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Researchers May Have Discovered Link Between Chronic Kidney Disease and Cardiovascular Disease

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06/09/2023
medicalnewstoday.com

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Design by MNT; Photography by ljubaphoto/Getty Images & Peter Cade/Getty Images
  • Vascular calcification, mineral deposits on blood vessel walls, are common in chronic kidney disease patients.
  • Researchers say small extracellular vesicles (sEVs) —small, enclosed structures outside cells — may play a role in vascular calcification developing.
  • This occurs through a signaling pathway called VEGFA.
  • Treatment of people with chronic kidney disease with VEGFA inhibitors may lessen associated vascular calcification.

Chronic kidney disease is a condition where the kidneys are damaged and can’t filter blood normally.

Diabetes and high blood pressure are responsible for two-thirds of chronic kidney disease cases, according to the National Kidney Foundation.

In the United States, 15% of people, or 37 million people, have chronic kidney disease, according to the Centers for Disease Control and Prevention.

Symptoms of kidney disease can include:

  • feeling more tired than normal
  • a poor appetite
  • muscle cramping at night
  • swollen feet and ankles
  • puffiness around eyes, especially in the morning
  • dry, itchy skin
  • need to urinate more frequently

People with chronic kidney disease have a high risk of developing heart disease.

“Most folks that have kidney disease usually die not from kidney disease but from cardiovascular disease,” Dr. Paul Welling, a professor of medicine, nephrology, and physiology at John Hopkins Medicine in Maryland, told Medical News Today.

The mechanisms behind increased cardiovascular risk in people with chronic kidney disease are not completely understood.

“It isn’t like we’re walking into this blind,” said Welling. “There are known pathways, but they probably don’t fully explain all of the complex biology.”

Researchers from Tokyo Medical and Dental University (TMDU) believe they have uncovered a possible link between cardiovascular disease and chronic kidney disease.

Their findings are published in Circulation Research, a journal of the American Heart Association.

Vascular calcification occurs when calcium builds up on the walls of blood vessels. It’s associated with cardiovascular disease mortality.

“Patients with chronic kidney disease experience accelerated vascular calcification, that differs compared with persons without chronic kidney disease,” said Dr. Nisha Bansal, an associate professor in the Division of Nephrology at the University of Washington School of Medicine and vice-chair of the American Heart Association’s Kidney in Heart Disease Science Committee who was not involved in the study.

Vascular smooth muscle cells in the blood vessel walls can undergo a process called phenotypic switching, where the cells alter from a contractile state that maintains normal function to a non-contractile state.

Chronic kidney disease can promote this phenotypic switching. It marks an early step toward developing cardiovascular disease.

For this study, researchers focused on the role of small, enclosed structures outside cells called small extracellular vesicles (sEVs).

“Circulating small extracellular vesicles (sEVs) carry and propagate signaling molecules, including proteins, microRNAs (miRNAs), and DNA between cells,” Bansal told Medical News Today.

The mechanism of these sEVs in chronic kidney disease was not clear prior to this study, the researchers wrote in their paper.

The study had multiple pieces to it.

Welling, who was not involved in the research, called it “impressive in its breadth.”

“They covered a lot of territory,” he said.

For one part of the study, the researchers gave rats a diet containing 0.75% adenine for 4 weeks to produce metabolic abnormalities resembling chronic renal failure in humans. They collected serum from these rats before euthanizing them.

Researchers then performed calcification assays using isolated sEVs and sEV-depleted serum collected from control and rats with simulated chronic kidney disease. They reported that sEVs, but not sEV-depleted serum, accelerated calcification in vascular smooth muscle cells.

Researchers also took mice, which were fed adenine and a high-Pi-containing diet, and injected them with GW4869, a systemic inhibitor of sEV biogenesis on aortic vascular calcification. They reported that circulating sEVs decreased in mice with simulated chronic kidney disease who were injected with GW4869 were about half of those in the other mice.

Next, researchers collected sEVs from chronic kidney disease model rats and performed a comprehensive miRNA transcriptome analysis using Affymetrix GeneChip miRNA 4.0.

The researchers then set out to determine whether people with chronic kidney disease were deficient in these miRNAs by studying the miRNA expression levels of 37 people with chronic kidney disease. The average age of these patients was 71 and 27% were female.

Researchers found that in circulating sEVs of rodents modeled to have chronic kidney disease and humans with chronic kidney disease that four miRNAs were decreased. Specifically, those were miR-16-5p, miR-17-5p, miR-20a-5p, and miR-106b-5p.

Researchers also performed a simulation on a computer and experimental analyses of the target genes of the miRNAs. They found that all four the miRNAs targeted a gene for a protein called VEGFA.

“They identified a particular cellular fragment that regulates expression of a specific protein (VEGFA) that may contribute to calcification in [chronic kidney disease],” explained Bansal.

The researchers speculate that treating people with chronic kidney disease with VEGFA inhibitors may lessen vascular calcification. Targeting the sEVs themselves may also have therapeutic potential.

“Currently, our therapies to treat or prevent vascular calcification in persons with kidney disease remain very limited,” Bansal said. “Better understanding of possible contributing mechanisms would allow for development of more targeted cardiovascular therapies in persons with chronic kidney disease.”

Furthermore, testing the expression level of each miRNA could predict calcification of the abdominal aorta in people with chronic kidney disease

Welling added that there is currently a lot of interest in “the way that organs talk to each other through these vesicles.”

“And this study provides a way to start to think seriously about this… mechanism by which the failing kidney is talking to the vasculature,” he said.

One limitation of the study, he said, is its use of rat models.

“Unfortunately, we don’t have a ton of great animal models for [chronic kidney disease]. This is one,” Welling said. “They did their best that they could do with it, but it may not reflect all of the forms of [chronic kidney disease] that we see in human patients.”

Welling said he hopes future research takes ideas presented in this study and looks at them in depth in humans.

“To see if this mechanism that works in this model of [chronic kidney disease] and rats really is applicable to to human disease,” he said.

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