PKD Alert: Participate in Accelerating Clinical Trials, Paying to Live: Transplant Costs

ACT Alert (Accelerating Clinical Trials)

From PKD Foundation

ADPKD patients needed for curcumin study

Help play a key role in PKD research! Patient participation in clinical studies is essential to discovering treatments and a cure for PKD.

Are you or someone you know interested in participating? There is a new research study being conducted to understand if the dietary supplement, curcumin, improves the function of blood vessels in children and young adults with autosomal dominant polycystic kidney disease (ADPKD).

Study Details:

• Participants must be between the ages of 6 to 25 and diagnosed with ADPKD.
• The study involves a physical exam and medical history, blood draw, non-invasive testing of blood vessel function and an MRI of your kidneys.
• A travel stipend is available

Kidney Transplants

From WRDW-TV Channel 12, Augusta, GA

Paying to Live: Pricey transplants put spotlight on cost of living with disease and recovery

The organ transplant list at Augusta University currently had 891 people waiting for vital organs. While they wait, those people are crunching the numbers for what their health will cost them.

That gift comes with a high price even with insurance.

If Shelia Reeves had one wish, it would be for more time. Reeves has lupus and it's attacking her kidneys. She's been on the waiting list for a kidney for over four years.

“I went through the surgery for dialysis and was on dialysis for like a month and a half until my body just couldn't take the surgeries and dialysis,” Reeves said.

So now, she has to get rid of all the dialysis supplies she bought. They can't be returned or even donated.

Reeves’ only option is now a transplant. Since she's running out of time, her family started looking at options for a living donor and found her daughter is a match.

“The biggest surprise was the money that's involved,” Reeves said. “I thought once you have a donor, it's pretty much, when does this process start? But, it's not a fast process.”

Take Medicare for example. With most plans, you pay your deductible, then you pay 20 percent of the costs. But 20 percent is a lot when you're talking about hundreds of thousands of dollars.

In 2017, Kaiser Health estimated the average cost for a kidney transplant, the pre-care, the post-care, the drugs -- all said and done – at over $400,000. If you need a new liver? Over $800,000. And if you need more than one organ, the priciest surgeries, like heart and lung transplants can cost up to $2.5 million. Twenty percent of that is $500,000.

“I worry about the money,” Reeves said. “You still have to do daily living, household expenses.”

Once you get a transplant, patients have to take anti-rejection drugs -- typically for life. Those can run up to $2,500 a month. If you can't prove you'll be able to pay for them, transplant hospitals can deny your surgery. You'll get a letter like a patient up in Michigan received that said, “You are not a candidate for a heart transplant at this time due to needing a more secure plan for immunosupressive medication coverage. The committee is recommending a fundraising effort of $10,000.”

Shelia's Medicare will cover some but not all of the cost for those pricey drugs, which is why her doctors referred her to a non-profit that will help match what she raises if she can raise $10,000.

But raising that kind of cash when some days you can barely raise yourself out of bed, can feel like an impossible task.

“I miss working,” Reeves said. “A lot of people just say, ‘I wish I didn't have to work and could just stay home.’ Never. I was never that type of person. I've been working since I was 15.”

It brings the reality into focus. You have to pay to live. It's a hard pill to swallow -- even harder than all the pills needed to maintain care as someone with Lupus.

“My family, my grandkids, my husband -- we've been married over 25 years,” Reeves said. “I want a little more time to be with them.”

We haven't found any transplant program that accepts uninsured patients. Here's a surprising twist: we found if your kidney problems are what allowed you to qualify for Medicare in the first place, you are booted off of Medicare three years after your transplant.

But remember pricey those drugs are usually for life.

PKD: Discover Mechanism, PKD Fundraising, Crack Down on Dialysis Profits in California

Understanding How PKD Develops

From Daily Nexus, University of California, Santa Barbara, by Jacqueline Wen
UCSB Researchers Discover Mechanism Potentially Accelerating Progression of Polycystic Kidney Disease

PKD progression is depicted, with a normal kidney represented on the right side of each diagram for comparison. / Courtesy of Wikimedia Commons

Polycystic kidney disease is an inherited disorder causing clusters of cysts to form in the kidneys that may lead to eventual kidney failure. Autosomal dominant polycystic kidney disease (ADPKD) makes up about 90% of all PKD cases and affects over 600,000 Americans and 12.4 million people worldwide.

Individuals with PKD can face symptoms such as elevated blood pressure, possible development of cysts in other organs like the liver, higher chances to develop brain aneurysms and kidney stones and chronic side or back pain. Although there is currently no cure for PKD, numerous supportive treatments and lifestyle changes may help control symptoms and slow down or reduce loss of kidney function.

Much research is being done on PKD, including in Thomas Weimbs’ lab at UCSB.

In their paper published in the Journal of Clinical Investigation, the lab members identify a tubule dilation mechanism that may accelerate the formation of kidney cysts.

Based on diet, our metabolism results in the formation of different substances such as calcium phosphate, calcium oxalate and uric acid. Microcrystal versions of these molecules are produced daily and get harmlessly excreted through normal kidney function.

But for individuals with a propensity to form kidney stones, crystal deposits can get lodged in renal tubules. This may lead to kidney stone formation and cause health complications.

“You can imagine that if you’re trying to filter the urine out — and the kidney has a lot of tubes — and if the kidney stones get stuck in any of these tubes, the kidney would stop working. There wouldn’t be any kidney function equivalent to filter any more urine out. So there has to be a way to deal with these little microcrystals before they become stones,” Jacob Torres, a postdoctoral researcher in the Weimbs’ lab and the lead author of the study, said.

The scientists found that in response to calcium oxalate crystal deposition, a protective mechanism is triggered in which renal tubules dilate to flush out these lodged crystals.

While researchers in the natural sciences field studying kidney stones have observed dilated tubules before, “it has not previously been recognized as an active protective mechanism,” the paper states.

The fact that the tubules dilate and how or why the dilation happens hadn’t been thoroughly analyzed until now. The endogenous crystal clearing mechanism was “kind of unlooked at up to this point,” Torres said.

Their findings further show that calcium phosphate deposition led to increased cyst formation and PKD progression. Calcium oxide crystal deposition in mice activated mTOR and Src/Stat3 signaling pathways accompanying tubule dilation.

“In a lot of diseases, mTOR is dysregulated because it’s either overactive or underactive. Most of these are overactive diseases like cancer or PKD — that’s when mTOR is doing too much. And that kind of tells cells that they can grow and proliferate,” Torres explained.

The study reports that blocking mTOR signaling diminished tubule dilation and stopped effective crystal excretion. This suggests that these pathways are implicated in ADPKD and renal cyst growth, the investigators wrote.

Courtesy of the Journal of Clinical Investigation

Additionally, their results conclude that this protective mechanism can be a “third-hit” trigger accelerating PKD progression through causing dilated tubules to “overshoot” to form cysts.

Reminiscent to the third-hit model in the cancer field, the concept expresses that mutations “accumulate on top of each other” before individual cysts form in ADPKD, Torres described. The first hit occurs when a gene responsible for ADPKD gets mutated, either in PKD1 or PKD2. After several gene mutations and potentially through an environmental stressor, a somatic mutation may occur in a renal tubule cell (the second hit) and cause or continue a disease through a kidney insult, triggering a repair response (the third hit).

“There’s a lot of debate about what kind of sufficient trigger is the cause [of the third hit],” Torres said. “Studies show that now you need to have an injury on top of that second [hit] in order to cause a cyst to form … And so our research is kind of building on that idea that microcrystals are acting as that third hit, the ‘some other injury’ trigger that’s causing the cyst to form.”

The protective mechanism “is probably broken in PKD,” according to Torres. “And then that might be a way to prevent the progressive decline of kidney function by minimizing or mitigating the crystal burden that patients have. So it kind of leads to a therapy or therapeutic approach for individuals that have PKD.”

Potential treatments such as modifying diet can help reduce kidney stone formation and crystal deposition, Torres said. Taking steps like drinking less soda, which contains high levels of phosphoric acid, and avoiding foods rich in uric acid or rich in oxalate such as spinach and beans, can help individuals with PKD. Increasing water intake and taking citrate supplements can also help.

“A big piece of the puzzle is because PKD is a genetic disease, there’s probably not going to be a silver bullet where people can just take this one thing and it’s going to fix everything. So it’s probably going to be a bunch of behavioral stuff that people are gonna have to do … to make the biggest impact. And because it’s so slowly progressing, people can preserve kidney function or extend it for 10, 20 years. They effectively cure the disease because they don’t need to get a kidney transplant,” Torres stated.

He continued, “That’s another big finding — just being able to put the power in people’s hands rather than them waiting for somebody to find the cure for them. It’s something that they can actually act upon just using some basic science.”

In a joint effort with other individuals involved in the PKD field, Torres worked with different models of polycystic rats and eventually with humans with PKD. He highlights the “interesting” collaborative aspect that “blended all these different fields together to come up with the synthesis for our overall model of how these crystals are triggering this disease.”

Torres is next interested in detailing the different pathways implicated in the mechanism at the cellular and molecular level.

“In the paper, we touched on them a little bit, but we don’t go into full detail. So that would be the next thing, just figuring out what exactly is going on. [We] always want to know a little more, flush the story out a little better.”




Walk for PKD

From WCVB-TV Channel 5, ABC Affiliate Boston

Nearly $60K raised in Boston Walk for PKD

Polycystic kidney disease is one of the most common life-threatening genetic diseases and there is no cure.

But support from the 2019 Boston Walk for PKD is hoping to help change that.

5 Investigates reporter Kathy Curran took part in the event, which was held at Artesani Park in Brighton.

Hundreds of thousands of people in America and millions worldwide are affected by the disease.

The Boston Walk for PKD has raised over $58,000 for PKD research. The event is one of dozens of that are being held around the country. Over $720,000 has been raised nationwide.

Dialysis Politics

From American Prospect, by ALEXANDER SAMMON

California Cracks Down on Dialysis Profiteering

For a state legislative session, California’s most recent cycle was unusually high-profile. A number of bills with national implications were passed this year in Sacramento, including landmark legislation on employee classification status for gig economy workers, a bill establishing statewide rent control, and a proposal that clears the way for NCAA athletes to be paid for use of their image and likeness. It’s not often that bills in state capitals win the support of a host of presidential candidates and, more notably still, LeBron James.

Less prominent, though critically important, was the passage of AB-290, a bill that will dramatically curtail some of the more flagrant profiteering of the outpatient kidney dialysis industry. That measure, authored by Assemblyman Jim Wood, passed both houses of the legislature, and is now awaiting the signature of Governor Gavin Newsom.

Wood’s bill targets a mechanism he described as a “scam,” wherein the country’s two largest outpatient kidney dialysis providers, DaVita and Fresenius, make use of one of the country’s largest charities, the American Kidney Fund, to goose their profits. The AKF offers financial assistance to low-income kidney dialysis patients, all of whom are covered by Medicare, thanks to a 1972 federal law that makes kidney patients of all ages eligible for Medicare payments that partially defray the high costs of dialysis. But the Fund doesn’t merely help mitigate costs that Medicare may not cover, it also encourages those patients to migrate to private insurance plans, which providers like DaVita and Fresenius can bill for four times the Medicare rate—for the exact same treatment. Seeking to take advantage of that glaring financial incentive, the two companies donate roughly a quarter of a billion tax-deductible dollars to the AKF. Those private insurance patients account for a massive percentage of the companies’ profits, which total roughly $4 billion a year combined.

AB-290 will curtail that arrangement significantly, capping the insurance reimbursement rate at the same level as the Medicare rate, and limiting the incentive for the American Kidney Fund to move its patients into the private insurance market. The bill would allow patients already on AKF-subsidized private plans to continue their treatment uninterrupted, but would bar dialysis companies from steering people to third-party payers in the future. It is slated to go into effect in 2022.

AB-290 isn’t the first attempt to rein in this arrangement. A similar bill, SB 1156, was vetoed by former Governor Jerry Brown in 2018 after he determined it to be overly broad. And an attempt to effectuate such regulation by ballot measure in 2018, Proposition 8, was downed by a vote margin of nearly 20 percent.

The ballot measure’s failure was largely due to massive funding from the industry, which spent over $100 million to help sink the proposition. Predictably, AB-290 was met with a similarly well-funded opposition campaign. The industry spent millions of dollars on media and lobbying, including television ads and an astroturf campaign called Dialysis is Life Support. The American Kidney Fund has threatened to withdraw from California, on the grounds that the bill would threaten its national charter, though two independent legal opinions disputed that assessment. AB-290 has extended AKF the option of requesting a third assessment, which should clarify the nature of that threat.

The industry’s efforts managed to win a handful of concessions, beyond the option of that third review. Initially, the bill stipulated it could take effect as soon as 2020—and if the AKF declines to request that third assessment, some preliminary aspects of it can go into effect on July 1 of next year. But the bill was amended to push the start date for revised reimbursement rates to January 1, 2022, and to grandfather in those already enrolled with third-party payers.

AB-290 falls short of being a cure-all for the dialysis industry. Because DaVita and Fresenius control 70 percent of the market, their duopoly position has allowed them to get away with understaffing and Medicare and Medicaid price gouging. That’s resulted in major settlements, including a $495 million penalty in 2015 after a suit was brought alleging DaVita had conspired to overcharge the government. The suit included reports from whistle-blowers who described doctors at DaVita clinics throwing out partially used medicine vials to increase the number of vials they could charge for. “What DaVita did, instead of charg[ing for] one vial, they’d give 50 milligrams of this vial [and] put the residual into the trash,” Dr. Alon Vainer, a medical director at dialysis clinics in Georgia, who was involved with the suit, told CNN. Then, they’d open up a new vial, use only part of it again, and throw the remainder in the trash. DaVita denied the allegation, but paid out the hefty settlement, on the heels of another $400 million settlement just one year prior.

Still, the bill comes as a major victory, and an important precedent-setter for some of the battles within the health care industry that are likely forthcoming with Medicare for All now a front-and-center concern for the Democratic presidential field. Kidney dialysis is just a small corner of the broader medical market, and similar legal battles to reel in prices could well be on the horizon. Even though the cost-saving effects of AB-290 won’t be realized until 2022, the success of the legislation itself could open the door for more aggressive legislation in the future.

PKD Research: Blocking Effects of MicroRNA-17, Dialysis Centers Limiting Kidney Transplants?

PKD Research

From News Medical

Promising new drug being developed for polycystic kidney disease

Researchers have developed a potential new drug for the treatment of Polycystic kidney disease (PKD) – a deadly genetic condition affecting the kidneys that leads to formation of swellings or cysts within the kidney that cause it to fail. The results of the initial animal testing of the drug have been published in the latest issue of the Nature Communications. The study is titled, “Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease.”

Kidney disease. 3d illustration, Credit: Crystal Light / Shutterstock

Dr. Vishal Patel, Associate Professor of Internal Medicine at UT Southwestern and senior author of the study explained that for this experiment they used lab mice and their potential new drug called the “anti-miR-17 oligonucleotide RGLS4326” was capable of reducing the kidney size by 50 percent among the mice models of PKD. Patel explained that PKD that is genetically inherited (also called Autosomal dominant PKD) affects around 12 million people globally and leads to end stage kidney failure by the age of 60 in many individuals. Patel said, “Once the kidneys have failed, the only options for survival are dialysis or a kidney transplant. A large percentage of ADPKD patients on dialysis die each year while waiting for a donated kidney.”

The authors wrote, “Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease.”

The researchers explained that ADPKD has a progressive course until the kidneys are swollen with the cysts and the organ fails. At present the only treatment available for PKD remains Jynarque (generically called Tolvaptan). Tolvaptan however is associated with a risk of severe liver damage says the label warning.

Dr. Patel said, “We earlier showed that levels of a tiny RNA fragment called microRNA-17 are increased in models of ADPKD. MicroRNA-17 interferes with the normal function of other, beneficial RNAs, causing kidney cysts to grow. RGLS4326, as the new drug is called in development, works by blocking the harmful microRNA-17.”

The authors explain, “Aberrant activation of miRNAs has been shown to promote the progression of multiple human diseases; therefore, miRNA inhibition has emerged as an attractive therapeutic strategy.” Stopping these miRNAs has been found to halt many diseases in their progression. They explain that “miR-17 miRNAs family is upregulated in both human and murine forms of ADPKD, and their deletion or inhibition attenuates cyst growth in mouse PKD models.”

The new molecule RGLS4326 is a short oligonucleotide inhibitor that stops microRNA-17 or miR-17. The molecule was developed from the screening of a large number (more than 190) of anti-miR-17 oligonucleotides from which it was found to be specific for inhibiting ADPKD. The early studies reveal that the molecule targets and accumulates in the kidney and the cysts present in the collecting ducts. At the level of translation within the cells, this molecule is capable of displacing the miR-17 and also stops the expression of Pkd1 and Pkd2 genes. This mechanism of action makes this new drug a potential therapy for ADPKD explain the researchers.

Thus the researchers came together to develop new therapies for this deadly kidney disease. The team from UT Southwestern and Regulus Therapeutics Inc. (the latter is a biopharmaceutical company in California that helped developed the molecule) collaborated on this study. The molecule was found to be delivered directly at the kidneys bypassing the liver and thus was found to be safe for the liver.

The study looked at in vitro preparations of kidney cysts and found the drug to be able to inhibit the growth of the cysts. It was then experimented on multiple mice PKD models after administering the drug subcutaneously by injection.

For the human cyst in vitro studies the team used cyst cultures from human ADPKD donors. RGLS4326 treatment was found to de-repress the mRNAs of predicted miR-17 target genes. Further the expression of miR-17 target encoded proteins polycystin-1 (PC1) and polycystin-2 (PC2) was raised by two times and four times respectively. The team next cultured the molecule with the cysts and found “significant reduction of in vitro cyst growth and proliferation in a concentration-dependent manner.” Overall the molecule was not toxic to the kidney cells that did not have ADPKD, the team noted.

Next the team used mice models to study the movement of the drug within a live system. Following a subcutaneous injection, the drug was found to be rapidly absorbed into the plasma and was found to reach the kidneys. The preference of the drug for the kidney in comparison to the liver was 13:8, the researchers wrote.

Now within mice models of ADPKD they noted the effects of RGLS4326. They found that the molecule when injected subcutaneously was capable of displacing miR-17 from polysomes within 24 hours. Peak displacement of the miR-17 was seen after a week and the effects persisted for up to two weeks, the team wrote. They injected the drug in both normal and PKD models of the mice at different doses and found that in both normal and PKD mice the displacement of the miR-17 was seen. In multiple mice models of ADPKD, the miR-17 inhibition was clearly proven with the new molecule. As a next step long term use of the drug was seen on mouse models and its safety and efficacy was established.

Regulus Therapeutics has started preliminary human phase 1 trials since last year. Meanwhile the drugs watchdog Food and Drugs Administration (FDA) has called for more information on the new molecules from the animal studies before human trials could be allowed to start said Dr. Patel. Authors concluded, “The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD.”

The study was funded by Regulus Therapeutics and Dr. Patel also received funds by way of grants from the National Institutes of Health and the Department of Defense.

Kidney Transplants

From Renal and Urology news, Jody A. Charnow

Study: Kidney Transplant Access Less Likely at For-Profit Dialysis Centers

Patients in the United States who receive dialysis at for-profit rather than nonprofit facilities are less likely to have access to kidney transplantation, according to a new report published in JAMA.

In a retrospective cohort study of 1,478,564 patients treated at 6511 dialysis facilities, Rachel E. Patzer, PhD, MPH, of Emory University School of Medicine in Atlanta, and colleagues found that receiving dialysis at a for-profit facility compared with a nonprofit facility was associated with a significant 64%, 48%, and 56% decreased likelihood of being placed on a deceased donor kidney transplantation waiting list, receiving a living donor kidney transplant, and receiving a deceased donor kidney transplant, respectively.

To the investigators’ knowledge, no previous studies have examined the relationship between dialysis facility profit status and both living donor or deceased donor kidney transplantation.

Dr Patzer’s team categorized dialysis facility ownership as nonprofit small chains, nonprofit independent facilities; for-profit large chains (more than 1000 facilities), for-profit small chains (less than 1000 facilities), and for-profit independent facilities. They referred to DaVita and Fresenius Medical Care as large for-profit chain 1 and large for-profit chain 2, respectively.

Of the 1,478,564 patients, 109,030 (7.4%) received care at 435 nonprofit small chain facilities; 483,988 (32.7%) received care at 2239 large for-profit chain 1 facilities; 482,689 (32.6%) received care at 2082 large for-profit chain 2 facilities; 225,890 (15.3%) received care at 997 for-profit small chain facilities; and 98,680 (6.7%) received care at 434 for-profit independent facilities.

Compared with patients who received dialysis at nonprofit small chain dialysis facilities, those treated at nonprofit independent facilities were almost 2.4 times more likely to be placed on the deceased donor transplantation waiting list, Dr Patzer and her collaborators reported. Patients who received dialysis at large for-profit chain 1, large for-profit chain 2, for-profit small chain, and for-profit independent chain facilities were 43%, 46%, 44%, and 40% less likely to be placed on the deceased donor transplantation waiting list, respectively

In addition, compared with patients receiving dialysis in nonprofit small chain dialysis facilities, those receiving dialysis at nonprofit independent facilities were 71% more likely to receive a deceased donor transplant, whereas patients treated at large for-profit chain 1, large for-profit chain 2, for-profit small chain, and for-profit independent chain facilities were 40%, 41%, 40% and 41% less likely to receive a deceased donor transplant, respectively.

Patients who switched from a nonprofit to a for-profit facility were more likely to be placed on the deceased donor transplant waiting list or receive a deceased or living donor kidney compared with patients who initiated and continued dialysis at for-profit facilities, Dr Patzer and her colleagues reported.

Patients who received dialysis at all for-profit facilities were 48% less likely to receive a living donor transplant compared with patients who were treated at all nonprofit facilities, according to the investigators.

In an accompanying editorial, L. Ebony Boulware, MD, MPH, of Duke University School of Medicine in Durham, North Carolina, and coauthors said findings of the new study, taken together, “paint a bleak and discouraging picture on the function of the dialysis industry in assisting patients’ access to kidney transplantation overall, and they draw a particularly concerning light on how the business practices of different dialysis organizations might influence patients’ access to life-enhancing therapy.”

Reference

Gander JC, Zhang X, Ross K, et al. Association between dialysis facility ownership and access to kidney transplantation. JAMA. 2019;322:957-973. doi: 10.1001/jama.2019.12803

Boulware LE, Wang V, Powe NR. Improving access to kidney transplantation: Business as usual or new ways of doing business? JAMA. 2019;322:931-933.

PKD: Major Contributing Cause Can be Kidney Stones, PKD Awareness Day

PKD Research

From futurity.org

HOW CRYSTALS TRIGGER CYST GROWTH IN SERIOUS KIDNEY DISEASE

A process thought to protect the kidneys may trigger rapid cyst growth in people with polycystic kidney disease, a new study shows.

For people with polycystic kidney disease (PKD), life can be a never-ending cycle of symptoms: aches and pains, abdominal swelling, kidney stones, and high blood pressure. The disease frequently leads, at worst, to a suite of major issues, including kidney failure, cysts in the liver, and vascular problems, including strokes.

PKD is a “fairly common genetic disorder,” according to the National Institutes of Health. It affects roughly 600,000 people in the United States, with the more common autosomal dominant (AD) form affecting roughly one in 500 to 1,000 people.

The disease remains somewhat of a mystery and has no cure, researchers say. Meanwhile, treatment of various symptoms and complications put a heavy economic burden on the healthcare system, and dramatically lower patients’ quality of life.

“Most patients will eventually form these big cystic kidneys, and they will need dialysis or a kidney transplant, both of which are not great options,” says Thomas Weimbs, a biochemist at the University California, Santa Barbara.

‘THIRD-HIT’ TRIGGER

In a step toward disrupting the cycle that leads to cyst formation in the kidneys, the Weimbs lab uncovered a previously unrecognized mechanism that accelerates cystogenesis. The rapid dilation of the tubules that conduct waste away from the kidneys in the form of urine is a “third-hit” trigger that results in rapid cyst growth, according to the paper in the Journal of Clinical Investigation.

The kidneys are the hard-working filtration system that removes waste from the blood. Blood enters the nephrons (the kidneys’ basic functional unit) where waste and fluid pass through the renal tubules, while cells and proteins remain in the blood. Some fluid and nutrients get reabsorbed into circulation while excess fluid and waste become urine that flows to the bladder. Each human kidney contains roughly a million such tubules, Weimbs says.

During this filtration process, waste products—such as calcium oxalate, calcium phosphate, and uric acid—tend to concentrate and precipitate into crystals in the renal tubules. In healthy people, these millions of microscopic crystals form but flush away with the urine, while other factors prevent the runaway growth and retention of these crystals in the tubules. The formation and accumulation of these crystals, if left unchecked, can lead to kidney stones.

To prepare to flush out these crystals the renal tubules rapidly dilate, and then return to normal after the crystals have cleared. This dilation is a mechanism that scientists had not previously recognized, Weimbs says.

“It was not understood how the bulk of these crystals are flushed out,” he says. Until now, researchers thought stuck crystals crossed through into the kidneys’ interstitial tissue to be reabsorbed, but the new research shows that’s not the case for most crystals.

CRYSTALS AND CYSTS

In normal-functioning kidneys, the tubule dilation acts as a protective mechanism. The deposition of oxalate crystals in particular triggers the rapid activation of protein signaling pathways (mTOR and Src/STAT3) that regulate cell growth and proliferation, accompanied by the rapid dilation of the entire tubule system to dislodge the microcrystals.

“In kidneys genetically preconditioned to form these cysts, we found that these crystals can trigger the same dilation, but instead of going back to normal those tubules overshoot and form cysts,” Weimbs says.

In people with ADPKD, the rapid and constant tubule dilation is seen as a “third hit” physical injury that results in cyst formation. According to the “third hit” model of cystogenesis, three events must occur to form individual cysts: the first two are genetic mutations, while the third is a physiological damage/repair response, resulting in an overcompensation by the renal tubule that leads to formation of the fluid-filled sacs.

Trauma and other assaults to the kidneys are fairly rare, Weimbs says, but the microcrystals could present a persistent and relevant type of injury in ADPKD patients that could trigger the damage/repair response.

The findings suggest that contrary to conventional assumptions that abnormalities in tissue architecture or metabolic abnormalities during ADPKD progression lead to increased kidney stones, the opposite may be the case: More crystals lead to the progression of ADPKD. Additionally, it is possible that ADPKD progression and kidney stone formation reinforce each other, the study shows.

This opens up the possibility that the same well-established practices for keeping kidney stones at bay may also prove effective for slowing the progression of ADPKD, Weimbs says. “Our research suggests that the rate of progression could be at least in part determined by something like diet.”

Recommendations for preventing kidney stones, such as avoiding certain foods, increasing water intake, and prescription citrate therapy, could also prove beneficial for those with polycystic kidney disease, he says.

Additional collaborators on the work are from UC Santa Barbara; the Mayo Clinic College of Medicine; University Children’s Hospital Bonn in Germany; the University of Oklahoma; the University of Messina in Italy; the University of Florida; and the University of Alabama.

Source: UC Santa Barbara

PKD Awareness

From Healio

New patient registry launches on PKD Awareness Day

The PKD Foundation has launched a new patient registry as part of Polycystic Kidney Disease Awareness Day, held on Sept. 4.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of PKD, which causes multiple cysts that form in the kidneys. Parents with PKD have a 50% chance of passing the disease to their children, according to the PKD Foundation. ADPKD is the fourth leading cause of kidney failure.

In a blog, the foundation said the ADPKD registry is the first secure, nationwide network for patients to provide data on their condition. The registry uses an online portal to collect data, allowing researchers to study a wide variety of information from groups of patients. “This collection of information will help researchers better understand the natural progression of the disease. Over time, the data in the registry will generate new insights on how PKD symptoms change as patients age and provide a broader view of life with PKD,” the foundation said.

The aim of the registry is also to connect patients to other research studies taking place throughout the country.

“Based on the answers provided through online questionnaires, the registry will be able to determine what research a participant may qualify for and then provide them with information about the study,” the foundation said.

Nicole Harr, director of community engagement for the foundation and a patient with PKD, said the registry will have value connecting patients with each other.

“I was diagnosed with PKD 17 years ago,” she wrote in the blog. “Before my diagnosis, I never gave much thought to clinical trials, research and patient registries ... After my diagnosis, I searched for hope and found it in research.”

Other resources for kidney patients and professionals include the PKDnetwork.org, supported by Otsuka Pharmaceutical Development & Commercialization Inc. and Otsuka America Pharmaceutical Inc. The network is a source for physicians specializing in PKD and other chronic kidney diseases (including ADPKD) and contains educational events and resources for professionals, as well as a PKD disease progression simulator to help doctors understand the rate of disease progression for ADPKD and to enhance dialogues between doctors and their patients

Otsuka has also launched pkdinfo.com, a patient-focused website with information about ADPKD, including how to manage the disease, how to seek help from physicians, and professional resources for patients and caregivers. –by Mark E. Neumann

PKD Research: Prevent Cyst Growth Mechanisms, PKD Walk: San Antonio, Artificial Kidney Update, Donated Kidneys Thrown Away

PKD Research: Preventing Cyst Growth

From MedicalXpress, by Sonia Fernandez, University of California - Santa Barbara

Researchers examine cyst growth in patients with polycystic kidney disease

For people with polycystic kidney disease (PKD), life can be a constant cycle of symptoms: aches and pains, abdominal swelling, kidney stones, high blood pressure. At worst, the disease frequently leads to a suite of major issues, including kidney failure, cysts in the liver and vascular problems, including strokes. According to the National Institutes of Health, PKD is a "fairly common genetic disorder," affecting roughly 600,000 people in the United States, with the more common autosomal dominant (AD) form affecting roughly one in 500 to 1,000 people.

"Most patients will eventually form these big cystic kidneys, and they will need dialysis or a kidney transplant, both of which are not great options," said UC Santa Barbara biochemist Thomas Weimbs, whose research specialty lies in the still somewhat mysterious disease, which has no cure. Meanwhile, treatment of various symptoms and complications put a heavy economic burden on the healthcare system and dramatically lower patients' quality of life.

In a step toward disrupting the cycle that leads to cyst formation in the kidneys, the Weimbs Lab has now uncovered a previously unrecognized mechanism that accelerates cystogenesis. Thought to be a response meant to protect the kidneys, the rapid dilation of the tubules that conduct waste away from the kidneys in the form of urine has been found to be a "third-hit" trigger that results in rapid cyst growth in those with ADPKD.

Their research is published in a paper that appears in the Journal of Clinical Investigation.

The kidneys are the hard-working filtration systems for our blood. Blood enters the nephrons (the kidneys' basic functional unit) where waste and fluid pass through the renal tubules, while cells and proteins stay in the blood. Some fluid and nutrients get reabsorbed into circulation while excess fluid and waste become urine that flows to the bladder. There are about a million such tubules in each human kidney, Weimbs said.

During this filtration process, waste products—such as calcium oxalate, calcium phosphate and uric acid—tend to concentrate and precipitate into crystals in the renal tubules. In healthy people, these millions of microscopic crystals form but are flushed away with the urine, while other factors prevent the runaway growth and retention of these crystals in the tubules. The formation and accumulation of these crystals, if left unchecked, could lead to kidney stones.

To prepare to flush out these crystals the renal tubules, it's been found, rapidly dilate, and then return to normal after the crystals have cleared. This dilation is a mechanism that had not been previously recognized, according to Weimbs.

"It was not understood how the bulk of these crystals are flushed out," he said. Until now, stuck crystals were thought to cross through into the kidneys' interstitial tissue to be reabsorbed, he added, but his team's research shows that is not the case for most crystals.

In normal-functioning kidneys, according to the study, the tubule dilation is seen as a protective mechanism. The deposition of oxalate crystals in particular triggers the rapid activation of protein signaling pathways (mTOR and Src/STAT3) that regulate cell growth and proliferation, accompanied by the rapid dilation of the entire tubule system to dislodge the microcrystals.

"In kidneys genetically preconditioned to form these cysts, we found that these crystals can trigger the same dilation, but instead of going back to normal those tubules overshoot and form cysts," Weimbs explained.

In individuals with ADPKD, the rapid and constant tubule dilation is seen as a "third hit" physical injury that results in cyst formation. According to the "third hit" model of cystogenesis, three events must occur to form individual cysts: the first two are genetic mutations, while the third is a physiological damage/repair response, resulting in an overcompensation by the renal tubule that leads to formation of the fluid-filled sacs. Trauma and other assaults to the kidneys are fairly rare, Weimbs said, but the microcrystals could present a persistent and relevant type of injury in ADPKD patients that could trigger the damage/repair response.

The researchers' results suggest that contrary to conventional assumptions that abnormalities in tissue architecture or metabolic abnormalities during ADPKD progression lead to increased kidney stones, the opposite may be the case: More crystals lead to the progression of ADPKD. Additionally, according to the study, it is possible that ADPKD progression and kidney stone formation reinforce each other.

This opens up the possibility that the same well-established practices for keeping kidney stones at bay may also prove effective for slowing the progression of ADPKD. "Our research suggests that the rate of progression could be at least in part determined by something like diet," Weimbs said. Recommendations for preventing kidney stones, such as avoiding certain foods, increasing water intake and prescription citrate therapy, could also prove beneficial for those with polycystic kidney disease, he said.

Artificial Kidney

From Daily Bruin, UCLA, BY EMI NAKAHARA
Four-year research collaboration results in potentially lifesaving implantable kidney

An artificial implantable kidney may pave the way for a new treatment for millions of people with chronic kidney disease.

A four-year research collaboration between UCLA and the University of Arkansas created a prototype artificial kidney able to purify human blood and remove its waste products without the need for dialysate, a solution that is typically used for kidney dialysis. Researchers plan to test the technology with a living pig as its first animal model Aug. 29.

The research is funded by the US Kidney Research Corporation, a private research company focused on waterless kidney replacement technology.

According to the National Kidney Foundation, 37 million people in the U.S. have chronic kidney disease, which is the ninth leading cause of death in the country. It can result in kidney failure, which requires the patient to undergo kidney dialysis – an artificial method of cleaning the blood of toxins and waste – or a kidney transplant to stay alive. Hemodialysis costs Americans $42 billion per year, of which $34 billion is paid via medicare, according to the Kidney Project at UC San Francisco.

A kidney transplant can replace dialysis as treatment, but there are more than 100,000 people on the waiting list nationwide, said Ira Kurtz, a UCLA professor of medicine who spearheaded the project.

“There’s not enough kidneys to go around,” he said. “Someone who’s waiting for a cadaveric kidney (i.e., a kidney from a deceased person) would have to wait for 10 years in Los Angeles.”

Kurtz, who is also the Kidney Research Corporation’s chief science/medical advisor, said the ultimate goal would be to create an artificial implantable kidney, which does not use water or dialysate fluid. This would not only save on resources and money, but also free up the patients’ time as well, he added.

Currently, the device is roughly the size of a suitcase, but the next goal is to shrink it smaller so it can be easily carried in a backpack, Kurtz said. This way, the patient can carry the device and continuously have their blood be cleaned without needing to go to a clinic or exchange dialysate fluid.

“There are other people who are trying to create a wearable artificial kidney, but those devices still use dialysate solution, so the person has to carry the solution, which we feel is crazy,” he said.

For hemodialysis, patients must be at a clinic or home for three and a half-hour long dialysis sessions three times a week. For peritoneal dialysis, patients undergo the session overnight daily. Hemodialysis requires very large amounts of water and dialysate in order to clean and get rid of toxins and waste from the blood, Kurtz said

“We couldn’t have that infrastructure in an ideal implantable kidney. I think there’s enough water used in hemodialysis per year in the United States to feed all the livestock in the states (for approximately a day and a half),” Kurtz said. “It’s a huge amount of water.”

The new prototype, however, uses filtration and electron deionization instead of dialysate fluid to clean the blood and create urine, Kurtz said. First, an ultrafiltration module takes in blood from the body, while preventing cells and important proteins from the blood from getting into the rest of the device.

Next, electron deionization units, or EDI, transport important ions, such as potassium and sodium, in and out of the blood in order to maintain a crucial balance in their concentration in the body. For example, too much potassium in the blood can lead to a heart attack, Kurtz said.

The device also uses a nanofilter to remove urea, a metabolic waste product, from the blood, and another to prevent important sugars from leaking from the blood into the urine, which can be fatal for the patient, he added.

“Urine has a certain chemistry from cells in the kidney, and we had to simulate them also,” Kurtz said.

Jamie Hestekin, a professor in chemical engineering at the University of Arkansas who led the development of the device, said a challenging part in building the EDI was the partial separation of the various important ions of the blood.

“You don’t want to remove everything,” Hestekin said. “Separating two things from each other completely is possible, but doing partial separation, removing things not needed and keeping those that are needed, is more complicated.”

Minhtri Nguyen, a UCLA professor of medicine specializing in kidney research, said an artificial implantable kidney device that doesn’t require dialysate would be a major advance in the field.

“In theory, it sounds good. But only by testing with an animal model and later in humans we can know for sure it’s effective,” he said. “If it is, it could change the way we practice nephrology.”

However, Nguyen said he was unsure of one aspect of the technology. Although the nanofiltration modules are responsible for removing excess urea from the blood, filtration alone cannot decrease the overall blood urea concentration, he said. Urea cannot be removed by the EDI units because it is not a charged molecule, and also cannot be easily removed by a selective membrane.

“Urea is tricky to remove, but it’s a very major solute,” he said. “If they can’t lower the concentration, that’s a big problem, and they might need to go back to the drawing board.”

So far, the device has performed well in laboratory simulations, using solutions and blood samples, Hestekin said.

He said he is cautiously optimistic for upcoming tests of the device with a live pig.

“It’s been performing really well, with tremendous progress in four years, despite its extremely challenging application,” Hestekin said. “We’re really hoping that the trial can show that with some more incremental progress we can actually get something that works long term.”



From New York Post, by Hannah Sparks

US throws away thousands of kidneys despite donor shortage: study

Despite the 93,000 patients in the US seeking a kidney transplant, a new report reveals that some 3,500 donated kidneys go unused and even thrown away every year.

A study published in JAMA Internal Medicine this week found that 17% of donated kidneys in the US were discarded during a 10-year period. By comparison, in France, only about 9% of donated kidneys went unused during the study period.

Why the waste? According to the report, doctors here in the US are less inclined to risk using lower-quality kidneys, even though previous studies have shown that even less desirable kidneys, such as older kidneys and those with abnormalities, are still better than dialysis.

In France, doctors are more willing to use kidneys from deceased patients who suffered from illnesses such as diabetes or hypertension.

Cost may also be a factor in US doctors’ reticence to use affected kidneys, since these transplants may also result in extended hospital stays.

And, without a consistent set of guidelines in the US, some regions discard more kidneys than others based on their own opinions about whether a kidney is viable, according to a 2016 study by the National Kidney Foundation. That study found that as many as 50% of discarded kidneys could have been transplanted.

The United Network for Organ Sharing (UNOS) — the US’ transplant governing body — attempted to improve the discard rate by creating a kidney donor profile index in 2012, which rates how long it predicts a kidney will hold up. The network even lowered its standards in 2014 so that lesser kidneys would be considered.

The problem is wide-reaching: More than 37 million Americans suffer from chronic kidney disease, with roughly 5,000 of these patients dying each year on the transplant waiting list.

Still, the number of wasted kidneys continues to rise, up to 30% in some regions, according to a study published in January 2019.

In the end, “risk-averse” policies in US transplant programs hit patients hardest, write Dr. Ryoichi Maenosono and Dr. Stefan G. Tullius of Brigham and Women’s Hospital, in a commentary article attached to the JAMA study.

“Hospital administrators and patients alike are attracted by superficial five-star ranking approaches that are easy to read but not necessarily reflective of the approach of individual programs aiming to provide their patients on waiting lists with the best opportunities.”

Walk for PKD

From KENS-TV, NBC Affiliate, San Antonio, TX

Seeking a cure with Walk for PKD | KENS Cares

One hundred percent of each donation funds lifesaving research to find treatments and a cure.

The San Antonio Walk for PKD is your chance to take a small step and make a big difference in the lives of those who have polycystic kidney disease.

One hundred percent of each donation funds lifesaving research to find treatments and a cure. Sign up and walk with KENS 5's Sarah Forgany and Cristina Blackwell on Saturday, September 14, 2019.


SATURDAY, SEPTEMBER 14

Register at: walkforpkd.org/sanantonio

Check-in/Onsite Registration: 7:30 a.m.

Penny Kids Dash: 8:15 a.m.

Walk Begins: 9:15 a.m.

Walk Distance: 1 mile or 3 mile route

OP Schnabel Park, Graff Pavilion

9606 Bandera Road

San Antonio, TX 78250

ABOUT PKD FOUNDATION

The PKD Foundation helps patients and loved ones learn about PKD and how to manage the disease while maintaining a high quality of life. They do this through promoting research, education, advocacy, support and awareness on a national level, along with direct services to local communities across the country.

The PKD Foundation is the only organization in the U.S. solely dedicated to finding treatments and a cure for polycystic kidney disease (PKD) and to improve the lives of those it affects. Since 1982, they have proudly funded $44 million in PKD research and leveraged $1.5 billion in government funding, while serving local communities across the country. Their vision #endPKD.