Office of Research & Development

VA RESEARCH QUARTERLY UPDATE
This Issue: Chronic Disease Care | Table of Contents: Spring 2018

Spotlight on Career Development Awardees

Staying heart-healthy: The importance of phosphorus for Vets with chronic kidney disease


Dr. Anna Jovanovich is a nephrologist at the VA Eastern Colorado Health Care System in Denver. Her research focuses on cardiovascular health in Veterans who have chronic kidney disease. (Photo by Shawn Fury)
Dr. Anna Jovanovich is a nephrologist at the VA Eastern Colorado Health Care System in Denver. Her research focuses on cardiovascular health in Veterans who have chronic kidney disease. (Photo by Shawn Fury)

Dr. Anna Jovanovich is a nephrologist at the VA Eastern Colorado Health Care System in Denver. Her research focuses on cardiovascular health in Veterans who have chronic kidney disease. (Photo by Shawn Fury)

Dr. Anna Jovanovich is a kidney specialist and a clinical researcher at the VA Eastern Colorado Health Care System in Denver. She splits her time between seeing patients and conducting research. She is also an assistant professor at the University of Colorado, Denver.

The thrust of her clinical research is investigating the effects of kidney disease on the body—specifically cardiovascular or heart disease. Veterans and others with chronic kidney disease are at a much higher risk of developing heart disease, compared with the general population. In fact, they are more likely to suffer a cardiovascular event, such as a heart attack, than progress to needing dialysis or transplant.

They also may need help managing the level of certain chemicals within their bodies. In a healthy person, the kidney monitors and controls the level of many hormones, minerals, and other chemicals within the body. One of those is phosphorus—a mineral found in certain types of food, like milk. In the body, phosphorus is a necessary component for many cellular functions. One form of phosphorus—phosphate—is essential for building healthy bones and driving cellular metabolism.

People with advanced kidney disease may not be able to adequately control the level of phosphorus within their body. If diet modification does not work, they may need to take phosphate binders—drugs that bind to excess phosphate in the gut and help the body excrete it.

VARQU spoke with Jovanovich about her Career Development Award to study the potential effectiveness of phosphate binders in preventing cardiovascular disease.

Can you explain what chronic kidney disease is?

Chronic kidney disease is the gradual loss of kidney function over time. The main job of the kidneys is to balance what we take in and what we put out, basically. Substances like water, salt, and other electrolytes are regulated by the kidneys. And the kidneys also excrete toxins in the urine. So when the kidneys fail, they can't do that job anymore.

The kidneys are also important for regulating blood pressure, and they produce hormones that control red blood cell production and vitamin D, as well as regulate phosphorus and calcium homeostasis. Again, if the kidneys fail, some of these processes are disrupted. Usually, people with chronic kidney disease don't feel sick or ill until their disease is very advanced. So it is largely a very silent disease, in terms of how a person actually feels.

How prevalent is chronic kidney disease in the general population?

Chronic kidney disease in the general population in the U.S. has a prevalence of about 13 to 15 percent, depending on what year you look at. But in the Veteran population that is treated at VA, the prevalence is much, much higher. Some studies have reported it to be 20 percent, and one recent study—in a single region—has reported the prevalence of chronic kidney disease to be 47 percent in Veterans. This is significantly higher than in the general adult U.S. population.

How is chronic kidney disease usually diagnosed?

Because it is such a silent disease, the only way we can tell if people have chronic kidney disease is through blood and urine tests. If a Veteran receives usual care through a primary care doctor at the VA, it's pretty standard to do at least annual blood tests. And part of these blood tests measure kidney function. There is a substance called creatinine, which is made by the muscles and excreted through the kidneys. When kidney function declines, the level of creatinine rises in the blood—so that is what we test for. We look for higher levels of creatinine in the blood to indicate chronic kidney disease. Protein and/or red blood cells in the urine can also indicate kidney disease.

Dr. Anna Jovanovich and her research assistant are next to a scanner in the vascular lab, which is used to measure the elasticity of blood vessels.  (Photo by Shawn Fury)
Dr. Anna Jovanovich and her research assistant are next to a scanner in the vascular lab, which is used to measure the elasticity of blood vessels. (Photo by Shawn Fury)

Dr. Anna Jovanovich and her research assistant are next to a scanner in the vascular lab, which is used to measure the elasticity of blood vessels. (Photo by Shawn Fury)

Why is it important to regulate the level of phosphorus in a person's blood?

Phosphorus is needed by the body—it is one of the main minerals for structure and strength. Eighty-five percent of our body's total phosphorus is found in the bone and teeth. And it's also important for energy—the main energy compound within the cells uses phosphorus. We get phosphorus from the foods we eat and excrete the excess into our urine via the kidneys.

As the kidneys fail, they are not as able to excrete extra phosphorus, so blood levels of phosphorus rise. Even phosphorus that is on the high-end of the normal laboratory range has been associated with a higher risk of cardiovascular disease, in large epidemiologic studies.

Most people with moderate and even severe kidney disease can control their phosphorus levels with diet alone. That means avoiding foods that are high in phosphorus. But some people with very severe advanced chronic kidney disease, certainly people on dialysis, have to take phosphate binders—which are medications that you take with food. When the food and phosphate binders mix in your intestines, the phosphate binders attach to the phosphorus in your food so that the phosphorus is not absorbed into your intestine. With these medications, along with a low phosphate diet, we can control the blood levels of phosphorus.

Let's talk about your Career Development Award. Can you tell us what your research is about?

We want to find out if a phosphate binder can improve vascular function in people with moderate to severe chronic kidney disease who have normal phosphorus levels and are not yet on dialysis. This is a single-center randomized controlled trial: We are giving half the participants a phosphate binder, and half of the participants a placebo. We will measure vascular function at baseline and then after three months of treatment to see if there is any difference between the two groups, in terms of how vascular function has changed over a three-month period.

We will use two measures. One of the measures is called flow-mediated dilation (FMD), which is a measure of endothelial function. Endothelial cells are the cells that line the inside of blood vessels. FMD has been associated with cardiovascular disease events.

We will also measure vascular stiffness as another measure of vascular function. We measure this through something called aortic pulse wave velocity. So we are actually able to measure the time it takes the blood to travel from the carotid artery to the femoral artery—from the neck to the groin. The faster the blood travels, the stiffer the vessel. That's another measure of vascular function that has been associated with cardiovascular disease.

By measuring vascular function we can get an idea of the health of the blood vessels, and therefore the health of the heart.

Where would you like to see your research go from here?

This small trial that I am conducting will lay the groundwork for a larger trial looking at endpoints that are more important to patients—like lowering the risks of heart attacks or stroke, sudden cardiac death, or death.

I'm also interested in looking at other factors that are associated with the systemic effects of chronic kidney disease, in particular cardiovascular disease. I'm working on submitting a [VA Merit Review application] looking at how bile acids affect vascular function, and whether dietary changes may affect those levels and possibly improve vascular function—specifically vascular stiffness.

I just received a small grant to look at vascular function after acute kidney injury. Acute kidney injury is an abrupt decline of kidney function, which is usually reversible. However, even if kidney function gets better, people who experience acute kidney injury may go on to develop chronic kidney disease and have a higher risk of cardiovascular events.

So this small grant will look at vascular function after acute kidney injury to see if we can understand how the body changes after acute kidney injury. And we can then look for ways to lay the groundwork to treat the blood vessels after acute kidney injury to eventually lower the risk of cardiovascular disease and other bad outcomes that are associated with acute kidney injury.


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