Regulation of Ca2+, Pi and Mg2+ Balance Flashcards
Ca2+
Ca2+
Ca2+
Ca2+
In what forms does Calcium exist in our body?
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.
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?
total plasma level: 5.0 mEq/L
biologically active plasma level: 2.4 mEq/L
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?
Multiply plasma calcium by .6 because we can only calculate the filterable amount.
As we have said, Ca+ can be bound to proteins, such as plasma albumin.
Discuss why [hydrogen] and [calcium] are considered frenemies.
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.
Hypoalbuminemia–> ____ plasma Ca2+
Hyperalbuminemia–> _____ plasma Ca2+
- 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
Another name for calcitriol is __________
Vitamin D
Role of calcitriol (vitamin D)
- 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.
Overall: the net effect of calcitriol is to increase serum Ca2+ and Pi.
How does it so in the:
- bone
- instestine
- kidney
-
Bone
- Promotes osteoid mineralization by controlling the proper ratio of calcium and phosphate.
- Stimulates osteoclasts to resorb (break down) bone
-
Intestine
- Increases calcium and phosphate absorption
-
Kidney
- Increases calcium and phosphate reabsorption
What does calcitonin do?
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.
Calcitonin is used to treat:
- Osteoporosis
- Paget’s disease
- Hypercalcemia
Main fx of PTH
- Increase serum Ca2+
- Decrease serum Pi
PTH acts on the [bone, intestine and kidney].
What are its effects on each?
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
Excess PTH can cause what (3):
1. Hypercalcemia
2. Hypophosphatemia
3. Hypercholermic metabolic acidosis
What is the primary way our body senses Ca2+ levels?
CaSR (Calcium sensing receptor)
How does CaSR work?
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.
Recall: What is the role of NKCC2 channels in Ca2+ concentration?
- 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.
Draw what happens when we have low plasma Ca2+
Draw how we obtain high plasma Ca2+.
What are the tubular sites and mechanisms of Ca2+ reabsorption?
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.
Ca2+ reabsorption in the proximal tubule
- 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.
In the proximal tubule, how do volume contraction and expanision affect Ca2+ reabsorption?
- 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.
Ca2+ reabsorbtion in the thick ascending limb
Why does ADH stimulate Ca2+ reabsorption in the thick ascending limb?
- 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.
Ca2+ reabsorption in the DT
Acidemia _____ Ca2+ excretion by ________.
Alkalemia _____ Ca2+ excretion by ________.
Acidemia increases Ca2+ excretion by inhibiting TRPV5.
Alkalemia decreases Ca2+ excretion by stimulating TRPV5.
Draw renal handling of decreased Ca2+
Is Ca2+ secreted in the kidney?
No.
60% of plasma calcium can be filtered at the glomerulus. Why?
Because 40% is bound to proteins.
summary of Ca2+ renal regulation
____% of phosphate is reabsorbed by the PT.
What are the 3 big players?
80% of [phosphate] is reabsorbed by the PT.
Big players are:
- Na+/Pi transporters
- PTH and Ca2+
- FGF-23
Na+/Pi symporter
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.
FGF-23 receptors help us to excrete phosphate. What secretes FGF-23 and in response to what?
FGF-23 is secreted by the bone is response to [PTH, calcitriol and hyperphosphatemia] and increases phosphate excretion.
Calcitriol is made by _______________ and converted from inactive form –> active form by _____________, which is regulated by what 3 things?
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
What inhibits renal 1alpha-hydroxylase?
High Ca2+ (CaSR)
Some vitamin D can get filtreed at the glomerulus. If so, what happens?
It undergoes endocytosis by PT cells and is reabsorbed.
What are the major regulatory factors of Ca+ and phosphate transport? (6)
- FGF-23
- PTH, decreases serum phosphate by increasing renal excretion
- 1,25 (OH)2D3- increases serum phosphate by increasing intestinal phosphate absorption
- Insulin- lowers serum levels by shifting P into cells
- Dietary phosphate intake
- Renal function
What is the most important hormone that regulates Pi excretion?
PTH
Increase PTH –> inhibits Na/Pi transporters and Na+/H antiporter on the apical membrane of PT cells.
Chronic acidosis ____ Pi excretion
Chronic alkalosis ____ Pi excretion
Chronic acidosis increases Pi excretion
Chronic alkalosis decreases Pi excretion
What is calbindin?
Calbindin is a Ca2+ buffer that prevents the apoptosis of cells when there is too much intrallceular Ca2+
In the PT:
Ca is mainly reabsorbed paracellular. However, it can be transported transcellular via what two mechanisms?
- Ca2+ ATPase
- Na/Ca2+ exchanger
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?
Apical cell membrane has [TRPV5/V6 receptors]
BL membrane has NCE (Na/Ca2+ exchanger)
What stimulates calcitonin to be released?
Hypercalcinemia.
Decrease in ECV will cause what?
+ 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—
Metabolic alkalosis
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.
Mg reabsorption in the proximal tubule
20% Mg is reabsorbed in the PT via paracellular following Na and h2o.
Mg reabsorption in the TAL
70% of Mg reabsorption occurs in the TAL.
- Reabsorption will depend on the NKCC2 transporter, which creates a + TEPD that will drive Mg+ reabsorption.
*
What can inhibit Mg reabsorption in the TAL?
High Ca2+–> + CaSR–> inhibit the NKCC2 transporter.
This disrupts the + TEPD that would cause Mg to move paracellulary, which decreases reabsorption.
Mg+ reabsorption in the DT?
10% of reabsorption of Mg occurs.
[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.
Dietary depletion of Mg will do what to Mg reabsorption?
Increase via paracellular transport
What 3 things cause increase Mg reabsorption?
1. PTH
2. Metabolic alkalosis- increases paracellular permeability
3. ECF volume contraction
What causes a decrease in Mg reabsorption? (2)
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.
