Lecture 22: Calcium and Magnesium, physiology and disorder Flashcards
What are the crucial functions of calcium?
- essential co-factor in enzymatic processes such as coagulation and mitosis
- Intracellular second messenger
- Skeletal support
- used for muscular contraction and tone
What is the distribution of calcium in the body?
99% of body calcium is in the skeleton
1% is in the ECF
Of the 99% in skeleton, only 1% of that 99% is exchangeable with blood upon hormonal stimuli
ECF Ca = 1-3 mM
ICF Ca = <10^-3 mM
-thus there is a very favorable gradient for calcium to flow into the cell
Calcium inside of the cell is kept VERY LOW, and even when calcium does come into the cell due to the steep gradient, Ca is sequestered by binding proteins, the mitochondria, by SRC ATPase, etc
What is the distribution of calcium in the blood?
40% of blood calcium is bound to protein (albumin)
10% is part of circulating complexes (with phosphate, citrate, etc)
50% is in free ionized form
-this is the active fraction
The complex and free ionized (60%) are filtered in kidney, whereas those bound to protein are not
What consists of the biologically active portion of calcium? Significance?
Only the FREE ionized fraction
Significance: If you have low serum albumin, you reduce the total serum calcium, but not the ionized fraction
-thus you have low total serum calcium but is irrelevant since there is no change in free calcium in serum
Corrected serum Ca = serum calcium + 0.8 * (4 – serum albumin)
Free ionized calcium can be measured directly by ion sensitive electrode
What is the acid-base effect on free ionized and protein bound calcium?
Hydrogen ion competes with calcium for albumin binding
In acidemia, less calcium is bound to albumin and more is in free ionized fraction
Thus higher the pH, the more calcium is bound to albumin, the less calcium is freely floating, because there is less H+ to compete for albumin binding sites
What is a likely causes of hypocalcemia if patient’s total serum calcium is reduced but shows no signs of hypocalcemia?
Patients = acidotic, so less calcium bound to albumin but more calcium in serum to protect from effects of hypocalcemia
How does alkalosis lead to hypocalcemia symptoms?
Alkalosis = more calcium bound to albumin = less free ionized calcium = hypocalcium
How is calcium steady-state regulated in the body?
- Intestine
- regulated by Vit D
- Kidney
- regulated by CaSR
- Bone
- regulated by PTH
What are the hormones/factors that regulate calcium metabolism?
- Vitamin D regulates absorption of Ca from blood
- more vitamin D = more Ca absorption
- PTH regulates Ca resorption from the bone
- more PTH = more Ca in serum due to breakdown of bone
- Calcium levels in lumen of nephron regulate excretion by acting on calcium sensing receptors (CaSR)
What are the characteristics of PTH?
Binds to cell surface receptors in bone and kidney
Secretion is regulated by plasma calcium concentration
More calcium = less PTH
Negative feedback loop
Has the following function:
1. increases osteoclastic resorption
-acts directly on osteoblasts to activate osteoclasts
2. increases calcium reabsorption
3. stimulates 1,25 vit D synthesis
-thus indirectly affects GI uptake
4. decreases phosphate absorption/increases phosphate excretion
What are the characteristics of the calcium sensing receptors?
- located in parathyroid and LoH/DCT of nephron
- in the parathyroid, activation if CaSR will downregulate PTH synthesis
- in the kidney, activation of CaSR will suppress calcium transport in LoH/DCT
What is PTH related peptide (PTHrP)?
A peptide that is usually locally acting for cartilage differentiation and lactation
But if PTHrP levels are high enough, it can have similar actions to PTH
What is calcidiol?
25 OH vitamin D
Storage and plasma metabolite
What is calcitriol?
1,25 OH vitamin D
The most active form of vitamin D
What does one measure to determine vitamin D levels?
Calcidiol levels, since this is the storage unit
Vitamin D is a very ambiguous term: Can be the parent vitamin D (ergocalciferol/cholecalciferol) Calcidiol (storage of vit D) Calcitriol = active form of vit D So three forms
How is vitamin D made?
- dietary vitamin D
- UV light + 7 dehydrocholesterol in the skin
Usually is 25 hydroxyation takes place in the liver
1,25 hydroxylation occurs in the kidney
What are the actions of calcitriol?
- increases calcium and phosphate absorption
- increases activity of luminalintestinal calcium channel (TRPV6), albindin and basolateral active calcium transporters
- suppresses PTH transcription
- binds to vitamin D receptor in nucleus of parathyroid cells
- increases renal tubular calcium reabsorption
- Increases osteoblast/osteoclast activity
- potentiates PTH action
In kidney failure, most electrolytes accumulate because they cannot be secreted (example is hypernatremia with volume overload). Why then do you get HYPOcalcemia in kidney failure?
Because calcium levels are regulated at the level of the GI tract
In kidney failure, calcitriol and intestinal calcium absorption fall, therefore making the serum calcium fall as well
How is calcium handled along the nephron?
Parallels that of Na reabsorption
65% of Ca reabsorbed in PCT
25% of Ca reabsorbed in TAL
How is calcium reabsorbed in the proximal tubule?
- passive paracellular transport
- Solvent drag
- some calcium channels in the apical membrane
Calcium is basically reabsorbed with sodium
What is the significance of salt and calcium reabsorption being so closely linked?
Salt loading = calciuric (you want to excrete more salt and hence excrete more calcium)
Salt depletion = anticalciuric (because you need to reabsorb more salt and hence more Ca)
What is the only ion that is NOT primarily reabsorbed in the proximal tubule?
Magnesium
Only 15-25% of filtered magnesium is rebsorbed in prox tubule
How is calcium uptake regulated in the TAL?
Calcium will bind to CaSR and INHIBIT NKCC2 tranporters as well as ROMK transporters,
Thereby inhibiting sodium reuptake
This makes sense because if you have too much calcium in tubule, you would want to excrete more, and the only way you can secrete Ca is if you secrete Na concomitantly too
Thus calcium is natriuretic as well
Mechanism: lowers level of cAMP to decrease NKCC2 transporter
Thus CaSR and PTH have OPPOSITE effects on TAL, since CaSR downregulates cAMP and thus NKCC2 where as PTH upregulates cAMP and thus NKCC2
How is calcium reabsorbed in the TAL?
Usually the NKCC2 channel creates a positive lumen gradient that allows Ca and Mg to diffuse paracellularly into the blood