Small change in blood acidity could prove detrimental to kidney disease patients

A University of Manchester scientist has discovered that very small changes in the level of acidity in blood may have a detrimental impact on the health of patients with kidney disease.

Chronic Kidney Disease (CKD) is common in the UK.  It is estimated that about one in five men and one in four women between the ages of 65 and 74 has some degree of CKD. The leading single cause of CKD is diabetes which is increasing so it’s expected that more patients will be diagnosed with CKD in the future.

Dr Donald Ward from the Faculty of Life Sciences has been studying the impact of kidney disease on the body. He has found that very small changes in the pH (acidity) level in the blood prevents the body from being able to accurately monitor calcium levels. This leads to too much of the hormone PTH being released which is likely to lead to a greater risk of calcium and phosphate from the bone damaging the arteries. This often proves fatal to patients with CKD. His research has been published in the Journal of the American Society of Nephrology. 

Dr Donald Ward

He says: “It was not realised before that the blood pH changes we see in patients with kidney disease can have an impact on their ability to monitor blood calcium levels. My research has demonstrated that the effect of those changes may be more significant than previously thought and thus might need to be looked at more carefully by clinicians.”

Dr Ward’s research focussed on the high level of parathyroid hormone (PTH) in patients suffering from CKD. This causes the body to release calcium and phosphate from the bones which can then damage their blood vessels. 

Dr Ward explains why this is so harmful: “The diseased kidneys prevent the body getting rid of both excess phosphate and excess acidity. So if that acidity also causes the body to release more PTH then this could compound the problem by releasing further phosphate from the bone. This vicious circle might accelerate the potentially fatal calcification of the arteries.” 

He continues: “What is so important about this research is that we have demonstrated that changes in PTH release can be prompted by very small changes in blood pH level. Before, it was assumed that only a larger change in acidity would cause problems for patients.”

The research was funded by Kidney Research UK. Elaine Davies, Director of Research Operations, from the charity says: “Donald’s work has used novel pharmacological and molecular tools in generating these new findings which increase our knowledge about the complex balance that clinicians need to consider when treating patients with CKD.”

Dr Ward is hoping to take his research to the next step, testing for therapeutic targets that could lead to better treatments for CKD.

Source: Manchester University

In mice, vaccine stops urinary tract infections linked to catheters

To adhere to catheters and start urinary tract infections, bacteria extend microscopic fibers with sticky proteins at their ends. Scientists have developed a vaccine that blocks the EbpA protein, visible as a white bulge above, and stops infections in mice. Credit: John Heuser

The most common type of hospital-associated infection may be preventable with a vaccine, new research in mice suggests.

The experimental vaccine, developed by researchers at Washington University School of Medicine in St. Louis, prevented urinary tract infections associated with catheters, the tubes used in hospitals and other care facilities to drain urine from a patient's bladder.

Each day a catheter is present in the urethra and the bladder, the risk of urinary tract infection increases. Nearly every patient who has a catheter for more than 30 days acquires a urinary tract infection. The infections make urination painful and can damage the bladder. If untreated, bacteria can cross into the bloodstream and cause sepsis, a potentially life-threatening complication.

"Catheter-associated urinary tract infections are very common," said first author Ana Lidia Flores-Mireles, PhD, a postdoctoral research associate at the School of Medicine. "Antibiotic resistance is increasing rapidly in the bacteria that cause these infections, so developing new treatments is a priority."

The study is available online Sept. 17 in Science Translational Medicine.

Manufacturers typically coat catheters with antibiotics to reduce the risk of infection. But Flores-Mireles and her colleagues in the laboratory of Scott Hultgren, PhD, showed that inserting catheters into the bladder provokes an inflammatory response that results in the catheter being covered with fibrinogen, a blood-clotting protein.

Fibrinogen shields bacteria from the antibiotics and provides bacteria with a landing pad to adhere to and food to consume as they establish an infection, the research revealed.

"The bacteria use long, thin hairs known as pili to anchor themselves to the fibrinogen, and then they can start to form biofilms, which are slimy coatings on the surface of the catheter composed of many bacteria," said co-author Michael Caparon Jr., PhD, professor of molecular microbiology. "The biofilms protect the bacteria from antibiotics and immune cells, further prevent them from being washed from the body by the flow of urine, and make it possible for bacteria to seed the lining of the bladder with infections."

The urethra and bladder of a mouse are too small to insert a full catheter into, but the scientists showed that surgically implanting a small segment of catheter into the bladder via the urethra increased vulnerability to infection in a similar fashion.

Working with Enterococcus faecalis, a common cause of catheter-associated urinary tract infections, Flores-Mireles showed that a protein on the end of the pili, EbpA, binds to fibrinogen and makes it possible for the bacteria to begin forming biofilms.

When Flores-Mireles prevented the bacteria from making EbpA, they couldn't start infections.

"This protein is like the anchor of a boat," she said. "Without the anchor, the infection is at the mercy of the waves and gets washed away."

Next, the researchers injected the mice with a vaccine containing EbpA. The vaccine caused the animal's immune systems to produce antibodies that blocked EbpA and stopped the infectious process.

The scientists are testing to see if the vaccine helps mice clear established infections of E. faecalis. They also are working to develop a monoclonal antibody that blocks EbpA to prevent catheter-associated infections in the urinary tract and elsewhere in the body.

"We took a closer look at this protein and found that one-half of it is essential for binding to fibrinogen to induce infections," Flores-Mireles said. "The segment of genetic code that makes this part of the protein is also found in the genes of many other bacteria that cause urinary tract infections, so a vaccine, antibody or drug that blocks this part of the protein may help prevent other infections linked to catheters in the urinary tract and in other parts of the body."

Source: Washington University in St. Louis