Tag Archive for: kidney disease

Marva Moxey-Mims

Continuing Medical Education: Disparities in pediatric kidney disease

Marva Moxey-Mims

Marva Moxey-Mims, M.D.

Join Children’s National Hospital for a pre-recorded Continuing Medical Education (CME) presentation on Disparities in Pediatric Kidney Disease. The session, featuring Marva Moxey-Mims, M.D., Division Chief of Nephrology at Children’s National, offers one (1) CME credit.

Learning Objectives:

  • Recognize racial differences in chronic kidney disease (CKD) progression and end-stage kidney disease (ESKD) in children
  • Understand the impact of apolipoprotein 1 (APOL1) genetic mutations on CKD and ESKD
  • Recognize disparities in kidney transplant access and allograft survival

Click here to view the presentation.

To claim credit for this presentation, please follow these steps:

  1. Log into your INOVA CME account, or create an account: cme.inova.org
  2. Credit for this session can be claimed in one of two ways:
    1. Text session code “TAPMUG” to 703-260-9391
    2. Enter the session code “TAPMUG” at cme.inova.org/code​​​​​

You have 30 days from February 22, 2024, to claim credit.

group photo from nephrology training in Jamaica

Update: Collaboration across borders to improve access to nephrology care

Marva Moxey-Mims, M.D., division chief of Nephrology at Children’s National, has a grant from the International Pediatric Nephrology Association (IPNA) to bring care to children with kidney disease in Jamaica.

During her recent trip, Dr. Moxey-Mims was joined by peritoneal dialysis nurse, Jennifer Carver, RN, and three pediatric nephrologists in Jamaica, Drs. Maolynne Miller, Nadia McClean and Sandrica Peart. Together, they trained close to 30 nurses from three hospitals across the island, including the Bustamante Children’s Hospital, the University Hospital of the West Indies — both in Kingston — and the Cornwall Regional Hospital in Montego Bay.

Nurses were given hands-on training in using peritoneal dialysis cycler machines and manual peritoneal dialysis. The training is part of an initiative that focuses on:

  • Improving clinical training of staff (medical, nursing, and allied health) involved in caring for children with kidney disease
  • Developing and upgrading services for children and adolescents with kidney diseases
  • Educating the community on disease awareness and prevention strategies

“Our ability to offer innovative training and resources to nurses underscores our commitment to ensuring children throughout Jamaica receive the essential care they require,” said Dr. Moxey-Mims. “This signifies to both domestic and international audiences that we’re upholding our pledge to health equity.”

PKD Foundation Pediatric Clinic

Children’s National designated as Polycystic Kidney Disease (PKD) Foundation Pediatric Clinic

PKD Foundation Pediatric ClinicChildren’s National Hospital has been designated as a Pediatric Clinic by the Polycystic Kidney Disease (PKD) Foundation, the only organization in the U.S. solely dedicated to finding treatments and a cure for PKD. This elite designation is given to nephrology practices and clinics that meet patient-centered, specialized PKD criteria established by the PKD Foundation.

As a designated Pediatric Clinic by the PKD Foundation, the Inherited and Polycystic Kidney Diseases (IPKD) Program within the Division of Nephrology at Children’s National offers comprehensive care with the coordination and support of an integrated healthcare team, access to top PKD experts with leading research, and a network of specialists and other providers for referrals, partnerships and mentoring.

“This achievement has been made possible with the support of the PKD Foundation and our Division of Nephrology as we join hands to provide next-level PKD focused care for our patients and families,” says Ashima Gulati, M.D., Ph.D., pediatric nephrologist at Children’s National.

“As PKD providers, it reminds us that we are all part of the larger PKD community with our patients and caregivers at the center. I am delighted that the Children’s National Division of Nephrology is part of this initiative that aligns with the mission of the PKD Foundation to move promising PKD therapies into clinical practice and focuses on providing the best possible PKD care as of today,” Gulati said.

2023 with a lightbulb

The best of 2023 from Innovation District

2023 with a lightbulbAdvanced MRI visualization techniques to follow blood flow in the hearts of cardiac patients. Gene therapy for pediatric patients with Duchenne muscular dystrophy. 3D-printed casts for treating clubfoot. These were among the most popular articles we published on Innovation District in 2023. Read on for our full list.

1. Advanced MRI hopes to improve outcomes for Fontan cardiac patients

Cardiac imaging specialists and cardiac surgeons at Children’s National Hospital are applying advanced magnetic resonance imaging visualization techniques to understand the intricacies of blood flow within the heart chambers of children with single ventricle heart defects like hypoplastic left heart syndrome. The data allows surgeons to make critical corrections to the atrioventricular valve before a child undergoes the single ventricle procedure known as the Fontan.
(3 min. read)

2. Children’s National gives first commercial dose of new FDA-approved gene therapy for Duchenne muscular dystrophy

Children’s National Hospital became the first pediatric hospital to administer a commercial dose of Elevidys (delandistrogene moxeparvovec-rokl), the first gene therapy for the treatment of pediatric patients with Duchenne muscular dystrophy (DMD). Elevidys is a one-time intravenous gene therapy that aims to delay or halt the progression of DMD by delivering a modified, functional version of dystrophin to muscle cells.
(2 min. read)

3. New model to treat Becker Muscular Dystrophy

Researchers at Children’s National Hospital developed a pre-clinical model to test drugs and therapies for Becker Muscular Dystrophy (BMD), a debilitating neuromuscular disease that is growing in numbers and lacks treatment options. The work provides scientists with a much-needed method to identify, develop and de-risk drugs for patients with BMD.
(2 min. read)

4. First infants in the U.S. with specially modified pacemakers show excellent early outcomes

In 2022, five newborns with life-threatening congenital heart disease affecting their heart rhythms were the first in the United States to receive a novel modified pacemaker generator to stabilize their heart rhythms within days of birth. Two of the five cases were cared for at Children’s National Hospital. In a follow-up article, the team at Children’s National shared that “early post-operative performance of this device has been excellent.”
(2 min. read)

5. AI: The “single greatest tool” for improving access to pediatric healthcare

Experts from the Food and Drug Administration, Pfizer, Oracle Health, NVIDIA, AWS Health and elsewhere came together to discuss how pediatric specialties can use AI to provide medical care to kids more efficiently, more quickly and more effectively at the inaugural symposium on AI in Pediatric Health and Rare Diseases, hosted by Children’s National Hospital and the Fralin Biomedical Research Institute at Virginia Tech.
(3 min. read)

6. AAP names Children’s National gun violence study one of the most influential articles ever published

The American Academy of Pediatrics (AAP) named a 2019 study led by clinician-researchers at Children’s National Hospital one of the 12 most influential Pediatric Emergency Medicine articles ever published in the journal Pediatrics. The findings showed that states with stricter gun laws and laws requiring universal background checks for gun purchases had lower firearm-related pediatric mortality rates but that more investigation was needed to better understand the impact of firearm legislation on pediatric mortality.
(2 min. read)

7. Why a colorectal transition program matters

Children’s National Hospital recently welcomed pediatric and adult colorectal surgeon Erin Teeple, M.D., to the Division of Colorectal and Pelvic Reconstruction. Dr. Teeple is the only person in the United States who is board-certified as both a pediatric surgeon and adult colorectal surgeon, uniquely positioning her to care for people with both acquired and congenital colorectal disease and help them transition from pediatric care to adult caregivers.
(3 min. read)

8. First-of-its-kind holistic program for managing pain in sickle cell disease

The sickle cell team at Children’s National Hospital received a grant from the Founders Auxiliary Board to launch a first-of-its-kind, personalized holistic transformative program for the management of pain in sickle cell disease. The clinic uses an inter-disciplinary approach of hematology, psychology, psychiatry, anesthesiology/pain medicine, acupuncture, mindfulness, relaxation and aromatherapy services.
(3 min read)

9. Recommendations for management of positive monosomy X on cell-free DNA screening

Non-invasive prenatal testing using cell-free DNA (cfDNA) is currently offered to all pregnant women regardless of the fetal risk. In a study published in the American Journal of Obstetrics and Gynecology, researchers from Children’s National Hospital provided context and expert recommendations for maternal and fetal evaluation and management when cfDNA screening is positive for monosomy X or Turner Syndrome.
(2 min. read)

10. Innovation in clubfoot management using 3D anatomical mapping

While clubfoot is relatively common and the treatment is highly successful, the weekly visits required for Ponseti casting can be a significant burden on families. Researchers at Children’s National Hospital are looking for a way to relieve that burden with a new study that could eliminate the weekly visits with a series of 3D-printed casts that families can switch out at home.
(1 min. read)

11. Gender Self-Report seeks to capture the gender spectrum for broad research applications

A new validated self-report tool provides researchers with a way to characterize the gender of research participants beyond their binary designated sex at birth. The multi-dimensional Gender Self-Report, developed using a community-driven approach and then scientifically validated, was outlined in a peer-reviewed article in the American Psychologist, a journal of the American Psychological Association.
(2 min. read)

12. Cardiovascular and bone diseases in chronic kidney disease

In a study published by Advances in Chronic Kidney Disease, a team at Children’s National Hospital reviewed cardiovascular and bone diseases in chronic kidney disease and end-stage kidney disease patients with a focus on pediatric issues and concerns.
(1 min. read)

Marva Moxey-Mims

Revolutionizing pediatric nephrology one patient at a time

Marva Moxey-Mims

“With each kidney transplant, we’re not just restoring the health of children, we’re pioneering progress and setting new benchmarks for the field of pediatric nephrology,” says Marva Moxey-Mims, M.D., chief of Nephrology at Children’s National Hospital.

“With each kidney transplant, we’re not just restoring the health of children, we’re pioneering progress and setting new benchmarks for the field of pediatric nephrology,” says Marva Moxey-Mims, M.D., chief of Nephrology at Children’s National Hospital. “We offer not just treatment, but a chance for our patients to flourish and live their best life.”

Big picture

The Kidney Transplantation Program at Children’s National is the only one of its kind in the Washington, D.C., region focused on the needs of children and teens with kidney disease.

Performing an average of 15-20 kidney transplants per year, the program’s latest one- and three-year graft and patient survival data from the Scientific Registry for Transplant Recipients is 100%.

“Our program surpasses national numbers, reflecting a commitment to exceptional care, superior patient outcomes and a focus on setting a new standard for excellence in transplant support,” says Dr. Moxey-Mims.

Children’s National leads the way

At the forefront of groundbreaking treatment, the nephrology team is pioneering progress by providing innovative care and resources. One example is the hospital’s collaboration with the National Kidney Registry and MedStar Georgetown Transplant Institute’s Living Donor Program. This provides a greater chance of finding more suitable donors for difficult-to-match children and has resulted in altruistic donations.

“Through living kidney donations, we redefine the timeline for pediatric transplants. Children experience shorter waits and swifter paths to renewed health compared to the national wait list,” says Asha Moudgil, M.D., medical director of the Kidney Transplantation Program at Children’s National. “It’s a testament to our commitment to making a difference in every child’s life.”

That commitment is also seen in the hospital’s focus on making sure families have the resources they need during their medical journey.

“Caring for a child with renal disease is an immense challenge, not only for the young patients but also for their families. The demanding schedule of hospital visits, often three times a week, adds an extra layer of stress and disruption to daily life,” says Dr. Moudgil.

Through grant funding from donors and national programs, families with children undergoing kidney transplants and dialysis can receive financial assistance. In some cases, families receive up to $2,000 of mortgage or rental payment assistance. Families can also receive funds for medication co-pays and other expenses incurred around the time of the transplant.

“In the face of medical adversity, these funds become a source of support,” says Dr. Moudgil. “We make sure every family, regardless of financial constraints, can access the care and resources their child needs.”

Bottom line

Children’s National is at the forefront of pediatric kidney transplantation. “Our unique approach ensures every facet of a patient’s journey is considered,” says Dr. Moxey-Mims. “We’ve created an environment where success is not just a medical outcome but a comprehensive and sustained improvement in a child’s overall quality of life.”

Learn more about our latest advances in pediatric Nephrology.

doctor explaining menstrual cycle

Reproductive healthcare is key for adolescents with chronic kidney disease

doctor explaining menstrual cycle

In a report, Drs. Moxey-Mims and Brunson review the current state of reproductive healthcare for adolescents in the U.S., including those with chronic kidney disease.

In a report from the Journal of the American Society of Nephrology, Marva Moxey-Mims, M.D., division chief of nephrology at Children’s National Hospital and Celina Brunson, M.D., medical director of dialysis, review the current state of reproductive healthcare for adolescents in the United States. They also explore the limited information available for pregnancy in adolescents with chronic kidney disease, including concerns for the impact of pregnancy on progression of kidney disease, and the potential fetotoxic effects of medications prescribed for some types of kidney disease and in kidney transplantation. They describe barriers to access to important information for reproductive healthcare options, which may be exacerbated after the overturning of Roe v. Wade.

This work gives pediatric nephrologists information that can help them provide appropriate information and support to their adolescent patients with chronic kidney disease.

“This work will provide guidance around reproductive healthcare options for those with chronic kidney disease. We need to learn to be comfortable about ways to educate and help our teens with chronic kidney disease to optimize their overall health,” says Moxey-Mims.

Read more about the report from the Journal of the American Society of Nephrology.

sister center team

Collaboration across borders to improve access to nephrology care

sister center teamChildren’s National Hospital is joining the International Pediatric Nephrology Association (IPNA) to bring care to children with kidney disease in Jamaica. With early screenings, diagnosis and optimal treatments, this collaboration will help decrease the morbidity and mortality associated with renal disease.

“This partnership shows our hospital’s willingness to assist with education and resources in a country will fewer resources,” says Marva Moxey-Mims, M.D., division chief of Nephrology at Children’s National. “This is a signal to those within and outside the United States that we live our stated commitment to health equity.”

This effort will focus on:

  • Improving clinical training of staff (medical, nursing and allied health) involved in caring for children with kidney disease
  • Developing and upgrading services for children and adolescents with kidney diseases
  • Educating the community on disease awareness and prevention strategies

IPNA facilitates the exchange of knowledge and expertise about kidney disease in children in the areas where care is needed most.

“I am excited about our ability to provide specialized clinical training and additional resources to our colleagues in Jamaica,” says Dr. Moxey-Mims. “This will empower them to provide improved care to children with kidney disease on the island through multidisciplinary teams.”

colored illustration of kidney x-ray

Partnership with CMS and HRSA addresses national kidney shortage

colored illustration of kidney x-ray

Children’s National Hospital is proud to announce that it is participating in the Centers for Medicare & Medicaid Services (CMS) and Health Resources & Services Administration (HRSA)’s new End-Stage Renal Disease Treatment Choices Learning Collaborative (ETCLC). This effort will focus on addressing kidney disease prevention and treatment, including improved access to kidney transplants in the United States.

The ETCLC will engage transplant centers, Organ Procurement Organizations (OPOs), large donor hospitals, patients and donor family members to identify highly effective practices currently in use and spread the use of these practices throughout the organ procurement, kidney care and kidney transplant community to achieve the following three AIMs:

  • AIM #1: Increase the number of deceased donor kidneys transplanted
  • AIM #2: Decrease the current national discard rate of all procured kidneys
  • AIM #3: Increase the percentage of change for kidneys recovered for transplant in the 60-85 Kidney Donor Profile Index score group

The ETCLC brings the potential for collaboration, communication and innovation across geography into reality. By participating in the ETCLC, Children’s National will benefit by:

  • the creation of efficiencies and reduction of duplicative efforts in kidney patient care
  • exposure to new, innovative ideas regarding the kidney transplant process
  • the enhancement of communication and relationship building within the kidney care community
  • the application of substantive changes to improve the donation and transplantation system
cystic kidney disease

American Heart Association grant funds study of vascular complications in ADPKD

cystic kidney disease

Ashima Gulati, M.D., Ph.D., pediatric nephrologist at Children’s National Hospital recently was awarded a grant from the American Heart Association. Dr. Gulati’s work will aim to identify the genetic determinants of vascular complications in autosomal dominant polycystic kidney disease (ADPKD).

Cerebrovascular complications such as vascular aneurysms and anomalies are an important cause of morbidity in ADPKD that need to be studied. The goal of Dr. Gulati’s research is to contribute to knowledge towards using molecular medicine to inform individual genetic risk of clinically significant vascular complications in ADPKD.

This work addresses a clinically significant vascular complication in ADPKD, the most common inherited form of kidney failure world-wide.

Kristen Sgambat, Ph.D., and Asha Moudgil, M.D.

Kristen Sgambat, Ph.D., R.D. and Asha Moudgil, M.D. receive Editors’ Choice Award

Kristen Sgambat, Ph.D., and Asha Moudgil, M.D.

Children’s National Hospital researchers Kristen Sgambat, Ph.D., and Asha Moudgil, M.D., were presented with the 2021 AJKD Editors’ Choice Award.

The American Journal of Kidney Disease (AJKD) announced the selection of the 2021 AJKD Editors’ Choice Award, recognizing outstanding articles published in their journal this year.

Children’s National Hospital researchers Kristen Sgambat, Ph.D., and Asha Moudgil, M.D., were presented with the 2021 AJKD Editors’ Choice Award for their July 2021 study, Social determinants of cardiovascular health in African American children with chronic kidney disease: An analysis of the chronic kidney disease in children (CKiD).

The study is the first to investigate the relationship between race, socioeconomic factors and cardiovascular health in children with chronic kidney disease. Dr. Sgambat, Dr. Moudgil and their collaborators found that African American children with chronic kidney disease had increased evidence of socioeconomic challenges, including food insecurity, reliance on public insurance, lower household incomes and lower levels of maternal education. These children had worse cardiovascular outcomes than Caucasian children with the same chronic kidney conditions. Notably, the cardiovascular outcomes of the two groups became more alike when statistical analysis was applied to equalize their socioeconomic factors. This suggests that these socioeconomic indicators do play a role in adverse cardiovascular health outcomes observed among African American children with chronic kidney disease.

“The findings of this study are important because they highlight the urgent need to shift the clinical research paradigm to investigate how social, rather than biological, factors contribute to racial differences in health outcomes,” said Dr. Sgambat. “Future studies should focus on the impact of systemic racism on cardiovascular health among children with chronic kidney disease, an area not well-studied so far.”

Denver Brown

New grant to conduct single center pilot trial of alkali therapy in children with CKD

Denver Brown

Denver D. Brown, M.D., recipient of the Child Health Research Career Development Award.

Linear growth (i.e., height) impairment is commonly observed in children with chronic kidney disease (CKD). Several studies have suggested metabolic acidosis, a frequent consequence of mild to moderate CKD in children, as a contributing factor to linear growth failure in these patients. Grant awardee Denver D. Brown, M.D., aims to conduct a pilot trial in children with mild metabolic acidosis and CKD, comparing differences in linear growth between an observation period versus a period of supplementation with alkali therapy (i.e., treatment for metabolic acidosis).

“This grant is so important because there has never been a clinical trial of alkali therapy in children with CKD despite its frequent use in this population” says Dr. Brown. “This research has the potential to better inform treatment practices with the aim of improving the care of our young, vulnerable patients.”

The Child Health Research Career Development Award (CHRCDA) of $125,000 will support Dr. Brown in her efforts to carry out this pilot trial.

“Funding for this pilot study could lay the groundwork for a large, randomized controlled clinical trial, which would help fill a major gap in knowledge as to the precise benefits of alkali therapy, especially regarding growth in children with impaired kidney function.”

colored x-ray showing kidneys and spine

New report advances improved way to diagnose kidney disease

colored x-ray showing kidneys and spine

The findings outline a new race-free approach to diagnose kidney disease, recommending the adoption of the new eGFR 2021 CKD EPI creatinine equation.

Patients with kidney disease will benefit from an improved approach, according to a new report.

The findings outline a new race-free approach to diagnose kidney disease, recommending the adoption of the new eGFR 2021 CKD EPI creatinine equation. This calculation estimates kidney function without a race variable. The report also recommends increased use of cystatin C combined with serum creatinine as a confirmatory assessment of eGFR or kidney function.

The effort is being spearheaded by a team of national nephrology experts that includes Marva Moxey-Mims, M.D., chief of the Division of Nephrology at Children’s National Hospital.

“This final report is important in recommending a uniform approach to the calculation of eGFR without the inclusion of race,” Dr. Moxey-Mims says. “This will avoid a piecemeal approach where eGFR is calculated differently at different health care facilities, potentially causing confusion.”

The final report, published in the American Journal of Kidney Diseases and the Journal of the American Society of Nephrology, was drafted with considerable input from hundreds of patients, family members, medical students, clinicians, scientists, health professionals and other stakeholders. This will help achieve consensus for an unbiased and most reasonably accurate estimation of GFR so that laboratories, clinicians, patients and public health officials can make informed decisions to ensure equity and personalized care for patients with kidney diseases.

“Patients, professionals and other stakeholders can have confidence in this estimate that is relying solely on biologic measures. Hopefully, these can evolve even further as the science progresses,” Dr. Moxey-Mims says. “My hope is that health systems and labs will adopt these changes expeditiously.”

plate of food

Looking back one year later – Keeping it Renal: Global Cuisine for Kids

plate of food

The cookbook introduces a variety of culturally diverse kidney-friendly recipes that kids of all ages love.

It has been one year since the Children’s National Hospital Department of Nephrology released their cookbook “Keeping it Renal: Global Cuisine for Kids” and we are still receiving requests for this collection of recipes. In order to stay healthy, most children with kidney disease have to limit or avoid foods that are high in certain minerals including sodium, potassium and phosphorus. “Children on dialysis have to give up a lot of what they like to eat. This cookbook introduces a variety of culturally diverse kidney-friendly recipes that kids of all ages love. By learning to cook these recipes, our patients can take an active role in their own healthcare and learn some fun new skills,” said Kristen Sgambat, Ph.D., R.D., and Asha Moudgil, M.D., medical director of transplant.

It is often challenging for children and their families to balance these dietary restrictions with proper nutrition and enjoyable mealtimes. “This cookbook offers novel and exciting recipes that patients and families may not be aware of. Seeing these options can help patients see that a renal diet does not have to be bland or repetitive and thus improve patients’ outlook on treatment and motivate them to adhere to the dietary restrictions,” said Kaushalendra Amatya, Ph.D., pediatric psychologist for Nephrology and Cardiology at Children’s National.

As an innovative way to facilitate adherence to these limitations, our nephrology department collaborated with our patient families to create the cookbook “Keeping it Renal: Global Cuisine for Kids,” a compilation of their favorite kidney-friendly recipes.

Children’s National is one of the top pediatric hospitals in NIH funding, and our nephrology program ranks number 7 in the country, according to U.S. News & World Report. The Kidney Transplantation Program is the only one of its kind in the Washington, D.C., area focused on the needs of children and teens with kidney disease. Committed to providing the best quality care to all of our pediatric dialysis and transplant patients, we are always looking for new ways to support our patient families.

If you would like to receive a copy of the Keeping it Renal: Global Cuisine for Kids cookbook, please send your request to: emorrow@childrensnational.org.

 

High magnification micrograph of focal segmental glomerulosclerosis

Reducing urinary protein for patients with FSGS slows kidney decline

High magnification micrograph of focal segmental glomerulosclerosis

High magnification micrograph of focal segmental glomerulosclerosis (FSGS).

Reducing the amount of protein in the urine of patients with focal segmental glomerulosclerosis (FSGS), a rare disease in which scar tissue forms on the parts of the kidneys that filter waste from the blood, can significantly slow declines in kidney function and extend time before patients’ kidneys fail, a new analysis by a Children’s National Hospital researcher and her colleagues shows. These findings, published online Aug. 10, 2020, in the American Journal of Kidney Disease, could provide hope for patients who are able to lower their urinary protein with available treatments but aren’t able to achieve complete remission, the researchers say.

FSGS affects about seven per every million people in the general population. However, in the United States, it’s responsible for between 5 and 20% of all cases of end stage kidney disease (ESKD), a condition in which the kidney function declines enough that patients can’t survive without dialysis or a kidney transplant. There are no proven treatments specifically targeting FSGS, but steroids and other immunosuppressants have shown promise in clinical trials.

One characteristic sign of FSGS is proteinuria, in which too much protein is present in patients’ urine. Most clinical trials of FSGS treatments have focused on complete remission of proteinuria as a sign that the intervention is working. However, says Marva Moxey-Mims, M.D., researcher and chief of the Children’s National Division of Nephrology, only a fraction of patients meet that end goal. Instead, many patients achieve some reduction in proteinuria, but it’s been unclear whether those reductions lead to significant benefits for kidney health.

To investigate this question, Dr. Moxey-Mims and her colleagues used data from the National Institutes of Health-funded FSGS clinical trial that took place between November 2004 and May 2008. Participants in this study — 138 patients who developed proteinuria due to FSGS between the ages of 2 and 40 and didn’t respond to steroids — received one of two different immunosuppressant regimens. They received frequent checkups including urinary protein tests during the duration of the study and were followed for a maximum of 54 months.

Results showed that about 49% of the study participants’ proteinuria improved by 26 weeks of treatment on either regimen. More importantly, says Dr. Moxey-Mims, these patients retained significantly better kidney function over time, determined by a test called estimated glomerular filtration rate (eGFR), compared to those whose urinary protein remained high. The greater the reduction in proteinuria, the better their kidney function remained, and the longer their kidneys remained active before they developed ESKD.

“Even a modest reduction in proteinuria, as small as 20 or 30%, had an impact on these patients’ kidney health,” Dr. Moxey-Mims says.

Dr. Moxey-Mims notes that the finding could impact the design of clinical trials for FSGS treatments. Currently, these trials typically must include large numbers of patients to show a benefit if complete remission of proteinuria — which only occurred in about 20% of patients in the National Institute of Diabetes and Digestive and Kidney Diseases trial — is used as the end point.

If researchers use a range of proteinuria reduction as end points, she says, it could be easier to see if a drug or other intervention is working.

Similarly, she says, patients with FSGS and their doctors should view any proteinuria reduction as a positive.

“They shouldn’t be discouraged if they can’t reach full remission,” Dr. Moxey-Mims says. “Doctors and patients alike can feel reassured that if they’re reducing protein in the urine to some degree, then patients are getting some benefit.”

 

Nephrology at Children's National

2020 at a glance: Nephrology at Children’s National

The Children’s National Division of Nephrology is consistently recognized by U.S. News & World Report as one of the top programs in the nation.

kidney ultrasound

Using computers to enhance hydronephrosis diagnosis

kidney ultrasound

Researchers at Children’s National Hospital are using quantitative imaging and machine intelligence to enhance care for children with a common kidney disease, and their initial results are very promising. Their technique provides an accurate way to predict earlier which children with hydronephrosis will need surgical intervention, simplifying and enhancing their care.

We live in a time of great uncertainty yet great promise, particularly when it comes to harnessing technology to improve lives. Researchers at Children’s National Hospital are using quantitative imaging and machine intelligence to enhance care for children with a common kidney disease, and their initial results are very promising. Their technique provides an accurate way to predict earlier which children with hydronephrosis will need surgical intervention, simplifying and enhancing their care.

Hydronephrosis means “water in the kidney” and is a condition in which a kidney doesn’t empty normally. One of the most frequently detected abnormalities on prenatal ultrasound, hydronephrosis affects up to 4.5% of all pregnancies and is often discovered prenatally or just after birth.

Although hydronephrosis in children sometimes resolves by itself, identifying which kidneys are obstructed and more likely to need intervention isn’t particularly easy. But it is critical. “Children with severe hydronephrosis over long periods of time can start losing kidney function to the point of losing a kidney,” says Marius George Linguraru, DPhil, MA, MSc, principal investigator of the project; director of Precision Medical Imaging Group at the Sheikh Zayed Institute for Pediatric Surgical Innovation; and professor of radiology, pediatrics and biomedical engineering at George Washington University.

Children with hydronephrosis face three levels of examination and intervention: ultrasound, nuclear imaging testing called diuresis renogram and surgery for the critical cases. “What we want to do with this project is stratify kids as early as possible,” Dr. Linguraru says. “The earlier we can predict, the better we can plan the clinical care for these kids.”

Ultrasound is used to see whether there is a blockage and try to determine hydronephrosis severity. “Ultrasound is non-invasive, non-radiating, and does not expose the child to any risk prenatally or postnatally,” Dr. Linguraru says. Ultrasound evaluations require a trained radiologist, but there’s a lot of variability. Radiologists have a grading system based on the ultrasound appearance of the kidney to determine whether the hydronephrosis is mild, moderate or severe, but studies show this isn’t predictive of longer term outcomes.

Children whose ultrasounds show concern will be referred to diuresis renogram. Costly, complex, invasive and irradiating, it tests how well the kidney empties. Although appropriate for good clinical indications, doctors try to minimize its use. “Management of hydronephrosis is complex,” Dr. Linguraru says. “We want to use ultrasound as much as possible and much less diuresis renogram.”

For those patients whose kidney is obstructed and eventually need surgical intervention, the sooner that decision can be made the better. “The more you wait for a kidney that is severely obstructed, the more function may be lost. If intervention is required, it’s preferable to do it early,” Dr. Linguraru says. Of course for the child whose hydronephrosis will likely resolve itself, intervention is not the best option.

Marius George Linguraru

“With our technique we are measuring physiological and anatomical changes in the ultrasound image of the kidney,” says Marius George Linguraru, DPhil, MA, MSc. “The human eye may find it difficult to put all this together, but the machine can do it. We use quantitative imaging to do deep phenotyping of the kidney and machine learning to interpret the data.”

Dr. Linguraru and the multidisciplinary team at Children’s National Hospital, including radiology and urology clinicians, are putting the power of computers to work interpreting subtleties in the ultrasound data that humans just can’t see. In their pilot study they found that 60% of the nuclear imaging tests could have been safely avoided without missing any of the critical cases of hydronephrosis. “With our technique we are measuring physiological and anatomical changes in the ultrasound image of the kidney,” Dr. Linguraru says. “The human eye may find it difficult to put all this together, but the machine can do it. We use quantitative imaging to do deep phenotyping of the kidney and machine learning to interpret the data.”

Results of the initial study indicate that kids who have a mild condition can be safely discharged earlier and the model can predict all those kids with obstructions and accelerate their diagnosis by sending them earlier to get further investigation. Dr. Linguraru says. “There are only benefits: some kids will get earlier diagnosis, some earlier discharges.”

The team also has a way to improve the interpretation of diuresis renograms. “We analyze the dynamics of the kidney’s drainage curve in quantifiable way. Using machine learning to interpret those results, we showed we can potentially discharge some kids earlier and accelerate intervention for the most severe cases instead of waiting and repeating the invasive tests,” he says. The framework has 93% accuracy, including 91% sensitivity and 96% specificity, to predict surgical cases, a significant improvement over clinical metrics’ accuracy.

The next step is a study connecting all the protocols. “Right now we have a study on ultrasound, a study on nuclear imaging, but we need to connect them so a child with hydronephrosis immediately benefits,” says Dr. Linguraru. Future work will focus on streamlining and accelerating diagnosis and intervention for kids who need it, both in prospective studies and hopefully clinically as well.

Hydronephrosis is an area in which machine learning can be applied to pediatric health in meaningful ways because of the sheer volume of cases.

“Machine learning algorithms work best when they are trained well on a lot of data,” Dr. Linguraru says. “Often in pediatric conditions, data are sparse because conditions are rare. Hydronephrosis is one of those areas that can really benefit from this new technological development because there is a big volume of patients. We are collecting more data, and we’re becoming smarter with these kinds of algorithms.”

Learn more about the Precision Medical Imaging Laboratory and its work to enhance clinical information in medical images to improve children’s health.

brain network illustration

$2.5M to protect the brain from metabolic insult

brain network illustration

The brain comprises only 2% of the body’s volume, but it uses more than 20% of its energy, which makes this organ particularly vulnerable to changes in metabolism.

More than 30 million Americans have diabetes, with the vast majority having Type 2 disease. Characterized by insulin resistance and persistently high blood sugar levels, poorly controlled Type 2 diabetes has a host of well-recognized complications: compared with the general population, a greatly increased risk of kidney disease, vision loss, heart attacks and strokes and lower limb amputations.

But more recently, says Nathan A. Smith, MS, Ph.D., a principal investigator in Children’s National Research Institute’s Center for Neuroscience Research, another consequence has become increasingly apparent. With increasing insulin resistance comes cognitive damage, a factor that contributes significantly to dementia diagnoses as patients age.

The brain comprises only 2% of the body’s volume, but it uses more than 20% of its energy, Smith explains – which makes this organ particularly vulnerable to changes in metabolism. Type 2 diabetes and even prediabetic changes in glucose metabolism inflict damage upon this organ in mechanisms with dangerous synergy, he adds. Insulin resistance itself stresses brain cells, slowly depriving them of fuel. As blood sugar rises, it also increases inflammation and blocks nitric oxide, which together narrow the brain’s blood vessels while also increasing blood viscosity.

When the brain’s neurons slowly starve, they become increasingly inefficient at doing their job, eventually succumbing to this deprivation. These hits don’t just affect individual cells, Smith adds. They also affect connectivity that spans across the brain, neural networks that are a major focus of his research.

While it’s well established that Type 2 diabetes significantly boosts the risk of cognitive decline, Smith says, it’s been unclear whether this process might be halted or even reversed. It’s this question that forms the basis of a collaborative Frontiers grant, $2.5 million from the National Science Foundation split between his laboratory; the lead institution, Stony Brook University; and Massachusetts General Hospital/Harvard Medical School.

Smith and colleagues at the three institutions are testing whether changing the brain’s fuel source from glucose to ketones – byproducts from fat metabolism – could potentially save neurons and neural networks over time. Ketones already have shown promise for decades in treating some types of epilepsy, a disease that sometimes stems from an imbalance in neuronal excitation and inhibition. When some patients start on a ketogenic diet – an extreme version of a popular fat-based diet – many can significantly decrease or even stop their seizures, bringing their misfiring brain cells back to health.

Principal Investigator Smith and his laboratory at the Children’s National Research Institute are using experimental models to test whether ketones could protect the brain against the ravages of insulin resistance. They’re looking specifically at interneurons, the inhibitory cells of the brain and the most energy demanding. The team is using a technique known as patch clamping to determine how either insulin resistance or insulin resistance in the presence of ketones affect these cells’ ability to fire.

They’re also looking at how calcium ions migrate in and out of the cells’ membranes, a necessary prerequisite for neurons’ electrical activity. Finally, they’re evaluating whether these potential changes to the cells’ electrophysiological properties in turn change how different parts of the brain communicate with each other, potentially restructuring the networks that are vital to every action this organ performs.

Colleagues at Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital and Harvard Medical School, led by Principal Investigator Eva-Maria Ratai, Ph.D.,  will perform parallel work in human subjects. They will use imaging to determine how these two fuel types, glucose or ketones, affect how the brain uses energy and produces the communication molecules known as neurotransmitters. They’re also investigating how these factors might affect the stability of neural networks using techniques that investigate the performance of these networks both while study subjects are at rest and performing a task.

Finally, colleagues at the Laufer Center for Physical and Quantitative Biology at Stony Brook University, led by Principal Investigator Lilianne R. Mujica-Parodi, Ph.D., will use results generated at the other two institutions to construct computational models that can accurately predict how the brain will behave under metabolic stress: how it copes when deprived of fuel and whether it might be able to retain healthy function when its cells receive ketones instead of glucose.

Collectively, Smith says, these results could help retain brain function even under glucose restraints. (For this, the research team owes a special thanks to Mujica-Parodi, who assembled the group to answer this important question, thus underscoring the importance of team science, he adds.)

“By supplying an alternate fuel source, we may eventually be able to preserve the brain even in the face of insulin resistance,” Smith says.

Kidney transplants at Children's National

2019 at a glance: Nephrology at Children’s National

Nephrology at Children's National
Zhe Han

$2M NIH grant for treating disease linked to APOL1

Zhe Han

Children’s researcher Zhe Han, Ph.D., has received a $2 million award from the National Institutes of Health (NIH) to study new approaches to treat kidney disease linked to inheriting Apolipoprotein L1 (APOL1) risk alleles. These risk alleles are particularly common among persons of recent African descent, and African Americans are disproportionately affected by the increased risk in kidney disease associated with these risk alleles.

Han, an associate professor in Children’s Center for Genetic Medicine Research, has established a leading research program that uses the fruit fly Drosophila as a model system to study how genetic mutations lead to disease.

Drosophila is a very basic model, but studies in the fly have led to major breakthroughs in understanding fundamental biological processes that underlie health and disease in humans,” Han says. “Since coming to Children’s National five years ago, I have focused a significant part of my research studying particular fly cells called nephrocytes that carry out many of the important roles of human kidney glomeruli, units within the kidney where blood is cleaned. Working together with clinician colleagues here, we have demonstrated that these Drosophila cells can be used to very efficiently study different types of renal disease caused by genetic mutations.”

The APOL1 risk alleles are genetic variants, termed G1 and G2, found almost exclusively in people of African ancestry and can lead to a four-fold higher risk of end-stage kidney disease, the last of five stages of chronic kidney disease. Exactly how inheriting these risk alleles increases the risk of kidney disease remains an unanswered question and the focus of considerable research activity. Han’s laboratory has developed a Drosophila model of APOL1-linked renal disease by producing the G1 and G2 forms of APOL1 specifically in nephrocytes. This led to defects in fly renal cells that strikingly overlap with disease-associated changes in experimental model and human kidney cells expressing APOL1 risk alleles.

The new NIH award will fund large-scale screening and functional testing to identify new treatment targets and new drugs to treat kidney disease linked to APOL1. Using a genetic screening approach, Han’s lab will identify nephrocyte “modifier” genes that interact with APOL1 proteins and counter the toxic effects of risk-associated G1 and G2 variants.

The team also will identify nephrocyte genes that are turned on or off in the presence of APOL1 risk alleles, and confirm that such “downstream” APOL1-regulated genes are similarly affected in experimental model and human kidney cells. The potential of the newly identified “modifier” and “downstream” genes to serve as targets of novel therapeutic interventions will be experimentally tested in fly nephrocytes in vivo and in cultured mammalian kidney cells.

Finally, the Drosophila model will be used as a drug screening platform for in vivo evaluation of positive “hits” from a cell-based APOL1 drug screening study in order to identify compounds that are most effective with the fewest side effects.

“These types of studies can be most efficiently performed in Drosophila,” Han adds.  “They take advantage of the speed and low cost of the fly model system and the amazing array of well-established, sophisticated genetic tools available for the fly. Using this model to elucidate human disease mechanisms and to identify new effective therapies has truly become my research passion.”

DNA strands on teal background

NUP160 genetic mutation linked to steroid-resistant nephrotic syndrome

DNA strands on teal background

Mutations in the NUP160 gene, which encodes one protein component of the nuclear pore complex nucleoporin 160 kD, are implicated in steroid-resistant nephrotic syndrome, an international team reports March 25, 2019, in the Journal of the American Society of Nephrology. Mutations in this gene have not been associated with steroid-resistant nephrotic syndrome previously.

“Our findings indicate that NUP160 should be included in the gene panel used to diagnose steroid-resistant nephrotic syndrome to identify additional patients with homozygous or compound-heterozygous NUP160 mutations,” says Zhe Han, Ph.D., an associate professor in the Center for Genetic Medicine Research at Children’s National and the study’s senior author.

The kidneys filter blood and ferry waste out of the body via urine. Nephrotic syndrome is a kidney disease caused by disruption of the glomerular filtration barrier, permitting a significant amount of protein to leak into the urine. While some types of nephrotic syndrome can be treated with steroids, the form of the disease that is triggered by genetic mutations does not respond to steroids.

The patient covered in the JASN article had experienced persistently high levels of protein in the urine (proteinuria) from the time she was 7. By age 10, she was admitted to a Shanghai hospital and underwent her first renal biopsy, which showed some kidney damage. Three years later, she had a second renal biopsy showing more pronounced kidney disease. Treatment with the steroid prednisone; cyclophosphamide, a chemotherapy drug; and tripterygium wilfordii glycoside, a traditional therapy, all failed. By age 15, the girl’s condition had worsened and she had end stage renal disease, the last of five stages of chronic kidney disease.

An older brother and older sister had steroid-resistant nephrotic syndrome as well and both died from end stage kidney disease before reaching 17. When she was 16, the girl was able to receive a kidney transplant that saved her life.

Han learned about the family while presenting research findings in China. An attendee of his session said that he suspected an unknown mutation might be responsible for steroid-resistant nephrotic syndrome in this family, and he invited Han to work in collaboration to solve the genetic mystery.

By conducting whole exome sequencing of surviving family members, the research team found that the mother and father each carry one mutated copy of NUP160 and one good copy. Their children inherited one mutated copy from either parent, the variant E803K from the father and the variant R1173X, which causes truncated proteins, from the mother. The woman (now 29) did not have any mutations in genes known to be associated with steroid-resistant nephrotic syndrome.

Some 50 different genes that serve vital roles – including encoding components of the slit diaphragm, actin cytoskeleton proteins and nucleoporins, building blocks of the nuclear pore complex – can trigger steroid-resistant nephrotic syndrome when mutated.

With dozens of possible suspects, they narrowed the list to six variant genes by analyzing minor allele frequency, mutation type, clinical characteristics and other factors.

The NUP160 gene is highly conserved from flies to humans. To prove that NUP160 was the true culprit, Dr. Han’s group silenced the Nup160 gene in nephrocytes, the filtration kidney cells in flies. Nephrocytes share molecular, cellular, structural and functional similarities with human podocytes. Without Nup160, nephrocytes had reduced nuclear volume, nuclear pore complex components were dispersed and nuclear lamin localization was irregular. Adult flies with silenced Nup160 lacked nephrocytes entirely and lived dramatically shorter lifespans.

Significantly, the dramatic structural and functional defects caused by silencing of fly Nup160 gene in nephrocytes could be completely rescued by expressing the wild-type human NUP160 gene, but not by expressing the human NUP160 gene carrying the E803K or R1173X mutation identified from the girl’s  family.

“This study identified new genetic mutations that could lead to steroid-resistant nephrotic syndrome,” Han notes. “In addition, it demonstrates a highly efficient Drosophila-based disease variant functional study system. We call it the ‘Gene Replacement’ system since it replaces a fly gene with a human gene. By comparing the function of the wild-type human gene versus mutant alleles from patients, we could determine exactly how a specific mutation affects the function of a human gene in the context of relevant tissues or cell types. Because of the low cost and high efficiency of the Drosophila system, we can quickly provide much-needed functional data for novel disease-causing genetic variants using this approach.”

In addition to Han, Children’s co-authors include Co-Lead Author Feng Zhao, Co-Lead Author Jun-yi Zhu, Adam Richman, Yulong Fu and Wen Huang, all of the Center for Genetic Medicine Research; Nan Chen and Xiaoxia Pan, Shanghai Jiaotong University School of Medicine; and Cuili Yi, Xiaohua Ding, Si Wang, Ping Wang, Xiaojing Nie, Jun Huang, Yonghui Yang and Zihua Yu, all of Fuzhou Dongfang Hospital.

Financial support for research described in this post was provided by the Nature Science Foundation of Fujian Province of China, under grant 2015J01407; National Nature Science Foundation of China, under grant 81270766; Key Project of Social Development of Fujian Province of China, under grant 2013Y0072; and the National Institutes of Health, under grants DK098410 and HL134940.