From MedicalXpress
Mini-kidneys grown in lab reveal renal disease secrets
Kidney organoids grown in the lab and suspended in a lab dish show the formation of cysts (right) in the disease model of polycystic kidney disease. Normal kidney organoids are on the left. Credit: Freedman Lab/UW Medicine
Polycystic kidney disease affects 12 million people. Until recently, scientists have been unable to recreate the progression of this human disease in a laboratory setting.
That scientific obstacle is being overcome. A report coming out next week shows that, by substituting certain physical components in the organoid environment, cyst formation can be increased or decreased.
Benjamin Freedman, assistant professor of medicine in the Division of Nephrology at the UW School of Medicine, and his team at the Kidney Research Institute, led these studies in conjunction with scientists at other institutions in the United States and Canada. Freedman and his group also are investigators at the UW Medicine Institute for Stem Cell and Regenerative Medicine
They outlined their methods and results in a paper to be published Oct. 2 in Nature Materials
"Beforehand, we had shown that these organoids could form PKD-like cysts, but what's new here is that we've used the model to understand something fundamental about that disease," said Freedman.
As one example, the team found that PKD mini-kidneys grown in free-floating conditions formed hollow cysts that were very large. These cysts could easily be seen. In contrast, PKD mini-kidneys attached to plastic dishes stayed small.
According to Nelly Cruz, the lead author of the paper, other manipulations to the organoid also affect the progression of polycystic kidney disease.
"We've discovered that polycystin proteins, which are causing the disease, are sensitive to their micro-environment," she explained. "Therefore, if we can change the way they interact or what they are experiencing on the outside of the cell, we might actually be able to change the course of the disease." Cruz is a research scientist in the Freedman lab.
In another paper to be published in Stem Cells, Freedman and his team discuss how podocytes, which are specialized cells in the body that filter blood plasma to form urine, can be generated and tracked in a lab environment. Study of gene-edited human kidney organoids showed how podocytes form certain filtration barriers, called slit diaphragms, just as they do in the womb. This might give the team insight into how to counter the effects of congenital gene mutations that can cause glomerulosclerosis, another common cause of kidney failure.
aken together, these papers are examples of how medical scientists are making progress toward developing effective, personalized therapies for polycystic kidney disease and other kidney disorders.
"We need to understand how PKD works," Freedman said. "Otherwise, we have no hope of curing the disease."
"And our research," he added, "is telling us that looking at the outside environment of the kidney may be the key to curing the disease. This gives us a whole new interventional window.
From Business Wire
(Palladio), a privately held biopharmaceutical company founded to develop medicines that make a meaningful impact on the lives of patients with orphan diseases of the kidney, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to lixivaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).
There are currently no drug treatments approved for ADPKD in the United States.
The FDA’s Office of Orphan Drug Products grants orphan drug designation to support the development of drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of diseases or disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 people but are not expected to recover the costs of drug development and marketing. Orphan drug designation provides eligibility for certain benefits, including seven years of market exclusivity following receipt of regulatory approval, tax credits for qualified clinical trials, and exemption from FDA application fees.
“ADPKD is a serious progressive, inherited disease that typically affects multiple generations of entire families. Lixivaptan has the potential to slow the progression of ADPKD and possibly delay the need for dialysis or a kidney transplant,” said Lorenzo Pellegrini, Ph.D., Founder and Chief Executive Officer of Palladio. “The granting of orphan drug designation is an important milestone in the lixivaptan development program.”
About Lixivaptan:
Lixivaptan is a potent, selective vasopressin V2 receptor antagonist. This mechanism of action has clinical proof of concept to delay the progression of the autosomal dominant form of PKD. Lixivaptan was previously administered to 1,673 subjects across 36 clinical studies as part of a prior clinical development program for the treatment of hyponatremia. Palladio expects to leverage lixivaptan’s large body of data generated in the hyponatremia clinical program to repurpose lixivaptan and advance its development for the treatment of ADPKD.
About Polycystic Kidney Disease (PKD) – Key Facts and Figures:
PKD is an inherited genetic disease that affects thousands of people in the United States and millions globally. ADPKD is the most common type of PKD. A person with ADPKD has a 50 percent chance of passing the disease on to each of his or her children. The disease is characterized by uncontrolled growth of fluid-filled cysts in the kidney, which can each grow to be as large as a football. Symptoms often include kidney infections and chronic pain. The continued enlargement of cysts and replacement of normal kidney tissue causes irreversible loss of renal function. In the United States, approximately 2,500 new people with PKD require dialysis or a kidney transplant every year, making PKD the 4th leading cause of kidney failure. There is no cure for PKD.
From Wired Magazine, by Megan Molteni
EVERY WEEK, TWO million people across the world will sit for hours, hooked up to a whirring, blinking, blood-cleaning dialysis machine. Their alternatives: Find a kidney transplant or die.
In the US, dialysis is a roughly 40-billion-dollar business keeping 468,000 people with end-stage renal disease alive. The process is far from perfect, but that hasn't hindered the industry's growth. That's thanks to a federally mandated Medicare entitlement that guarantees any American who needs dialysis—regardless of age or financial status—can get it, and get it paid for.
The legally enshrined coverage of dialysis has doubtlessly saved thousands of lives since its enactment 45 years ago, but the procedure’s history of special treatment has also stymied innovation. Today, the US government spends about 50 times more on private dialysis companies than it does on kidney disease research to improve treatments and find new cures. In this funding atmosphere, scientists have made slow progress to come up with something better than the dialysis machine-filled storefronts and strip malls that provide a vital service to so many of the country's sickest people.
Now, after more than 20 years of work, one team of doctors and researchers is close to offering patients an implantable artificial kidney, a bionic device that uses the same technology that makes the chips that power your laptop and smartphone. Stacks of carefully designed silicon nanopore filters combine with live kidney cells grown in a bioreactor. The bundle is enclosed in a body-friendly box and connected to a patient’s circulatory system and bladder—no external tubing required.
The device would do more than detach dialysis patients—who experience much higher rates of fatigue, chronic pain, and depression than the average American—from a grueling treatment schedule. It would also address a critical shortfallof organs for transplant that continues despite a recent uptick in donations. For every person who received a kidney last year, 5 more on the waiting list didn’t. And 4,000 of them died.
There are still plenty of regulatory hurdles ahead—human testing is scheduled to begin early next year1—but this bioartificial kidney is already bringing hope to patients desperate to unhook for good.
Innovation, Interrupted
Kidneys are the body’s bookkeepers. They sort the good from the bad—a process crucial to maintaining a stable balance of bodily chemicals. But sometimes they stop working. Diabetes, high blood pressure, and some forms of cancers can all cause kidney damage and impair the organs' ability to function. Which is why doctors have long been on the lookout for ways to mimic their operations outside the body.
The first successful attempt at a human artificial kidney was a feat of Rube Goldberg-ian ingenuity, necessitated in large part by wartime austerity measures. In the spring of 1940, a young Dutch doctor named Willem Kolff decamped from his university post to wait out the Nazi occupation of the Netherlands in a rural hospital on the IJssel river. There he constructed an unwieldy contraption for treating people dying from kidney failure using some 50 yards of sausage casing, a rotating wooden drum, and a bath of saltwater. The semi-permeable casing filtered out small molecules of toxic kidney waste while keeping larger blood cells and other molecules intact. Kolff's apparatus enabled him to draw blood from his patients, push it through the 150 feet of submerged casings, and return it to them cleansed of deadly impurities.
In some ways, dialysis has advanced quite a bit since 1943. (Vaarwel, sausage casing, hello mass-produced cellulose tubing.) But its basic function has remained unchanged for more than 70 years.
Not because there aren’t plenty of things to improve on. Design and manufacturing flaws make dialysis much less efficient than a real kidney at taking bad stuff out of the body and keeping the good stuff in. Other biological functions it can’t duplicate at all. But any efforts to substantially upgrade (or, heaven forbid, supplant) the technology has been undercut by a political promise made four and a half decades ago with unforeseen economic repercussions.
In the 1960s, when dialysis started gaining traction among doctors treating chronic kidney failure, most patients couldn't afford its $30,000 price tag—and it wasn’t covered by insurance. This led to treatment rationing and the arrival of death panels to the American consciousness. In 1972, Richard Nixon signed a government mandate to pay for dialysis for anyone who needed it. At the time, the moral cost of failing to provide lifesaving care was deemed greater than the financial setback of doing so.
But the government accountants, unable to see the country’s coming obesity epidemic and all its attendant health problems, greatly underestimated the future need of the nation. In the decades since, the number of patients requiring dialysis has increased fiftyfold. Today the federal government spends as much on treating kidney disease—nearly $31 billion per year—as it does on the entire annual budget for the National Institutes of Health. The NIH devotes $574 million of its funding to kidney disease research to improve therapies and discover cures. It represents just 1.7 percent of the annual total cost of care for the condition.
But Shuvo Roy, a professor in the School of Pharmacy at UC San Francisco, didn’t know any of this back in the late 1990s when he was studying how to apply his electrical engineering chops to medical devices. Fresh off his PhD and starting a new job at the Cleveland Clinic, Roy was a hammer looking for interesting problems to solve. Cardiology and neurosurgery seemed like exciting, well-funded places to do that. So he started working on cardiac ultrasound. But one day, a few months in, an internal medicine resident at nearby Case Western Reserve University named William Fissell came up to Roy and asked: “Have you ever thought about working on the kidney?”
Roy hadn’t. But the more Fissell told him about how stagnant the field of kidney research had been, how ripe dialysis was for a technological overhaul, the more interested he got. And as he familiarized himself with the machines and the engineering behind them, Roy began to realize the extent of dialysis' limitations—and the potential for innovation.
Limitations like the pore-size problem. Dialysis does a decent job cleansing blood of waste products, but it also filters out good stuff: salts, sugars, amino acids. Blame the polymer manufacturing process, which can’t replicate the 7-nanometer precision of nephrons—the kidney's natural filters. Making dialysis membranes involves a process called extrusion, which yields a distribution of pore sizes—most are about 7nm but you also get some portion that are much smaller, some that are much larger, and everything in between. This is a problem because that means some of the bad stuff (like urea and excess salts) can sneak through and some of the good stuff (necessary blood sugars and amino acids) gets trapped. Seven nanometers is the size of albumin—a critical protein that keeps fluid from leaking out of blood vessels, nourishes tissues, and transports hormones, vitamins, drugs, and substances like calcium throughout the body. Taking too much of it out of the bloodstream would be a bad thing. And when it comes to the kidney’s other natural functions, like secreting hormones that regulate blood pressure, dialysis can’t do them at all. Only living cells can.
“We were talking about making a better Bandaid,” Roy says. But as he and Fissell looked around them at the advances being made in live tissue engineering, they started thinking beyond a better, smaller, faster filter. “We thought, if people are growing ears on the backs of mice, why can’t we grow a kidney?”
It turned out, someone had already tried. Sort of. [Read more]
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