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Renal Cram Deck > SM 198a - Calcium and Phosphate > Flashcards

SM 198a - Calcium and Phosphate Flashcards

1
Q

FGF-23 will ___________ production of 1,25-OH2 Vitamin D3 (active) by [stimulating/inhibiting] __________________.

A

FGF-23 will decrease production of 1,25-OH2 Vitamin D3 (active) by inhibiting 25 alpha hydroxylase .

FGF-23 is secreted in response to too much serum phosphorous

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2
Q

What belongs in box E?

A

1,25-OH2-D3

The active form of vitamin D3

PTH upregulates 1 alpha hydroxylase activity -> more 1,25-OH2-D3 -> works to increase serum Ca2+

FGF23 inhibits 1 alpha hydroxylase activity -> less 1,25-OH2-D3 -> works to decrease serum Ca2+

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3
Q

Which 3 enzymes are important for the synthesis of active vitamin D?

A
  • 25 alpha hydroxylase (liver)
    • Cholecalciferol -> 25-OH-D3
  • 24 alpha hydroxylase (renal PCT cell)
    • 25-OH-D3 -> inactive 24,25-OH2-D3
  • 25 alpha hydroxylase (renal PCT cell)
    • 25-OH-D3 -> active 1,25-OH2-D3

Also: UV light to convert 7-dehydrocholesterol to cholecalciferol

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4
Q

What is the effect of PTH on Ca2+ reabsorption in the intsetine?

A

PTH has no direct effect on Ca2+ reabsorption in the intestine

Vitamin D (1,25 Hydroxy-D3) is the primary regulator of Ca2+ reabsorption in the intestine

However, PTH secreted in response to low Ca2+ increases activation of vitamin D in the kidney, thus indirectly increaseing Ca2+ reabsorption in the intestine

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5
Q

How does FGF-23 affect phosphorous homeostasis?

A

FGF-23 promotes the excretion of phosphorous to lower serum phosphorous levels

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6
Q

What factors regulate PTH secretion from the chief cells of the parathyroid gland?

A
  • Promote PTH synthesis and release
    • Low Ca2+ levels
  • Inhibit PTH synthesis and release
    • High Ca2+ levels
    • High vitamin D
    • FGF-23
    • Phosphorous
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7
Q

What is the effect of gastric acid on Ca2+ reabsorption?

A

Gastric acid enhances Ca2+ absorption

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8
Q

Low PTH is a physiological response to ____________

A

Low PTH is a physiological response to high Ca2+

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9
Q

Describe Ca2+ reabsorption in the thick ascending limb of the loop of Henle

A
  • K+/Na+/2Cl- cotransporter (NKCC2) in the apical membrane gets these ions from the lumen to the epithelial cell
  • Na+/K+ ATPase on the basolateral membrane moves Na+ into the interstitium and K+ into the epithelial cell – electrically neutral
  • Chloride channels on the basolateral membrane transport Cl- ions are into the insterstitium
  • ROMK on the apical membrane pumps K+ back into the lumen -> positive charge in the lumen
  • This positive charge drives paracellular Ca2+ reabsorption through claudin 16
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10
Q

What is the most common cause of hypocalcemia?

A

Low PTH

  • Usually post-surgical
    • Thyroidectomy, parathyroidectomy, radial neck dissection
  • Autoimmune or genetic possible
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11
Q

Describe the clinical manifestation of hyposphosphatemia

A
  • Neuro
    • Lethergy
    • Paraesthesia
    • Siezure
  • Cardiac
    • Arrhythima
    • Hypotension
  • Hematologic
    • Hemolysis
  • Skeletal
    • Bone demineralization (to increase serum phosphate)
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12
Q

______ is the single most important factor that affects PTH secretion

A

Serum Ca2+ level is the single most important factor that affects PTH secretion

  • High Serum Ca2+
    • Ca2+ binds to CaSR on the chief cells of the parathyroid gland
    • Inhibits PTH production and secretion
  • Low Serum Ca2+
    • Ca2+ does not bind to CaSR
    • PTH is produced and released from the chief cells of the parathyroid gland
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13
Q

What stimulus promotes the secretion of FGF-23?

What is the effect?

A

FGF-23 is secreted in response to too much serum phosphorous

FGF-23 -> Decreased Vitamin D synthesis -> decreased phosphorous absorption from the intestine

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14
Q

In primary hyperparathyroidism, would you expect the following serum levels to be high or low?

Calcium:

Phosphorous:

1,25-OH2-D3:

A
  • Calcium: High
    • ​Increased renal reabsorption
    • Increased active vitamin D -> increased intestinal reabsorption
    • Increased resorption from bone
  • Phosphorous: Low
    • ​Decreased renal reabsorption
  • 1,25-OH2-D3: Varies
    • Increased vitamin D synthesis in the kidney, but some studies have shown that primary hyperparathyroidism is associated with vitamin D deficiency
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15
Q

What is the role of CaSR on Ca2+ reabsorption in the distal convoluted tuble?

A

In the DCT, CaSR is located on the apical membrane

  • CaSR senses increased Ca2+ in the urine
    • If Ca2+ in the urine is high, CaSR stimulates increased reabsorption of PO4 to prevent kidney stone formation
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16
Q

What factors affect GI absorption of calcium?

A
  • Increase absorption
    • Vitamin D (1,25-OH2-D3)
      • PTH indirectly, by increasing Vitamin D syntheisis
    • Gastric acid
  • Decrease abosrption
    • Billiary and pancratic insufficiency
      • Ca2+ binds to unabsorbed fat and is excreted
    • Serum hypercalcemia
      • Via CaSR, which binds to Ca2+ and inhibits the effects of vitamin D
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17
Q

What is the effect of PTH on reabsorption of Ca2+ in the kidney?

A

PTH is secreted when Ca2+ is low, and workds to increase reabsorption of Ca2+ in the thick ascending limb of the loop of Henle

  • PTH increases Claudin 16 production
  • Ca2+ must pass through Claudin 16 in order to be reabsobed paracellularly in the thick ascending limb
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18
Q

Describe the process of intestinal absorption of phosphorous

A

Transcellular transport:

  • NaPi-IIb: Lumen -> intestinal cell
    Absorbs HPO4- with 2 Na+
  • Unknown channel: Intestinal cell -> interstitium

There is also a paracellular pathway

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19
Q

What substance regulates Calcium absoprtion in the intestine?

A

1,25 Hydroxy-D3 (The active form of vitamin D)

  • If Ca2+ levels are high, Ca2+ binds to the Ca2+ sensing receptor (CaSR)
    • CaSR downregulates 1,25 Hydroxy-D3 synthesis
    • Decreased 1,25 Hydroxy-D3 -> decreased Ca2+ absorption
  • If Ca2+ levels are low, CaSR does not downregulate 1,25 Hydroxy-D3 synthesis
    • The presence of 1,25 Hydroxy-D3 -> Ca2+ absorption
20
Q

What is the effect of CaSR activation on the epithelial cells of the thick ascending loop?

A

CaSR binds to Ca2+ when serum Ca2+ levels are elevated

Binding of Ca2+ to CaSR downregulates Ca2+ reabsorption:

  • Decreased ROMK activity
    • -> Decreased liminal positivity
    • -> Decreased driving force for Ca2+ reabsorption
  • Decreased Claudin 16 production
    • -> Fewer channels for paracellular Ca2+ reabsorption in the thick ascending limb of the loop of Henle
21
Q

Describe the clinical manifestation of hyperphosphatemia

A
  • Symptoms of hypocalcemia
    • Phosphorous binds to Ca2+, thus reducing the amount of ionized Ca2+
    • Bone fractures, stomach cramps, dysrhythmia, irritability, anxiety, carpopedal spasm, siezure
  • Itching
  • Metastatic calcifications
22
Q

What are the expected levels for a patient with hyperparathyroidism?

Calcium:

Phosphorous:

A

Calcium: high

Phosphorous: low

PTH = increased renal Ca2+ reabsorption and phosphorous excretion

23
Q

Describe the process of phosphorous reabsorption in the renal tubules

A
  • NaPi-IIa and NaPi-IIc: Lumen -> Tubular epithelial cell
  • Unknown channel: Tubular epithelial cell -> interstitium
24
Q

What factors regulate phosphorous reabsorption in the renal tubules?

A
  • FGF-23
    • ​Acts on FGFR-1 and Klotho to promote the excretion of phosphorous
  • PTH
    • ​Promotes the excretion of phosphorous by preventing reabsorption
25
Q

What is the effect of vitamin D on PTH in the parathyroid cell?

A

When Vitamin D reaches a threshold level in the serum, it binds to VDR in the chief cell and inhibits production of PTH.

-> decreased GI absorption, renal reabsorption of Vitamin D

26
Q

FGF-23 plays a very important role in the regulation of vitamin D and PTH.

How?

A

FGF-23 is the key negative feedback mechanism -
basically FGF-23 is yelling
“CALM DOWN WE HAVE ENOUGH SERUM CA2+”

  • Vitamin D
    • Increases FGF-23 expression in bone
    • -> FGF-23 acts on the kidney to decease vitamin D synthesis
  • PTH
    • Increases FGF-23 express
    • -> FGF-23 acts on teh parathyroid to decrease PTH
27
Q

What factors affect HPO4- absorption in the intestine?

A

Vitamin D (1,25 Hydroxy-D3) increases abosrption of HPO4- in the intestine

28
Q

How does vitamin D affect Ca2+ homeostasis?

A

Increased levels of active vitamin D (1,25 Hydroxy-D3) increase Ca2+ absorption in the intestinal epithelium

  • 1,25 Hydroxy-D3 binds to the Vitamin D Receptor (VDR)
  • VDR acts on the nucleus to increase production of TRPV6, Calbindin, Ca2+ ATPase or Na+/Ca2+
    • All of these proteins are required for Ca2+ reabsorption in the intestine
29
Q

What are the clinical manifestations of hypocalcemia?

A
  • Neuro
    • Anxiety, irritability, tetany, twitching, carpopedal spasm, seizure
  • Bone
    • Fractures
  • GI
    • Cramps
  • Cardiac
    • Prolonged QT, dysrhythmia
  • Blood
    • Hypercoagulable state
30
Q

What is the effect of calcitonin on serum Ca2+?

A

Calcitonin lowers serum Ca2+

  • Increases renal excretion
  • Decreases bond resorption
31
Q

What is the DDx for hypercalcemia with low PTH?

A

Low PTH is a normal response to high Ca2+ - the CaSR system is working to suppress PTH secretion

So, what could be causing persistent high Ca2+ in the setting of low PTH?

  • If PTHrP is elevated, malignancy is likely
  • If 1,25-OH2-D3 is elevated, tumor or granulomatous disorder
    • Produces 25 alpha hydroxylase that activates vitamin D
  • If 25-OH-D3 is elevated, vitamin D intake is too high
  • If Vitamin D and PTHrP are normal, consider myeloma, Vitamin A, or thyrotropin
32
Q

What is the most common cause of hyperphosphatemia?

A

Decreased kidney function resulting in impaired phosphorous excretion

Exacerbated by…

  • Excess intake
  • Cellular breakdown (cells contain a lot of phosphorous)
33
Q

What factors regulate Ca2+ reabsorption in the DCT?

A
  • Vitamin D (1,25 Hydroxy-D3)
    • Increases Ca2+ reabsorption
  • PTH
    • Increases Ca2+ reabsorption
  • CaSR on the luminal epithelium
    • Senses increased Ca2+ in the filtrate
    • If Ca2+ is high, CaSR will derease reabsorption of PO4
      • This will protect against stone formation
34
Q

How does hypoerphosphatemia lead to hypocalcemia?

A

Hyperphosphatemia

  • -> Increased FGF-23 + Reduced 1,25-OH2-D3
    • Increased FGF-23 further reduces 1,25-OH2-D3 synthesis
  • Low active vitamin D -> Hypocalcemia
35
Q

What are the major causes of hypercalcemia?

A
  • Parathyroid mediated (too much PTH)
  • Non-parathyroid mediated
    • Malignancy
    • Vitamin D intoxication
    • Chronic granulomatous disease
  • Medications
    • Thiazides
    • Lithium
  • Misc
    • Hyperthyroid
    • Immobilization
    • Milk alkali syndrome
36
Q

What is secondary hypothyroidism?

What are the most common causes?

A

Secondary hypothyroidism = hypocalcemia in the setting of high PTH

(PTH is not doing its job increasing serum Ca2+ - think of this like reduced effect of PTH, rather than low PTH)

Causes:

  • Vitamin D deficiency
  • Loss of Ca2+ from the circulation
    • Ca2+ is being used up by something else
  • Drugs or medications that affect Ca2+ binding
  • Disorders of Mg2+ metabolism: Low Mg2+ leads to low Ca2+
    • Mg2+ is preferentially reabsorbed, resulting in decreased Ca2+ reabsorption
37
Q

Describe the clinical presentation of hypercalcemia

A
  • Painful bones
    • Weakness, bone pain, osteopenia
  • Renal stones
    • Polyuria, nephrolithiasis, AKI
  • Abdominal groans
    • Nausea, vomiting, constipation, pancreatitis
  • Psychic moans
    • Confusion, fatigue
  • Heart
    • Bradycardia, short QT
38
Q

How do PTH and FGF-23 affect 1-alpha-hydroxylase activity?

A
  • PTH stimulates 1 alpha hydroxylase
    • Works to create more active vitamin D3
    • -> Works to increase serum Ca2+
  • FGF-23 inhibits 1 alpha hydroxylase
    • Works to decrease active vitamin D3
      • Increased synthesis of the waste product
        24,25-OH2-D3
    • -> Decrease serum Ca2+
      *
39
Q

If serum phosphorous levels are high, how would you expect FGF-23 levels to change?

A

High serum phosphorous

  • -> Increased FGF-23
    • ​-> decreased reabsorption of phosphorous
      • -> Increased excretion of phosphorous
40
Q

Describe the process of Ca2+ reabsorption in the DCT

A

Very similar to Ca2+ reabsorption in the intestine

Difference = PTH has a direct effect on Ca2+ reabsorption in the kidney

  • TRPV5: Lumen -> Epithelial cell
  • Calbindin: Luminal side of cell -> basolateral side of cell
  • Na+/Ca2+ exchanger and Ca2+ ATPase: Basolateral side of the cell -> interstitium
    • Both are active transport mechanisms
41
Q

What is the typical picture of a chronic kidney disease patient?

  • Phosphate:
  • FGF23:
  • Active Vitamin D:
  • Calcium:
A
  • Phosphate: high
  • FGF23: high
  • Active Vitamin D: low
  • Calcium: low
42
Q

PTH will ___________ production of 1,25-OH2 Vitamin D3 (active) by [stimulating/inhibiting] __________________.

A

PTH will increase production of 1,25-OH2 Vitamin D3 (active) by stimulating 25 alpha hydroxylase

43
Q

Describe the process of Calcium absorption in the intestine

A
  • TRPV6: Lumen -> intestinal epithelial cell
  • Calbindin: Luminal side of cell -> serum side of the cell via
    (still stays inside of the intestinal epithelial cell)
  • Ca2+ ATPase or Na+/Ca2+ exchange:
    Serum side of the cell -> serum
    • Both are active transpor mechanisms; Intracellular [Ca2+] is lower than extracellular [Ca2+]
44
Q

What is the effect of PTH on Ca2+ homeostasis?

A

PTH is the major regulator of Ca2+ movement in and out of the bones

  • Hypocalcemia -> PTH secretion -> increased Ca2+ resorption from the bones -> Ca2+ levels return to normal
  • Hypercalcemia -> Decreased PTH secretion -> more bone formation
45
Q

How does chronic kidney disease affect phosphorous homeostasis?

How does this effect Vitamin D, Calcium, PTH, and FGF23?

A

Chronic kidney disease ->

  • Reduced renal phosphate clearance
  • -> Hyperphosphatemia
  • -> Increased FGF-23 + Decreased 1,25-OH2-D3 synthesis
    • Increased FGF-23 further reduces 1,25-OH2-D3 synthesis
  • -> Reduced renal Ca2+ reabsorption and GI absorption
  • -> Hypocalcemia
  • -> Increased PTH in response to hypocalcemia, but without increase in Ca2+ levels
    • = secondary hyperparathyroidism

Renal Cram Deck (24 decks)

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