kidney
Chipping Away at the Causes of Polycystic Kidney Disease
Posted on by Lawrence Tabak, D.D.S., Ph.D.
It’s often said that two is better than one. That’s true whether driving across the country, renovating a kitchen, or looking for a misplaced set of car keys. But a recent study shows this old saying also applies for modeling a kidney disease with two very complementary, cutting-edge technologies: an organoid, a living miniaturized organ grown in a laboratory dish; and an “organ-on-a-chip,” silicon chips specially engineered to mimic the 3D tissue structure and basic biology of a human body organ.
Using this one-two approach at the lab bench, the researchers modeled in just a few weeks different aspects of the fluid-filled cysts that form in polycystic kidney disease (PKD), a common cause of kidney failure. This is impossible to do in real-time in humans for a variety of technical reasons.
These powerful technologies revealed that blood glucose plays a role in causing the cysts. They also showed the cysts form via a different biological mechanism than previously thought. These new leads, if confirmed, offer a whole new way of thinking about PKD cysts, and more exciting, how to prevent or slow the disease in millions of people worldwide.
These latest findings, published in the journal Nature Communications, come from Benjamin Freedman and colleagues at the University of Washington School of Medicine, Seattle [1]. While much is known about the genetic causes of PKD, Freedman and team realized there’s much still much to learn about the basics of how cysts form in the kidney’s tiny tubes, or tubules, that help to filter toxins out of the bloodstream.
Each human kidney has millions of tubules, and in people with PKD, some of them expand gradually and abnormally to form sacs of fluid that researchers liken to water balloons. These sacs, or cysts, crowd out healthy tissue, leading over time to reduced kidney function and, in some instances, complete kidney failure.
To understand cyst formation better, Freedman’s team and others have invented methods to grow human kidney organoids, complete with a system of internal tubules. Impressively, organoids made from cells carrying mutations known to cause PKD develop cysts, just as people with these same mutations do. When suspended in fluid, the organoids also develop telltale signs of PKD even more dramatically, showing they are sensitive to changes in their environments.
At any given moment, about a quarter of all the fluids in the body pass through the kidneys, and this constant flow was missing from the organoid. That’s when Freedman and colleagues turned to their other modeling tool: a kidney-on-a-chip.
These more complex 3D models, containing living kidney cells, aim to mimic more fully the kidney and its environment. They also contain a network of microfluidic channels to replicate the natural flow of fluids in a living kidney. Combining PKD organoids with kidney-on-a-chip technology provided the best of both worlds.
Their studies found that exposing PKD organoid-on-a-chip models to a solution including water, glucose, amino acids, and other nutrients caused cysts to expand more quickly than they otherwise would. However, the cysts don’t develop from fluids that the kidneys outwardly secrete, as long thought. The new findings reveal just the opposite. The PKD cysts arise and grow as the kidney tissue works to retain most of the fluids that constantly pass through them.
They also found out why: the cysts were absorbing glucose and taking in water from the fluid passing over them, causing the cysts to expand. Although scientists had known that kidneys absorb glucose, they’d never connected this process to the formation of cysts in PKD.
In further studies, the scientists gave fluorescently labeled glucose to mice with PKD and could see that kidney cysts in the animals also took up glucose. The researchers think that the tubules are taking in fluid in the mice just as they do in the organoids.
Understanding the mechanisms of PKD can point to new ways to treat it. Indeed, the research team showed adding compounds that block the transport of glucose also prevented cyst growth. Freedman notes that glucose transport inhibitors (flozins), a class of oral drugs now used to treat diabetes, are in development for other types of kidney disease. He said the new findings suggest glucose transport inhibitors might have benefits for treating PKD, too.
There’s much more work to do. But the hope is that these new insights into PKD biology will lead to promising ways to prevent or treat this genetic condition that now threatens the lives of far too many loved ones in so many families.
This two-is-better-than-one approach is just an example of the ways in which NIH-supported efforts in tissue chips are evolving to better model human disease. That includes NIH’s National Center for Advancing Translational Science’s Tissue Chip for Drug Screening program, which is enabling promising new approaches to study human diseases affecting organ systems throughout the body.
Reference:
[1] Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease. Li SR, Gulieva RE, Helms L, Cruz NM, Vincent T, Fu H, Himmelfarb J, Freedman BS. Nat Commun. 2022 Dec 23;13(1):7918.
Links:
Polycystic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Your Kidneys & How They Work (NIDDK)
Freedman Lab (University of Washington, Seattle)
Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute
Finding the ‘Tipping Point’ to Permanent Kidney Damage
Posted on by Lawrence Tabak, D.D.S., Ph.D.
Healthy human kidneys filter more than 30 gallons of blood each day on average, efficiently removing extra fluid and harmful toxins from the body. If injured, the kidneys have a remarkable capacity for repair. And, yet, in more than one in seven U.S. adults, including disproportionately people with diabetes and hypertension, the daily wear and tear on these vital organs has passed a “tipping point” toward irreparable damage and the onset of chronic kidney disease (CKD) [1].
Defining this tipping point has been a major challenge for a variety of technical reasons. But in a study just published in the journal Science Translational Medicine, researchers have discovered a molecular switch involved in controlling the transition from normal tissue repair to incomplete, or permanent, damage [2]. The NIH-supported researchers also suggest a possible drug candidate to control this switch and slow the progression of CKD.
Also impressive is that the team broke through these longstanding technical problems without probing or testing a single person with CKD. They made their discovery using kidney organoids, or miniature human kidneys, that are grown in a lab dish and naturally model the repair process that takes place in our bodies.
The latest findings come from a team led by Ryuji Morizane, Massachusetts General Hospital and Harvard Medical School, Boston. The researchers recognized that earlier studies in animal models had identified processes involved in kidney injury and repair. But so far, there’s been limited success in translating those discoveries into clinical advances. That’s because many potential treatments that have appeared safe and effective in animal models have proven to be either damaging to the kidneys or ineffective when studied in humans.
To continue the search, the Morizane lab generated human kidney organoids from induced pluripotent stem cells (iPSCs) and other sources that include multiple essential renal tissue types. Using their tiny human kidneys, Morizane and colleagues, including first author Navin Gupta, sought the molecules responsible for the transition from complete to incomplete kidney repair.
The team repeatedly exposed kidney organoids to the cancer chemotherapy drug cisplatin, which can damage the kidneys as an unwanted side effect. Afterwards, examining single cells from the organoid, the researchers looked for underlying changes in gene activity associated with the transition from kidney repair to permanent kidney damage.
All told, their studies identified 159 genes in 29 different pathways that activate when kidneys fully repaired themselves. They found that many of those genes, including two called FANCD2 and RAD51, grew less active as kidney damage became irreversible. These genes encode proteins that are known to play a role in a process whereby cells repair broken strands of DNA.
Further study of stored biopsied kidney tissue from people with diabetic kidney disease, the most common cause of kidney failure, corroborated the organoid data tying a loss of FANCD2 activity to incomplete repair of kidney tissue. That’s encouraging because it suggests the new discoveries made in kidney organoids exposed to cisplatin may be relevant to people suffering from various forms of kidney injury.
One of the big advantages of organoid studies is the ability to rapidly screen for promising new drug candidates in the lab. And, indeed, the researchers found that a drug candidate called SCR7 helped to maintain FANCD2 and RAD51 activity in chemotherapy-injured organoids, preventing irreversible damage.
While much more study is needed, the findings suggest a potentially promising new way to prevent the kidneys from reaching their “tipping point” into permanent damage, CKD, and the risk for kidney failure. They also suggest that further studies in kidney organoids may lead to treatments targeting other kidney diseases.
These latest findings also highlight important progress in human tissue engineering, with implications for a wide range of conditions. In addition to making fundamental new biomedical discoveries as this new study has done, one of the great hopes of such efforts, including NIH’s National Center for Advancing Translational Sciences’ Tissue Chip for Drug Screening, is to improve predictions of whether new drug candidates will be safe or toxic in humans, speeding advances toward the most promising new therapies.
March happens to be National Kidney Month, and it’s especially important to raise awareness because 90 percent of people with CKD don’t even know they have it. So, if you or a loved one is at risk for CKD, be vigilant. Meanwhile, the work continues through studies like this one to find better leads to help control CKD.
References:
[1] Chronic kidney disease in the United States, 2021. Centers for Disease Control and Prevention.
[2] Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair. Gupta N, Matsumoto T, Hiratsuka K, Garcia Saiz E, Galichon P, Miyoshi T, Susa K, Tatsumoto N, Yamashita M, Morizane R. Sci Transl Med. 2022 Mar 2;14(634):eabj4772
Links:
Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
National Kidney Month 2022 (NIDDK)
Morizane Lab (Harvard Medical School, Boston, MA)
Tissue Chip for Screening (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Biomedical Imaging and Bioengineering; National Center for Advancing Translational Sciences
Singing “If Not Now”
Posted on by Dr. Francis Collins
What a thrill it was to perform the song, “If Not Now,” with my daughter Margaret Collins. We sang the duet at the conclusion of the Women in Nephrology’s annual Nancy Gary Memorial Luncheon Lecture. Margaret, a nephrologist, and I delivered this year’s lecture titled “Two Generations of Perspective on Women in Medicine.” This song’s message seemed so very appropriate to leave with these leaders and mentors in nephrology. We delivered the lecture on November 9. 2019 at the Walter Washington Convention Center, Washington, D.C., and I share the video to encourage others to take the words of this song “to the next level.” Credit: Diane Baker
Building Nanoparticles for Kidney Disease
Posted on by Dr. Francis Collins
Great things sometimes come in small packages. That’s certainly true in the lab of Eun Ji Chung at the University of Southern California, Los Angeles. Chung and her team each day wrap their brains around bioengineering 3-D nanoparticles, molecular constructs that measure just a few billionths of a meter.
Chung recently received an NIH Director’s 2018 New Innovator Award to bring the precision of nanomedicine to autosomal dominant polycystic kidney disease (ADPKD), a relatively common inherited disorder that affects about 600,000 Americans and 12 million people worldwide.
By age 60, about half of those battling ADPKD will have kidney failure, requiring dialysis or a kidney transplant to stay alive. For people with ADPKD, a dominantly inherited gene mutation causes clusters of fluid-filled cysts to form in the kidneys that grow larger over time. The cysts can grow very large and displace normal kidney tissue, progressively impairing function.
For Chung, the goal is to design nanoparticles of the right size and configuration to deliver therapeutics to the kidneys in safe, effective amounts. Our kidneys constantly filter blood, clearing out wastes that are removed via urine. So, Chung and her team will exploit the fact that most molecules in the bloodstream measuring less than 10 nanometers in diameter enter the kidneys, where they are gradually processed and eliminated from the body. This process will give nanoparticles time to bind there and release any therapeutic molecules they may be carrying directly to the cysts that cluster on the kidneys of people with ADPKD.
Chung’s research couldn’t be more timely. Though ADPKD isn’t curable right now, the Food and Drug Administration (FDA) last year approved Jynarque™ (tolvaptan), the first treatment in the United States to slow the decline in kidney function in ADPKD patients, based on tests of the rate of kidney filtration. Other approved drugs, such as metformin and rapamycin, have shown potential for repurposing to treat people with ADPKD. So, getting these and other potentially life-saving drugs directly to the kidneys, while minimizing the risk of serious side effects in the liver and elsewhere in the body, will be key.
Most FDA-approved nanoparticle therapies are administered intravenously, often for treatment of cancer. Because ADPKD is chronic and treatment can last for decades, Chung wants to develop an easy-to-take pill to get these nanoparticles into the kidneys.
But oral administration raises its own set of difficulties. The nanoparticles must get from the stomach and the rest of the gastrointestinal tract to the bloodstream. And then if nanoparticles exceed 10 nanometers in diameter, the body typically routes them to the liver for clearance, rather than the kidneys.
While Chung brainstorms strategies for oral administration, she’s also considering developing a smart bandage to allow the nanoparticles to pass readily through the skin and, eventually, into the bloodstream. It would be something similar to the wearable skin patch already featured on the blog.
In the meantime, Chung continues to optimize the size, shape, and surface charge of her nanoparticles. Right now, they have components to target the kidneys, provide a visual signal for tracking, enhance the nanoparticle’s lifespan, and carry a therapeutic molecule. Because positively charged molecules are preferentially attracted to the kidney, Chung has also spent untold hours adjusting the charge on her nanoparticles.
But through all the hard work, Chung and her team continue to prove that great things may one day come in very small packages. And that could ultimately prove to be a long-awaited gift for the millions of people living with ADPKD.
Links:
Polycystic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Video: Faculty Profile – Eun Ji Chung (University of Southern California, Los Angeles)
Chung Laboratory (USC)
Chung Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases
Using Frogs to Tackle Kidney Problems
Posted on by Dr. Francis Collins
Many human cells are adorned with hair-like projections called cilia. Scientists now realize that these specialized structures play many important roles throughout the body, including directing or sensing various signals such as fluid flow. Their improper function has been linked to a wide range of health conditions, such as kidney disease, scoliosis, and obesity.
Studying cilia in people can be pretty challenging. It’s less tricky in a commonly used model organism: Xenopus laevis, or the African clawed frog. This image highlights a healthy patch of motile cilia (yellow) on embryonic skin cells (red) of Xenopus laevis. The cilia found in humans and all other vertebrates are built from essentially the same elongated structures known as microtubules. That’s why researchers can learn a lot about human cilia by studying frogs.
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