Divalent Cations Flashcards
Where is almost all of the calcium in our body contained? Where is the remaining calcium stored?
> 99% is stored in bone
0.1% in the ECF
Calcium is important for… (4)
- bone formation
- blood coagulation
- cell growth
- regulating the threshold for excitation in nerves and muscles
Where is almost all of the phosphate in our body contained? Where is the remaining phosphate stored?
85-90% is stored in bone
10-15% in cells
1% in ECF
What is the importance of phosphate for our cells? Wha about our urine?
Cells: phosphate is part of our DNA, RNA, ATP
Urine: phosphate is an important urinary buffer
The calcium and phosphate in bone exist as…
hydroxyapatite
Ca10(PO4)6(OH)2
2 factors that determine calcium homeostasis
- Total amount of calcium in the body
- Distribution of calcium between bone and the ECF compartments
Total amount of calcium in the body depends on…
GI tract absorption vs renal excretion
The distribution of calcium between bone and ECF compartments depends on…
parathyroid hormone
Movement of calcium between ECF and bone is mediated by…
hormone PTH
Of the total calcium in our body, 40% is… and 60% is…
40% is protein-bound
60% is ultrafilterable.
Ultrafilterable means it can freely pass through the filtration membrane of the kidneys.
Two types of ultrafilterable calcium and their percentages.
Complexed to anions (10%)
Ionized calcium (50%)
What is PTH? When and where is it secreted?
Parathyroid hormone, a polypeptide secreted by parathyroid glands (4) in response to a decrease in plasma ionized calcium.
A drop in calcium levels is sensed by…
a calcium-sensing receptor in the parathyroid glands.
How does PTH raise plasma calcium levels? (3)
- Stimulates bone resorption (release of Ca and phosphate from bone)
- Increases calcium reabsorption in the GI tract
- Increases calcium reabsorption in the kidneys
How does PTH increase intestinal calcium. reabsorption?
Increases 1-alpha hydroxylase, an enzyme that helps produce calcitriol (active vitamin D).
Calcitriol promotes calcium reabsorption from the gut.
What are the 3 types of disease states where PTH levels are too high?
Primary, secondary and tertiary hyperparathyroidism
Define primary hyperparathyroidism
Overproduction of PTH due to an adenoma (benign tumour) on one of the parathyroid glands.
Characterized by:
- Hypercalcemia (high Ca)
- Hypophosphatemia (low PO3)
Define secondary hyperparathyroidism
Hyperplasia of all 4 parathyroid glands seen in advanced chronic kidney disease (CKD).
Characterized by:
- High plasma phosphate
- Low plasma calcium
- Low calcitriol
Define tertiary hyperparathyroidism
Usually seen in long-term dialysis patients. Prolonged secondary hyperparathyroidism causing glands to start releasing PTH autonomously (acts like primary HPTH but all 4 glands are involved).
Characterized by:
- Hypercalcemia (high Ca)
- High plasma phosphate
What is calcitriol? What is its main action?
It is active vitamin D (1,25-dihydroxy-cholecalciferol).
Its main action is to enhance calcium and phosphate reabsorption from the gut. This makes more calcium available for bone formation (also prevents hypocalcemia and hypophosphophatemia).
What stimulates the production of calcitriol? (2)
- Low calcium (causing high PTH)
- Low phosphate
How does calcitriol raise calcium and phosphate levels? (3)
- Increases calcium and phosphate reabsorption from the GI tract
- Works synergistically with PTH to stimulate bone resorption
- Works synergistically with PTH to enhance Ca reabsorption in the kidney
How does calcitriol feed back on PTH?
While PTH stimulates calcitriol production, calcitriol feeds back to suppress PTH production (by stimulating a calcitriol receptor on the PTH glands).
What are the two types of receptor on the parathyroid glands?
- Calcium-sensing receptor (CaSR)
- Calcitriol receptor
PTH mobilizes PO4 from bone, yet its net effect is to lower PO4 in the body. How?
Because PTH also increases renal excretion of PO4, which overpowers the bone resorption.
Why does PTH lower PO4 (why does our body not want excessive PO4 when trying to increase Ca levels)?
Phosphate can start to complex with calcium, which decreases free calcium in the blood. Therefore, PTH increases calcium and promotes PO4 excretion. :)
What is calcitonin? What stimulates its production? What is its action?
Peptide hormone produced by C cells of the thyroid gland. It is stimulated by an increase in serum Ca. It inhibits bone resorption.
How is calcium reabsorbed in the PCT?
Reabsorbed passively down the favourable electrochemical gradients created by sodium and water reabsorption (paracellularly).
How is calcium reabsorbed in the thick ascending limb of the loop of Henle?
Recycling of potassium through ROMK channel creates a positive charge in the tubular lumen. This drives calcium ions out of the tubular lumen (paracellular movement down electrical gradient).
What is the function of the calcium-sensing receptor on the basolateral side of the thick ascending limb of LOH?
The CaSR detects extracellular calcium concentrations in the blood and interstitial fluid surrounding the TAL.
If serum calcium is high, it will decrease reabsorption. If serum calcium is low, it will increase reabsorption.
Where is the calcium-sensing receptor (CaSR) expressed? (2)
Multiple tissues, including parathyroid gland and kidney (basolateral membrane of TAL)
What is the role of the CaSR in the kidney? What is its role in the parathyroid glands?
Parathyroid glands: Detects calcium levels to either increase or decrease PTH
Kidney: Detects calcium levels to increase or decrease paracellular Ca reabsorption
How is calcium reabsorbed in the distal convoluted tubule?
8% of filtered calcium gets reabsorbed in the DCT.
Ca reabsorption in the DCT is upregulated by PTH.
What part of the nephron is under the influence of PTH?
PTH upregulates Ca reabsorption in the distal convoluted tubule (DCT)!
What is the only part o the nephron in which calcium and sodium reabsorption are NOT coupled?
DCT
(reabsorption of Ca in DCT is hormonally regulated)
Other than hormones and electrochemical gradients, what 2 other factors regulate calcium reabsorption by the nephron?
- The filtered load of calcium (GFR x ionized calcium)
- Acidosis
How does the filtered load of calcium impact calcium reabsorption in the nephron?
Higher filtered loads generally lead to increased absolute calcium reabsorption, and vice versa.
How does acidosis and alkalosis impact calcium reabsorption in the nephron?
Acidosis: increases calcium excretion
Alkalosis: decreases calcium excretion
Common causes of hypercalcemia (6)
- Primary hyperparathyroidism
- Excess production of calcitriol (e.g. sarcoidosis)
- Excess ingestion of calcium or active vit. D
- Malignancy (usually due to calcium release from bones)
- Prolonged immobilization
- Thiazie diuretics
How can thiazide diuretics cause hypercalcemia?
Thiazide diuretics result in volume contraction (hypovolemia). To restore intravascular volume, the kidneys will reabsorb more sodium (and thus water) in the PCT. This creates favourable electrochemical gradients for passive reabsorption of calcium in the PCT (paracellular).
What are the symptoms of hypercalcemia? (4)
Think of the mnemonic!
- Bone pain
- Kidney stones
- Poor appetite, nausea, vomiting, abdominal pain
- Confusion, lethargy
Bones, stones, groans & psychiatric overtones.
Describe the normal physiologic response to hypercalcemia.
Decreased PTH
- Less Gi absorption
- Less bone resorption
- Less kidney reabsorption
Decreased 1,25D
- Less GI absorption
- Less bone resorption
Stimulation of CaSR in kidney
- Less reabsorption in the TAL
Increased calcitonin
- Less bone resorption
Causes of hypocalcemia (4)
- Hypoparathyroidism
- Vitamin D deficiency (extreme)
- Low magnesium
- Chronic kidney disease (CKD)
Name 2 causes of hypoparathyroidism
- Congenital
- Removal of parathyroid glands
Symptoms/signs of hypocalcemia (3)
- Neuromuscular irritability
- Seizures
- Arrhythmias
Describe the normal physiologic response to hypocalcemia. (3)
- Increased PTH secretion
- Increased bone resorption
- Increased absorption in GI
- Increased reabsorption in kidney
- Increased 1,25D - Increased 1,25D
- Increased GI absorption - Decreased stimulation of CaSR
- Increased paracellular uptake in TAL
- Increased PTH secretion by parathyroid glands
Describe the distribution of phosphate in the body (percentages).
Bone (85-90%)
Cells/ICF (10-15%)
ECF (<1%)
~10% is protein-bound.
How much total body phosphate is protein-bound?
Only about 10%
What regulates phosphate homeostasis? (2)
- The amount of phosphate in the body
- Distribution of phosphate between bone and the ICF and ECF compartments
What determines the amount of phosphate in the body? How is phosphate homeostasis maintained in a steady state?
The amount of phosphate in the body is determined by GI absorption vs renal excretion. In a steady state, GI absorption = renal excretion.
What stimulates GI absorption of phosphate?
Calcitriol
Release of phosphate from bone is always associated with…? Why?
Always associated with release of calcium from bone (because the same hormones that stimulate calcium resorption - PTH & calcitriol - stimulate PO4 resorption).
What stimulates phosphate release from bone?
PTH and calcitriol
How is phosphate handled in the nephron?
- PO4 is mostly freely filtered through glomerulus (only 10% is bound to plasma proteins)
- The majority of PO4 reabsorption occurs in the PCT
What transporter mediates PO4 reabsorption in the PCT?
Na-phosphate co-transporter (luminal membrane of PCT).
Phosphate excretion is stimulated by 3 factors (name them). What do they act on to have their effect?
- Plasma phosphate
- PTH
- FGF-23
They inhibit the Na-PO4 co-transporter in the PCT, inhibiting reabsorption (increase excretion).
What happens if a patient has a low phosphate diet or hypophosphatemia?
A low phosphate diet (i.e. low serum PO4) results in upregulation of the Na-PO4 co-transporter, which increases PO4 reabsorption.
Causes of hypophosphatemia (3)
- GI losses
- Renal losses (Fanconi syndrome, primary hyperparathyroidism)
- Shift from ECF into ICF (acute alkalosis, B-adrenergic stimuli)
How does high PO4 affect PTH secretion? (3)
- High PO4 directly stimulates PTH secretion
- High PO4 reduces serum Ca by binding Ca
- Decreases 1-alpha-hydroxylase, which decreases calcitriol, which decreases serum Ca, which stimulates PTH
How does PTH mediate renal phosphate excretion?
High PTH decreases activity of the Na-phosphate cotransporter in the PCT, resulting in less phosphate reabsorption (more phosphate excretion).
What happens to calcium and phosphate balance in renal failure? What happens to PTH?
Low GFR decreases the filtered load of PO4, which decreases the amount of excreted PO4 (increase in serum PO4).
Increased serum PO4 binds Ca and reduces calcitriol, resulting in decreased Ca levels.
Low calcium and high PO4 increase PTH secretion.
Note: This is secondary hyperparathyroidism!
3 causes of hyperphosphatemia
- Renal failure (most common)
- Hypoparathyroidism
- Release of phosphate from cells (muscle breakdown after crush injury or tumour cells after chemo - tumour lysis syndrome)
Describe the normal response to hyperphosphatemia. (3)
- Decreased calcitriol (less PO4 absorption in GI)
- Increased PTH (increased renal PO4 excretion)
- Direct downregulation of Na-PO4 cotransporter (increased renal PO4 excretion)
What is Fanconi syndrome?
A congenital or acquired condition in which patients have proximal tubular dysfunction causing glucose, amino acid, phosphate and bicarbonate wasting in their urine, as well as hypokalemia. Can result in hypophosphatemia (low PO4).
Describe the distribution of magnesium in the body (percentages). How much is bound to protein? How much is free?
60-65% in bone
35-40% intracellular
~1% ECF
30% bound to protein
70% free
What is the most important determinant of renal magnesium excretion?
Plasma Mg concentration
How is plasma magnesium reabsorbed in the TAL?
Exactly like Ca: By passive paracellular reabsorption down electrochemical gradients generated by Na and water.
What transporter in the DCT drives Mg reabsorption?
TRPM6 (active transcellular reabsorption)
Causes of lowplasma magnesium (2)
- GI losses
- Renal losses
Name 3 causes of renal magnesium losses
Diabetes
Diuretics
Other drugs that block Mg reabsorption in the TAL or DT (e.g. chemo drugs)
