Ca2+,Pi,Mg2+ Regulation

Question 1

• What is normal plasma Ca2+ level

Answer 1

• 5.0 mEq/L

Question 2

• Where is Ca2+ stored in the body?

Answer 2

• 99% Bone
• 1% ICF
• 0.1% ECF

Question 3

• Normal level of biologically active plasma?

Answer 3

• 2.4 mEq/L

Question 4

• How much of Ca2+ is filterable at the glomerulus?
• Which Ca2+ is NOT freely filterable at the glomerulus?

Answer 4

• 60% (the filtered Ca2+ is the calcium that is ionized or diffusible complexes)
• Protein bound Ca2+

Question 5

• H+ and Ca2+ compete for binding on which plasma protein?
• Which is the stronger of the two?

Answer 5

• Albumin
• H+

Question 6

• Hypoalbuminemia _ plasma Ca2+
• Hyperalbuminemia _ plasma Ca2+

Answer 6

• Increases
• Decreases

Question 7

• Acidosis _ plasma Ca2+ levels
• Alkalosis _ plasma Ca2+ levels

Answer 7

• Increases (More acid, more H+ binding to albumin, less binding sites for Ca2+)
• Decreases (predisposes to hypocalcemic tetany-also why acute alkalosis can mimic hypocalcemia)

Question 8

• What is the name of the biologically active form of Vitamin D?

Answer 8

Calcitriol

(Has other names, but she said to focus on this one)

Question 9

• What is the overall goal of calcitriol?
• Through which receptor does calcitriol work?
• Where are these receptors located?

Answer 9

• Increase serum Ca2+ and Pi
• VDR (Vitamin D receptors)
• Throughout the body (we will talk about bone, intestines, and kidney)

Question 10

• How does calcitriol act on bone?

Answer 10

• Promotes osteoid mineralization
• Osteoclastic mediated bone resorption (taking Ca2+ out of bone and putting it back into the blood stream-remember goal is to increase overall serum Ca2+ and Pi levels)

Question 11

• How does calcitriol act on the intestine?

Answer 11

• Increases Ca2+ absorption (30% dietary intake)
• Increases phosporus absorption

Question 12

• How does calcitriol act on the kidney?

Answer 12

• Stimulates phosphate reabsorption
• Stimulates Ca2+ reabsorption (by acting on NKCC?*)

Question 13

• What is the overall goal of calcitonin?
• What is it stimulated by?

Answer 13

• Increased excretion of Ca2+ and Pi
• Decreases activity and number of osteoclasts
• Stimulated by hypercalcemia (makes sense since the overall goal is to increase excretion of Ca2+)
• ALSO OPPOSES PTH

Question 14

• How does calcitonin act on bone?

Answer 14

• Inhibits osteoclast mediated bone resorption (so keeps the Ca2+ in the bones and prevents it from coming back out into the blood stream)
• Also decreases the activity and number of osteoclasts

Question 15

• How does calcitonin act on the kidney?

Answer 15

• Promotes phosphate and Ca2+ excretion

Question 16

• Pharmacological doses of Calcitonin can be used to treat:

Answer 16

• Hypercalcemia
• Paget’s disease
• Osteoporosis (leaves Ca2+ in bone)

Question 17

• What is the overall goal of PTH?

Answer 17

• Increase Serum Ca2+ and Decrease Serum Pi

Question 18

• How does PTH work on bone?

Answer 18

• Increased osteoclastic resorption (which increases Ca2+ going from bone back into the bloodstream)

Question 19

• How does PTH work on intestinal cells?

Answer 19

• Increases Ca2+ and Pi ABsorption INDIRECTLY via Calcitriol

Question 20

• How does PTH act on the kidney?

Answer 20

• Stimulates reabsorption of Ca2+ in the DCT
• Decreases reabsorption of Pi in the PCT
• Decreases activity of the Na+/H+ antiporter
• Decrease in bicarbonate reabsorption

Question 21

• Excess PTH can cause

Answer 21

• Hypercalcemia
• Hypophosphatemia
• Hyperchloremic metabolic acidosis

Question 22

• What is the CaSR?
• Where is it located?
• What is it’s function?

Answer 22

• Ca2+ sensing receptor
• Located on the basolateral membrane of the cells of the Thick Ascending Limb of the LOH
• Inhibits Ca2+ reabsorption when plasma Ca2+ is high
• (Also inhibits the NKCC and K+ leak channels on APICal membrane)

Question 23

• How do you calculate filtered load of Ca2+?

Answer 23

Remember that only 60% of Ca2+ is freely filtered at the glomerulus (other 40% is bound to proteins, which are not, under normal circumstances, freely filterable)

Filtered Load= GFR x [Plasma Conc] x (% Filterability)

Filtered Load of Ca2+= GFR x [Plasma Conc] x 0.6

Question 24

• In which areas of the neprhon is Ca2+ reabsorption passive?
• In which areas is it active?

Answer 24

• Passive in the PCT and the TAL of LOH
• Active in the distal tubule (major site of regulation)

Question 25

* How much Ca2+ is reabsorbed in the PCT? * How is the Ca2+ reabsorbed?

Answer 25

* 65-70% * Primarily Paracellularly * Some reabsorbed transcellularly * Diffuses down conc gradient into cell via Ca2+ channels on apical membrane * Exits cell via Ca2+ ATPase or Na-Ca2+ antiporters located on the basolateral membrane

Question 26

* Volume contraction _ Ca2+ reabsorption * Why?

Answer 26

* Increases * Na+ and Ca2+ parallel each other in PT

Question 27

* How does Ca2+ reabsorption occur in the TAL? * Which hormone acts on the TAL to increase Ca2+ reabsorption and how does it do so?

Answer 27

* **Primarily paracellularly** (**reabsorption parallels Na+)** * **Dependent on TEPD (lumen + voltage**) * ADH-because it increases NaCl reabsorption in the TAL, and Ca2+ parallels Na+ so it is also reabsorbed)

Question 28

Loop diuretics inhibit _ reabsorption in the TAL of the LOH. They can thus be used (indirectly) to treat \_

Answer 28

* Na+ * Hypercalcemia (since Ca2+ reabsorption in the TAL parallels Na+ reabsorption)

Question 29

* ​Is the TEPD in the tubular lumen of the distal tubule positive or negative? * How does this impact Ca2+ reabsorption in the distal tubule?

Answer 29

* Negative * Requires Ca2+ reabsorption to be ACTIVE (requires ATP) since Ca2+ likes to be in the negatively charged lumen

Question 30

* **How is Ca2+ reabsorbed in the distal tubule?**

Answer 30

* Crosses **apical membrane via TRPV5/TRPV6 channels** * **Crosses basolateral membrane via Na+-Ca2+ exchanger**

Question 31

* What conditions/hormones act on the TRPV5 to ENHANCE Ca2+ reabsorption? * What conditions decrease activity of the TRPV5 and thus DECREASE Ca2+ reabsorption?

Answer 31

* PTH, Vitamin D, Calcitriol, **Alkalosis** * **Acidosis**

Question 32

* **How do you calculate filtered load of phosphate?**

Answer 32

* **Filtered load of phosphate= GFR x [Plasma conc of Pi] x 1** * **Use 1 as % filterability since Pi is freely filtered at the glomerulus**

Question 33

* How much Pi is reabsorbed in the proximal tubule? * How is Pi reabsorbed in the proximal tubule?

Answer 33

* 80% * **Reabsorption is primarily driven by the Na+/K+ ATPase on the basolateral membrane** * **This creates a gradient for Na+ to move into the cell** * **Na+-Pi transporter on the APICAL membrane** * **Pi crosses the BASOLATERAL membrane via its own unknown transporter**

Question 34

* How does **FGF23** regulate Pi reabsorption? * When is it secreted?

Answer 34

* Secreted by bone in response to PTH, calcitriol and hyperphosphatemia * **inhibits activity of the Na+-Pi symporter on the APICAL surface of the early proximal tubule**

Question 35

* Which enzyme converts Vitamin D into its highly active form? * Where is this enzyme located

Answer 35

* CYP1alpha (**renal one alpha hydroxylase)** * **Proximal tubule of the kidney**

Question 36

* What upregulates renal 1alpha-hydroxylase expression?\*

Answer 36

* Low calcium * Low phosphate * High PTH

Question 37

* What inhibits renal 1 alphahydroxylase expression?

Answer 37

* High Ca2+ (via CaSR)

Question 38

* What happens to the vitamin D that is filtered at the glomeruls=us?

Answer 38

* Undergoes endocytosis * Reabsorbed by PT

Question 39

* How does insulin impact Pi levels?

Answer 39

* Lowers serum levels by shifting Pi into cells

Question 40

\_ **is the most important hormone that regulates Pi excretion**

Answer 40

* **PTH** * PTH **inhibits Na+-Pi symporter on the APICAL membrane of the proximal tubule and inhibits the Na+/H+ antiporter on the APICAL membrane** * **PTH also works on the distal tubule to increase Ca2+ reabsorption**

Question 41

* Where is Mg2+ reabsorbed in the neprhon? * Where is most Mg2+ reabsorbed in the neprhon?

Answer 41

* Proximal tubule, thick ascending limb of LOH, Distal tubule**​** * **Most reabsorption of Mg2+ occurs in the thick ascending limb of the LOH**

Question 42

* How does Mg2+ reabsorption occur in the proximal tubule? * How much Mg2+ is reabsorbed here?

Answer 42

* Mg2+ reabsorbed paracellularly, following movement of Na+ and H2O * 20%

Question 43

* How is Mg2+ reabsorbed in the thick ascending limb of the LOH?

Answer 43

* Paracellularly * **Mg2+ reabsorption in TAL dependent on uptake of Na+ and K+ via NKCC2 (which depends on lumen positive voltage of TAL)**

Question 44

* How is Mg2+ reabsorbed in the distal tubule?

Answer 44

* **Crosses APICAL membrane via TRPM 6** * **Crosses BASOLATERAL membrane via unknown mechanism** * **Electrical potential is primary driver of Mg2+ influx into the cell (since Mg2+ concentration is similar intracellularly and extracellularly)**

Question 45

* **_Regulators of Mg2+ reabsorption_**

Answer 45

* Dietary depletion (increases reabsorption) * PTH (increases reabsorption) * Metabolic acidosis (decreases reabsorption by decreasing membrane permeability of Mg2+) * Metabolic alkalosis (increases reabsorption by increasing paracellular permeability of Mg2+) * ECF volume expansion (decreases reabsorption-Na+ reabsorption also decreasing d/t decreased activity of the NKCC at TAL) * ECF volume contraction (increases Mg2+ reabsorption)