kidney tubules
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
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.
Pursuing Precision Medicine for Chronic Kidney Disease
Posted on by Dr. Francis Collins
Caption: Scanning electron micrograph showing a part of one of the kidney’s glomerular filters, which are damaged in people with chronic kidney disease (CKD). The cells with the lacy cytoplasmic extensions are called podocytes.
Credit: Kretzler Lab, University of Michigan Health System, Ann Arbor
Every day, our kidneys filter more than 30 gallons of blood to allow excretion of molecules that can harm us if they build up as waste. But, for more than 20 million Americans and a growing number of people around the world, this important function is compromised by chronic kidney disease (CKD) [1]. Some CKD patients are at high risk of progressing to actual kidney failure, treatable only by dialysis or kidney transplants, while others remain generally healthy with stable kidney function for many years with minimal treatment.
The dilemma is that, even when CKD is diagnosed early, there’s been no good way to predict which individuals are at high risk for rapid progression. Those individuals would potentially benefit from more intensive measures to slow or prevent kidney failure, such as drug regimens that tightly control blood pressure and/or blood glucose. So, I’m pleased to report that NIH-funded researchers have made some progress toward developing more precise strategies for identifying individuals at high risk for kidney failure. In recent findings published in Science Translational Medicine [2], an international research team has identified a protein, easily detectable in urine, which appears to serve as an early warning sign of CKD progression.
A wide range of conditions, from diabetes to hypertension to the autoimmune disease lupus, can contribute to the gradual loss of kidney function seen in people with CKD. But research suggests that once kidney damage reaches a critical threshold, it veers off to follow a common downhill course, driven by shared cell signaling pathways and almost independent of the conditions causing it. If there was an easy, reliable way to determine when a CKD patient’s kidneys are approaching this threshold, it could open the door to better strategies for protecting them from kidney failure.
With this need in mind, a team, led by Matthias Kretzler and Wenjun Ju of the University of Michigan, began analyzing gene activity in kidney biopsy samples donated by 164 CKD patients and stored in the European Renal cDNA Bank. Specifically, the researchers looked for patterns of gene activity that corresponded with the patients’ estimated glomerular filtration rates, an indicator of renal function frequently calculated as part of a routine blood workup. Their first pass produced a list of 72 genes that displayed varying levels of activity that corresponded to differences in the patients’ estimated glomerular filtration rates. Importantly, the activity of many of those genes is also increased in cell signaling pathways thought to drive CKD progression.
Further study in two more groups of CKD patients, one from the United States and another from Europe, whittled the list down to three genes that best predicted kidney function. The researchers then zeroed in on the gene that codes for epidermal growth factor (EGF), a protein that, within the kidney, seems to be produced specifically in tubules, which are key components of the waste filtration system. Because EGF appears to enhance tubular repair after injury, researchers had a hunch that it might serve as a positive biomarker of tubular function that could be combined with existing tests of glomerular filtration to detect progression of CKD at an earlier stage.
In groups of CKD patients from the United States and China, the researchers went on to find that the amount of EGF in the urine provides an accurate measure of the protein’s activity in the kidney, making it a promising candidate for a simple urine test. In fact, CKD patients with low levels of EGF in their urine were four times more likely than those with higher EGF levels to have their kidney function worsen within a few years.
These lines of evidence suggest that, if these findings are replicated in additional studies, it may be possible to develop a simple EGF urine test to help identify which individuals with CKD would benefit the most from aggressive disease management and clinical follow-up. Researchers also plan to explore the possibility that such a urine test might prove useful in the early diagnosis of CKD, before there are any other indications of kidney disease. These are very promising new findings, but much remains to be done before we can think of applying these results as standard of care in the clinic. For example, the EGF work needs to be replicated in larger groups of CKD patients, as well as CKD patients with diabetes.
Beyond their implications for CKD, these results demonstrate the power of identifying new biologically important indicators directly from patients and then testing them in large, diverse cohorts of people. I look forward to the day when these sorts of studies will become possible on an even larger scale through our U.S. Precision Medicine Initiative Cohort.
References:
[1] National Chronic Kidney Disease Fact Sheet, 2014. Centers for Disease Control and Prevention.
[2] Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PX, Mariani LH, Eichinger FH, Berthier CC, Randolph A, Lai JY, Zhou Y, Hawkins JJ, Bitzer M, Sampson MG, Thier M, Solier C, Duran-Pacheco GC, Duchateau-Nguyen G, Essioux L, Schott B, Formentini I, Magnone MC, Bobadilla M, Cohen CD, Bagnasco SM, Barisoni L, Lv J, Zhang H, Wang HY, Brosius FC, Gadegbeku CA, Kretzler M; ERCB, C-PROBE, NEPTUNE, and PKU-IgAN Consortium. Sci Transl Med. 2015 Dec 2;7(316):316ra193.
Links:
Chronic Kidney Disease: What Does it Mean to Me? (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Personalized Molecular Nephrology Research Laboratory (University of Michigan)
C-Probe (University of Michigan)
Precision Medicine Initiative Cohort Program (NIH)
NIH Support: National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases
