Lecture 21: Phosphate Physiology and Disorders Flashcards
What is normal plasma phosphate?
2.5-4.5 mg/dl or ~1 mmol/L
Inorganic phosphorus is actually what is measured
Where is phosphate stored in the body?
Primarily in the bone and muscle
6000 mg/Day gets filtered
Only 900 mg/Day gets excreted from urine
So 5100 mg/Day gets reabsorbed
Dietary phosphate deficiency
Is very rare because it is in all
Preservatives
Does phosphate require vitamin D for uptake?
Not really Phosphate is absorbed well Without vitamin D Vitamin D is needed for Calcium uptake
What are the metabolic effects of phosphate?
What are the metabolic effects of phosphate?
- Actions on bone
i. high levels suppress bone resorption
ii. low levels stimulate bone resorption and prevent normal bone mineralization - Actions on kidney
i. High levels suppress active (1-OH) vitamin D synthesis
ii. low levels stimulate (1-OH) vitamin D synthesis - Adequate amounts necessary for cellular energy metabolism
How is plasma phosphate transported through the nephron?
Phosphate is primary reabsorbed in the proximal tubule in a pathway similar to glucose
Like glucose, there is a Tm or max transport rate
-if the filtered load P(phosphate)*GFR is below the Tm, reabsorption is complete
-if it is above Tm, the increment above Tm is wholly excreted in the urine
Tm = saturation point for reabsorption
What does having a Tm for phosphate reabsorption suggest?
Suggests a transport system involving a carrier-mediated system
-a fixed number of transporters with a fixed carrying capacity
What is the mechanism of phosphate transport on the proximal tubule?
Na/PO4 transporters located on the apical membrane
Syntheized in ER
Secondary active movement due to Na/K ATPase
What regulates the Na/PO4 symporter of proximal tubule?
- dietary phosphate
- PTH
- FGF-23
What does a low phosphate diet stimulate? High phosphate diet?
Low phosphate = stimulates Na/PO4 activity
High phosphate = inhibits Na/PO4 activity
Why does it make sense for PTH to INHIBIT the Na/PO4 symporter?
PTH is released in order to increase calcium levels in the blood
Phosphate in the blood complexes with calcium to form a compound that won’t increase body’s calcium level
Thus, PTH wants to inhibit Na/PO4 symporter and stimulate phosphate excretion in order to maintain Ca levels
High plasma phosphate leads to PTH secretion
How does PTH affect the rate of excretion vs plasma concentration curve?
It LOWERS the Tm for phosphate reabsorption, so more phosphate will be excreted at a lower concentration of phosphate flowing through the proximal tubul
What is the mechanism of PTH action?
PTH binds to PTH1R receptor on basolateral membrane
Increases cAMP that then phosphorylates protein that anchors Na/PO4 on the apical membrane
Thus, Na/PO4 is then transported by vesicles away from plasma membrane and destroyed
Thus PTH = downregulation of Na/PO4 channel
What are the actions of FGF-23 in relation to phosphate regulation?
Produced in the bone
Promotes phosphate excretion
Reduces activation of vitamin D (primary biologic activity)
Over expressed in hypophosphatemia and under expressed in hyperphosphatemia
What are the clinical consequences of hypophosphatemia?
Ricketts and osteomalacia
What are the effects of low phosphate diet or fall in plasma PO4?
Urinary phosphate falls rapidly, even in animals without parathyroid glands
Important because it is one of the first thing you check if you have a phosphate problem in patient
What are the mechanisms of low phosphate diet?
Somehow phosphate level is sensed by proximal tubule
Na/PO4 receptors are upregulated and not degraded
What is the integrated effect of INCREASED phosphate on the body?
Increased Phosphate = decreased serum Ca
Decreased serum Ca = increased PTH = increased renal phosphate excretion
Thus normalizes serum phosphate
Also, increased phosphate = decreased 1,25 vitamin D synthesis = decreased intestinal/renal phosphate absorption
What is the effect of DECREASED
Phosphate in the body?
Decrease phosphate = increased Ca = Decreased PTH = decreased renal Phosphate excretion As well as Increase vitamin D synthesis and Increased intestinal/renal absorption Of phosphate
What are other factors that may Influence
phosphate balance?
- GI factors
- evidence for gut-kidney axis
- FGF-23
- Phosphatonins
What are the key characteristics of FGF-23?
Synthesized in bone and may act to modulate bone/cartilage development
Needs a co-factor/receptor Klotho for action to occur
Acts on kidney to increase PO4 EXCRETION
Similar to PTH effects
May act as a regulator of vitamin D activation
-released in response to increased vitamin D
-acts at kidney to suppress Vitamin D 1-hydroxylase
Very complicated and published in 2013
Still in development
What happens when there is an acute minimal fall in plasma phosphate?
Happens commonly (esp after glucose infusion) No clinical consequences as there are large stores of cell phosphate to buffer falls in intracellular levels
What are the characteristics of hypophosphatemia in a chronic setting?
Severe reductions of plasma to <1.5 mg/dl can be seen in setting of chronic STARVATION
-may see critical reductions in cell ATP and severe clinical consequences
What are the physiologic responses to a sustained fall in plasma phosphate?
- Decreased PTH release (vit D effect, increased ionized Ca, effect of PTH on parathyroid gland)
- Reduced urinary phosphate (acute and related to reduced PTh/direct renal effect)
- Increased 1-hydroxylation of 25-OH vitamin D
- Increased bone resorption (vit D effect and direct effect on bone)
- increased calcium excretion due to vitamin D effect
FGF-23 also plays a role
What are the physiologic responses to a sustained rise in plasma?
- Increased PTH release (reduced vit D effect, reduced Ca and effect on parathyroid)
- Increased plasma FGF-23
- Increased urinary phosphate (acute and related to increased PTH and FGF-23…also direct renal effect)
- Decreased 1-hydroxylation of vitamin D
- Decreased bone resorption
- Decreased calcium excretion
5 and 6 due to vitamin D effect and direct effect on bone