Regulation of Ca2+, Pi and Mg2+ Balance

Question 1

Ca2+

Ca2+

Ca2+

Ca2+

Question 2

In what forms does Calcium exist in our body?

Answer 2

1. Ionized

2. Bound to plasma proteins

3. Complexed in a non-ionized form.

-The ionized forms and the non-ionized forms are considered biologically active.

Question 3

As we have discussed, 99% of calcium is stored in bone, 1% in ICF and 0.1% in ECF.

What is the total plasma level and the biologically active plasma level?

Answer 3

total plasma level: 5.0 mEq/L

biologically active plasma level: 2.4 mEq/L

Question 4

Recall that protein-bound solutes cannot be filtered by the glomerulus. Only 60% of calcium is not protein-bound: therefore, when you calculate filtered load, you have to do what?

Answer 4

Multiply plasma calcium by .6 because we can only calculate the filterable amount.

Question 5

As we have said, Ca+ can be bound to proteins, such as plasma albumin.

Discuss why [hydrogen] and [calcium] are considered frenemies.

Answer 5

H+ and Ca2+ compete for binding on albumin, which is negatively charged.

• Increase H+ ions (acidosis) –> bind to albumin–> increase the amount of free Ca2+–> increase the filtered load of Ca2+.
• Decrease in H+ ions (alkalosis) –> decrease the amount of free Ca2+ bc it is bound to albumin. This can predispose ppl to hypocalcemic tetany.

Question 6

Hypoalbuminemia–> ____ plasma Ca2+

Hyperalbuminemia–> _____ plasma Ca2+

Answer 6

• Hypoalbuminemia–> increases plasma Ca2+ because there are less albumin proteins for Ca2+ to bind to
• Hyperalbuminemia–> decrease plasma Ca2+ because there are more albumin proteins for Ca2+ to bind to

Question 7

Another name for calcitriol is __________

Answer 7

Vitamin D

Question 8

Role of calcitriol (vitamin D)

Answer 8

• Calcitriol (vitamin D) works with PTH to reabsorb bone by stimulaing osteoclasts (breaks up bone)–> Increase plasma concentrations of Ca2+ and phosphate
• It has different effects on bone, kidney and intestines.

Question 9

Overall: the net effect of calcitriol is to increase serum Ca2+ and Pi.

How does it so in the:

1. bone
2. instestine
3. kidney

Answer 9

1. Bone
   
   1. Promotes osteoid mineralization by controlling the proper ratio of calcium and phosphate.
   2. Stimulates osteoclasts to resorb (break down) bone
2. Intestine
   
   1. Increases calcium and phosphate absorption
3. Kidney
   
   1. Increases calcium and phosphate reabsorption

Question 10

What does calcitonin do?

Answer 10

Calcitonin does the opposite of calcitriol and PTH: decrease plasma Ca2+ levels by acting on the [bone and kidney].

• Bone: Decreases osteoclast activity and number.
• Kidney: + excretion of Ca2+ and P.

Question 11

Calcitonin is used to treat:

Answer 11

1. Osteoporosis
2. Paget’s disease
3. Hypercalcemia

Question 12

Main fx of PTH

Answer 12

1. Increase serum Ca2+
2. Decrease serum Pi

Question 13

PTH acts on the [bone, intestine and kidney].

What are its effects on each?

Answer 13

Bone

• Increases osteoclastic activity–> Ca2+ resorption

Intestine

• Increases Ca2+/Pi absorption indirectly by working with Calcitriol.

Kidney

• Increases reabsorption of Ca2+, mainly in the DCT
• Decreases reabsorption of Pi in the PCT
• Decreases Na/H antitransporter
• Decreases HCO3- reabsorption

Question 14

Excess PTH can cause what (3):

Answer 14

1. Hypercalcemia

2. Hypophosphatemia

3. Hypercholermic metabolic acidosis

Question 15

What is the primary way our body senses Ca2+ levels?

Answer 15

CaSR (Calcium sensing receptor)

Question 16

How does CaSR work?

Answer 16

CaSR is expressed on the interstitial (BL) side of the cell (detecting ECF calcium levels).

• When plasma Ca2+ is high, CaSR is activated to inhibit reabsorption of calcium on the apical side, specifically by inhibiting NKCC2 channels.

Question 17

Recall: What is the role of NKCC2 channels in Ca2+ concentration?

Answer 17

• NKCC2 channels are needed for the paracellular reabsorption of Ca2+, because they cause a net influx of negative ions by allowing of [Na+ in, a K+ in, two Cl-] in, and a K out (via potassium leak channels).
• This net negative influx creates a net positive electrical gradient in the intertubular fluid, which allows Ca2+ to be reabsorbed paracellularly.

Question 18

Draw what happens when we have low plasma Ca2+

Answer 18

Question 19

Draw how we obtain high plasma Ca2+.

Answer 19

Question 20

What are the tubular sites and mechanisms of Ca2+ reabsorption?

Answer 20

Proximal tubule is the main site of calcium reabsorption (65-70%).

• The transport is passive and paracellular due to high concentration and follows sodium and water.

Thick ascending limb:“lumen positive voltage” established by the NKCC2 transporter drives Ca2+ reabsorption via a paracellular path.

• CaSR is located on the BL surface: increase in peritubular Ca2+ decreases Ca2+ reabsorption

Distal tubule actively reabsorbs only ~8% of Ca2+, but is the major site of regulation.

• DT has renal epithelial Ca2+ channels called “TRPV5” that is regulated by Calcitrol.
• Also has a Ca2+ binding protein (calbindin) that prevents adverse consequences (apoptosis) of excessive intracellular Ca2+ concentration.

Question 21

Ca2+ reabsorption in the proximal tubule

Answer 21

• Primarily paracellular: Ca2+ diffusion from the proximal tubule follows water and sodium – this means if sodium and water reabsorption decreases in the proximal tubule, so will the reabsorption of calcium (same with increase in sodium and water reabsorbtion).
• However, there are some channels for calcium to be transported transcellularly, and it is when this happens that calbindin becomes necessary.
• Reabsorbed via: Ca2+ ATPase, or a Na+/Ca2+ exchanger.

Because volume contraction is compensated for by an increase in the reabsorption of sodium and water, we see a concomitant increase in calcium reabsorption in times of volume contraction.

In times of volume expansion, the opposite is true.

Question 22

In the proximal tubule, how do volume contraction and expanision affect Ca2+ reabsorption?

Answer 22

• Because volume contraction is compensated for by an increase in the reabsorption of sodium and water, we see a increase in calcium reabsorption during volume contraction.
• Volume expansion–> opposite is true.

Question 23

Ca2+ reabsorbtion in the thick ascending limb

Answer 23

Question 24

Why does ADH stimulate Ca2+ reabsorption in the thick ascending limb?

Answer 24

• ADH increases reabsorption of NaCl in the thick ascending limb in order to increase the osmolality of the medullary interstitium.
• Because Ca2+ has a tendency to follow Na+, ADH also increases reabsorption of Ca+ in the thick ascending limb.

Question 25

Ca2+ reabsorption in the **DT**

Answer 25

Question 26

Acidemia _____ Ca2+ excretion by \_\_\_\_\_\_\_\_. Alkalemia _____ Ca2+ excretion by \_\_\_\_\_\_\_\_.

Answer 26

Acidemia **increases** Ca2+ excretion by **inhibiting TRPV5.** Alkalemia **decreases** Ca2+ excretion by **stimulating TRPV5.**

Question 27

Draw renal handling of **decreased Ca2+**

Answer 27

Question 28

Is Ca2+ secreted in the kidney?

Answer 28

**No.**

Question 29

60% of plasma calcium can be filtered at the glomerulus. Why?

Answer 29

Because 40% is bound to proteins.

Question 30

summary of Ca2+ renal regulation

Answer 30

Question 31

**\_\_\_\_% of phosphate is reabsorbed by the PT.** What are the 3 big players?

Answer 31

**80%** of [phosphate] is reabsorbed by the PT. Big players are: 1. **Na+/Pi transporters** 2. **PTH and Ca2+** 3. **FGF-23**

Question 32

**Na+/Pi symporter**

Answer 32

**Na+/Pi symporter** is located in the early PT. * **Reabsorbed Na+ and Pi** across the apical membrane * Na+ moves across BL membrane via **Na+K ATPase.** * **Pi** moves across the BL membrane via its own transporter, which is unknown.

Question 33

**FGF-23 receptors help us to excrete phosphate.** What secretes FGF-23 and in response to what?

Answer 33

FGF-23 is secreted by the bone is response to **[PTH, calcitriol and hyperphosphatemia]** and **increases phosphate excretion.**

Question 34

Calcitriol is made by _______________ and converted from inactive form --\> active form by \_\_\_\_\_\_\_\_\_\_\_\_\_, which is regulated by what 3 things?

Answer 34

Calcitriol is made by **proximal tubule epithelial cells.** Calcitriol is converted from inactive form--\> active via **renal** **1-a hydroxylase,** which is upregulated by * Low Ca2+ * Low Pi * High PTH

Question 35

What inhibits **renal 1alpha-hydroxylase**?

Answer 35

**High Ca2+ (CaSR)**

Question 36

Some vitamin D can get filtreed at the glomerulus. If so, what happens?

Answer 36

**It undergoes endocytosis by PT cells and is reabsorbed.**

Question 37

What are the major regulatory factors of Ca+ and phosphate transport? (6)

Answer 37

1. FGF-23 2. PTH, decreases serum phosphate by increasing renal excretion 3. 1,25 (OH)2D3- increases serum phosphate by increasing intestinal phosphate absorption 4. Insulin- lowers serum levels by shifting P into cells 5. Dietary phosphate intake 6. Renal function

Question 38

What is the most important hormone that **regulates Pi excretion?**

Answer 38

**PTH** ## Footnote Increase PTH --\> inhibits Na/Pi transporters and Na+/H antiporter on the apical membrane of PT cells.

Question 39

Chronic acidosis ____ Pi excretion Chronic alkalosis ____ Pi excretion

Answer 39

Chronic acidosis **increases** Pi excretion Chronic alkalosis **decreases** Pi excretion

Question 40

What is calbindin?

Answer 40

Calbindin is a Ca2+ buffer that prevents the apoptosis of cells when there is too much intrallceular Ca2+

Question 41

In the PT: Ca is mainly reabsorbed paracellular. However, it can be transported transcellular via what two mechanisms?

Answer 41

1. Ca2+ ATPase 2. Na/Ca2+ exchanger

Question 42

Ca2+ in the distal tubule occurs at 8% and is the major site of regulation. However, due to the - TEPD, it must be reabsorbed actively. How?

Answer 42

Apical cell membrane has **_[TRPV5/V6 receptors]_** BL membrane has **_NCE (Na/Ca2+ exchanger)_**

Question 43

What stimulates calcitonin to be released?

Answer 43

Hypercalcinemia.

Question 44

Decrease in ECV will cause what?

Answer 44

+ sympathetics --\> increase Na2+ reabsorption in the PCT --\> Ca2+ reabsorption will then depend on the TEPD and solvent drag, which depends on Na+ reabsorption. *----this is the case we see in volume contraction---*

Question 45

Metabolic alkalosis

Answer 45

Metabolic alkalosis will decrease the amount of free Ca2+--\> Decreasing the amount that can be freely filtered --\> decreasing the amount we excrete and increasing reabsorption by stimulating **TRPV5.**

Question 46

Mg reabsorption in the proximal tubule

Answer 46

20% Mg is reabsorbed in the PT via paracellular following Na and h2o.

Question 47

Mg reabsorption in the TAL

Answer 47

70% of Mg reabsorption occurs in the TAL. * Reabsorption will depend on the NKCC2 transporter, which creates a + TEPD that will drive Mg+ reabsorption. *

Question 48

What can inhibit Mg reabsorption in the TAL?

Answer 48

**High Ca2+--\> + CaSR--\> inhibit the NKCC2 transporter.** This disrupts the + TEPD that would cause Mg to move paracellulary, which decreases reabsorption.

Question 49

Mg+ reabsorption in the DT?

Answer 49

10% of reabsorption of Mg occurs. ## Footnote [Mg] is the same outside and inside the cell. Thus, **electrical potential** will be the driver of Mg influx. TRPM6 receptors on the apical membrane will bring the Mg inside the cell and transport across the BL membrane is unknown.

Question 50

Dietary depletion of Mg will do what to Mg reabsorption?

Answer 50

Increase via paracellular transport

Question 51

What 3 things cause **increase Mg reabsorption**?

Answer 51

**1. PTH** **2. Metabolic alkalosis- increases paracellular permeability** **3. ECF volume contraction**

Question 52

What causes a **decrease in Mg reabsorption?** (2)

Answer 52

**1. Metabolic acidosis**- decreases the paracellular permeability of Mg **2. ECF volume expansion** due to less Na/H20 being reabsorbed, so less Mg is reabsorbed.