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.