It took Richard Nelson 23 years to find the cause of the rare genetic kidney disease that had affected his father, himself, and three of his five siblings. For years his physicians at the Mayo Clinic thought he was experiencing polycystic kidney disease. But 7 years ago, they realized that a different rare genetic kidney disease called mucin-1 (MUC-1) kidney disease was likely to blame and referred him to a team of clinicians and researchers from the Broad Institute in Cambridge, MA, and Wake Forest University School of Medicine in Winston-Salem, NC.
Nelson's journey is typical of what many patients and families with rare genetic forms of kidney diseases face as they seek answers and treatment. “There are hundreds of thousands of people in the world [who] are alone, desperate, and suffering who have no answers,” Nelson said.
But patient advocates, clinicians, and scientists across the country are leveraging rare kidney disease patient registries to help patients find answers faster and to accelerate the development of treatments for rare kidney diseases, including MUC-1 kidney disease and Dent disease.
Nelson and his family have joined more than 1000 families and 2000 people from all over the world participating in the Wake Forest Rare Inherited Kidney Disease registry (1). The registry has helped scientists identify five genes that cause rare, inherited, autosomal-dominant kidney diseases (2). The registry has also yielded new insights about the natural history of MUC-1 kidney disease and is laying the necessary groundwork for a clinical trial of an experimental treatment expected to begin within the next 2 years.
“It gives all of us a tremendous amount of hope because we can see incrementally how we are helping to move things forward,” said Nelson, who is chairman and trustee of the Rare Kidney Disease Foundation, an organization he helped found in 2018.
Anthony Bleyer, MD, MS, a professor at Wake Forest University School of Medicine and leader of its Rare Inherited Kidney Disease team, began hunting for genetic causes of rare, inherited kidney diseases in 1995 while treating a large North Carolina family who was referred to him for care for autosomal-dominant kidney disease and gout, which had affected multiple generations. In 2002, Bleyer and colleague Thomas Hart, DDS, PhD, identified genetic mutations in a gene encoding a protein called uromodulin (UMOD) that caused this inherited form of kidney disease (3). “We thought it was really rare,” Bleyer said. “There had been about 15 families described in the literature in the United States.”
Bleyer decided to build a patient registry to learn more about the condition and help patients and families with the condition. He and the team he assembled, including Associate Project Managers Victoria Robins, RN, a nurse, and Kendrah Kidd, MS, a research scientist who developed the database for the registry, sought referrals from academic centers and independent physicians and set up a website to help patients find the registry directly. The registry started with 5 to 10 families and has grown steadily since to include patients from around the world. Twenty-five percent of families in the registry found the Rare Inherited Kidney Disease team independently through an internet search (4). Patients and physicians may also email the team at kidney@wakehealth.edu.
Over time, they discovered that a subset of the families did not have a mutation in the UMOD gene. These families also did not have gout despite having a similar disease presentation with no proteinuria and bland urinary sediment. To identify a genetic cause, Bleyer teamed up with Eric Lander, PhD, founding director emeritus at the Broad Institute. Using DNA collected from the participants in the registry, in 2013, they identified a mutation hidden deep in the gene, encoding a protein, called MUC-1, as the cause (5).
In 2019, Anna Greka, MD, PhD, associate professor of medicine at Harvard Medical School and a member of the Broad Institute, and her colleagues helped explain how the mutation causes the disease (6). Greka showed that the MUC-1 gene mutation causes misshapen proteins to form and accumulate inside cells that line the tubules in the kidneys. The tubules are a vital part of the kidney's filtering units or nephrons. “It's like an accumulation of toxic trash that can never be removed,” she said. “Ultimately, the tubule cells die, which results in the nephron not being able to function anymore.”
Even though patients with MUC-1 kidney disease are born with this mutation, it can take decades for symptoms of the condition to appear, Greka said. She explained that 2 million nephrons in the kidney provide humans with more kidney-filtering capacity than they need to survive, which is why individuals can donate one kidney. But as misshapen proteins accumulate, a growing number of nephrons die. “If you have enough of those nephrons coming offline, eventually the kidney doesn't work,” she said.
But Greka also demonstrated—using kidney organoids grown from patients from the registry who agreed to participate in the study—that administering an experimental drug could clear the mangled proteins. The team has licensed this experimental treatment to a startup company working in stealth mode to bring it to the clinic. A clinical trial is expected to start sometime in the next 2 years, Greka said. In the meantime, she and her colleagues are working on better understanding the disease and searching for other potential treatments.
“Our job is to continue to dig deeper into the mechanism and understand it further because that may give us a handle on another therapy,” she said. Patients continue to be critical partners in the work. Greka said she and her colleagues frequently host patients in the laboratory, and the visits help patients understand the research process and help inspire the researchers to continue to dig.
Bleyer, Greka, and their collaborators now have a longitudinal study underway that collects and analyzes serum creatinine from participating patients every 4 months. The study will provide vital information about the natural history of the disease and help lay the groundwork for future clinical trials. Greka explained that the study would help identify biomarkers that can be used in the trial to determine if the drug is working. “The registry is of enormous value in being able to advance our discoveries in the clinic and hopefully make meaningful therapies for patients,” Greka said.
Already, the registry is yielding insights that are helping answer key questions for patients. For example, data from the registry showed that women with autosomal-dominant tubulointerstitial kidney diseases are less likely to have hypertension during pregnancy than women with other forms of kidney diseases and have good maternal and fetal outcomes (7).
Breaking down silos
A new collaboration between the Dent Disease Foundation and RareX is underway to grow a new registry for Dent disease (8). This rare, inherited kidney disease causes kidney stones, proteinuria, and chronic kidney disease. RareX is the research arm of a nonprofit organization called Global Genes that works to provide information and resources for individuals affected by rare diseases (9).
The RareX registry platform is already home to disease registries, including approximately 2200 patients, primarily individuals with rare, neurodevelopmental disorders. The platform is now expanding into kidney diseases to bring together registry data on many rare diseases in a consistent format that a range of scientists can use. Karmen Trzupek, BS, MS, senior director of scientific programs at Global Genes, explained that a single institution often operates rare disease registries with limited funding and infrastructure. Pharmaceutical companies may hold other data, she said. The data may not be in a standardized or structured format or easily accessible by others, which can limit the usefulness of the data to other researchers, Trzupek explained. “RareX breaks down those silos,” said Jill Goodrich, co-executive director of the Dent Disease Foundation.
RareX has built its platform with a consistent structure and format for all its registries. It creates standardized surveys for collecting “head-to-toe” data about symptoms and natural disease history. For example, some individuals with Dent disease also have intellectual disabilities or sleep difficulties. The RareX platform has symptom surveys usable across conditions. “By bringing together lots of rare disease communities, we can leverage some of the shared symptoms across diseases,” Trzupek said. Combining numerous rare diseases also ensures that resources are available even for conditions with fewer affected individuals or less interest from researchers or drug companies.
Enabling disease-agnostic research allows scientists to develop new insights into rare diseases and the symptoms they cause. For example, Goodrich noted that her father had Dent disease but died without a diagnosis because, at the time, his symptoms were not traditionally associated with the disease. But more recent discoveries have given scientists a more expansive view of the potential Dent disease symptoms, she said.
“Things that you wouldn't think were connected are now being connected,” Goodrich said. Those connections may help identify people who otherwise might go undiagnosed.
Bringing together larger groups of patients with rare diseases may also make the conditions more appealing to researchers or pharmaceutical companies, said Jennifer Meyer, RN, co-executive director of the Dent Disease Foundation. The RareX initiative is funded by philanthropies and through work commissioned by pharmaceutical companies to help assimilate data from disparate sets or identify potential trial participants, Trzupek said. But patient data are not sold. “Patients own their data and choose how [they are] used,” Trzupek said.
The Dent Disease Foundation has worked closely with researchers at the Wake Forest Institute for Regenerative Medicine and experts from the Mayo Clinic's Rare Kidney Stone Consortium Registry, which also houses a Dent disease registry (10).
There are currently 20 patients with Dent disease enrolled in the RareX registry. The Dent Disease Foundation is recruiting more patients to enroll through its website (8). Older studies suggest that approximately 250 families are affected by Dent disease worldwide, Meyer said. But she and Goodrich believe the number is much greater based on their networking with patients and Dent disease specialists at meetings such as ASN's Kidney Week. Goodrich explained that even within families affected by Dent disease, individuals may not understand the X-linked, recessive inheritance of Dent disease. So, they may not suspect other relatives' symptoms are caused by Dent disease. “RareX allows us to make the connections needed to administer relief to our community and hopefully find a cure,” Goodrich said.
“Tip of the iceberg”
The patients currently enrolled in the Wake Forest registry likely represent just the “tip of the iceberg” of patients with rare, inherited kidney diseases affecting the tubules, Greka said. She said many patients likely do not know they have the disease. Bleyer estimated that 1% of patients with kidney failure have a UMOD mutation, and a similar number have MUC-1 mutations. Based on the registry data, Bleyer estimated that there are 28,000 patients in the United States with MUC-1 kidney diseases and another 28,000 with kidney diseases caused by UMOD mutations.
Bleyer and Greka urged clinicians and patients to seek genetic testing for patients with unexplained kidney diseases, particularly if there is a family history. Greka suggested that physicians and patients should also pursue testing in cases with bland urinary sediment without proteinuria, even in people without a family history or in individuals with prevalent conditions such as diabetes or obesity that may increase the risk of kidney diseases. “With rapidly expanding access to genetic testing in the United States, we should all be thinking about the genetic underpinnings of diseases in our patients and sending them for those tests,” she said.
Genetic testing for 120 genetic kidney diseases, including UMOD, is widely available through commercial laboratories, Greka said. The Broad Institute offers free genetic testing for the MUC-1 mutation for individuals with a family history of kidney diseases and a bland urinary sediment because traditional genetic testing does not capture this mutation. Greka said she and her colleagues are also developing ways to make the testing more widely available.
There is also a great need to grow the registries. Nelson noted that participants regularly receive email updates through the registry, keeping them abreast of the latest developments and giving them opportunities to participate in research. Growing the registries may also increase the likelihood of successful clinical trials that lead to new treatments and provide more insight about the diseases, Greka said. Nelson added that finding and recruiting more families and inviting them to participate are key objectives of the foundation. “We are focused on building this community and finding more [families],” Nelson said. “By throwing in together, we can absolutely affect the outcome and support progress.”
References
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Atrium Health. Wake Forest Baptist. Inherited kidney disease. https://www.wakehealth.edu/condition/i/inherited-kidney-disease
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Devuyst O, et al. Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers 2019; 5:60. doi: 10.1038/s41572-019-0109-9
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Hart TC, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002; 39:882–892. doi: 10.1136/jmg.39.12.882
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Bleyer AJ, et al. Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases. Genet Med 2020; 22:142–149. doi: 10.1038/s41436-019-0617-8
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Kirby A, et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 2013; 45:299–303. doi: 10.1038/ng.2543
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Dvela-Levitt M, et al. Small molecule targets TMED9 and promotes lysosomal degradation to reverse proteinopathy. Cell 2019; 178:521–535.e23. doi: 10.1016/j.cell.2019.07.002
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Bleyer AJ, et al. Maternal health and pregnancy outcomes in autosomal dominant tubulointerstitial kidney disease. Obstet Med, October 19, 2022. https://journals.sagepub.com/doi/10.1177/1753495X221133150
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RareX. Dent disease—data collection program. Accessed April 10, 2023. https://dentdisease.rare-x.org/
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Rare Kidney Stone Consortium. Dent disease. Accessed April 10, 2023. https://www.rarekidneystones.org/dent/
