autosomal recessive polycystic kidney disease Archives

$6M gift powers new PKD clinical and research activities

November 14, 2019

PKD is a genetic disorder characterized by clusters of fluid-filled sacs (cysts) multiplying and interfering with the kidneys’ ability to filter waste from the blood.

When Lisa M. Guay-Woodford, M.D., McGehee Joyce Professor of Pediatrics at Children’s National Hospital, considers a brand-new gift, she likens it to 6 million gallons of “rocket fuel” that will power new research to better understand polycystic kidney disease.

Dr. Guay-Woodford received a $5.7 million dollar gift to support PKD clinical and research activities. PKD is a genetic disorder characterized by clusters of fluid-filled sacs (cysts) multiplying and interfering with the kidneys’ ability to filter waste from the blood. The kidneys’ smooth surface transforms to a bumpy texture as the essential organs grow oversized and riddled with cysts.

The extraordinary generosity got its start in an ordinary clinical visit.

Dr. Guay-Woodford saw a young patient in her clinic at Children’s National a few times in 2015. The child’s diagnosis sparked a voyage of discovery for the patient’s extended family and, ultimately, they attended a presentation she gave during a regional meeting about PKD. That led to a telephone conversation and in-person meeting as they invited her to describe “the white space” between what was being done at the time to better understand PKD and what could be done.

“It’s the power of the art and science of medicine. They come to see people like me because of the science. If we can convey to patients and families that who they are and their unique concerns are really important to researchers, that becomes a powerful connection,” she says. “The art plus the science equals hope. That is what these families are looking for: We give people the latest insights about their disease because information is power.”

The infusion of new funding will strengthen the global initiative’s four pillars:

Coordinated care for children and families impacted by renal cystic disease. The Inherited and Polycystic Kidney Disease (IPKD) program, launched September 2019, includes a cadre of experts working together as a team in the medical home so that “in a single, one-stop visit, Children’s National can address the myriad concerns they have,” she explains. A multi-disciplinary team that includes nephrologists, hepatologists and endocrinology experts meets weekly to ensure the Center of Excellence provides the highest-caliber patient care. The team includes genetic counselors to empower families with knowledge about genetic risks and testing opportunities. A nurse helps families navigate the maze of who to call about which issue. Psychologists help to ease anxiety. “There is stress. There is fear. There is pain that can be associated with this set of diseases. The good news is we can control their medical issues. The bad news is some children have difficulty coping. Our psychologists help children cope so they can be a child and do the normal things that children do,” she says.
Strengthening global databases to capture PKD variations. The team will expand its outreach to other centers located around the world – including Australia, Europe, India and Latin America – caring for patients with both the recessive and dominant forms of polycystic kidney disease, to better understand the variety of ways the disease can manifest in children. “We really don’t know a lot about kids with the dominant form of the disease. How hard should we push to control their blood pressure, knowing that could ease symptoms? What are the ramifications of experiencing acute pain compared with chronic pain? How much do these pain flareups interfere with daily life and a child’s sense of self,” she asks. Capturing the nuances of the worldwide experience offers the power of harnessing even more data. And ensuring that teams collect data in a consistent way means each group would have the potential to extract the most useful information from database queries.
Filling a ‘desperate need’ for biomarkers. Developing clinical trials for new therapies requires having biomarkers that indicate the disease course. Such biomarkers have been instrumental in personalizing care for patients with other chronic conditions. “We are in desperate need for such biomarkers, and this new funding will underwrite pilot studies to identify and validate these disease markers. The first bite at the apple will leverage our imaging data to identify promising biomarkers,” she says.
Genetic mechanisms that trigger kidney disease. About 500,000 people in the U.S. have PKD. In many cases, children inherit a genetic mutation but, often, their genetic mutation develops spontaneously. Dr. Guay-Woodford’s research about the mechanisms that make certain inherited renal disorders lethal, such as autosomal recessive polycystic kidney disease, is recognized around the world. The fourth pillar of the new project provides funding to continue her lab’s research efforts to improve the mechanistic understanding of what triggers PKD.

Serving patients with polycystic kidney disease

January 14, 2019

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.”

Internationally renowned pediatric nephrologist named to NIH advisory council

January 4, 2018

Lisa M. Guay-Woodford, M.D

Pediatric nephrologist Lisa M. Guay-Woodford, M.D., has been named to a three-year term as adviser serving on the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Kidney, Urologic and Hematologic Diseases subcouncil.

Dr. Guay-Woodford, Director of the Center for Translational Science at Children’s National, is an internationally recognized expert in the mechanisms that modulate the clinical severity of certain inherited renal disorders, such as autosomal recessive polycystic kidney disease. She holds the Richard L. and Agnes F. Hudson Professorship in Health Services Research at Children’s National.

NIDDK, like other grant-awarding institutes within the National Institutes of Health (NIH), looks to its advisory councils for feedback on procedures that govern staff and manage its grant portfolios. The institute, the fifth largest at the NIH, supports clinical research about internal medicine and related subspecialties for many of the most common chronic health conditions.

“It is a tremendous honor to be asked to serve on this important council. I look forward to providing advice and perspective on the exciting portfolio of NIDDK-funded projects,” Dr. Guay-Woodford says.

Lisa Guay-Woodford: minimizing kidney disease effects

February 16, 2017

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.

The artist chose tempera paint for her oeuvre. The flower’s petals are the color of Snow White’s buddy, the Bluebird of Happiness. Each petal is accentuated in stop light red, and the blossom’s leaves stretch up toward the sun. With its bold strokes and exuberant colors, the painting exudes life itself.

It’s the first thing Lisa M. Guay-Woodford, M.D., sees when she enters her office. It’s the last thing she sees as she leaves.

Dr. Guay-Woodford, a pediatric nephrologist, is internationally recognized for her research into the mechanisms that make certain inherited renal disorders, such as autosomal recessive polycystic kidney disease (ARPKD), particularly lethal. She also studies disparate health disorders that have a common link: Disruption to the cilia, slim hair-like structures that protrude from almost every cell in the human body and that play pivotal roles in human genetic disease.

Sarah, the artist who painted the bright blue flower more than 20 years ago when she was 8, was one of Dr. Guay-Woodford’s patients. And she’s part of the reason why Dr. Guay-Woodford has spent much of her career focused on the broader domain of disorders tied to just a single defective gene, such as ARPKD.

“It dates back to when I was a house officer and took care of kids with this disorder,” Dr. Guay-Woodford says. “Maybe 30 percent die in the newborn period. Others survive, but they have a whole range of complications.”

Two of her favorite patients died from ARPKD-related reasons in the same year. One died from uncontrolled high blood pressure. The other, Sarah, died from complications from a combined kidney and liver transplant.

“The picture she drew hangs in my office,” she says. “She was a wonderful kid who was really full of life, and what she chose really mirrored who she was as a person. We put up lots of those sorts of those things in my office. It’s a daily reminder of why we do the things we do and the end goal.”

ARPKD is characterized by the growth of cysts in the liver, the kidney – which can lead to kidney failure – and complications within other structures, such as blood vessels in the heart and brain, according to the National Institutes of Health. About 1 in 20,000 live births is complicated by the genetic disorder. The age at which symptoms arise varies.

“Given the way it plays out, starting in utero, this is not a disease we are likely to cure,” she says. “But there are children who have very minimal complications. The near-term goal is to use targeted therapies to convert the children destined to have a more severe disease course to one that is less complicated so that no child suffers the full effects of the disease.”

That’s why it is essential to attain detailed knowledge about the defective gene responsible for ARPKD. To that end, Dr. Guay-Woodford participated in an international collaboration – one of three separate groups that 14 years ago identified PKHD1 as the defective gene that underlies ARPKD.

“The progress has been slow, partly because the gene and its protein products are very complex,” she says. “The good news is the gene has been identified. The daunting news is the identification did not leap us forward. It is just sort of an important step in what is going to be a fits-and-starts kind of journey.”

The field is trying to emulate the clinical successes that have occurred for patients with cystic fibrosis, which now can be treated by a drug that targets the defective gene, attacking disease at a fundamental level. Patient outcomes also have improved due to codifying care.

When she was a resident in the 1980s, children with cystic fibrosis died in their teens. “Now, they’re living well into their 40s because of careful efforts by really astute clinicians to deliver a standardized approach to care, an approach now enhanced by a terrific new drug. We measure quality care in terms of patient outcomes. That has allowed us to really understand how to effectively use antibiotics, physical therapy and how to think about nutrition – which makes a hugely important contribution that previously had been underappreciated.”

Standardizing clinical approaches dramatically improved and extended patients’ lives. “For renal cystic disease, we are beginning to do that better and better,” she adds.

There’s no targeted medicine yet for ARPKD. But thanks to an international conference that Dr. Guay-Woodford convened in Washington in 2013, such consensus expert recommendations have been published to guide diagnosis, surveillance and management of pediatric patients with ARPKD.

“There is an awful lot we can do in the way we systematically look at the clinical disease in these patients and improve our management. And, if you can overlay on top of that specific insights about why one person goes one way in disease progression versus another way, I think we can boost the baseline by developing good standards of care,” she says.

“Science does march on. There are a number of related research studies that are expanding our understanding of ARPKD. Within the next decade, we probably will be able to capitalize on not just the work in ARPKD but work in related diseases to learn the entry points for targeting therapies. That way, we can build a portfolio of markers of disease progression and test how effective these potential therapies are in slowing the course of the disease.”

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