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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
What is the effect of vitamin D on PTH in the parathyroid cell?
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
FGF-23 plays a very important role in the regulation of vitamin D and PTH. How?
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
What factors affect HPO4- absorption in the intestine?
Vitamin D (1,25 Hydroxy-D3) **increases abosrption of HPO4-** in the intestine
28
How does vitamin D affect Ca2+ homeostasis?
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
What are the clinical manifestations of hypocalcemia?
* Neuro * Anxiety, irritability, tetany, twitching, carpopedal spasm, seizure * Bone * Fractures * GI * Cramps * Cardiac * Prolonged QT, dysrhythmia * Blood * Hypercoagulable state
30
What is the effect of calcitonin on serum Ca2+?
Calcitonin lowers serum Ca2+ * Increases renal excretion * Decreases bond resorption
31
What is the DDx for hypercalcemia with low PTH?
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
What is the most common cause of hyperphosphatemia?
Decreased kidney function resulting in **impaired phosphorous excretion** Exacerbated by... * Excess intake * Cellular breakdown (cells contain a lot of phosphorous)
33
What factors regulate Ca2+ reabsorption in the DCT?
* 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
How does hypoerphosphatemia lead to hypocalcemia?
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
What are the major causes of hypercalcemia?
* **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
What is secondary hypothyroidism? What are the most common causes?
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
Describe the clinical presentation of hypercalcemia
* **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
How do PTH and FGF-23 affect 1-alpha-hydroxylase activity?
* **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
If serum phosphorous levels are high, how would you expect FGF-23 levels to change?
High serum phosphorous * -\> **Increased FGF-23** * ​-\> decreased reabsorption of phosphorous * **-\> Increased excretion of phosphorous**
40
Describe the process of Ca2+ reabsorption in the DCT
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
What is the typical picture of a chronic kidney disease patient? * **Phosphate:** * **FGF23:** * **Active Vitamin D:** * **Calcium:**
* **Phosphate:** high * **FGF23:** high * **Active Vitamin D:** low * **Calcium:** low
42
PTH will ___________ production of 1,25-OH2 Vitamin D3 (active) by [stimulating/inhibiting] \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
PTH will **_increase_** production of 1,25-OH2 Vitamin D3 (active) by **_stimulating 25 alpha hydroxylase_**
43
Describe the process of Calcium absorption in the intestine
* **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
What is the effect of PTH on Ca2+ homeostasis?
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
How does chronic kidney disease affect phosphorous homeostasis? How does this effect Vitamin D, Calcium, PTH, and FGF23?
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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