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Building Nanoparticles for Kidney Disease

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Eun Ji Chung
Photo courtesy of Eun Ji Chung

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

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Cilia

Credit: Vanja Krneta-Stankic and Rachel K. Miller, University of Texas Health Science Center at Houston

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.


Snapshots of Life: Bring on the Confetti!

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Renal Pericytes

Credit: Heinz Baumann, Sean T. Glenn, Mary Kay Ellsworth, and Kenneth W. Gross, Roswell Park Cancer Institute, Buffalo, NY

If this explosion of color reminds you of confetti, you’re not alone—scientists think it does too. In fact, they’ve even given the name “Confetti mouse” to a strain of mice genetically engineered so that their cells glow in various combinations of red, blue, yellow, or green markers, depending on what particular proteins those cells are producing. This color coding, demonstrated here in mouse kidney cells, can be especially useful in cancer research, shedding light on subtle molecular differences among tumors and providing clues to what may be driving the spread, or metastasis, of cancer cells beyond the original tumor site.

Not only is the Confetti mouse a valuable scientific tool, this image recently earned Heinz Baumann and colleagues at the Roswell Park Cancer Institute, Buffalo, NY, a place of honor in the Federation of American Societies for Experimental Biology’s 2015 Bioart competition. Working in the NIH-funded lab of Kenneth Gross, Baumann’s team created a Confetti mouse system that enables them to manipulate and explore in exquisite detail the expression of proteins in renal pericytes, a type of cell associated with the blood filtration system in the kidney.


Pursuing Precision Medicine for Chronic Kidney Disease

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Section of glomerular filters

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