Strike three

August 26, 2019

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.
Research on this study was conducted also by Jacob A. Torres (lead author), Mina Rezaei, Caroline Broderick and Luois Lin at UCSB; Xiaofang Wang and Vicente E. Torres at Mayo Clinic College of Medicine; Bernd Hoppe at University Children's Hospital Bonn in Germany; Benjamin D. Cowley Jr. at University of Oklahoma; Vicenzo Savica at University of Messina in Italy; Saeed Khan at University of Florida; and Ross P. Homes and Michael Mrug at University of Alabama.

University of California - Santa Barbara

Related Science Articles from Brightsurf:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.

Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.

Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.

Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.

World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.

PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.

Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.

Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.

Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.

Read More: Science News and Science Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to