Tag Archive for: kidney disease

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.

Lisa M. Guay-Woodford, M.D

Serving patients with polycystic kidney disease

Lisa M. Guay-Woodford, M.D

Lisa M. Guay-Woodford, M.D., is internationally recognized for her examination of the mechanisms that make certain inherited renal disorders particularly lethal, a research focus inspired by her patients.

When Children’s National pediatric nephrologist Lisa Guay-Woodford, M.D., was an intern at Boston Children’s Hospital, a baby with autosomal recessive polycystic kidney disease (ARPKD) was admitted to one of the hospital’s neonatal intensive care units (NICU). This disease, which causes cysts to form in the kidney and liver, kills about one-fifth of babies within the newborn period due to related problems that affect lung development.

But this baby seemed like a survivor, Dr. Guay-Woodford remembers. The child passed the newborn period and graduated from the NICU, although she went home with severe blood pressure issues. Along with a team of colleagues, Dr. Guay-Woodford helped to manage this patient’s care, juggling normal infant concerns with her ARPKD.

As far as Dr. Guay-Woodford knew at the time, this baby was beating the odds against her, growing and thriving. But one day near the end of her internship period, Dr. Guay-Woodford was called to the emergency department. Her patient was in a hypertensive crisis that ultimately killed her.

“It was absolutely devastating to all of us. This was supposed to be a good news kind of story, that she survived the newborn period and had gone home and was growing and developing,” Dr. Guay-Woodford says. “I realized then that a big part of the tragedy of this disease is how little we knew about it.”

Dr. Guay-Woodford vowed to change that. Since then, she’s devoted her career to studying ARPKD and other inherited kidney diseases.

After finishing her residency and fellowship in Boston, Dr. Guay-Woodford was recruited to the University of Alabama, where she began caring for a cadre of 40 patients with inherited renal disorders. Fueled by the research questions that arose while working with these patients, she and her colleagues searched for PKD-related genes in the cpk mouse model, an animal that mimics many of the features of human ARPKD.

Dr. Guay-Woodford and her team cloned several of the key genes that caused recessive PKD in this mouse and other mouse models and eventually went on to identify the first major genetic modifier of PKD in these animals – a gene that wasn’t directly responsible for the disease but could sway its course. In time, her collaborative group became one of two that co-indentified the major gene responsible for human ARPKD. In 2005, Dr. Guay-Woodford led a team of investigators at the University of Alabama-Birmingham to establish one of just four PKD translational core centers funded by a National Institutes of Health P30 grant.

After moving to Children’s National in 2012, Dr. Guay-Woodford still co-directs this PKD translational core center while also caring for patients at her inherited renal disorders clinic. She and her colleagues here and beyond continue to work with mouse models of this disease, trying to ferret out the vast network of genes that interact in ARPKD and their specific roles.

“You can use a variety of strategies to compare these patients’ gene portfolios with those of healthy patients and pick out the disease genes. But at the end of the day, to me, that’s just the opening chapter,” she says. “To really make a story, you’ve got to understand what is it that gene does, what protein it makes, and how that protein works together with others involved in this disease.”

She and her team also are currently working with a pharmaceutical company to develop the first clinical trial to test a treatment for ARPKD. This effort has relied heavily on a clinical database that Dr. Guay-Woodford and colleagues worldwide maintain to track patients with this and related conditions. Through the extensive collection of clinical information in this database – including a variety of data on patients’ gestation and birth, growth, and kidney structure and function – the team has identified a core cohort of patients whose disease is rapidly progressing, a characteristic that makes them prime candidates to test this potential new treatment.

“Everything I do in the clinic informs the work I do in the lab, and everything I do in the lab is to help the patients I see in the clinic. It’s this constant dance back and forth between our human patients and animal models,” she says. “One day, this dance will help lessen the burden of this disease for these kids and their families.”

pill bottles and pills

Enhancing pediatric nephrology clinical trial development

Fewer than 50 percent of pharmaceuticals approved by federal authorities are explicitly approved for use in kids, and even fewer devices are labeled for pediatric use.

When children develop kidney disease, it can play out in dramatically different ways. They can experience relatively mild disorders that respond to existing treatments and only impact their lives for the short term. Children also can develop chronic kidney disease that defies current treatments and can imperil or end their lives.

Fewer than 50 percent of pharmaceuticals approved by federal authorities are explicitly approved for use in kids, and even fewer devices are labeled for pediatric use. Congress has offered incentives to manufacturers who study their treatments in children, but the laws do not require drug makers to demonstrate statistical significance or for the clinical trial to improve or extend children’s lives.

To overcome such daunting obstacles, the American Society of Pediatric Nephrology established a Therapeutics Development Committee to forge more effective public-private partnerships and to outline strategies to design and carry out pediatric nephrology clinical trials more expeditiously and effectively.

“We have seen how other pediatric subspecialties, such as cancer and arthritis, have leveraged similar consortia to address mutual concerns and to facilitate development of new therapeutics specific to those diseases,” says Marva Moxey-Mims, M.D., chief of the Division of Nephrology at Children’s National Health System and a founding committee member. “As a group, we aim to collectively identify and remedy the most pressing needs in pediatric nephrology. As just one example, the committee could help to increase the number of sites that host research studies, could expand the pool of potential study volunteers and could lower the chances of duplicating efforts.”

A paper summarizing their efforts thus far, “Enhancing clinical trial development for pediatric kidney diseases,” written by Dr. Moxey-Mims and 15 co-authors, was published online Aug. 30 by Pediatric Research. The journal’s editors will feature the review article in the “Editor’s Focus” of an upcoming print edition of the publication.

The committee is comprised of academic pediatric nephrologists, patient advocates, private pharmaceutical company representatives and public employees at the Food and Drug Administration and the National Institutes of Health. But it is likely to grow in size and in stakeholder diversity.

Already, committee members have learned that they achieve better results by working together. Early communication can avoid flaws in designing clinical trials, such as overestimating the volume of clinical samples that can feasibly be collected from a small child, or that could misinterpret the type of data needed to secure federal approval.

While public and private investigators took similar approaches to clinical trial design, academic investigators were more conceptual as they summarized their study design Road Map. Industry representatives, by contrast, included more granular detail about study organization and milestones along the path toward regulatory approval.

According to the study authors, both groups understand the critical role that patients and families can play in early research study design, such as accelerating patient recruitment, bolstering the credibility of research and helping to translate research results into actual clinical practice.

“We are pleased to have created a forum that allows participants to share valuable viewpoints and concerns and to understand how regulations and laws could be changed to facilitate development of effective medicines for children with kidney disease,” says Dr. Moxey-Mims. “We hope the relationships and trust forged through these conversations help to speed the development and approval of the next generation of therapies for pediatric renal disease.”

A close-up of Dr. Marva Moxey Mims at Children's National.

Children’s National welcomes Marva Moxey-Mims, M.D., renowned nephrologist, as incoming Division Chief

A close-up of Dr. Marva Moxey Mims at Children's National.

Marva Moxey-Mims, M.D., a leading expert in chronic kidney disease and glomerular disease who has conceptualized and overseen multicenter clinical studies aimed at improving chronic kidney disease treatment, has been named Chief of Pediatric Nephrology at Children’s National Health System.

Dr. Moxey-Mims comes to Children’s National from the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health where she served as Deputy Director for clinical science and oversaw a research portfolio that included clinical trials for kidney disease and genitourinary dysfunction in adults and children. As Pediatric Nephrology Division Chief, Dr. Moxey-Mims plans to add new staff and restructure a division already ranked among the nation’s leaders by U.S. News & World Report in order to carve out dedicated time for research and improve care for children with kidney disease.

”Children’s National is honored to welcome Dr. Moxey-Mims as the new leader for our talented nephrology team,” says Robin Steinhorn, M.D., senior vice president of the Center for Hospital-Based Specialties. “She brings unparalleled expertise in this field, is a member of a number of influential national committees and has authored more than 90 scientific publications, including peer-reviewed articles and book chapters. Under her guidance, Pediatric Nephrology at Children’s is well-positioned to continue to lead the nation in clinical care and research.”

“I want to inspire the division,” Dr. Moxey-Mims says. “I want the faculty to be happy in their work here and to look forward to coming to work every day. I want them to have enough time to pursue their academic interests, so clinicians not only continue to provide excellent patient care but also can conduct research. All of the staff has potential projects in mind; it’s just a matter of finding the time to do them.”

From a pragmatic standpoint, Children’s pediatric nephrologists will start with what is feasible: Continuing and expanding current cross-disciplinary research projects.

“There are some research projects that will be important to pursue, but we just don’t have the building blocks in place right now to move in that specific direction,” Dr. Moxey-Mims says. “However, continuing ongoing collaborations with our colleagues in neonatologyoncologyhematology and urology are reasonable places to start. I agree with the cliché that success breeds success. If we have an established collaboration and can build on it, that is how we start expanding our research enterprise.”

To that end, the division is in the early stage of joining an existing consortium that is studying four types of glomerular disease, conditions caused by varying mechanisms that often lead to kidney failure. “Information that is gathered will inform care going forward,” she says. “Part of what is being done in these studies is obtaining a better understanding of how disease progresses in different groups of children and adults and quantifying the impact of varying treatment approaches. It’s very exciting for Children’s National to be a new player in this.”

Dr. Moxey-Mims received her undergraduate degree from McGill University in Montreal and her medical degree from Howard University in Washington, D.C. She completed her pediatric residency and clinical pediatric nephrology training at Children’s National and from 1994 to 1999 worked at Children’s National as a staff nephrologist.

“Returning to Children’s has been a wonderful homecoming,” Dr. Moxey-Mims says. “I wanted to return to the hospital setting and have direct exposure to patients. I missed that. In this new role, I can participate in patient care, as well as foster an environment that spurs even more research. It’s really the best of both worlds.”

cancer-patient-Sully-Shields

New approach improves pediatric kidney cancer outcomes

cancer-patient-Sully-Shields

Wilms tumor, also known as nephroblastoma, is the most common pediatric kidney cancer, typically seen in children ages three to four. Compared to patients with unilateral Wilms tumors, children with bilateral Wilms tumors (BWT) have poorer event-free survival (EFS) and are at higher risk for later effects such as renal failure. The treatment of BWT is challenging because it involves surgical removal of the cancer, while preserving as much healthy kidney tissue as possible to avoid the need for an organ transplant.

A new Children’s Oncology Group (COG) study published in the September issue of the Annals of Surgery demonstrated an exciting new approach to treating children diagnosed with BWT that significantly improved EFS and overall survival (OS) rates after four years when compared to historical rates. Jeffrey Dome, M.D., Ph.D., Vice President of the Center for Cancer and Blood Disorders at Children’s National Health System, was co-senior author of this first-ever, multi-institutional prospective study of children with BWT.

Historically, patients with BWT have had poor outcomes, especially if they have tumors with unfavorable histology. In this study, Dr. Dome and 18 other clinical researchers followed a new treatment approach consisting of three chemotherapy drugs before surgery rather than the standard two drug regimen, surgical removal of cancerous tissue within 12 weeks of diagnosis, and postoperative chemotherapy that was adjusted based on histology.

The study found that preoperative chemotherapy expedited surgical treatment, with 84 percent of patients having surgery within 12 weeks of diagnosis. The new treatment approach also vastly improved EFS and OS rates for patients participating in the study. The four-year EFS rate was 82.1 percent, compared to 56 percent on the predecessor National Wilms Tumor Study-5 (NWTS-5) study. The four-year OS rate was 94.9 percent, compared to 80.8 percent on NWTS-5.

“I am very encouraged by these results, which I believe will serve as a benchmark for future studies and lead to additional treatment improvements, giving more children the chance to overcome this diagnosis while sparing kidney tissue,” says Dr. Dome.

A total of 189 patients at children’s hospitals, universities and cancer centers in the United States and Canada participated in this study. These patients will continue to be followed for 10 years to track kidney failure rates. This study was funded by grants from the National Institutes of Health to the Children’s Oncology Group.

Patricio Ray

Toward a better definition for AKI in newborns

Patricio Ray

The National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting of expert neonatologists and pediatric nephrologists, including Dr. Patricio Ray, to review state-of-the-art knowledge about acute kidney injury in neonates and to evaluate the best method to assess these patients’ kidney function.

Each year, thousands of infants in the United States end up in neonatal intensive care units (NICUs) with acute kidney injury (AKI), a condition in which the kidneys falter in performing the critical role of filtering waste products and excess fluid from the blood to produce urine. Being able to identify neonates during the early stages of AKI is critical to doctors and clinician-scientists who treat and study this condition, explains Patricio Ray, M.D., a nephrologist at Children’s National Health System.

Without an accurate definition and early identification of newborns with AKI, it is difficult for doctors to limit the use of antibiotics or other medications that can be harmful to the kidneys. Neonates who have AKI should not receive large volumes of fluids, a treatment that can cause severe complications when the kidneys do not properly function.

Until recently, there was no standard definition for AKI, leaving doctors and researchers to develop their own guidelines. Lacking set criteria led to confusion, Dr. Ray says. For example, different studies estimating the percentage of infants in NICUs with AKI ranged from 8 percent to 40 percent, depending on which definition was used. In 2012, a group known as the Kidney Disease Improved Global Outcome (KDIGO) issued practice guidelines for AKI that provide a standard for doctors and researchers to follow. They focus largely on measuring the relative levels of serum creatinine, a protein produced by muscles that is filtered by the kidneys, and the amount of urine output, which typically declines in adults and older children with failing kidneys.

The problem with these guidelines, Dr. Ray explains, is they are not sensitive enough to identify newborns experiencing the early stages of AKI during the first week of life. Newborns can have high serum creatinine levels during the first week of life due to residual levels transferred from mothers through the placenta. Also, because their kidneys are immature, failure often can mean higher – not diminished – urine production.

In 2013, the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, convened a meeting of leading neonatologists and pediatric nephrologists – including Dr. Ray – to review state-of-the-art knowledge about AKI in neonates and to evaluate the best manner to assess kidney function in these patients. They published a summary of their discussion online June 12, 2017 in Pediatric Research.

Among other findings, the group concluded that the current definition of AKI lacks the sensitivity needed to identify the early stages of AKI in neonates’ first week of life. They also said that more research was needed to fill this gap.

That’s where Dr. Ray’s current research comes in. Working with fellow Children’s Nephrologist Charu Gupta, M.D., and Children’s Neonatologist An Massaro, M.D., the three clinician-scientists reviewed the medical records of 106 infants born at term with a condition known as hypoxic ischemic encephalopathy (HIE), in which the brain doesn’t receive enough oxygen. Not only does this often lead to brain injury, but it also greatly increases the risk of AKI.

Because these babies had been followed closely in the NICU to assess the possibility of AKI, their serum creatinine had been checked frequently. The researchers found that about 69 percent of the infants with HIE followed at Children’s National never developed signs of kidney failure during their first week of life. These babies’ serum creatinine concentrations dropped by 50 percent or more by the time they were 1 week old, about the same as reported previously in healthy neonates. Another 12 percent of the infants with HIE developed AKI according to the definition established by the KDIGO group in 2012. These infants:

  • Required more days of mechanical ventilation and medications to increase their blood pressure
  • Had higher levels of antibiotics in their bloodstreams
  • Retained more fluid
  • Had lower urinary levels of a molecule that their kidneys should have been cleared and
  • Had to stay in the hospital longer

A third group of the infants with HIE, about 19 percent, did not meet the standard criteria for AKI. However, these babies had a rate of decline of serum creatinine that was significantly slower than the normal newborns and the infants with HIE who had excellent outcomes. Rather, their outcomes matched those of infants with established AKI.

Dr. Ray notes that by following the rate of serum creatinine decline during the first week of life physicians could identify neonates with impaired kidney function. This approach provides a more sensitive method to identify the early stages of AKI in neonates. “By looking at how fast babies were clearing their serum creatinine compared with the day they were born, we could predict how well their kidneys were working,” he says. Dr. Ray and colleagues published these findings July 2016 in Pediatric Nephrology.

He adds that further studies will be necessary to confirm the utility of this new approach to assess the renal function of term newborns with other diseases and preterm neonates. Eventually, he hopes this new approach will become uniform clinical practice.

Coenzyme Q10

Supplement might help kidney disease

Coenzyme Q10

A research team was able to “rescue” phenotypes caused by silencing the fly CoQ2 gene by providing nephrocytes with a normal human CoQ2 gene, as well as by providing flies with Q10, a popular supplement.

A new study led by Children’s National research scientists shows that coenzyme Q10 (CoQ10), a popular over-the-counter supplement sold for pennies a dose, could alleviate genetic problems that affect kidney function. The work, done in genetically modified fruit flies — a common model for human genetic diseases since people and fruit flies share a majority of genes — could give hope to human patients with problems in the same genetic pathway.

The new study, published April 20 by Journal of the American Society of Nephrology, focuses on genes the fly uses to create CoQ10.

“Transgenic Drosophila that carry mutations in this critical pathway are a clinically relevant model to shed light on the genetic mutations that underlie severe kidney disease in humans, and they could be instrumental for testing novel therapies for rare diseases, such as focal segmental glomerulosclerosis (FSGS), that currently lack treatment options,” says Zhe Han, Ph.D., principal investigator and associate professor in the Center for Cancer & Immunology Research at Children’s National and senior study author.

Nephrotic syndrome (NS) is a cluster of symptoms that signal kidney damage, including excess protein in the urine, low protein levels in blood, swelling and elevated cholesterol. The version of NS that is resistant to steroids is a major cause of end stage renal disease. Of the more than 40 genes that cause genetic kidney disease, the research team concentrated on mutations in genes involved in the biosynthesis of CoQ10, an important antioxidant that protects the cell against damage from reactive oxygen.

Drosophila pericardial nephrocytes perform renal cell functions including filtering of hemolymph (the fly’s version of blood), recycling of low molecular weight proteins and sequestration of filtered toxins. Nephrocytes closely resemble, in structure and function, the podocytes of the human kidney.  The research team tailor-made a Drosophila model to perform the first systematic in vivo study to assess the roles of CoQ10 pathway genes in renal cell health and kidney function.

One by one, they silenced the function of all CoQ genes in nephrocytes. If any individual gene’s function was silenced, fruit flies died prematurely. But silencing three specific genes in the pathway associated with NS in humans – Coq2, Coq6 and Coq8 – resulted in abnormal localization of slit diaphragm structures, the most important of the kidney’s three filtration layers; collapse of membrane channel networks surrounding the cell; and increased numbers of abnormal mitochondria with deformed inner membrane structure.

Journal of the American Society of Nephrology September 2017 cover

The flies also experienced a nearly three-fold increase in levels of reactive oxygen, which the study authors say is a sufficient degree of oxidative stress to cause cellular injury and to impair function – especially to the mitochondrial inner membrane. Cells rely on properly functioning mitochondria, the cell’s powerhouse, to convert energy from food into a useful form. Impaired mitochondrial structure is linked to pathogenic kidney disease.

The research team was able to “rescue” phenotypes caused by silencing the fly CoQ2 gene by providing nephrocytes with a normal human CoQ2 gene, as well as by providing flies with Q10, a readily available dietary supplement. Conversely, a mutant human CoQ2 gene from an patient with FSGS failed to rescue, providing evidence in support of that particular CoQ2 gene mutation causing the FSGS. The finding also indicated that the patient could benefit from Q10 supplementation.

“This represents a benchmark for precision medicine,” Han adds. “Our gene-replacement approach silenced the fly homolog in the tissue of interest – here, the kidney cells – and provided a human gene to supply the silenced function. When we use a human gene carrying a mutation from a patient for this assay, we can discover precisely how a specific mutation – in many cases only a single amino acid change – might lead to severe disease. We can then use this personalized fly model, carrying a patient-derived mutation, to perform drug testing and screening to find and test potential treatments. This is how I envision using the fruit fly to facilitate precision medicine.”

Related resources:
News release: Drosophila effectively models human genes responsible for genetic kidney diseases
Video: Using the Drosophila model to learn more about disease in humans