What is Hyperphosphatemia?
Phosphate is a mineral that can be found in good quantities in our body. We normally have between 500 to 800 grams of it, with the vast majority, around 85%, located in our bones in the form of a crystal called hydroxyapatite. About 10% is present in our muscles and bones, combining with proteins, sugars and fats. The remaining phosphate is scattered in fluid inside and outside our cells.
In a healthy adult, the amount of phosphate in the blood, also called plasma, is normally between 2.5 to 4.5 milligrams per deciliter (mg/dl) with men having a slightly higher concentration than women. Children have higher levels of phosphate, normally ranging between 4 to 7 mg/dl. If the levels in the blood are higher than 4.5 mg/dl, this condition is called hyperphosphatemia. Phosphate is very important for our bodies because it participates in several key biological functions, like making ATP, the energy source of cells, and acting as an essential component of our DNA. Phosphate also helps in maintaining the pH balance inside our cells.
Adults normally take in about 1000 milligrams of phosphate through their diet every day. Most of this phosphate gets absorbed primarily in the small intestine. The absorption can occur passively just by diffusion, or actively via a helper protein called sodium-dependent phosphate co-transporter type IIb (NPT2b).
Our kidneys play a significant role in maintaining phosphate balance in the body. They get rid of ninety percent of the phosphate our body doesn’t need. Because phosphate isn’t bound to a particular protein, albumin, it can easily move through the mini filters action our kidneys, the nephrons, have. The amount of active nephrons plays a major role in maintaining phosphate balance; about 75% of the phosphate that goes through the kidney filters is taken back up, while the rest is lost in the urine. Our kidneys do this with help from a transporter called Type II Na/Pi co-transporter (NPT-2a). However, the exact amount of phosphate reabsorbed can be affected by other factors such as our body’s hydration status, the levels of certain hormones, and the levels of phosphate in the blood.
Phosphate balance in our body is affected by hormones such as calcitriol, PTH, and phosphatonins, including fibroblast growth factor 23 (FGF-23). Receptors for vitamin D, FGF-23, PTH, and a calcium-sensing receptor known as CaSR are key players in maintaining phosphate balance. The balance is achieved by phosphate absorption in the intestines, how the kidneys handle phosphate, and the storage and release of phosphate from our bones and cells. Sometimes, insulin and certain metabolic conditions can also make our cells temporarily take up more phosphate.
There are different types of sodium-dependent phosphate co-transporters, the helper proteins involved in phosphate absorption. These proteins rely on another protein called Na/K-dependent ATPase to function. There are three main types of these co-transporter proteins: NPT1, which is found in the kidneys; NPT2, which has three forms (NPT2a, NPT2c, and NPT2b) and can be found in different body tissues; and Type III co-transporters that regulate phosphate balance inside cells and found all over the body.
The parathyroid hormone, or PTH, is important for controlling calcium and phosphate levels via kidney and bone functions. It also turns on vitamin D in the kidneys, which helps in absorbing calcium in the gut and turning over bone. This hormone, made in the parathyroid cells, is rapidly released when blood calcium levels are low and quickly used up by the liver and kidneys. Any changes in blood calcium levels are detected by a sensor called calcium-sensing receptor (CaSR) on the parathyroid cells. The activation of this sensor with high calcium levels can turn off PTH release and lower the reabsorption of calcium in the kidneys. Conversely, high phosphate levels can lead to low calcium levels, which can have similar effects. However, high phosphate alone can also directly stimulate PTH production as well as parathyroid cell growth. Certain medications like penicillin, steroids, and some diuretics can cause phosphate levels to rise.
1, 25 dihydroxycholecalciferol is an active form of Vitamin D. It boosts phosphate absorption in intestines and kidneys by increasing the expression of NPT2b, NPT2a, and NPT2c. It also enhances the action of another hormone called FGF23 while suppressing PTH.
FGF23 is a hormone mainly made by bone cells called osteocytes and, lesser extent, cells involved in forming bone or osteoblasts. This hormone, which is made of 251 building blocks or amino acids, inhibits the reabsorption of phosphate in the kidneys. It does that by binding to a specific protein complex and suppressing the effect of NPT2a and NPT2c. FGF23 also decreases the levels of active vitamin D by regulating two key enzymes in vitamin D metabolism.
What Causes Hyperphosphatemia?
Kidney failure is the most common reason for high levels of phosphate in the blood, also known as hyperphosphatemia. When kidneys aren’t working well and have a low filtration rate (less than 30 mL per minute), they struggle to filter out phosphate. This leads to an increase in the level of phosphate in the blood.
Other, less common reasons for hyperphosphatemia include ingesting too much phosphorus or your kidneys reabsorbing too much phosphorus.
Eating lots of phosphorus can occur if you use certain kinds of laxatives or enemas that contain phosphate, or if you have too much vitamin D in your system, which increases the amount of phosphate your intestines absorb.
Certain medical conditions like hypoparathyroidism (a lack of parathyroid hormones), overactive pituitary gland (acromegaly), and overactive thyroid (thyrotoxicosis), can also cause your kidneys to over-absorb phosphate, leading to hyperphosphatemia.
Hyperphosphatemia can also be due to gene-related factors. Some genetic deficiencies can lead to hypoparathyroidism, pseudohypoparathyroidism (a condition that mimics hypoparathyroidism), and reduced FGF-23 activity. FGF-23 is a hormone that helps regulate phosphate levels in the body.
Sometimes, lab tests can mistakenly suggest high phosphate levels in the blood. This is known as pseudohyperphosphatemia and can happen in patients who have high levels of proteins, fats, or bilirubin in their blood. This is due to certain substances interfering with the test that measures phosphate levels.
Risk Factors and Frequency for Hyperphosphatemia
Studies show that around 12% of patients admitted to large hospitals have an issue called hyperphosphatemia, which is high levels of phosphate in the blood. This doesn’t include patients with end-stage kidney disease, acute kidney injury, or those whose phosphate wasn’t measured when they were admitted.
Hyperphosphatemia is a condition that kidney doctors often see in their patients. In those with end-stage kidney disease, between 50 to 74% of them have hyperphosphatemia.
In another study involving children with cancer who received a certain medication (liposomal amphotericin), about 45% of them also developed hyperphosphatemia.
Signs and Symptoms of Hyperphosphatemia
Many people with Albright hereditary osteodystrophy don’t show symptoms. However, various internal health issues can cause symptoms to occur. In particular, the following symptoms should signal for medical attention:
- Excessive levels of phosphate in the blood (hyperphosphatemia), which can lead to dangerously low calcium levels (hypocalcemia), complex interactions among cells, and potential damage to tissues. The individual may also have calcifications in the skin, soft tissue around joints, and joint areas. Long term, these imbalances can weaken the bone and lead to fractures.
- Neurological changes affecting the central nervous system. These may include delirium, coma, seizures, overactive nerve and muscle responses, and signs of hyperreflexia. Patients may also experience muscle cramping (for example, cramping in the hands and feet) or muscle stiffening.
- Cardiovascular changes such as low blood pressure (hypotension) and failure of the heart to pump blood efficiently (heart failure).
- Excessive phosphate in the blood (hyperphosphatemia) can cause calcium-phosphate deposits throughout the body. This can lead to hardening of the blood vessels (vascular calcification and arteriosclerosis), high systolic blood pressure, widened pulse pressure, and subsequent enlargement of the left ventricle of the heart.
- Eye-related symptoms, which include specific types of damage or disease in the cornea (band-shaped keratopathy), cataracts, reddened eyes, or inflammation of the conjunctiva (conjunctivitis).
Testing for Hyperphosphatemia
If your doctor suspects you have high levels of phosphate in your blood, known as hyperphosphatemia, they may conduct a repeat phosphate test for confirmation. There are numerous factors influencing the levels of phosphate in your bloodstream. For instance, phosphate levels exhibit a daily rhythm – they peak around 3:00 am and reach their lowest around 11:00 am. Timing of the last dialysis session can also affect levels since dialysis removes phosphate.
It’s important to note that there can be a variation in phosphate levels in patients with Chronic Kidney Disease (CKD). In those cases, doctors might need to get several measurements before deciding on a phosphate lowering treatment. The usual test, which measures serum phosphate level and total phosphate excretion in urine, may not give a reliable overview of phosphate load in the body. Instead, fractional phosphate excretion, which measures how much phosphate each functioning kidney unit (nephron) is excreting, gives a better indicator.
Other tests that might be needed include renal function tests, vitamin D, serum calcium, and PTH (a hormone that regulates calcium levels in the body) levels. Certain combinations of these test results can suggest specific conditions. For example, increased BUN and creatinine with normal or elevated PTH and low calcium levels can indicate kidney insufficiency.
Some conditions can be identified by characteristic test results. For instance, a condition called tumor lysis syndrome might be suggested by markedly high phosphate levels along with low calcium and high potassium and uric acid levels. High phosphate levels with normal or high vitamin D and calcitriol levels and normal serum calcium, alkaline phosphatase, and PTH concentrations, may indicate a condition known as tumoral calcinosis.
Imaging, such as X-ray, is sometimes used to see if there are calcium deposits in the body associated with high phosphate levels.
For patients with normal kidney function, assessing urinary phosphate levels can help to distinguish between different causes of high phosphate levels. These might include increased reabsorption by the kidneys due to dehydration or certain types of tumors, or causes outside the kidneys such as muscle breakdown, laxative or enema use, or excessive phosphate intake.
The method for measuring phosphate levels typically involves a reaction involving phosphate ions and ammonium molybdate at a certain pH level. This forms a complex that can be measured either by ultraviolet absorption or after reduction to a blue-colored compound.
According to established guidelines (KDIGO), monitoring of serum phosphate levels is recommended for all patients with significantly reduced kidney function. For patients with estimated kidney function between 30 to 59 mL/min/1.73 m², checks of serum phosphate and calcium levels should occur every 6 to 12 months. If this estimated kidney function is between 15 to 29 mL/min/1.73 m² these checks should take place every 3 to 6 months.
Treatment Options for Hyperphosphatemia
According to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, managing excessive levels of phosphate (hyperphosphatemia) requires different strategies in patients on dialysis and those who aren’t. In patients on dialysis, phosphate levels must be lowered but there’s no specific target point. On the other hand, in patients with chronic kidney disease who aren’t undergoing dialysis, phosphate levels should be kept under 4.5 mg/dL.
If kidney function is good, the kidneys can expel extra phosphate. This process can be encouraged by injections of saline solutions and diuretics, which increase the volume of fluids in the body.
Diet can also play a big role in managing phosphate levels. Both people who need dialysis and those who don’t can benefit from limiting dietary phosphate. It might also be a good idea to look at where the phosphate in the diet is coming from, for example, from animal products, vegetable products, or food additives. Overly severe protein restriction, however, can be harmful over time.
For patients whose kidney function is impaired, dialysis may be an option.
If despite following a low-phosphate diet, the phosphate levels are remaining high, then medicines known as phosphate binders can be used. These medications work by reducing the amount of phosphate absorbed from the food we eat. They form an insoluble compound with phosphate that is then expelled through stools.
Certain types of phosphate binders include calcium-based binders and Magnesium carbonate which are effective but come with their own sets of pros and cons. Others include Sevelamer, Lanthanum Carbonate, Ferric Citrate and, Sucroferric Oxyhydroxide, each with their unique way of working and potential side effects.
In addition, medicines such as Nicotinic Acid and Nicotinamide and Tenapanor can also be used; they work by reducing the amount of phosphate the body absorbs from food.
Other treatment methods, such as peritoneal and hemodialysis, can remove some phosphate from the body, but they can’t keep up with the phosphate that comes in from a normal diet. Hence, more intensive dialysis might be required.
Finally, managing a condition called secondary hyperparathyroidism, which can occur with kidney disease, is also essential. This can be done using vitamin D metabolites and chemicals that interact with calcium-sensing receptors in the body.
All in all, it is crucial to maintain balanced levels of phosphate, calcium, and other elements in the body, adjusting their levels based on the individual needs of the patient.
What else can Hyperphosphatemia be?
There are several medical situations that can create misleading test results indicating high levels of phosphate in the body. These include:
- Waldenstrom macroglobulinemia
- Multiple myeloma
- Monoclonal gammopathy of unknown significance, all of which can lead to a false detection of high phosphate levels, a condition called pseudohyperphosphatemia
- Vitamin D intoxication: having too much Vitamin D in the body
- Rhabdomyolysis: a severe muscle tissue breakdown
- Tumor lysis syndrome: a rapid release of cells into the bloodstream caused by certain types of cancer treatment
- Pseudohypoparathyroidism: a condition where the body does not respond to parathyroid hormone properly, disrupting the balance of minerals in the body
What to expect with Hyperphosphatemia
Hyperphosphatemia is a condition where there’s too much phosphate in your blood. You usually can’t tell if you have hyperphosphatemia because it typically doesn’t cause any symptoms. The main reason people die from this condition is due to other health problems they have at the same time.
In the short term, hyperphosphatemia can lead to tetany, a condition where your muscles twitch and spasm due to low calcium levels in your blood. Additionally, high phosphate levels can lead to calcium and phosphate deposits forming in soft tissues, beneath your skin, and in joints.
Studies have found that dialysis patients with higher phosphate levels in their blood have a higher chance of dying. This means phosphate levels in the blood might help predict death rates and indicate how severe an illness is in critically ill patients who are getting kidney dialysis.
Moreover, a condition called acute phosphate nephropathy can occur, which can cause failure in recipients of kidney transplants. This disorder, caused by abnormalities in mineral and bone metabolism, has been reported in patients receiving a kidney.
Additionally, research done in intensive care units (ICUs) has found that patients with abnormal phosphate levels are more likely to have serious illnesses and a higher chance of dying.
Possible Complications When Diagnosed with Hyperphosphatemia
When patients undergoing dialysis have high levels of phosphate in their blood, it’s linked with a greater risk of death.
Many patients with chronic kidney disease (CKD) often die from heart disease, partly due to a buildup of calcium in the blood vessels. This frequently happened with around 80% of all dialysis patients, as seen in their computed tomography (CT) scans. If these patients also have high levels of calcium, excessive phosphate, and PTH hormone in their blood, it can lead to abnormal changes in their blood vessel cells and inflammation, causing calcification. Small calcium deposits in the coronary arteries increase the risk of plaque instability due to blood pressure. When large blood vessels, like the aorta, become hard due to calcification, it can lead to high blood pressure and an increased pulse rate.
Hyperphosphatemia means there’s too much phosphate in the blood, which binds with the calcium in your blood and reduces its levels. This triggers the release of PTH hormone, leading to secondary hyperparathyroidism. This condition causes a high rate of bone turnover, which releases calcium from the bone to normalize the serum calcium level.
High phosphate levels also block 1-alpha hydroxylase, a kidney enzyme needed for activating vitamin D. With less active vitamin D, less calcium gets absorbed in the intestine, causing less calcium and phosphate to be reabsorbed by the kidneys, resulting in weaker bones. Over time, bone density reduces and this can lead to abnormal bone structure, which could present itself as bone pain and fractures.
Hyperphosphatemia is also associated with tumor lysis syndrome, where it is accompanied by high amounts of potassium, purines, and proteins in the body, potentially causing an increase in uric acid and urea. Therefore, high uric acid and nitrogen levels in the blood are common complications of tumor lysis syndrome.
In a condition such as Rhabdomyolysis, a protein called myoglobin is released from damaged tissues, which can cause an acute kidney injury.
In patients who have just recovered from an acute kidney injury, high calcium levels can occur due to calcium and phosphate deposits within the body tissues being mobilized in response to a drop in blood phosphate levels.
