Calcium and Phosphate Physiology and their roles in CKD Flashcards
role of calcium in the body
skeletal development
excitable tissues
action potentials
cardiac and muscle contractility
roles of phosphate in the body
bone formation
ATP generation
membrane phospholipids
phosphorylation of second messengers - signaling
glycolysis
DNA/RNA synthesis
unloading O2 (2,3-BPG)
When are people appropriately in calcium excess?
during growth phase
pregnant mothers
What is the most common state of negative calcium balance?
osteoporosis - bone loss
1,25-dihydroxyvitamin D (main role, stimulus, inhibitor)
primarily regulates gut mineral absorption
main stimulus is PTH
main inhibitor is FGF23
calcium vs. phosphate absorption
20% calcium
67-75% phosphate
calcium uptake in the gut
channels and binding proteins induced by vitamin D
trans-cellular transport
phosphate uptake in the gut
paracellular transport
transcellular transport can be induced by 1, 25 vitamin D
transporter called NaPi2b (sodium/phosphate cotransporter)
linear absorption, nonsaturable function of intake
Where is calcium reabsorbed?
proximal tubule (67%)
thick ascending limb - paracellular (25%)
distal convoluted tuble - TRPV5 channel, transcellular and vitamin D dependent (8%)
What diseases impair calcium reabsorption?
mutations in ROMK and NKCC channels in the thick ascending limb
mutations of the calcium receptor
calcium sensing receptor
transmembrane protein in the basolateral membrane of the tAL
extracellular domain that binds calcium - constantly senses the calcium concentration
when many sites are bound, inteprets as high amounts of calcium
a way for the cell to contribute to regulating serum calcium
How does defects in the calcium receptor lead to polyuria?
calcium sensor activation stimulates calciuria
inactivates the ROMK channel as a result of activation
effectively impairs the NKCC channel
phosphate reabsorption in the kidneys
NAPi2a and NAPi2c in the proximal tubule
when presence, phosphate is absorbed through the cells
otherwise, it is paracellular transport
if phosphate gets past the proximal tubule, then will be excreted
10-15% fractional excretion
What ion is the collecting duct impermeable to?
chloride
this allows influx of sodium to promote efflux of potassium and hydrogen ions
What is the primary regulator of calcium reabsorption?
PHT - parathyroid hormone
job is to increase the ionized calcium concentration
What is the primary stimulus for PTH release?
concentration of ionized calcium in the blood
picked up by calcium receptors
functions of PTH
primarily regulates ionized calcium
raises serum calcium
increase bone resorption of calcium
increase calcium reabsorption in the kidney
stimulates conversion of 25D into 1,25D (activates vitamin D)increased absorption in GI tract
decreased phosphate reabsorption (phosphaturia)
inhibits CYP24
inhibits calciuria
How does PTH lead to decreased phosphate reabsorption?
decrease expression of NAPi2a anc NAPi2c in the proxmial tubule
How does PTH increase calcium reabsorption?
stimulates TRPV5 calcium transport in the distal tubule
What stimulates FGF23 expression?
increased phosphate intake
increased 1,25 D levels
serum phosphate may not be the primary stimulant
What cells make FGF23?
osteocytes
What cells make PTH?
chief cells int he parathyroids
functions of FGF23
main effect is to lower serum phosphate
stimulates phosphaturia (decreased reabsorption)
blocks the activation of 25D to 1,25D
stimulates CYP24
inhibits PTH
What are the functions of 1,25D
increased gut Ca absorption
increased gut phosphate absorption
feedback inhibition to suppress PTH
increased FGF23 production
stimulates 24-hydroxylase
What is the metablism of vitamin D?
vitamin D2/3 -> 25 vitamin D (liver) -> 1,25 vitamin D (kidney)
Where is aldosterone released from?
zona glomerulosa of the adrenal cortex
primary hyperparathyroidism
caused by benign tumor that continuously produces PTH
increased calcium
decreased phosphate
increased fracture risk
increased urine calcium
risk for stones
How does increased PTH increase urine calcium?
effect of ability of tubuels to reabsorb calcium is overwhelmed by the high concentration of calcium in the blood
higher filtered load leads to higher concentrations in the urine
How does increased PTH lead to kidney stones?
high filtered calcium and inproper reabsorption leads to prediliction for stones
What are the effects of primary hypothyroidism?
decreased calcium
increased phosphate
tetany - due to lack of calcium
What is the normal range of PTH?
10-65 pg/m
Does a PTH level of 60 pg/mL rule out primary parathyroidism?
a PTH of 60 in the setting of hypercalcemia does not rule out primary hyper parathyroidism - should be 0!
Is a PTH level of 30 pg/mL in hypocalcemia normal?
no, should be much higher
suggests hypoparathyrodism
What is the normal range of calcium in the blood?
8.5-10.5 mg/dL
What is the normal range of phosphate in the blood?
2.5-4.5 mg/dL
Rickets syndrome
bone weakness due to either deficiency in vitamin D, low blood calcium, or low blood phosphate
PTH related peptide
drives hypercalcemia
comonly secreted by cancer cells
organs involved in calcium/phosphate regulation
parathyroid
bone
gut
kidney
What is the normal fractional excretion of calcium?
about 2%
What are the phosphate/calcium regulator features in CKD?
low 1,25D
variable 25D
high PTH
high FGF23
low klotho expression
low normal calcium
high normal phosphate
NPT2b (NaPi2b)
active transport of phosphate in the guy
less important than passive phosphate transport
human deletion has no phosphate phenotype
NPT2a, NPT2c (NaPi2a,c)
in PCT
NPT2a mutations - Fanconi syndrome
NPT2c mutations - HHRH syndrome
relative roles vary in mammalian species
What is the time course of a disordered mineral metabolism in CDK?
1) increased FGF23 is the earliest alteration in mineral metabolism
2) gradually increasing FGF23 levels cause early decline in 1,25D levels
3) this frees PTH from feedback inhibition, leading to secondary hyperparathyroidism
4) all these changes occur long before increases in serum P levels are evident
What is the key finding in HHRH?
hypophosphatemia that is not FGF23 or PTH mediated
NaP12c deficiency
What is the key finding in tumoral calcinosis?
hyperphosphatemia with low FGF23 and low PTH
FGF23 deficiency
What is the key finding in familial hypocalciuric hypercalcemia (FHH)?
hypercalcemia with non-suppressed PTH = primary hyperthyroidism
What are the key findings in autosomal dominant hypoparathyroidism?
hypocalcemia + low PTH
Key finding in Vitamin D - dependent rickets type I
hypocalcemia and hypophosphatemia with secondary hyperparathyroidism
