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nephrology

Nephrology

Exploring the Link Between Childhood Adversity and Adult Heart Disease

Children’s of Alabama researchers are using an NIH grant to study the link between childhood adversity and adult heart disease.

Children’s of Alabama pediatric nephrologist Michael Seifert, M.D., and cardiorenal physiologist Jennifer Pollock, Ph.D., have received a five-year, National Institutes of Health-funded grant to explore the link between stressful childhood experiences and increased risk for cardiovascular disease in adulthood.

“We’re trying to study how exposure to early life stress (ELS) starts to have an effect in childhood on your cardiovascular system,” Seifert said. ELS includes adverse experiences such as physical and emotional abuse or neglect before age 18.

Studies over the last 20 years have linked ELS to adult-onset heart disease and other poor health outcomes like diabetes, mental illness, cancer and high-risk health behaviors. “But despite that, we still know relatively little about the mechanisms connecting the two,” Seifert said.

Seifert and Pollock will test their central hypothesis: ELS causes immune cell activation and inflammation, leading to vascular dysfunction and increasing the risk for hypertension and cardiovascular disease (CVD) later in life.

The investigators will follow a group of 300 adolescents from racially diverse backgrounds to identify critical clinical features and molecular pathways in ELS-associated CVD risk. Early research shows that this population has increased vascular stiffness and ambulatory diastolic blood pressure as well as pro-inflammatory metabolite and gene methylation patterns in plasma and circulating monocytes, respectively.

Seifert and Pollock will use comprehensive profiling to measure vascular stiffness and blood pressure and analyze the metabolome and epigenome—chemical signatures in blood and genes. The goal is to identify inflammatory and molecular pathways linked to cardiovascular changes. The grant also includes two basic science studies that will further inform the clinical trial and a similar study in young adults who had early-life stress exposure.

While it might seem counterintuitive to have nephrology specialists working on a cardiovascular health study, the two are closely linked. “We expect the same things increasing cardiovascular risk probably also increase chronic kidney disease risk,” Seifert said. “There is a lot of cross-talk between the cardiovascular system and the kidneys.” Findings may reveal new therapeutic targets. “This study has important translational potential,” Seifert said. “If we identify something in adolescence that’s driving this, maybe we can mitigate some effects of early-life stress.”

Nephrology

Initiative Aims to Reduce Fluid Overload in NICU Infants

A baby in a Neonatal Intensive Care Unit (Stock photo)

A new effort led by Children’s of Alabama pediatric nephrologist Lindsey Gordon, D.O., is taking aim at fluid overload and its harmful offshoots—including acute kidney injury, prolonged ventilation and hospital stays—in hopes of smoothing the path for infants in the NICU toward a healthier future. The initiative, dubbed CAN-U-P-LOTS, encapsulates a 10-step clinical practice bundle that will be tested over the coming year in collaboration with Children’s NICU clinicians.

Babies in the NICU face many grave health challenges, not least of which is fluid overload from IV medications and nutrition intended to keep them alive and help them thrive.

“New evidence shows how fluid overload in these neonates can cause a lot of problems in the long run, and many times, this can lead to a poor outcome,” Gordon, a third year fellow at Children’s and the University of Alabama at Birmingham (UAB), explained. “We’re trying to recognize the problem early to prevent some of these negative outcomes.”

Elements of the CAN-U-P-LOTS practice bundle include:

  • C: Evaluating the cause of fluid overload
  • A: Assessing albumin level and replenishing as needed
  • N: Limiting nephrotoxic medications that can hurt the kidneys
  • U: Assessing and treating high levels of uric acid and using dialysis for ultra-filtration to remove extra fluid
  • P: Perfusion to the kidneys by increasing blood pressure to ensure adequate blood flow
  • L: Lasix stress test and attempting diuretic use to assess if the kidneys respond
  • O: Monitoring urine output/obstruction carefully and considering placing a Foley catheter or doing a renal ultrasound to ensure no blockage
  • T: Monitoring total fluid intake with an eye toward reducing fluid amounts without sacrificing nutrition
  • S: Considering steroid use if a patient is on several vasopressors to further support blood pressure

Some NICU neonates have risk factors that confer a high risk for fluid imbalance, including patients:

  • with sepsis or acute kidney injury
  • receiving multiple antibiotics
  • being prepared for major surgery
  • requiring blood pressure support with multiple medications

“Preliminary data suggest that the vast majority of neonates admitted to the Children’s of Alabama NICU meet the criteria at least once for fluid overload problems,” Gordon said.

The CAN-U-P-LOTS effort “will produce valuable data that will help us understand whether and how this practice bundle can be implemented on a widespread basis,” said David Askenazi, M.D., director of the Children’s Pediatric and Infant Center for Acute Nephrology (PICAN).

“The idea started with a collaborative approach to help standardize care of these children and educate providers in an effort to equip the NICU team with these systematic tools, so babies don’t ever have to develop fluid overload—the soggy lungs or wet heart that will keep them sicker longer,” Askenazi said. “It takes a village because a project like this takes multiple people, conversations and opportunities to learn from one another.”

“Our hunch is it’s going to work,” he added. “If we can show clinical improvements in these vulnerable babies, we can communicate this to our colleagues to help babies around the country and world. We’re giving them 10 things to think about that can help them maximize medical management before these babies need dialysis.”

Upcoming Events

Children’s and UAB to Host International Neonatal Nephrology Symposium

The inaugural International Neonatal Nephrology Symposium (INNS) takes place in Birmingham in September 2024.

The Pediatric and Infant Center for Acute Nephrology (PICAN) at Children’s of Alabama and the University of Alabama at Birmingham (UAB) will host the inaugural International Neonatal Nephrology Symposium (INNS) September 11-15, 2024, at the Hilton Birmingham Downtown at UAB.

This symposium will bring together experts, researchers and clinicians from across the globe to share knowledge, exchange ideas and collaborate on the latest advancements in neonatal kidney disease. The event will provide a unique platform for networking and foster scientific dialogue that will contribute to improving outcomes in the youngest patients.

Topics

  • Practical aspects of neonatal kidney care—the science and the art
  • From crib to bench and back to the crib
  • Kidney health metrics in neonates and young children
  • Fetal kidney disease—a new era
  • Neonatal organ cross talk
  • Neonatal nephrology potpourri

Featured Workshops

  • Clinical roundtables—caring for neonates with kidney disease and their families
  • Hands-on practical skills sessions—tools to optimize care of neonates with kidney disease

For more information, visit www.childrensal.org/inns.

Nephrology

Desensitization Brings Hope to Children Waiting for a Kidney

Dr. Michael E. Seifert is the medical director of the Pediatric Kidney Transplant Program at Children’s of Alabama.

A new protocol at Children’s of Alabama is giving sensitized children who need a new kidney a brighter glimmer of hope for successful donor match and transplant.

Children who need a kidney transplant typically wait about a year or two for an organ. But if they’ve been exposed to external blood products, been pregnant or had a previous organ transplant, they could find themselves waiting up to five times longer. That’s because they’ve become sensitized to certain proteins that are foreign to their immune system, which results in high antibody levels that react to foreign tissues. “That makes finding a compatible transplant for them really, really problematic,” pediatric nephrologist Michael E. Seifert, M.D., said. Plus, those antibodies significantly increase the risk of an immediate rejection or graft failure.

Historically, finding a compatible kidney donor for sensitized patients has been challenging, but thanks to a process called desensitization, that’s changing for some. It involves using a combination of immunosuppressive therapies to try to reduce the immune reaction to potential donor organs. Although it’s been used in adults for years, pediatric centers like Children’s have only recently introduced their own protocols. “With these immunomodulatory therapies, we try to turn down the volume on their sensitization,” Seifert said. “You can’t get rid of it altogether. Once a patient is sensitized, they’re always sensitized to some extent.”

The desensitization protocol is a combination of plasmapheresis—a kind of dialysis for blood that removes some of the problematic antibodies and immune proteins—and IV and oral immunosuppressants to prevent the antibodies from returning. Together, Seifert said, “this creates a more potent and widespread ratcheting-down of the immune response that allows some transplants to be done safely.”

The process requires close collaboration between clinicians and the immunology, or HLA, laboratory to choose the right cocktail of immunosuppressants and the right time for transplant. While it’s still challenging to find compatible organs, Seifert says the therapies can help shorten the time on the waitlist for some patients and give them access to more donors.

The team has used the protocol on several children so far, one of whom was able to receive a transplant. “So far, the patients are doing really, really well on it,” Seifert said. “And it’s been a success. But it’s a more challenging transplant because they are still much more likely to reject this kidney than a straightforward kidney transplant. We balance that risk against the risks of remaining on the kidney transplant waitlist for several years, waiting for a compatible donor.”

The children also need more attention post-transplant to keep their immune system at bay without triggering complications like infections, and they’ll have to maintain that throughout their lives, Seifert said. They will also always have a higher risk of rejection and premature graft loss. Yet if the transplant fails, subsequent transplants become more challenging, given greater sensitization.

“It’s a Catch-22,” Seifert said, “in that we achieve our goal, which is getting them a transplant, but it’s a lot more work for us to keep that transplant going.”   

Nephrology

A New Protocol for Dialysis Catheter Use in Neonates After Cardiac Surgery

Dr. Tennille Webb is a pediatric nephrologist at Children’s of Alabama.

Cardiac surgery-associated acute kidney injury (CS-AKI) is a common complication following heart surgery involving cardiopulmonary bypass (CPB). One multicenter study found it occurred in 54% of neonates after the procedure. One option to reduce negative outcomes is to start prophylactic peritoneal dialysis (PD) immediately after surgery, which numerous studies have found improves outcomes. Children’s of Alabama is one of only a few pediatric hospitals in the country that provides prophylactic PD in this population. However, there is no consensus on the optimal time to initiate it.

To learn more about which neonates are most likely to benefit from prophylactic PD after cardiac surgery involving CPB, Children’s pediatric nephrologists Tennille Webb, M.D., MSPH, and David Askenazi, M.D., MSPH, reviewed four years of data from patients who developed CS-AKI to identify common characteristics. They also collaborated with cardiac intensivists to gain their perspective.

The team collected baseline data, which showed that about 13% of patients who needed PD didn’t receive it in the operating room (OR), while 51% of those who received PD didn’t need it. “This is undesirable,” Webb said, “because having a PD catheter is not without risks, such as infection.”

Based on their findings, Webb and Askenazi identified three risk factors that were independently associated with the need for PD:

  1. Pre-operative serum creatinine levels
  2. Day-of-surgery weight
  3. Having an open chest post-operatively
     

Using that information, they implemented a new prophylactic PD protocol. After implementing the new protocol, all neonates who eventually needed PD had the catheter inserted in the OR. “This is significant in avoiding delays in initiating PD, therefore mitigating worse outcomes,” Webb said. In addition, the number of unnecessary PD catheters fell by half. “This has huge implications in care delivery, including resources used and exposing children to therapies that are not needed,” she said.

Webb attributes the success to the team effort between nephrologists, cardiothoracic surgeons and cardiac intensivists. The team will continue to assess the impact of prophylactic PD on outcomes such as the duration of mechanical ventilation and fluid overload. “We are excited that we were able to develop and implement an evidence-based prophylactic PD protocol that has improved our ability to provide PD to this neonatal population,” Webb said.

Nephrology

Children’s Nephrologists Hope to Use Biomarkers to Better Identify Kidney Transplant Rejection

Dr. Michael E. Seifert is leading a study to evaluate biomarkers for their potential to predict kidney transplant rejection.

A new study at Children’s of Alabama aims to establish a new, non-invasive way to predict kidney rejection through the blood or urine with better accuracy than the current standard.

The study, Biomarkers from Multiple Platforms to Enhance Diagnosis of Rejection in Children and Young Adults after Renal Transplantation (BuMPER-CAR), is led by pediatric nephrologist Michael E. Seifert, M.D. He and the Children’s nephrology team are conducting it using a large biorepository of patients’ blood, urine and kidney biopsy tissue. With this, they’re evaluating individual biomarkers for their potential to predict rejection. They’re also trying to identify a panel of several biomarkers that may be more accurate and may provide results quickly.

“The idea with this study is, hopefully, we can not only find the patients that are having trouble but confirm the patients who are stable, so we can feel confident that we’re not missing something clinically by avoiding a biopsy in that patient.” The results, he said, could be transformative.

An estimated 1,000 children in the U.S. receive a kidney transplant each year—about 15 to 20 of them at Children’s of Alabama. While the procedure is usually successful, 10-15% of patients experience acute rejection each year, and most transplants fail after about 10-15 years. The standard for assessing the health of a transplant has been to measure creatinine blood levels and urine protein levels. If either is elevated, patients must undergo an invasive biopsy, which carries risks of complications—a heavy cost when only about 1 in 5 biopsies show signs of rejection, meaning most are unnecessary.

According to Seifert, one reason for the poor correlation between rejection and creatinine and protein levels is that the tests are “notoriously bad indicators” of transplant health. By the time the creatinine levels signal a problem, the kidney has often already suffered significant injury.

“On the flip side, there are lots of reasons why somebody’s creatinine might become abnormal, or they might start spilling protein in the urine that has nothing to do with rejection. But we must do biopsies to figure that out,” Seifert said. “So, we need better markers to tell us when the creatinine is a problem, so we can make better assessments.”

The study’s genesis came from a nephrology fellow who wanted to do a research project around biomarkers of kidney transplant diseases. A literature search revealed a plethora of “favorite” biomarkers to predict transplant rejection, but Seifert said there was no consensus on which biomarker worked best. “I think that’s part of the reason why, despite having really good data to support their clinical use, a lot of biomarkers remain on the outskirts of clinical medicine and aren’t being integrated into clinical practice,” he said.

The BuMPER-CAR study is funded in part by Natera, a molecular diagnostics company that manufactures a blood test that detects a form of DNA from the donor kidney, called donor-derived, cell-free DNA (dd-cfDNA), that can be a sign of kidney damage. However, the test is approved only for adults and has not been validated in children. One goal of the study is to set baseline levels for children.  

The study also assesses other biomarkers, including new ones in development at Natera and others developed in Seifert’s lab. Researchers hope to see if a panel of any of these biomarkers would perform better than any individual biomarker. They also want to know if the biomarkers can predict the type of rejection, which could help guide management.

Nephrology

Getting Creative to Address the Nursing Shortage in the Dialysis Unit

Dr. Sahar Fathallah-Shaykh is a pediatric nephrologist at Children’s of Alabama.

The pandemic hit the dialysis unit at Children’s of Alabama with a double whammy: increased census and staff shortages—particularly among nurses. “Similar to many other centers, we are searching for additional outstanding nurses” Children’s nephrologist Sahar Fathallah-Shaykh, M.D., said. Despite this deficit, the dialysis team is finding creative ways to give patients the attention they need while still prioritizing work-life balance for nurses.

Because of the nature of dialysis patients’ needs, it’s tough for the dialysis unit to compensate for staffing issues by limiting patient access. “We provide life-saving care, and patients have to get dialysis,” Fathallah-Shaykh said. “Otherwise, they cannot survive.” Children’s is also home to the only pediatric dialysis unit in the state. “The dialysis unit is not just a machine,” Fathallah-Shaykh said. “It’s not just a physician or just a nurse. It’s all of us working together. And if one is understaffed, that affects the whole dialysis unit.”

In addition, the unit provides dialysis to a significant number of infants and toddlers. While most dialysis patients wait about a year on average for a transplant, Fathallah-Shaykh says little infants or toddlers may have to wait until they’re big enough to be able to successfully receive a transplant. This can require them to be on dialysis longer.

Those patients also require dialysis four to five days a week, with one nurse assigned to a patient for three to four hours. “We have to be very careful to pay attention to details so we can do a good job,” Fathallah-Shaykh said.

The team has been working closely with the administration at Children’s to come up with alternatives. “It starts with recruiting more nurses and retaining nurses in their jobs,” Fathallah-Shaykh said. They also get help from nurses from other service areas, such as the intensive care unit, although they need significant training. “But they have some dialysis experience and have been a good help to us,” she said.

The team has also hired traveling nurses, but their availability is limited because they are in high demand nationwide. In some cases, physicians have stepped in to cover night calls. A newly hired nurse practitioner is also taking some of the pressure off and standardizing care.

For the long term, however, the unit is identifying ways to improve nurses’ work-life balance—the lack of which is one of the main reasons some healthcare professionals are changing careers. For example, dialysis nurses must be on-call at night for patients who require acute dialysis, so one change is to assign nurses to cover either acute dialysis on nights and weekends or chronic dialysis during the week to reduce the amount of on-call time overall. “We feel that dividing the acute dialysis from the chronic dialysis may help with a work-life balance and recruitment,” Fathallah-Shaykh said.

“We are very grateful for the nurses for everything they do,” she said. “Without them, these kids would not survive.”

Inside Pediatrics, Nephrology

Researchers Get One Step Closer to Non-invasive Test for Kidney Rejection

Doctor conducting kidney exam on child.

Monitoring kidney transplant rejection in children is akin to sticking your hand into five pots of water, four of which could burn you. The only surefire way to know if a child is rejecting the organ is with a biopsy. The procedure is invasive, requires anesthesia, carries risks of complications and is expensive. In other words, it’s very hot water. 

Yet every kidney transplant patient at Children’s of Alabama receives a routine biopsy six months after transplant. Only about one 1 in 5, however, actually show signs of rejection, meaning most of those biopsies were unnecessary. Now imagine there was a simple blood or urine test to tell which children were likely to reject the kidney and need a biopsy. That could mean going from 1 in 5 biopsies positive for rejection to 4 in 5 or 5 in 5, sparing hundreds of children from a painful procedure they don’t need.

Pediatric nephrologist Michael E. Seifert, MD, and his team have been working for years on developing such a test, using a large biorepository of patients’ blood, urine and kidney biopsy tissue collected throughout and after the transplant process.

Their work involves investigating gene expression in the tissue samples to find signals of rejection. But while they are good at identifying abnormalities from a piece of biopsy tissue, the process still has room for improvement. With the way tissue is processed, it’s difficult to determine if the abnormal signals are coming from cells that are relevant for rejection—such as immune cells—or from cells that don’t play a role in rejection.

Now, Seifert and his lab are using a novel technique called spatial transcriptomics, or spatial gene expression assays, which enable them to “see” the signals in the context of their natural habitat without destroying the underlying tissues.

“Spatial transcriptomics allows you to develop non-invasive biomarkers that are more reflective of the underlying biology of the disease you’re interested in, such as rejection,” Seifert said. And those more precise biomarkers could narrow down the number of patients who require biopsies. “This will help us understand the mechanisms of kidney transplant injury and rejection with much higher precision,” he said.

Before this technique, they used one of two methods to study gene expression in the tissue. One is to take the tissue, grind it up, see which genes are high and which are low, then develop a test based on the findings. The other is to separate a piece of biopsy tissue into its component cells and individually examine their gene expression. That’s more precise than the bulk gene expression or grinding method, Seifert said, but you lose any spatial context as to where in the tissue the cell came from.

One way to think about it is having all your furniture jammed into a pod in the front yard, taking a chair into the house, and hoping it’s the right piece for that spot by the window. But without the rest of the furniture in the room, it’s hard to know. With spatial transcriptomics, he said, you’re viewing the chair in context with the rest of the furniture.

“The spatial platform is a really incredible tool in that it allows you to be so precise in the areas of the kidney that you’re studying,” Seifert said. He can also isolate cells he’s interested in from the rest of the tissue without disturbing the tissue itself. “Being able to keep the tissue intact enables you to assign geographic locations for the different signals you’re getting when you test the tissue,” he said. 

“We’re just beginning to learn all the ways we can apply it to kidney transplant diseases.”

He and his team presented their first paper on their findings using the new platform at the American Transplant Congress in Boston in June.

Inside Pediatrics, Nephrology

With Parental Training, Children Undergo Home Dialysis While They Sleep         

The team at Children’s of Alabama’s Renal Care Center works hard to transition children and their families to home dialysis

Going to the hospital three to five times a week and being hooked up to a machine for hours at a time is no life for a child. Yet that’s exactly what children with end-stage kidney disease waiting for a transplant spend their time doing. Which is why the team at Children’s of Alabama’s Renal Care Center works so hard to transition children and their families to home dialysis. Currently, of the 30 children they have on dialysis, 17 are able to get their treatments at home.

“In general, home therapy is best for children,” said pediatric nephrologist and Renal Care Center director  Sahar Fathallah-Shaykh, MD. Since the dialysis is typically performed while the child sleeps, they miss less school and have more free time for friends and family. Plus, parents don’t miss work. Still, she said, “We understand that some parents don’t want to do it because it’s very stressful to be responsible for it.”

If parents do want to try home dialysis, the first step is a home visit from a social worker or dialysis nurse. They ensure there is enough space for the machines with the correct electrical outlets and an environment that doesn’t increase the risk of infection, which would require hospitalization. 

Next, the family meets with a dialysis coordinator to learn what’s expected of them. “We make sure we tell them everything ahead of time,” Fathallah-Shaykh said. Finally, the medical team holds a home dialysis selection meeting, where they decide if home dialysis is the right choice for the patient. If it is,  the next step is surgery to implant the catheter needed for home therapy.

Meanwhile,  caregivers undergo extensive training. “It’s a very standardized process to ensure they understand not only how we do things, but why,” Fathallah-Shaykh said. Before the child goes on home dialysis, they spend a couple days in the hospital, where the parents perform dialysis under the watchful eye of the dialysis nurses. “We make sure they’re doing it right, and they have no hesitancy or issues with doing it at home,” she said. When both parents and the Children’s team are comfortable, patients are sent home. “We’re here for them all the time,” Fathallah-Shaykh added.

There are two types of home dialysis: peritoneal dialysis, which uses the lining of the abdomen to filter blood inside the body through a catheter, and hemodialysis, a more complex procedure that requires the caregiver to insert two needles into the child’s fistula or graft, so blood can flow from the body to a machine where it is filtered and then sent back into the body. Children’s is one of only three pediatric centers in the country that train families to do hemodialysis at home. To date, the Children’s Renal Care Center has placed three children on home hemodialysis. 

Although hemodialysis has gotten easier in recent years with machines specifically developed for the home that are easier to set up, clean and disinfect, it’s still invasive. “And they have to deal with blood, which is a lot for some families,” Fathallah-Shayk said. “So we have to have motivated families to do that.” 

Hemodialysis training typically lasts several weeks, while peritoneal training may take only a few days or a week. Regardless of which process is used, she said, “We take our time to make sure families are comfortable doing it.”

Inside Pediatrics, Nephrology

Lecture Series helps Pediatric Nephrology Fellows Learn and Gain Confidence

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, MD, is a pediatric nephrologist at Children’s of Alabama and an associate professor in the Division of Nephrology at the University of Alabama at Birmingham.

At any given time, the nephrology department at Children’s of Alabama is training three fellows, one for each year of its three-year program. The program is one of the best in the country, but one thing it lacked until recently, according to pediatric nephrologist Michael E. Seifert, MD, was a formalized educational curriculum. 

To fill that need, the department started a weekly lecture series in July 2021. It runs throughout the academic year, and lectures focus on topics that correspond to content themes in the American Board of Pediatrics Pediatric Nephrology Certification Exam. The goal is to educate the fellows about topics they will encounter frequently—such as hypertension—or topics most fellows would have had limited experience with as pediatric residents—such as dialysis and kidney transplantation. 

It’s not the first time the department has offered lectures for fellows; the difference now is that it’s a formalized program.

“We always had some faculty give lectures for our fellows but had never organized a formal didactic curriculum for our fellowship program,” said Seifert, who’s the associate program director for the Pediatric Nephrology Fellowship program at the University of Alabama at Birmingham (UAB). “We often sent our fellows to formal lectures delivered through the adult nephrology program.  While these are high quality, they were often not relevant for pediatric nephrology.” 

In the new program, Division of Pediatric Nephrology faculty give the majority of the lectures. Occasionally, speakers also include guests from other divisions who speak on topics that might relate to kidney issues. For example, a urologist might speak on bowel and bladder dysfunction; a rheumatologist might provide a broader view of lupus, which often affects the kidney.

The fellows are also encouraged to prepare and deliver their own talks to develop some of their presentation and public speaking skills in a friendly environment. “They really appreciate that opportunity to hone their skills in a relatively low-risk setting,” Seifert said.

The didactic lectures are interspersed with journal clubs and case discussions. “We had a fellow recently who did a great presentation of a complex case that he was taking care of and how it spurred a quality improvement project,” pediatric nephrologist Erica Bjornstad, MD, said.

“We’re really trying to help build their confidence in clinical pediatric nephrology but also in how we can take that further beyond just clinical education to spur their research or quality improvement ideas,” she said.