional therapies for FA and also be used as an outcomes measure in ongoing clinical trials of FA.

Direct link:

Study Spurs Insights Into Chronic Kidney Disease


Identifying the best strategies to slow the progression to kidney failure for children with chronic kidney disease (CKD) is a constant challenge for clinicians. They must finely tune their treatment plans and judiciously anticipate when to begin dialysis or place patients on a kidney transplant waiting list.

The Chronic Kidney Disease in Children Study (CKiD) is a prospective cohort study that was initiated in 2003 to provide evidence to help inform these disease management decisions. A decade later, almost 900 children between the ages of 1 and 16 with decreased kidney function have entered the study. As a one of two clinical coordinating centers for CKiD, The Children’s Hospital of Philadelphia has contributed many research projects under the leadership of principal investigator Susan L. Furth, MD, chief of the division of nephrology.

The data collected from the CKiD has prompted new insights and approaches to improve care for children with CKD. These include a new gold standard in the measurement of kidney function, identification of acidosis and low birth rate as risk factors for poor growth, models to predict overall rates of decline of kidney function over time, and awareness that children with chronic kidney disease have a remarkable constellation of risk factors for heart disease.

“The rationale for CKiD was that chronic kidney disease and end stage renal disease in this country in adults really are a substantial burden,” Dr. Furth said. “The latest estimate is 10 million Americans have chronic kidney disease. It’s very likely that many of the origins of chronic kidney disease in adults start in children. We’ve found ways that we can intervene to extend life and promote the health of these kids.”

The primary goals of CKiD are to determine participants’ risk factors for decline in renal function, track their behavior and abilities to learn and think, monitor their growth, and evaluate possible connections to future cardiovascular disease. Several CHOP investigators recently have published studies related to CKiD and also presented their findings at the Pediatric Academic Societies Annual Meeting (PAS) held in May.

In a study presented at PAS by Michelle Denburg, MD, MSCE, an attending nephrology physician at CHOP, researchers used CKiD data to show for the first time that children with CKD have increased risk of fracture, especially among teenage boys. Children with CKD have problems with absorbing calcium from the foods that they eat, and often as their kidney function worsens, their calcium gets low. In order to compensate, their bodies secrete a hormone that takes calcium out of their bones, which weakens them.

The study results showed that the incidence of fracture in a CKiD cohort of 556 children was two-fold higher than general population rates. Fractures of the arm and elbow were most common. These findings support the need for future CKiD research that will focus on bone frailty as an important therapeutic target in the pediatric CKD population.

Erum A. Hartung, MD, also an attending nephrology physician at CHOP, and colleagues published a study in the May issue of Pediatric Nephrology that concentrated on the neurocognition of a particular group of children with autosomal recessive polycystic kidney disease (ARPKD) who are born with abnormal kidneys. A previous CKiD study demonstrated that children with CKD have normal IQs, but they have challenges in the areas of attention and their ability to make and carry out plans. Parents of children with ARPKD had expressed concerns that their children could face increased risks for behavior and learning difficulties because they have early onset CKD and more severe high blood pressure — both of which are known risk factors for neurocognitive deficits.

The study’s results were reassuring to parents because they showed that the cognitive function of children with ARPKD was comparable to children in the CKiD cohort with mild-to-moderate kidney disease from other causes. The investigators concluded that, “Further studies are needed to determine if these findings are applicable to children with more severe manifestations of ARPKD.” Dr. Hartung also shared this study’s results at the PAS.

Dr. Furth encourages other investigators and collaborators to access the “wealth of data” in the CKiD’s national database to conduct research projects that potentially could lead to better outcomes for children with CKD. In the meantime, the CKiD’s second wave has begun, which involves a cohort of about 280 children.

“We’re looking more at vascular health and added tests of vascular stiffness to this study as we move forward,” Dr. Furth said. “Increased stiffness of the blood vessels, as measured by pulse wave velocity, has been associated with increased risk of adverse cardiovascular events in adults. We’re trying to see if this happens even earlier in children.”

Dr. Furth also is excited about a new partnership called the 4C Study with investigators in Europe. The aim is to gather a total sample size of about 1,500 children, including CKiD study participants and another cohort from a recently concluded interventional study in children with CKD called the ESCAPE trial, in order to conduct a genome-wide search for genetic risk markers of CKD progression.

“We’re finding out if there are new genetic associations with structural abnormalities of the kidney and also if there’s genetic variability that contributes to things like accelerated kidney function decline or anemia,” Dr. Furth said.

The National Institute of Diabetes and Digestive and Kidney Diseases, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute, recently renewed funding for the CKiD. It is a cooperative agreement between the two clinical coordinating centers — CHOP and Children’s Mercy Hospital in Kansas City — a central biochemistry laboratory at the University of Rochester in New York, and a data coordinating center at Johns Hopkins School of Public Health in Baltimore.

Direct link:

New Center of Emphasis to Support Pharmacologic Research


Established to speed research from the bench to the bedside, The Children’s Hospital of Philadelphia Research Institute’s Centers of Emphasis concentrate investigator efforts and resources. Bringing together many of the most pioneering researchers in the country, CHOP Research’s Centers of Emphasis are well known for their consistently excellent, forward-thinking investigations.

The Research Institute’s nine current Centers — which include the Center for Applied Genomics, the Center for Childhood Cancer Research, PolicyLab, and the Center for Injury Research and Prevention — were recently joined by a tenth Center of Emphasis, the new Center for Clinical Pharmacology.

Led by Athena F. Zuppa MD, MSCE, the new Center for Clinical Pharmacology (CCP) will offer training in clinical pharmacology, bioanalytical support, and assistance with pharmacologic study design, implementation, and analysis. According to Dr. Zuppa, by “restructuring and rebuilding” on previously existing resources, the new Center of Emphasis provides a single, consolidated resource for investigators across the Institute interested in pharmacologic endeavors.

Dr. Zuppa first joined CHOP in 1996 as an intern after receiving her medical degree from SUNY Stony Brook. She was named an Assistant Professor of Anesthesia an Pediatric Critical Care Medicine in 2002, and — in addition to her new role leading the CCP — is now an Associate Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania and CHOP as well as associate director of Children’s Hospital’s PICU Fellowship Program. Dr. Zuppa has very active research program, and is currently supported by a number of grants, including an R01 that is funding her investigation of the impact of hypothermia on the pharmacokinetics of midazolam (used for sedation) and morphine (pain control) in children following cardiac arrest.

As Dr. Zuppa sees it, the CCP’s overarching structure will be supported by “three pillars”: training in clinical pharmacology, bioanalytical services, and pharmacostatistical support. “If there are investigators out there that want to do a pharmacology study, they can come to us, we can help them with study design, implementation, quantitative analysis of the biologic specimens, wrapping that up into a database, and then actually interpreting the data,” Dr. Zuppa said.

Dr. Zuppa also noted that along with Thomas Jefferson University, CHOP recently applied for a T32 award to support a training program in clinical pharmacology. If approved, the joint CHOP-Thomas Jefferson training program would “be one, if not the first, pediatric and adult clinical pharmacology training programs bridging pediatrics and adults,” she said.

In addition to Dr. Zuppa, other CHOP staff who will be contributing to the CCP include Director of the Bioanalytical Core Ganesh Moorthy, PhD, pharmacometrician Chee Ng, PhD, pediatric intensivist Adam S. Himebauch, MD, pediatric oncologist and Chair of the Children’s Oncology Group Peter C. Adamson, MD, director of clinical research in the Center for Childhood Cancer Research Frank M. Balis, MD, and pediatric oncologist and pharmacologist Elizabeth Fox, MD, head of the Developmental Therapeutics Program in the Division of Oncology. Dr. Zuppa noted that she is also actively looking to expand the new Center’s faculty and staff.

To learn more about the Research Institute’s Centers of Emphasis and organizational structure, see the Research Institute site.

Direct link:

Website Offers Expert Injury Tips in Spanish


A growing number of Spanish-speaking families in the United States look for health and parenting information online. Each year 8 million children – including nearly 1 million Hispanic children –experience an injury that requires emergency room care or a hospital stay. A team of experts at The Children’s Hospital of Philadelphia launched a new Spanish-language website,, to help Spanish-speaking parents help their children recover after an injury.

The website is a comprehensive free resource for parents, developed by a team of pediatricians, psychologists, trauma surgeons and trauma nurses, based on more than a decade of research on childhood injury and its emotional effect on kids and their parents.

“With all the doctors and nurses who treat a child when he or she is first hurt, it’s still parents who play the most important role in their child’s physical and emotional recovery,” said Flaura Koplin Winston, MD, PhD, a pediatrician, director of the Center for Injury Research and Prevention and co-developer of the English and Spanish websites. “Medical care is often brief, and parents may have questions later and not know where to turn. We created this site, with the guidance of parents, to help them find the information they want, exactly when they need it.”

Researchers at CHOP have developed and tested ways to identify traumatic stress reactions in Spanish- and English-speaking children. Based on the latest research, the team has created a wide range of Spanish and English tip sheets for children and parents about dealing with injury, illness, and being in the hospital. includes expert advice on everything from how to handle a hospital visit, to cast care and pain management, to what to do if a child is having nightmares after an accident.

For more information about emotional reactions to injury or to download resources and tip sheets, visit or

A full press release also available in Spanish at the following link:

Direct link:

CHOP Research CSO Named to PA Bio Board


In an example of how many Children’s Hospital investigators contribute their time and talents to social and professional organizations, Chief Scientific Officer and Executive Vice President of The Children’s Hospital of Philadelphia Research Institute Philip R. Johnson, MD, was recently named to Pennsylvania Bio’s Board of Directors.

Devoted to ensuring Pennsylvania “is the global leader in the biosciences by creating a cohesive community,” Pennsylvania Bio represents the life sciences industry in Pennsylvania. PA Bio’s more than 600 members include law firms, investment companies, medical device and pharmaceutical companies, and research centers, including the University of Pennsylvania and The Children’s Hospital of Philadelphia.

In addition to advocating on behalf Pennsylvania-based life science firms and organizations, PA Bio provides networking opportunities for its members and hosts a number of events. One of these is its Annual Dinner & Awards Celebration. At the 2014 dinner CHOP was honored with two awards for its business and research innovations. The Hospital landed the Deal of the Year award for its spinout of the gene company Spark Therapeutics, and the University of Pennsylvania and CHOP were jointly given the Patient Impact Award for their groundbreaking immune therapy research.

CHOP and Penn were honored for their collaborative investigation of using modified versions of patients’ own immune cells to attack and destroy tumors. Last year the partnership — which is led at CHOP by Stephan A. Grupp, MD, PhD, and at Penn by Carl H. June, MDled to extraordinary results: two children with acute lymphoblastic leukemia, the most common form of childhood leukemia, achieved a complete response after being treated with immune therapy. Since receiving the treatment one of those patients remains healthy and cancer-free.

Dr. Johnson joins a number of other business and professional leaders on the PA Bio board, including the University of Pennsylvania’s Arthur H. Rubinstein, MBBCh, Bristol-Myer Squibb’s Vice President of Business Development Graham Braizer, and GlaxoSmithKline’s Brian McVeigh, vice president of Worldwide Business Development Transactions

“It’s an honor to be named to Pennsylvania Bio’s Board of Directors,” Dr. Johnson said. “I look forward to working with my fellow board members, as well as the many member organizations, to support and grow the life sciences in Pennsylvania.”

To learn more about PA Bio, see the organization’s website.

Direct link:

Produced by The Children’s Hospital of Philadelphia Research Institute.

© 2017 by The Children’s Hospital of Philadelphia, All Rights Reserved.