BC 12/4/23: Regulation of Calcium, Magnesium, and Phosphate from Vander’s renal physiology 8th

Question 1

What is the most important hormone/factor in regulating urinary calcium and phosphorous reabsorption/excretion? And what is its net effect?

Answer 1

PTH. Overall net effect is to promote calcium reabsorption phosphorous excretion

Question 2

What are the effects of acidaemia and alkalaemia on calcium homeostasis in the kidney?

Answer 2

Acidaemia: increases urinary calcium excretion (stimulation of TRPV5 channel)
Alkalaemia: reduces urinary calcium excretion (inhibition of TRPV5 channel)

Question 3

What are the functions of iCa?

Answer 3

Ionized calcium is required for:
-Enzymatic reactions
-Membrane transport and stability
-Blood coagulation
-Nerve conduction
-Neuromuscular transmission
-Muscle contraction
-Vascular smooth muscle tone
-Hormone secretion
-Bone formation and resorption
-Control of hepatic glycogen metabolism
-Cell growth and division

Question 4

Major are the 2 major calcium homeostasis regulators?

Answer 4

• PTH (minute-to-minute)
• Calcitriol (day-to-day)

Question 5

What other hormones influence calcium homeostasis?

Answer 5

-FGF23
- Adrenal corticosteroids
-Estrogens
-Thyroxine
-Growth hormone
-Glucagon
-Prolactin

Question 6

What are the major target organs affected by calcium regulatory hormones?

Answer 6

• GI
• bone
• kidneys

Question 7

How is totCa distributed in the body?

Answer 7

-99% in skeleton as hydroxyapatite, Ca10(PO4)6(OH)2
-ECF (<1%)
-intracellular (0.01%)

Question 8

How can you find Calcium in plasma?

Answer 8

3 fractions:
- iCa (56%)
- Complexed Ca (10%)= bound to P, bicarbonate, sulfate, citrate, lactate) (10%)
- Protein bound (34%)

Question 9

How does low Ca cause tetany?

Answer 9

Hypocalcemia causes increased neuromuscular excitability by decreasing the threshold needed for the activation of neurons. As a result, neurons become unstable and fire spontaneous action potentials that trigger the involuntary contraction of the muscles, which eventually leads to tetany.
(From Vander’s: low levels of calcium fool sodium channels
into sensing more depolarization than actually exists, leading to spontaneous
firing of motor neurons. In turn, this firing triggers inappropriate muscle contraction,
called low-calcium tetany.)

Question 10

How does pH influences calcium level?

Answer 10

Increased pH (alkalosis)= increases protein binding, which decreases free calcium levels.
Acidosis= decreases protein binding, resulting in increased free calcium levels

Question 11

How is moment to moment regulation of plasma calcium achieved?

Answer 11

by moving calcium in and out of bone.

Question 12

T/F most of the dietary calcium is reabsorbed at the level of the jejunum.

Answer 12

F: Most dietary calcium simply passes through the GI tract to the feces.

Question 13

How is Ca absorbed in the small intestine?

Answer 13

Duodenum: active transcellular process= Calcium enters duodenal cells passively through Ca-selective channels (members of the TRP family), binds reversibly
to mobile cytosolic calcium binding proteins (calbindins), and is then
actively transported out the basolateral side via a Ca-ATPase and, to some extent, by a Na-Ca antiporter.
Lower small intestine: paracellular diffusion

Question 14

How much of the Ca is reabsorbed in the kidneys? And how much is secreted?

Answer 14

Reabsorbed 98% (65% in PCT, 20% in loop of Henle, rest in CDT and collecting duct), Secreted 0%

Question 15

How is Ca reabsorbed in the different portions of the kidneys?

Answer 15

• PCT: passive and paracellular transport. Water reabsorption in
  the PCT concentrates Ca and drives paracellular flux
• Thick ascending limb Henle’s loop: passive and paracellular transport. The
  lumen-positive potential is the major driving force.
• Distal tubule: active transcellular (same as GI tract= entrance via Ca-specific TRP channels, diffusion bound
  to calbindins and active exit across basolateral memb by a combination of
  Ca-ATPase and Na-Ca antiport activity.

Question 16

Why is saline the fluid of choice in hypercalcemia?

Answer 16

Increase Na= increase GFR= large amounts
of Ca-containing fluid pass through the kidneys to the urine.
Independent,
calcium-specific regulation of calcium excretion is exerted in the distal tubule via control of active calcium reabsorption.

Question 17

How is phosphate distributed in the body?

Answer 17

• bone (85%)= inorganic hydroxyapatite
• soft tissue (15%)= phospholipids, nucleic acids, phosphoprot.

Question 18

T/F most of the dietary phosphate is reabsorbed at the level of the small intestine.

Answer 18

T: 65%

Question 19

How is phosphate reabsorbed by the GI tract?

Answer 19

By paracellular diffusion and by transcellular active transport. The active component uses several different Na-phosphate symporters in the apical
membrane to bring phosphate into the intestinal enterocytes. The exit step is not characterized, but is presumed to be via a phosphate uniporter.

Question 20

T/F: the majority of phosphate in the blood is protein bound

Answer 20

F: only 5-10% if protein bound.

Question 21

How much of the filtered phosphate is reabsorbed in the PCT and how?

Answer 21

75%, Na-phosphate symporters (like in the GI tract) - tubular maximum-limited system= can be saturated

Question 22

How is the active form of vit D called? How is it produced?

Answer 22

Calcitriol. precursor is hydroxylated at the 25th position by the liver and then hydroxylated again at the first position by proximal tubular cells within the kidneys to yield the active form,.

Question 23

How do PTH and FGF23 redulate the production of calcitriol?

Answer 23

PTH stimulates it VS FGF23 inhibits it.

Question 24

What are the effects of calcitriol?

Answer 24

• stimulate transcellular
  absorption of Ca and, to a lesser extent, phosphate, by the duodenum
• stimulates the renal-tubular reabsorption
  of both calcium and phosphate
  = bone promoting hormone
• inhibits PTH (negative feedback)
• stimulated FGF23

Question 25

T/F PTH half life in plasma is approx 1h

Answer 25

F: <10min

Question 26

What are the stimuli for PTH secretion and what inhibits it?

Answer 26

Pro PTH:
-low Ca
- Acidosis
- catecholamines
- Prostaglandin E2
- High Phos
- Low calcitriol
- mild hypoMg for short period of time

Anti PTH:
- High iCa
- High Calcitriol (act on vit D rec in chief cells)
- prolonged/severe hypoMg (also reduces response of tissues to PTH)
- FGF-23 (fibroblast grow factor)

Question 27

What are the effects of PTH?

Answer 27

• PTH actions on bone acutely increase the movement of Ca and phosphate from the labile pool in bone into the ECF.
• PTH stimulates the bone remodeling process.
• PTH stimulates the hydroxylation step in the kidneys that generates calcitriol.
• PTH increases renal tubular calcium reabsorption (mainly DCT).
• PTH reduces the proximal tubular reabsorption of phosphate.

Question 28

T/F: constant high PTH promotes resorption of
hydroxyapatite VS intermittent administration promote
deposition

Answer 28

T. Primary hyperparathyroidism enhances bone reabsorption but intermittent PTH adm is used therapeutically in pt with osteoporosis to increase Ca deposition.

Question 29

Where if FGF23 (Fibroblast growth factor 23) synthetized and what are its effects?

Answer 29

Peptide hormone synthesized by osteoblasts
and osteocytes in bone.
Effects:
- decreases reabsorption of phosphate in PCT (similar to that of PTH)
- decreases production of calcitriol in PCT (opposite of PTH).
BUT RECEPTORS ARE IN DCT= suggested that
DCT cells, upon binding FGF23, signal nearby proximal tubule cells by
a paracrine messenger.

Question 30

What stimulate FGF23?

Answer 30

Stimulated by high phosphate and calcitriol.

Question 31

Describe the pathophys of hyperphosphatemia and hypoCa in CKD

Answer 31

CKD: drcreased GFR, calcitriol production, and phosph excretion. High phosphate= stimulated PTH and FGF23.
Low calcitriol= reduced Ca uptake from GI tract

Question 32

How is Mg distributed in the body?

Answer 32

• 99% intracellular.
  -2/3 total body Mg stored in bone
• 20% in muscle tissue
• 11% in other soft tissue

Question 33

Waht are the roles of Mg?

Answer 33

Plays an essential role in cellular metabolism
Enzymatic reactions, synthesis and stucture of proteins and polynucleotides. Cofactor for several enzymes.
Role in cell signaling, nerve transmission, oxidative phosphorylation, glycolysis, protein and DNA synthesis

Question 34

How is EC Mg distributed?

Answer 34

• 66% ionized
• 4% anion complexed
• 30% protein bound

Question 35

How is Mg handled in the kidneys?

Answer 35

• 20% of the filtered load is reabsorbed in the PCT (paracellular route).
• 70% in the thick ascending limb of the loop of Henle (paracellular route).
• Active reabsorption in DCT: Mg-specific class of TRP channels in apical memb. Flux driven primarily by negative memb potential. The basolateral exit step is active, but its mechanism is not established.

Question 36

What 2 electrolytes derangements are associated with hypoMg and why?

Answer 36

• hypoK:
  2 mechanisms:
  - Na/K ATPase
  - ROMK in DCT
• hypoCa: