Jaime Uribarri, MD, is a physician and clinical investigator. He is currently a professor of medicine and director of the Home Dialysis Program at The Mount Sinai School of Medicine in New York City. An expert in kidney and hypertension, Dr Uribarri has spent decades investigating the causes of kidney disease, a most common complication of diabetes and common aging, which led to publishing several articles exploring the effects of phosphorus on individuals with chronic kidney disease. Together with Helen Vlassara, MD, he was also among the first to explore the question of advanced glycation end products (AGEs) in food and their effects in healthy persons as well as in those with diabetes or with kidney disease of different causes.
Integrative Medicine: A Clinician’s Journal (IMCJ): How did you become interested in researching the effects of phosphorus on the body?
Dr Uribarri: Because of my field in medicine. I am a practicing nephrologist, so I deal with kidney disease, chronic kidney disease, and dialysis patients. One of the main medical problems today is phosphorus related. One of the kidney’s jobs is to eliminate phosphorus. This mineral is essential for nutrition and is present in many kinds of foods. Once you have kidney problems, you have difficulty eliminating phosphorus.
When it builds up in the body, it produces a lot of problems. It produces calcifications on the blood vessels, calcifications in soft tissues, bone disease, and so on. Therefore, the main reason for my interest comes from the field of nephrology, as I said.
IMCJ: You said that a main source of phosphorus is dietary. In particular, how is the Western diet predisposed to creating a high-phosphorous environment in the body?
Dr Uribarri: All of the phosphorus comes from the diet. Of course, base phosphorus is a mineral in rocks and other sources, but as far as humans are concerned, we ingest phosphorus from food. Phosphorus is present in a natural form, as I said, in many foods—meat in particular, dairy products, and a lot of plants. The intake of meat is very high in the Western diet; therefore, there is a tendency for a higher intake of natural phosphorus. What has become more important over time with processing of foods is that many foods are processed using phosphate salt. These additives increase, then, the content of phosphate in the food that we ingest.
The phosphate that comes as an additive is very well absorbed, so it supplies a very large amount of phosphorus to the body. So, let me repeat that there are 2 main sources of phosphorus in the food that we eat: One is contained naturally in the food and one is added during the processing of food. The latter has been increasing recently and is very predominant in the Western diet.
IMCJ: So the phosphate additives in the food are readily absorbed. Is there a significant difference between the ways the natural dietary phosphorus is absorbed by the body versus the additives?
Dr Uribarri: There is a significant difference. The additives are very easily absorbed, as I said. If I were to give a number, I would say that more than 90% of what gets into the intestine gets absorbed into the body. In terms of foods, if you consider somebody who has eaten an average, mixed diet, you find that only about 60% of that phosphorus gets absorbed and the remainder just comes out in the stools on a daily basis. That is so because the phosphorus contained naturally in food is not as well absorbed as the one in additives. Of the natural foods, dried plant foods in particular contain a form of phosphorus called phytate that is not that easily digested by humans, so a smaller percentage actually gets absorbed. If you take somebody who has eaten a lot of legumes, for example—if you do an analysis of a sample of that food, you will find a large amount of phosphorus. Only a fraction of that phosphorus actually gets absorbed into the body because of its presence as phytate.
IMCJ: Is the behavior of phosphorus in the body affected by other cofactors?
Dr Uribarri: Sure. Calcium in the body is very important. The main concern with excess phosphorus in the body is that it will combine with calcium and precipitate in the form of calcium phosphate of different shapes and sizes, and that is what produces the problem of calcification in different areas. The most important thing really is the level of kidney function. If you have very good kidney function, you can deal with a large supply of phosphorus coming into the body and simply get rid of it. As you lose kidney function, then that is when this becomes a problem. Some of the phosphorus may be retained and will precipitate with calcium to form calcifications.
IMCJ: Certainly, those with kidney disease are more susceptible to excess phosphorus issues, but may they just be the ones where it becomes obvious? There is a hypothesis that those high phosphorus intake levels are damaging for everybody. Is there any truth to that?
Dr Uribarri: There is current evidence. Over the past decade, there has been a lot of epidemiologic data showing that if you look at large cohorts who have been followed over the years and you relate the level of phosphorus in the blood, the serum phosphate, with the outcomes—in terms of mortality, in terms of heart attacks, in terms of cardiovascular disease—you find that the higher the level of serum phosphate, the worse the outcome and the higher the mortality. In people who are apparently healthy, even without any obvious kidney disease, there are several studies including a large number of people, showing that the higher the serum phosphate the higher the mortality. That raises clearly the point that with the higher dietary phosphorus intake that we have currently, even people with healthy kidneys should be concerned.
IMCJ: How does the body load of phosphorus affect vitamin-D metabolism?
Dr Uribarri: There is a relationship there, but in a sense they are kind of independent. Vitamin D tends to have more effect on calcium. The relationship between vitamin D and phosphorus is not as close as the relationship that we have between vitamin D and calcium. In general terms, when the phosphorus levels build up in the blood—the levels are higher—that tends to suppress the activation of vitamin D that occurs normally in the kidneys.
IMCJ: Is the kidney’s ability to activate 25(OH) vitamin D to calcitriol tied to overall renal function, or are they independent variables?
Dr Uribarri: They are very much connected. One of the normal functions of the kidneys is to activate and convert the prohormone vitamin D into 1,25-dihydroxyvitamin D, which is calcitriol. As renal dysfunction or impairment of any sort takes place, less and less of that activation occurs. Independent of kidney function, there are some other factors that also affect the activation of vitamin D. One of them is the level of calcium and the other is the level of phosphorus, as I mentioned before. The higher the phosphorus, the less the activation into calcitriol.
IMCJ: Are there other factors in the body that drive that relationship or the efficiency of conversion of vitamin D?
Dr Uribarri: Well, yes. There are many factors that affect this relationship. It is not very simple. In general terms, as I said, the activation is controlled by the kidney function, level of calcium, and levels of phosphorus, but also you have to include the parathyroid hormone, or PTH. This is a hormone produced by the parathyroid gland, mostly in response to any drop in the serum calcium. Whenever the serum calcium drops minimally, that stimulates the parathyroid hormones that on one hand will remove calcium from the bone, bringing serum calcium back to normal and on the other, will activate vitamin D in the kidneys so there is more calcitriol that now can absorb more calcium from the intestine. So, PTH clearly is another factor that has a tremendous influence in the activation from vitamin D into calcitriol. Then, over the past decade, we have become more and more aware of another factor, which is the fibroblast growth factor 23, or FGF23. That is another hormone produced by the bone that seems to be produced in response to phosphorus. It acts on activation in the sense that it suppresses the activation of vitamin D into calcitriol. The FGF23 release, if you will, seems to be controlled by the level of phosphorus. The higher the serum phosphorus, the more the release of the FGF23 and the less the activation for vitamin D into calcitriol. As with everything in the body, there is a multiplicity of factors that have a lot of interactions.
IMCJ: Phosphorus levels in the body are tightly regulated in a healthy body, but does that level stay fairly constant throughout time?
Dr Uribarri: There is a variation. The levels are lower in the morning in the fasting condition. They tend to increase a little bit following the intake of food. Also, there is a circadian variation that happens throughout the day. It tends to be a little bit higher in the evening than in the morning and related, even, to the intake of food. If you were to get, in the same individual, blood samples in the morning and in the evening, the numbers may not be exactly the same.
IMCJ: Has the reason behind the circadian variation in phosphorus levels been explained yet?
Dr Uribarri: No, it’s not very clear why it happens. No.
IMCJ: As a clinician, if you were going to try to assess the phosphorus load of a patient, how would you go about doing that?
Dr Uribarri: That is problematic. The most common way to do it is by measuring blood levels, and usually the traditional way to measure blood levels is in the morning after fasting. However, when you take somebody with normal kidney function who is getting a certain load of phosphorus, let’s say an intake of 1 gram of phosphorus per day, you get a certain serum phosphate level in the blood: 3.5 mg/dL for example. Then, if you take another person who is ingesting double that amount of phosphate, 2 grams over 24 hours, and the person also has normal kidney function, and you were to measure the fasting morning level of phosphate, it may not be any different. In the presence of normal kidney function, as you ingest the food and the phosphorus gets absorbed into circulation, the levels transiently increase, but then the kidneys get rid of the phosphorus over the next 24 hours. By the next morning, in the fasting condition, the levels of serum phosphate are back to normal.
That creates a problem in the sense that the levels of fasting morning serum phosphate do not tell you much about the overall load of phosphorus. That does not differentiate people who are eating a lot of phosphate or people who are not eating enough. If their intake is extreme—a lot or very low—that will show a difference. Within the most common range of intake, there will not be straight-forward differences in the level of fasting serum phosphate.
In reality, you will have to do serial levels of phosphorus throughout the day following food intake to get an idea of what will be the load. In day-to-day practicing medicine, that is very difficult to do. I mean, you cannot just take your patient, bring them into the laboratory, and have them lying there and be sampling blood every 2 hours throughout the day. The better way to do it would be a 24-hour urine collection and then measure the phosphorus. In general terms, if you are in a stable situation—you are not a growing kid with forming bone, for example—the amount of phosphorus that is absorbed by the intestine will simply be eliminated in the urine.
Therefore, if you measure the amount of phosphorus in a 24-hour collection, you will get a very good idea of how much phosphate load you are getting. The problem there is that you need to get a 24-hour collection, which is not sophisticated, but it is not so easy to do for most people. You have to be very careful and to make sure that none of the urine is missed. Again, the serum levels of fasting phosphate will not differentiate how much phosphorus you are eating and what your load is. The 24-hour urine measurement of phosphate will be better in that sense.
IMCJ: That being said, are there any clinical markers for phosphate load that can be observed during a physical examination and can suggest to a practitioner that further exploration may be necessary?
Dr Uribarri: No, unfortunately not. Because most of the other indicators are other labs. What are the levels of parathyroid hormone? What are the levels of FGF23? Those are tests that are not routinely done in clinical practice. You get them in very specific situations. So clinically, no, you do not get any clues. Somebody who has heavy phosphate load may look exactly the same as somebody who does not. There are also no clues you can get from the history, other than the dietary history.
IMCJ: In terms of dietary history, then, what types of things are the red flags?
Dr Uribarri: Well, again, you have to go through the regular way to determine the dietary intake of any nutrient or mineral like phosphate. That is by getting a detailed history, 3-day food records or 7-day food records, of whatever the patient has been eating and the amounts. When you are doing precise analysis, a dietician will then compare that with a database where we know the phosphate content for each one of those items. For example, you eat a piece of bread, and you get an idea of how large the piece of bread is. Then you go to the software database and look up bread, this particular brand and this amount, and that will give you an output of how much phosphate was consumed.
That’s how a dietician or nutritionist, or anyone for practical purposes, can determine dietary intake after getting a detailed history of what was consumed.
That is what has been done traditionally and that is the thing to do. One of the complicating issues about that, however, is that most of the dietary databases that we use come from a government organization. The US Department of Agriculture National Nutrient Database for Standard Reference is commonly used. As I told you, there is a large amount of phosphates that are used as additives and those will vary between brands of foods. They may not necessarily include a particular phosphate additive into these databases. Whenever we use the databases, we may be underestimating how much phosphorus is ingested. On top of that, if the average person wanted to get an idea of how much phosphorus is in the food, the government does not demand the description of the phosphorus content in their food labels, as you know. So there is no way to know.
IMCJ: In your estimation, what classes of foods are the biggest offenders when it comes to these phosphate additives?
Dr Uribarri: It will be meats products. Those tend to provide the most.
IMCJ: On the other side of the coin, you said underconsuming phosphate also can create some issues in the body. What might those be?
Dr Uribarri: Low levels of phosphate tends to produce problems to calcify bones, which is particularly important in a child whose bone mass should be increasing. This produces a condition called osteomalacia in which you do not deposit enough calcium phosphate in the bone. The bone is made up mostly of calcium and phosphorus. Even if you have adequate calcium, if you do not have enough phosphorus, that calcium cannot be deposited in bone at the stage in your life when you are growing and forming bone. Low phosphorus in the diet may significantly affect your ability to form bone. There are other effects of low phosphate in muscle and other tissues, but bone is the main consideration with low phosphorus.
IMCJ: What are you currently researching and what do you hope to learn from it?
Dr Uribarri: We are currently trying to initiate a study looking at the effect of different dietary phosphorus intakes on markers of bone and cardiovascular disease among healthy subjects. We hope this will give us some insight into the mechanisms of high dietary phosphorus-induced health problems.
IMCJ: Does phosphorus have cardiovascular effects beyond calcification and atherosclerosis?
Dr Uribarri: Phosphorus has many other cardiovascular effects beyond calcification, either directly or indirectly through its modification of levels of FGF23, etc.