Aug 22 2014

Award Will Support Novel Hemophilia Therapy Investigation

hemophilia

Dr. Ivanciu’s research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX).

The Children’s Hospital of Philadelphia’s Lacramioara Ivanciu, PhD, was one of five investigators who recently received funding through the Bayer Hemophilia Awards Program (BHAP). A “unique initiative dedicated to supporting innovative research and educational initiatives that benefit people with hemophilia,” the BHAP is administered by Bayer Healthcare, a subsidiary of the German pharmaceutical giant Bayer AG, and awards grants to hemophilia investigators and professionals.

An investigator in the Children’s Hospital’s Division of Hematology, Dr. Ivanciu’s research is focused on the design of novel bypass agents for the treatment of hemophilia. An inherited bleeding disorder, hemophilia is a lifelong disease that can require chronic management According to the CDC, each year in the U.S. approximately 400 babies with hemophilia are born.

Dr. Ivanciu’s research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX). A key part of the coagulation system, FIX deficiency results in Hemophilia B, which is most often treated by replacement FIX therapy. However, FIX replacement therapy requires multiple injections and high doses, as FIX has a short half-life.

“My research focus on bioengineering coagulation factor IX as a potential alternative strategy for hemophilia B therapy,” said Dr. Ivanciu. “The novel FIX variants are expected to have prolonged half-life and efficacy and thus, be more efficient at lower doses. This could greatly benefit the patients with hemophilia by reducing the therapeutic dose, an important goal in the replacement therapy,” said Dr. Ivanciu.

In addition, Dr. Ivanciu recently co-authored a paper published in Blood examining recombinant activated human Factor VII, and was the first author another paper also published in Blood that focused on two other coagulation factors, factor Xa and factor Va.

Saying she was “very pleased” to receive the BHAP Early Careeer Investigator award, Dr. Ivanciu noted that its support will allow her “to advance the understanding of bleeding disorders by developing and applying new systems models and therapeutics to these problems.”

“I am in a unique position to make meaningful contribution to the field and possibly advance new therapies for the treatment of hemophilia,” she added.

“BHAP, now in its twelfth year, continues to attract high-quality applicants who are committed to answering important scientific and medical questions. Through our support of their research, this year’s winners will contribute to a better understanding of hemophilia and bleeding disorders and ways to improve treatment and optimize patient outcomes,” said Bayer Healthcare’s Prasad Mathew, MD.

For more information hematology research and care at The Children’s Hospital of Philadelphia, see the Division of Hematology’s website.

Permanent link to this article: http://www.research.chop.edu/blog/award-will-support-novel-hemophilia-therapy-investigation/

Aug 20 2014

New Study Focuses on Nasal Steroids as OSA Treatment

nasal_steroidsRemoving a child’s tonsils and adenoids, or adenotonsillectomy, currently is the primary therapy for childhood obstructive sleep apnea syndrome (OSAS), but many parents remain wary about surgery and would welcome an alternative approach. Researchers from the Sleep Center at The Children’s Hospital of Philadelphia are set to launch the “Steroids for Pediatric Research in Kids (SPARK)” trial in September that will investigate the use of nasal corticosteroids as a possible treatment for OSAS.

OSAS is extremely common, according to Carole L. Marcus, MBBCh, director of CHOP’s Sleep Center. It is seen in 2 to 4 percent of children, but she maintains that it is greatly underdiagnosed. Usually, a blockage from enlarged tonsils or adenoids cause obstruction in breathing, called apneas and hypopneas, that repeatedly disrupt a child’s sleep. If OSAS is left untreated, it can result in significant complications, ranging from behavioral problems and sleepiness in mild-to-moderate cases, and cognitive abnormalities, high blood pressure, and growth disturbances in more severe cases.

One of the lessons that Dr. Marcus learned from being a co-investigator of the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT Study) — a large, randomized, multicenter control study that compared the effectiveness of surgery vs. watchful waiting for OSAS — was that better treatments and more therapeutic choices for families are needed. While adenotonsillectomy is relatively safe, about 3 percent of children will have significant hemorrhage postoperatively, and other complications can occur.

“Most families were hoping to hold off on surgery because they were scared,” Dr. Marcus said.

Over the past few years, several small, short-term studies have reported on nasal steroids as an alternative treatment for pediatric OSAS. They showed overall benefit for mild OSAS cases but did not study more severe cases; in addition, the results demonstrated tremendous individual variability. The American Academy of Pediatrics clinical practice guidelines for the diagnosis and management of OSAS issued in 2012, which Dr. Marcus chaired, included nasal steroids as a treatment option, but there was not enough evidence to give a strong recommendation.

Dr. Marcus and colleagues are launching the SPARK study to increase knowledge about the effect of nasal steroids and to identify which subgroups of patients with OSAS are most likely to benefit. For example, the research team will determine if children with asthma and/or atopy respond better to nasal steroids. Another subgroup they will focus on is African-American children because strong data from CHAT and other studies have shown that they have more severe OSAS and do not respond as well to surgery. Sophisticated genetic tests included in the SPARK study will help the investigators to further characterize responders vs. non-responders.

The double-blind, randomized control trial also will assess nasal steroids’ duration of action and possible side effects, which for a small minority of children include growth problems, ocular abnormalities, and adrenal suppression.

“Does the disease recur if you stop nasal steroids?” Dr. Marcus asked. “Is it cured forever? Do you keep doing sleep studies? If kids are on the steroids long-term, are you likely to see complications?”

In order to answer those questions, the study is designed to randomize children to receive either nasal steroids or placebo for three months. After three months, those in the nasal steroid arm of the study will be re-randomized to either ongoing steroids or placebo for another nine months.

The multidisciplinary study team will include investigators from general pediatrics and several specialty areas including sleep medicine, endocrinology, ophthalmology, allergy, and otolaryngology. They aim to recruit about 300 patients, with a goal of randomizing 156 participants, from these diverse practice settings.

“I’m hoping we’ll find a nonsurgical alternative for some children but that it also will lead to more personalized medicine,” Dr. Marcus said. “One treatment does not fit all.”

The National Heart, Lung, and Blood Institute is funding the research project.

For more information on the SPARK study, contact research coordinator Ruth Bradford.

Permanent link to this article: http://www.research.chop.edu/blog/new-study-focuses-nasal-steroids-osa-treatment/

Aug 18 2014

Investigating a New Approach to Eosinophilic Esophagitis

Eosinophilic EsophagitisMany of the major milestones in understanding eosinophilic esophagitis (EoE), a food allergy that affects the esophagus, began in research laboratories at The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.

Investigators discovered the first gene related to the disease, and they identified an immunological pathway that makes EoE distinctive from other food allergies. Now, they are pursuing a novel approach to cure the chronic disorder, as no medications are approved currently to treat EoE.

“If it works, it can potentially revolutionize clinical care,” said Jonathan Spergel, MD, who is leading the proof-of-concept study called SMILEE.

Dr. Spergel is co-director of CHOP’s Center for Pediatric Eosinophilic Disorders, which treats 1,500 patients with EoE from all over the world. About 70 percent of the patients have milk-induced EoE. When Dr. Spergel first began studying EoE, little was known about the disease, but diagnoses of this disorder are increasing rapidly as awareness grows.

“I have been fascinated to understand exactly who gets EoE, whose at risk, and what’s the best way of treating it,” said Dr. Spergel, who is also chief of CHOP’s allergy section.

During an allergic reaction to a food associated with EoE, high quantities of eosinophils, a type of white blood cell, congregate in the esophagus. This muscular tube that carries food from the throat to the stomach gets swollen. Children with EoE experience varying symptoms including belly pain, trouble swallowing, uncontrollable reflux, and failure to thrive.

Physicians currently approach EoE treatment two ways. First, is avoidance of the food that causes the allergic reaction. Second, is prescription of topical steroids to coat the esophagus. Dr. Spergel pointed out that these options do not address the underlying disease; they only control the symptoms.

“Can we do something better? That’s the question this study is asking,” Dr. Spergel said. “We’re trying to induce tolerance using a novel method — epicutaneous immunotherapy (EPITTM).”

EPIT is a desensitization method developed and patented by DBV Technologies (DBV) and uses Viaskin® technology. The application of a Viaskin per day involves maintaining an allergen on the skin of an allergic person for repeated and prolonged periods. DBV will provide a grant to The Children’s Hospital of Philadelphia to support the clinical trial. DBV and Dr. Spergel designed the double-blind, placebo-controlled, randomized trial to assess the effectiveness and safety of using an investigational new drug intended for EPIT, Viaskin® Milk, an allergen extract of milk administered via a skin patch.

“What we think happens is when the milk is absorbed through the skin, it interacts with antigen-presenting cells, which then induce T regulatory cells, and these T regulatory cells then cause the body not to be allergic anymore,” Dr. Spergel said.

Dr. Spergel anticipates that the SMILEE study will include participants ages 4 to 17. If it turns out that EPIT works, Dr. Spergel said it would be a major turning point for EoE treatment.

“We would be able to completely change the way we treat the disease,” Dr. Spergel said. “All these patients who have been unable to drink milk now would be able to drink milk and improve their quality of life.”

Dr. Spergel has other clinical studies under way of Viaksin® Peanut, another form of EPIT for patients with peanut allergies.

The SMILEE study also is supported by donations from grateful CHOP families.

Permanent link to this article: http://www.research.chop.edu/blog/investigating-new-approach-eosinophilic-esophagitis/

Aug 15 2014

Forced Looping Viable Strategy to Reverse Globin Switch

globinInvestigators at The Children’s Hospital of Philadelphia are exploring a new gene therapy approach that aims to reactivate the production of fetal hemoglobin as a potential intervention for patients with sickle cell disease. In the U.S., it is estimated that sickle cell disease affects 100,000 newborns, especially Hispanic-Americans and African-Americans.

The inherited disease distorts the red blood cells into a sickle shape, like the letter “C,” that blocks blood flow and damages blood vessels and many organs. A sickle cell gene mutation tells the body to make a defective type of hemoglobin, which is the oxygen transport protein in red blood cells.

Pre-empting the effects of this sickle cell gene mutation has been a focus of CHOP hematology researcher Gerd A. Blobel, MD, PhD, and the August edition of Cell reported his novel findings.  Dr. Blobel and his co-authors described how they altered the genetic architecture behind a developmentally controlled process called hemoglobin switching.

A form of hemoglobin that has anti-sickling properties is made only during the fetal period when red blood cells are produced by the liver. Shortly after birth, a transition occurs that silences the fetal globin genes as the bone marrow gradually takes over blood formation. Gene expression shifts to mostly create the adult form of hemoglobin, which in sickle cell disease will be the variant type.

Adult hemoglobin (HbA) almost completely replaces fetal hemoglobin (HbF) within six months after birth, which helps to explain why patients with sickle cell disease do not experience symptoms as newborns. It has been known for a long time that patients with sickle cell disease who have higher ratios of HbF tend to experience a milder course of the disease.

“A major driver in the field for many years has been to understand the molecular basis and the machinery that controls that switch,” Dr. Blobel said. “The goal is ultimately to overcome the silencing of the fetal globin genes and turn them back on.”

His research team’s particular strategy to manipulate gene expression not only elevates the amount of HbF but also downregulates the amount of faulty HbA, thereby reducing the sickle cell inducing properties of the mutated form of HbA.

The current study employs artificial zinc finger protein technology that Dr. Blobel and colleagues adapted for use in hemoglobin regulation and described in Cell two years ago. At the time, the zinc finger proteins were engineered in a way that they locate to specific sites on the chromosomes and foster contacts between chromosomal regulatory elements called promoters and enhancers that reside very far apart on the chromosome. This juxtaposition led to the formation of a chromosomal loop.

“Our 2012 study was the first in which such looped gene contacts were produced at a normal gene in its native location,” Dr. Blobel said. “We thought, now that we have this useful system, let’s explore whether it can be put to therapeutic use.”

In the present study, the researchers showed that they can use forced gene looping to override the stringent developmental gene expression of the globin gene cluster, which is composed of embryonic, fetal, and adult type genes responsible for the creation of hemoglobin. During development, a powerful enhancer for the expression of all these genes, called the locus control region (LCR), physically contacts the embryonic, then fetal, and later the adult genes via chromatin looping.

Dr. Blobel’s team designed zinc fingers in a way that they would promote looped contacts between the LCR and the fetal genes in adult red blood cells. This approach worked well and indeed enhanced the expression of fetal genes and reduced the level of the adult type genes. In the context of sickle cell disease, this would be a double benefit since both high fetal gene expression and low levels of the mutated toxic form of adult hemoglobin would ameliorate the disease.

“This is a novel way to manipulate gene expression via altering chromatin architecture,” Dr. Blobel said.

The researchers carried out the experiments in cultured blood cells from mice and humans. The next step is for the team to use a pre-clinical model to further test their strategy. This involves the use of genetically engineered mice bearing the human globin genes (including the sickle cell anemia gene mutation) in place of the mouse genes. These animals have manifestations of sickle cell disease similar to human patients. Blood stem cells from these mice will be modified with a viral gene transfer vector that expresses the zinc-fingered looping protein, and then used in bone marrow transplants to see if it can correct the disease in the animal model. If this is successful, the long-term goal is to start a clinical trial in humans.

The Sickle Cell Center at CHOP has a longstanding commitment to sickle cell disease research and is one of the largest programs of its kind in the U.S., providing comprehensive care to almost 1,000 patients. Dr. Blobel’s work is supported by funding from the National Institute of Diabetes Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute.

Permanent link to this article: http://www.research.chop.edu/blog/forced-looping-viable-strategy-reverse-globin-switch/

Aug 13 2014

Investigators Explore Safety of Rotavirus Vaccine in NICU

RoatvirusClinicians in neonatal intensive care units across the country are uncertain about when to administer rotavirus vaccination to infants whose medical conditions require prolonged hospital stays, so experts at The Children’s Hospital of Philadelphia conducted a study published in Pediatrics to explore safety concerns that remain unsettled.

Rotavirus (RV) affects nearly all children at some point, often with significant diarrhea. In premature infants it can lead to severe and potentially life-threatening diarrhea and dehydration. Preterm infants are more vulnerable to the infection, in part because they miss the transfer of maternal antibody in the third trimester of pregnancy. In early infancy they are not protected against common forms of rotavirus.

RotaTeq vaccine (RV5), which was developed at CHOP, is effective at preventing rotavirus gastroenteritis, but it must be administered by 104 days of age (14 weeks, six days). Current immunization guidelines state, “preterm infants in NICUs or nurseries who are age-eligible and clinically stable may be immunized at the time of discharge.”

These recommendations put hospitals with large NICUs that often handle complicated cases of prematurity or congenital abnormalities in a time squeeze because they tend to care for babies who must stay in the hospital longer than 104 days.

“We have a population that is at extraordinary risk because they have health problems beyond prematurity and longer lengths of stay, so many would miss out on receiving the vaccine,” said Kelly C. Wade, MD, PhD, MSCE, a neonatologist at CHOP. “We would be discharging babies into the community who don’t have rotavirus protection.”

After careful consideration and discussion, a team of CHOP experts from the Divisions of Neonatology, Infectious Disease, and Pharmacology decided in 2007 to include RV5 with inpatient routine two-month vaccinations to infants receiving some enteral nutrition, also known as tube feeding, regardless of length of NICU hospitalization.

“We believe that the benefit of protecting infants against rotavirus infections outweighs the minimal risk in administering rotavirus vaccine to NICU inpatients,” said Heather M. Monk Bodenstab, PharmD, a CHOP clinical pharmacist. “We are one of very few institutions that actually do this.”

The main reason the American Academy of Pediatrics (AAP) discourages rotavirus vaccination during hospitalization is the possibility that live attenuated virus theoretically could be transmitted to neighboring unvaccinated infants also residing in the NICU. While shedding of attenuated virus has been demonstrated in immunized infants’ stools, Dr. Monk pointed out that symptomatic disease transmission is rare.

Since CHOP’s policy is not in line with the AAP recommendations, Dr. Monk Bodenstab and Dr. Wade conducted the current study in order to give some guidance and build support for the safety of inpatient RV5 vaccination as a CHOP standard of practice. The investigators performed a retrospective chart review of electronic medical records of NICU patients who CHOP routinely vaccinated with RV5 between September 2008 and 2010. They also reviewed records for any unvaccinated patients who shared the same NICU area and nurses as the vaccinated infants within 15 days of vaccination. In particular, the study team wanted to identify any unvaccinated infants who had gastrointestinal symptoms and physician orders for bowel rest, abdominal imaging, and antibiotics within 24 hours of each other, which would suggest a strong clinical suspicion of viral gastroenteritis.

“One of the most interesting findings was that there were such a small percentage of unvaccinated infants who had clinical status changes, and those could be attributed to pre-existing gastrointestinal processes or other clinical conditions,” Dr. Monk Bodenstab said. “That was reassuring for us.”

Due to the study’s design limitations, however, the results do not indicate whether or not RV5 vaccination increased the risk of virus shedding or transmission in a NICU environment. The goal of future prospective studies will be to determine how long a baby who receives the vaccine is potentially shedding the virus, if universal precautions such as diligent hand hygiene can control the spread, and if other infants are exposed, whether or not they become sick.

“None of us has any data to say for sure what would be good practice,” Dr. Wade said. “I think the policy we have at CHOP is well thought out, and it is working for us, but it is not ready for complete dissemination.  We cannot say it is what every NICU should do because you have to factor in different levels of attention to hand hygiene, nurse-to-patient ratios, and room geography.”

Permanent link to this article: http://www.research.chop.edu/blog/investigators-explore-safety-rotavirus-vaccine-nicu/

Aug 11 2014

Celebrating Student Contributions to Injury Research

injury researchA recent event at the Center for Injury Research and Prevention (CIRP) celebrated the wide-ranging accomplishments of a number of students who have been working with CIRP staff and investigators. Held August 5th, the 9th Annual Student Research Day featured presentations that highlighted the scope and breadth of CIRP research, from those focused on teen driving-related topics to concussions to a study of injuries sustained by fans at Major League Baseball venues.

The students in the pediatric research training programs came to CIRP via various programs, including the CHOP Research Institute Summer Scholars Program (CRISSP) and Drexel University’s Co-op program. While many of the students hailed from Philadelphia-area schools — such as the University of Pennsylvania, Temple University, and Villanova University — students from Pennsylvania State University and the University of Kansas also presented.

The day was set up as a sort of “speed-dating” version of a symposium: Each student was given approximately five minutes to talk about his or her research, and at the end of the event a winner of the day’s best presentation was announced, chosen by CIRP investigators Helen Loeb, PhD, and Jessica H. Mirman, PhD. In all, the event featured 11 presentations.

Danielle Cole, a Drexel Co-op student, kicked off the symposium with a discussion of her work on the Cellie Coping Kit. Originally designed to help children and their families manage the physical and emotional challenges associated with cancer treatment, the kit includes its namesake plush toy, a pack of coping cards, and a booklet for caregivers. Over the past few months, Cole helped develop cards for a version of Cellie devoted to injuries, and has been working to raise money to support the project’s development. So far, she has raised $2,500 on her own.

Later in the day, Nicholas Janigian gave a presentation on “Spectator Injuries and Medical Events at MLB Ballparks.” A Villanova University undergraduate, Janigian’s interest in his topic stems from his love of sports and the fact that there is little mention of fan injuries in the scientific literature. Overall, Janigian found that there were approximately 35 instances of fan injuries between 2010 and 2014, including a bizarre case where a fan was blinded by a hot dog shot in the stands by the Kansas City Royals’ mascot Sluggerrr.

And in what turned out to be the day’s winning presentation, Richard Hanna, a BS/MS student at Drexel University, discussed his work improving digital models of child safety restraint systems (CRS). Specifically, Hanna has been using the XBOX Kinect motion detection gaming device to build accurate 3-D models of CRS devices. “CRS designs are in a constant state of flux,” Hanna said, which can lead to confusion and misuse, but having better models can help ameliorate that.

“The Center for Injury Research and Prevention’s annual Student Research Day event offers students the chance to show off their work, and this year was no different. This year’s impressive presentations showed the impact students make during their time at CIRP. We’re so proud of everything they accomplished,” said Carol Murray, MSS, MLSP, the Center’s training manager.

To learn more about the Center for Injury Research and Prevention, and the Center’s pediatric research training programs, visit the CIRP website.

Permanent link to this article: http://www.research.chop.edu/blog/celebrating-student-contributions-injury-research/

Aug 07 2014

Biodegradable Nanoparticles May Hold Therapeutic Use

biodegradable nanoparticlesNanoparticles have been heralded as a potentially “disruptive technology” in biomedicine, and as a changing platform that could replace conventional technologies, both as drug delivery vehicles and diagnostic tools to help discover and treat disease.

First, however, researchers must demonstrate the properly timed disintegration of these extremely small structures, a process essential for their performance and their ability to be safely cleared out of a patient’s body after their job is done. A new study presents a unique method to directly measure nanoparticle degradation in real time within biological environments.

“Nanoparticles are made with very diverse designs and properties, but all of them need to be eventually eliminated from the body after they complete their task,” said cardiology researcher Michael Chorny, PhD, of The Children’s Hospital of Philadelphia (CHOP). “We offer a new method to analyze and characterize nanoparticle disassembly, as a necessary step in translating nanoparticles into clinical use.”

Dr. Chorny and colleagues described this novel methodology recently in the Proceedings of the National Academy of Sciences.

The CHOP team has long investigated biodegradable nanoparticles for medical use. With diameters ranging from a few tens to a few hundreds of nanometers, these particles are 10 to 1000 times smaller than red blood cells. One major challenge continuously monitoring the fate of nanoparticles in model biological settings and in living cells without disrupting cell functions.

“Accurately measuring nanoparticle disassembly in real time directly in media of interest, such as the interior of a living cell or other types of complex biological milieu, is challenging. Our goal here was to develop such a noninvasive method providing unbiased results,” said Dr. Chorny.

The study team used a physical phenomenon called Förster resonance energy transfer, or FRET, as a sort of molecular ruler to measure the distance between the components of their particles. Researchers labelled their formulations with fluorescent probes exhibiting the radiationless transfer of energy, i.e., FRET, when located within the same particle.

This process results in a special pattern of fluorescence, a “fingerprint” of physically intact particles, which gradually disappears as particle disassembly proceeds. This change in the nanoparticle fluorescent properties can be monitored without separating the particles from their environment, allowing for undistorted, continuous measurements of their integrity.

The rate of disassembly is highly relevant to potential applications. For instance, some nanoparticles might carry a drug intended for quick action, while others should keep the drug protected and released in a controlled fashion over time. Creating formulation properties for these tasks may require carefully adjusting the time frame of the nanoparticle disassembly. This is where this technique can become a valuable tool, greatly facilitating the optimization process.

In the current study, the scientists analyzed how nanoparticles disintegrated both in liquid and semi-liquid media, and in vascular cells simulating the fate of particles used to deliver therapy to injured blood vessels. “We found that disassembly is likely to occur more rapidly early in the vessel healing process and slow down later. This may have implications for the design of nanoparticles intended for targeted drug, gene or cell therapy of vascular disease,” said Dr. Chorny.

While immediately relevant to restenosis therapy and magnetically guided delivery, the current research also has much broader potential applications, said Dr. Chorny. “Nanoparticles could be formulated with contrast agents for diagnostic imaging, or could deliver anticancer drugs to a tumor,” he said. “Our measuring tool can help researchers to develop and optimize their nanomedicine formulations for a range of medical uses.”

More information about the study is available on the Research website.

Permanent link to this article: http://www.research.chop.edu/blog/biodegradable-nanoparticles-may-hold-therapeutic-use/

Aug 05 2014

Climate Change Could Mean More Kidney Stones

kidney stones

The delay between high daily temperatures and kidney stone presentation was short, peaking within three days of exposure to hot days.

As daily temperatures increase, so does the number of patients seeking treatment for kidney stones. In a study that may both reflect and foretell climate change’s impact on human health, a research team found a link between hot days and kidney stones in 60,000 patients in several U.S. cities with varying climates.

“We found that as daily temperatures rise, there is a rapid increase in the probability of patients presenting over the next 20 days with kidney stones,” said Gregory E. Tasian, MD, MSc, MSCE, a pediatric urologist and epidemiologist at The Children’s Hospital of Philadelphia. Along with CHOP’S Ron Keren, MD, MPH, Dr. Tasian published the study team’s findings recently in Environmental Health Perspectives, the journal of the National Institute of Environmental Health Sciences.

Kidney stones are a painful condition that brings half a million patients a year to emergency rooms. While stones remain more common in adults, the numbers of children developing kidney stones have climbed at a dramatically high rate over the last 25 years. When patients cannot pass stones on their own, surgery may be necessary.

The investigators analyzed the records of more than 60,000 adults and children with kidney stones between 2005 and 2011 in Atlanta, Chicago, Dallas, Los Angeles and Philadelphia, in connection with weather data. Dr. Tasian and colleagues described the risk of stone presentation for the full range of temperatures in each city. The delay between high daily temperatures and kidney stone presentation was short, peaking within three days of exposure to hot days.

The study’s broader context is in patterns of global warming. The authors note that other scientists have reported that overall global temperatures between 2000 and 2009 were higher than 82 percent of temperatures over the past 11,300 years. Furthermore, increases in greenhouse gas emissions are projected to raise earth’s average temperatures by 2 to 8 ͦF (1 to 4.5 ͦC) by 2100.

“These findings point to potential public health effects associated with global climate change,” said Dr. Tasian. “However,” he cautioned, “although 11 percent of the U.S. population has had kidney stones, most people have not. It is likely that higher temperatures increase the risk of kidney stones in those people predisposed to stone formation.” Higher temperatures contribute to dehydration, which leads to a higher concentration of calcium and other minerals in the urine that promote the growth of kidney stones.

The researchers also found that very low outdoor temperatures increased the risk of kidney stones in three cities: Atlanta, Chicago and Philadelphia. The authors suggest that as frigid weather keeps people indoors more, higher indoor temperatures, changes in diet, and decreased physical activity may increase their risk of kidney stones. Moreover, the researchers argue that the number of hot days in a given year may better predict kidney stone risk than the mean annual temperature.

“Kidney stone prevalence has already been on the rise over the last 30 years, and we can expect this trend to continue, both in greater numbers and over a broader geographic area, as daily temperatures increase,” concluded Dr. Tasian. “With some experts predicting that extreme temperatures will become the norm in 30 years, children will bear the brunt of climate change.”

To read more about kidney stones and urology research, see the Hospital’s website.

Permanent link to this article: http://www.research.chop.edu/blog/climate-change-mean-kidney-stones/

Jul 31 2014

CKiD Study Spurs New Insights Into Chronic Kidney Disease

chronic kidney diseaseIdentifying 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.

chronic kidney diseaseIn 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.

Permanent link to this article: http://www.research.chop.edu/blog/ckid-study-spurs-new-insights-chronic-kidney-disease/

Jul 30 2014

Unique Collaboration Leads to “Dream Teams” to Advance Pediatric Research

dream teamTwo dedicated “dream teams” of investigators will shape innovative solutions to address unmet pediatric medical needs, as part of a research partnership with The Children’s Hospital of Philadelphia, Drexel University, and The Hebrew University of Jerusalem.

The joint projects each will receive $250,000 over two years in institutional funding, as administrators seek external investors interested in advancing exciting pediatric translational research with commercial viability. The dream teams rose to the top of 20 proposals submitted as a result of a research symposium in January that gave researchers from all three institutions the opportunity to connect and share ideas.

“We are thrilled by the potential for discovery that this portfolio of projects holds, and much of this important work should appeal to future donors,” said The Children’s Hospital of Philadelphia CEO Steven M. Altschuler, MD.

Funding these initial grants internally demonstrates the institutions’ commitment to be a hub of collaboration and exemplifies the inventive, diverse, and entrepreneurial spirit that formed their research consortium initiative. Dr. Altschuler, Drexel President John A. Fry, and The Hebrew University of Jerusalem President Menahem Ben-Sasson signed the research agreement in November as part of a trade mission that Philadelphia Mayor Michael A. Nutter took to Israel.

“These inaugural awards are just the beginning of what the ongoing collaboration between The Children’s Hospital of Philadelphia, Hebrew University and Drexel can accomplish,” said Drexel President John A. Fry. “Together we can create new and unique opportunities that will address unmet needs in pediatrics through innovative commercial pediatric therapeutics and diagnostics.”

One dream team will be based at Drexel with Amy Throckmorton, PhD, as the principal investigator of the “Giving Kids a Chance” project that will investigate a new intravascular blood pump for pediatric patients with congenital heart disease (CHD).

The treatment of single ventricle (SV) anomalies is a formidable and costly challenge for clinical teams caring for patients with CHD, which is the most common major birth defect affecting nearly 1 percent of all newborns. Palliative repair of a SV is generally performed in a series of open-heart procedures over several years. The end result is a man-made physiology in which a SV drives blood flow through the entire circulatory system without the presence of a “right-sided” pulmonary ventricle to pump blood to the lungs. A heart transplant is a treatment option in difficult cases, if the child can survive the waiting period.

As interest is growing about the use of mechanical assistance as a bridge-to-transplant or treatment strategy, the dream team aims to develop a uniquely designed, new therapeutic device for patients with dysfunctional SV physiology. Their goal is to advance the state-of-the-art in blood pump technology, reversing the deleterious characteristics of current approaches and helping to prevent premature congestive heart failure.

dream team

“These inaugural awards are just the beginning of an ongoing collaboration between The Children’s Hospital of Philadelphia, Hebrew University and Drexel can accomplish,” said Drexel President John A. Fry.

The interdisciplinary team will combine its broad expertise in engineering, pediatric cardiology, congenital heart and cardiothoracic surgery, medical device development, and manufacturing for artificial organs. Members from Drexel will include Dr. Throckmorton, J. Yasha Kresh, PhD, and Randy Stevens, MD. They will be joined by four investigators from CHOP: David J. Goldberg, MD; Matthew Gillespie, MD; Kevin K. Whitehead, MD, PhD; and Joseph Rossano, MD. Amnon Hoffman of The Hebrew University of Jerusalem and Amiram Nir of Hadassah Medical Center will round out the team.

They will work with four industry partners: Rotor Bearing Solutions International of Charlottesville, Va.; Cardiac Assist Inc. of Pittsburgh, Pa.; Applied Rapid Technologies of Fredericksburg, Va.; and Laserage Technology Corp. of Waukegan, Ill.

A second dream team will be based at CHOP with Robert J. Levy, MD, as the principal investigator of a research project “Pediatric Transcatheter Valve Replacements: Preventing Device Failure due to Structural Degeneration.”

These investigations also will focus on CHD with a concentration on Tetralogy of Fallot (TOF). These “blue babies” have insufficient oxygen and need cardiac surgery early in life. Postoperatively patients with TOF are left with chronic malfunction of their pulmonary valve.

Ongoing research at CHOP has demonstrated that transcatheter pulmonary valve (TPV) therapy — the current best option — is susceptible to oxidative damage and structural failure. This interdisciplinary team seeks to gain a better understanding of the inflammatory and oxidative events responsible and to inhibit the early inflammatory response to TPV. They will attempt to modify the TPV material with an antioxidant as a way to prevent oxidative damage to the TPV leaflets.

Dr. Levy will collaborate with Matthew Gillespie, MD from CHOP and Joseph H. Gorman, MD and Robert C. Gorman, MD, from Penn, along with Kenneth Barbee, PhD, and Kara Spiller, PhD, from Drexel, and Gershon Golomb from The Hebrew University of Jerusalem.

Permanent link to this article: http://www.research.chop.edu/blog/unique-collaboration-leads-dream-teams-advance-pediatric-research/

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