Phosphate, calcium and magnesium homeostasis

Definitions & Key takeaways

Phosphate, calcium, and magnesium are essential minerals that play important roles in various bodily functions, including bone health, nerve function, and muscle contractions. The body maintains a delicate balance or "homeostasis" of these minerals through a complex interplay of hormones, enzymes, and other regulatory mechanisms.

Phosphate plays a role in bone and teeth formation, and in the synthesis of DNA and RNA. Calcium is also essential for the formation of bones and teeth, muscle contractions, and nerve function. Magnesium is important for the formation of bones and teeth, and for muscle contractions and nerve function. Imbalances in these minerals can lead to various health problems such as osteoporosis, kidney stones, and muscle weakness or cramps.

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Phosphate is a negative ion noted as PO4, while calcium, noted as Ca and magnesium, noted as Mg, are positive ions. Now, about 85 percent of the phosphate, along with 99 percent of calcium and about 60 percent of magnesium are located in the bone matrix.
Phosphate and calcium combine to form calcium phosphate, which makes up the hard bone matrix of bones and teeth, and magnesium helps strengthen it.
Okay, now, let’s start talking specifics about phosphate. The remaining 15 percent of phosphate is found almost entirely in the intracellular fluid, or ICF, while only less than 0.5 percent is found in the extracellular fluid, or ECF.
Now, most of the ECF is made up of plasma and in the plasma, 90% of phosphate circulates free, while 10 percent is bound to plasma proteins.
Phosphate plasma levels range between 2.5 and 4.5 milligrams per deciliter. Phosphate is a component of nucleotides that make up the DNA and RNA, high-energy molecules, like adenosine tri-phosphate and metabolic intermediates.
Phosphate also acts as a buffer for hydrogen. Okay, now, phosphate comes from our diet and the daily recommended phosphate intake is about 1 gram per day and we can get it from chicken, turkey or pork.
Once ingested, phosphate is absorbed in the GI tract into the bloodstream and then goes where it’s needed- such as the bone- and the rest is excreted.
Okay, let’s see how phosphate is handled by the kidneys. See, the kidneys are made up of lots and lots of nephrons, and each nephron is made up of a renal corpuscle and a renal tubule.
The renal corpuscle, in turn, is made up of the glomerulus, which is a tiny clump of capillaries, and Bowman’s capsule surrounding it.
So, blood gets to the glomerulus through the afferent arteriole, which is a branch of the renal artery, and leaves the glomerulus through the efferent arterioles.
These vessels act like a coffee filter, allowing everything but red blood cells and proteins to pass from the bloodstream into Bowman’s capsule - which is connected to the renal tubule.
And the resulting fluid is called filtrate. Now, upon exiting the glomerulus, the efferent arterioles divide into capillaries a second time, forming the peritubular vessels, which wrap around the segments of the renal tubule: the proximal convoluted tubule, the U- shaped loop of Henle, which has a descending and ascending limb, the distal convoluted tubule, and the collecting duct.
As filtrate passes through the renal tubule, ions like phosphate, calcium and magnesium are filtered from the capillaries into the lumen of the tubule, and reabsorbed from the lumen into the capillaries, depending on the amount of sodium in the bloodstream.
The phosphate from the plasma that isn’t bound to proteins, specifically about 90 percent of it will be filtered by the glomerular capillaries.
Next, in the proximal convoluted tubule or in the PCT, 70 percent of the filtered phosphate is reabsorbed. This is done by a sodium-phosphate cotransporter located in the proximal tubule cells.
Okay, now, phosphate actually has a so called transport maximum or T m for short. This means that at some point, the sodium-phosphate cotransporters get saturated with phosphate.
When this happens, the T m is reached and the remaining phosphate in the lumen is excreted. Okay, let’s move on and talk about calcium.
The 1 percent of calcium that’s not in the bones is found in the ICF and the ECF - specifically in the plasma. Plasma calcium concentration is about 5 to 10 milliequivalents per liter and it can be found in three forms: about 40 percent of the plasma calcium is bound to proteins like albumin, 10 percent is bound to anions like phosphate or citrate and the remaining 50 percent is the ionized or free form.
Calcium is essential for muscle contraction, enzyme activity and blood coagulation. It also helps with releasing neurotransmitters from neurons, as well as releasing hormones from the endocrine glands.
Calcium also comes from our dairy products like milk, cheese and yoghurt, and the recommended daily intake is about 1 gram per day.
Once ingested, it’s absorbed into the bloodstream and just like with phosphate, most of it goes to the bone. The rest circulates the bloodstream either freely or bound to plasma proteins or anions such as phosphate or citrate, and some of it is excreted by the kidneys.
So inside the kidneys, unbound plasma calcium is filtered by the glomerular capillaries into the Bowman’s capsule and it enters the renal tubule.
In the PCT, about 67 percent of the filtered calcium is reabsorbed, which is exactly the same percentage as sodium reabsorption in the PCT.
This is not a coincidence, as studies suggest that calcium reabsorption may be secondary to sodium and water reabsorption in the PCT - but the exact mechanism is still not clear.
As a result, if sodium reabsorption is inhibited, calcium reabsorption will be inhibited too and when sodium reabsorption is high, like with dehydration, calcium reabsorption is increased as well.
In the TAL, about 25% of the filtered calcium is reabsorbed and it’s also tightly coupled with sodium reabsorption. In the TAL, there’s the sodium-potassium-chloride cotransporter or NKCC2, which reabsorbs sodium, potassium, and chloride into the bloodstream.
As such, they shuttle one sodium into the cell, down its concentration gradient, and that powers the movement of one potassium and two chlorides into the cell as well.
Now, the Na/K ATPase pumps 3 sodium ions into the interstitial fluid in exchange for letting two potassium ions into the cell in order to maintain the low sodium concentration inside the cell.
Finally, both chloride and potassium move from the cell back into the lumen of the TAL, through special channels on the apical side of the cells that simply “leak” these ions passively.
The passive movement of potassium generates an electrochemical gradient- also called a lumen positive potential difference- that increases the reabsorption of calcium and magnesium through a paracellular pathway - meaning, these ions don’t use any channels, but rather they sneak between two epithelial cells and go back in the bloodstream.
Finally, the distal tubule reabsorbs about 8 percent of the calcium and here’s where calcium reabsorption is finely tuned.
In the distal tubule, calcium reabsorption is not coupled with sodium reabsorption, and it’s regulated by a hormone called PTH, made by the parathyroid glands in the neck.
In fact, both calcium and phosphate homeostasis is regulated by PTH. So, when blood calcium levels decrease, that stimulates PTH secretion.
PTH acts on 3 organs. In the bone, it activates osteoclasts, which are the cells that break down bone tissue, and as a result, calcium and hydrogen phosphate are released into the bloodstream.
PTH also increases intestinal absorption of calcium. Finally, in the kidneys, PTH binds to a specialized receptor on the surface of distal tubule cells, which triggers an intracellular signalling pathway that ends up increasing calcium reabsorption.
To regulate phosphate excretion, PTH inhibits the sodium-phosphate cotransporter in the PCT, decreasing phosphate reabsorption, and increasing urinary excretion of phosphate - also called phosphaturia.
Calcium homeostasis in particular is also regulated by two other molecules: calcitonin, which is produced by the parafollicular cells of the thyroid gland, and vitamin D.
Calcitonin does the exact opposite of PTH, so it decreases plasma calcium levels and increases renal calcium excretion. Finally, vitamin D promotes calcium absorption in the gut, so it increases plasma levels of calcium.
Finally, just a few words on magnesium. The 40% of magnesium that’s not in the bones is distributed in muscles and other soft tissues.
Only about 1 percent of magnesium, or a normal range of 1.4 to 2 milliequivalents per liter, is found in the plasma. Just like with calcium, the total plasma magnesium can be divided into three fractions: about 20 percent of the magnesium is bound to proteins, then there’s magnesium bound to anions like phosphate and citrate and free, ionized magnesium.
Magnesium acts as a cofactor in a lot of enzymatic reactions. Some examples of reactions include glucose and fat breakdown, the production of antioxidants like glutathione, enzymes and proteins, synthesis of DNA and RNA, as well as regulation of cholesterol production.
Because of its crucial role in enzymatic reactions, magnesium helps maintain good nerve and muscle function, including the cardiac muscle - so symptoms of magnesium deficiency include muscle spasms and cardiac arrhythmias.
We get magnesium from foods like kale, avocado and bananas, and the daily recommended intake is about 400 milligrams per day.
From the GI tract, it gets into the bloodstream and circulates either bound or unbound to plasma proteins and also some of it is excreted.
Okay, let’s see how the kidneys handle magnesium. About 80 percent of the magnesium from the plasma can be filtered by the glomerular capillaries, since 20 percent is bound to proteins and can’t be filtered.
In the PCT, about 30 percent of the filtered magnesium is reabsorbed. This is thought to be a passive process that’s driven by sodium reabsorption.
In the TAL about 60 percent of the filtered magnesium is reabsorbed through a paracellular way. Alright, as a quick recap, phosphate, calcium and magnesium are mostly found in the bone matrix.
Calcium and phosphate make up the bone matrix, and magnesium strengthens it. Phosphate plasma levels range between 2.5 and 4.5 milligrams per deciliter.
Phosphate is mostly reabsorbed in the PCT using the sodium-phosphate cotransporter. Calcium plasma levels are about 5 to 10 milliequivalents per liter.
60% of calcium is mostly reabsorbed in the PCT through a mechanism that’s tightly coupled with sodium reabsorption, while 25 percent of it is reabsorbed in the TAL through a paracellular pathway.
Both calcium and phosphate are regulated by PTH, which increases phosphate excretion and increases calcium reabsorption.
Calcium is also regulated by calcitonin which decreases calcium reabsorption and vitamin D that promotes calcium absorption in the gut.
Magnesium plasma levels are about 1.4- 2 milliequivalents per liter. About 30 percent of the filtered magnesium is reabsorbed in the PCT, 60 percent of it is reabsorbed in the TAL through a paracellular pathway, while in the distal tubule only 5 percent magnesium is reabsorbed.