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Renal Week 2 > Lecture 21: Phosphate Physiology and Disorders > Flashcards

Lecture 21: Phosphate Physiology and Disorders Flashcards

1
Q

What is normal plasma phosphate?

A

2.5-4.5 mg/dl or ~1 mmol/L

Inorganic phosphorus is actually what is measured

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2
Q

Where is phosphate stored in the body?

A

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

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3
Q

Does phosphate require vitamin D for uptake?

A 
Not really
Phosphate is absorbed well
Without vitamin D
Vitamin D is needed for
Calcium uptake
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4
Q

What are the metabolic effects of phosphate?

A

What are the metabolic effects of phosphate?

  1. Actions on bone
    i. high levels suppress bone resorption
    ii. low levels stimulate bone resorption and prevent normal bone mineralization
  2. Actions on kidney
    i. High levels suppress active (1-OH) vitamin D synthesis
    ii. low levels stimulate (1-OH) vitamin D synthesis
  3. Adequate amounts necessary for cellular energy metabolism
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5
Q

How is plasma phosphate transported through the nephron?

A

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

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6
Q

What does having a Tm for phosphate reabsorption suggest?

A

Suggests a transport system involving a carrier-mediated system
-a fixed number of transporters with a fixed carrying capacity

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7
Q

What is the mechanism of phosphate transport on the proximal tubule?

A

Na/PO4 transporters located on the apical membrane
Syntheized in ER
Secondary active movement due to Na/K ATPase

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8
Q

What regulates the Na/PO4 symporter of proximal tubule?

A
  1. dietary phosphate
  2. PTH
  3. FGF-23
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9
Q

What does a low phosphate diet stimulate? High phosphate diet?

A

Low phosphate = stimulates Na/PO4 activity

High phosphate = inhibits Na/PO4 activity

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10
Q

Why does it make sense for PTH to INHIBIT the Na/PO4 symporter?

A

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

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11
Q

How does PTH affect the rate of excretion vs plasma concentration curve?

A

It LOWERS the Tm for phosphate reabsorption, so more phosphate will be excreted at a lower concentration of phosphate flowing through the proximal tubul

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12
Q

What is the mechanism of PTH action?

A

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

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13
Q

What are the actions of FGF-23 in relation to phosphate regulation?

A

Produced in the bone
Promotes phosphate excretion
Reduces activation of vitamin D (primary biologic activity)
Over expressed in hypophosphatemia and under expressed in hyperphosphatemia

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14
Q

What are the clinical consequences of hypophosphatemia?

A

Ricketts and osteomalacia

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15
Q

What are the effects of low phosphate diet or fall in plasma PO4?

A

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

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16
Q

What are the mechanisms of low phosphate diet?

A

Somehow phosphate level is sensed by proximal tubule

Na/PO4 receptors are upregulated and not degraded

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17
Q

What is the integrated effect of INCREASED phosphate on the body?

A

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

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18
Q

What is the effect of DECREASED

Phosphate in the body?

A 
Decrease phosphate = increased Ca =
Decreased PTH = decreased renal
Phosphate excretion
As well as
Increase vitamin D synthesis and
Increased intestinal/renal absorption 
Of phosphate
19
Q

What are other factors that may Influence

phosphate balance?

A
  1. GI factors
    • evidence for gut-kidney axis
  2. FGF-23
  3. Phosphatonins
20
Q

What are the key characteristics of FGF-23?

A

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

21
Q

What happens when there is an acute minimal fall in plasma phosphate?

A 
Happens commonly (esp after glucose infusion)
No clinical consequences as there are large stores of cell phosphate to buffer falls in intracellular levels
22
Q

What are the characteristics of hypophosphatemia in a chronic setting?

A

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

23
Q

What are the physiologic responses to a sustained fall in plasma phosphate?

A
  1. Decreased PTH release (vit D effect, increased ionized Ca, effect of PTH on parathyroid gland)
  2. Reduced urinary phosphate (acute and related to reduced PTh/direct renal effect)
  3. Increased 1-hydroxylation of 25-OH vitamin D
  4. Increased bone resorption (vit D effect and direct effect on bone)
  5. increased calcium excretion due to vitamin D effect
    FGF-23 also plays a role
24
Q

What are the physiologic responses to a sustained rise in plasma?

A
  1. Increased PTH release (reduced vit D effect, reduced Ca and effect on parathyroid)
  2. Increased plasma FGF-23
  3. Increased urinary phosphate (acute and related to increased PTH and FGF-23…also direct renal effect)
  4. Decreased 1-hydroxylation of vitamin D
  5. Decreased bone resorption
  6. Decreased calcium excretion
    5 and 6 due to vitamin D effect and direct effect on bone
25
Q

What are the consequences of sustained hypophosphatemia in setting of chronic depletion of total body stores?

A
  1. musculoskeletal like osteopenia/osteomalacia
  2. cardiomyopathy/arrhythmias
  3. respiratory failure/wearing ventilator
  4. Neurologic like seizures and hallucinations
  5. Hematologic
    -hypoxia (impaired O2 delivery)
    -hemolysis
    -leukocyte dysfunciton
  6. Metabolic
    -due to metabolic acidosis
    -also due to glucose intolerance
    All of these relate DIRECTLY to consequences of ATP deficiency
26
Q

What step in glycolysis requires phosphate? Significance?

A

The step that converts Glyceraldehyde phosphate (GAP) to 1,3 bisphophogycerate
Enzyme = triose phosphate dehydrogenase
Significance: No phosphate = no glycolysis = no ATP can be made from glycolysis
Example: no ATP = decreased levels of 2,3 BPG in RBCs
-decreased 2,3 BPG levels in RBCs = greater O2 affinity for hemoglobin and consequent tissue hypoxia
-also no ATP can lead to hemolysis

27
Q

What are causes of hypophosphatemia?

A
  1. Intracellular shift
  2. Decreased phosphate absorption
  3. Increased Renal Phosphate Excretion
28
Q

What are factors that usually lead to intracellular shift of phosphate?

A
  1. Carbohydrate infusions
  2. Hormonal effects due to catecholamines and insulin
  3. Respiratory alkalosis
  4. Rapid Cellular Proliferation
    -leukemic blast crisis
    -hungry bone syndrome
    Usually acute and inconsequential
    Mechanism = utilization of phosphate in the formation of glycogen or intermediaries of glucose metabolism
29
Q

What is hungry bone syndrome?

A

Condition following removal of hyperactive parathyroid glands

- patients of hyperactive parathyroid glands are depleted of calcium and phosphate and will thus take up a shitload of serum Ca and phosphate once parathyroid glands are removed
- hungry bones = they are hungry for that serum phosphate/calcium lol
30
Q

What are the factors that lead to decreased phosphate absorption?

A
  1. Malabsorption
    -low Phosphate due to renal losses in setting of GI malabsorption of Ca and Vit D, secondary hyperparathyroidism
  2. Phosphate binding antacids (esp the ones containing aluminum)
  3. Vitamin D deficiency
    -although predominant cause of low PO4 in this setting is renal loss due to hyperparathyroidism, which is caused by calcium deficiency
  4. dietary phosphate deprivation (very rare)
    So decreased phosphate absorption is usually secondary to hyperparathyroidism as cause for hypophosphatemia
31
Q

What are the factors that lead to increased renal phosphate excretion?

A
  1. Hyperparathyroidism
  2. Oncogenic osteomalacia
  3. Genetic defects in phosphate metabolism
  4. Alcoholism
    • alcohoics may have diffuse renal tubulopathy, which is characterized by phosphate wasting
  5. Diuretics like Diamox that inhibits proximal tubule and can produce as much phosphaturia as PTH
  6. ADHR
  7. X-linked phosphatemic rickets
32
Q

What hormone increases secretion/excretion of phosphate?

A

PTH

33
Q

What are the key characteristics of oncogenic osteomalacia?

A

A rare praneoplastic syndrome in which patients develop hypophosphatemia

  • patient has excess renal phosphate wasting and low calcitriol (1,25 vit D) DESPITE having osteomalacia, muscle wasting and hypophosphatemia in serum
  • tumors make a shitload of FGF-23, which leads to increased phosphate wasting

Thus, increased FGF-23 levels = increased phosphate wasting!!
-this can be caused by decreased metabolism (defect in PHEX, the enzyme that breaks down FGF-23) as well as increased production of FGF-23

34
Q

What is the MoA of hypophosphatemia in X-linked hypophosphatemia?

A

X-linked hypophosphatemia is due to defect in PHEX, the endopeptidase that is responsible for breaking down FGF-23

35
Q

What is phosphatonin?

A

Proteins that regulate phosphate metabolism specifically
Example: FGF-23
Increased phosphatonin (or FGF-23) = increased phosphate wasting

36
Q

ADHR = autosomal dominant hypophosphatemic rickets

A

autosomal dominant hypophosphatemic rickets
Decreased metabolism of FGF23
Increased elvels of FGF 23

37
Q

What is the pathophysiology of a 71 yo with 1 year history of fatigue and malaise
Diagnosed with CHF
Serum calcium = 11.3 mg/dL
Serum phosphate = 1.3 mg/dL
Intact PTH elevated to 241 pg/ml (10-65 pg/ml is average)

A

Hyperfunctioning parathyroid gland
Once parathyroid adenoma was resected, cardiac function improved
Pathophys:
Hyperparathyroidism  decreased proximal tubular phosphate transport  reduced serum PO4 - decreased cellular ATP  decreased 2,3 BPg  decreased cardiac muscle function due to less oxygen  CHF

38
Q

Pathophys of 54 yo with alcoholism was found unconscious at home
Generalized seizure in ED
Rapid rise in CPK with presence of large Hb and 0-2 RBCs in urine to suggest rhabdomyolysis
Severe hypophosphatemia was noted (phosphate = 1.1 mg/dL
Pathophys of rhabdo?

A
  1. Ethanol depletes PO4 in body
  2. glucose infusions in the hospital  increased glycolytic demand  utilization of cell PO4 in glycolysis  decreased PO4
  3. Poor intake of nutrition promotes catabolism of muscle cells which depletes PO4
39
Q

How does depletion of phosphate lead to rhabdomyolysis? Significance?

A

Less PO4  reduced cell ATP  reduced muscle cell intergrity  rhabdomyolysis
Significance: That’s why you get patients with high CPK levels (creatinine phosphokinase) who are alcoholics, because of muscle tissue breakdown

40
Q

When do you need to monitor phosphate levels in the hospital?

A

Every 12 hours once patient is in hospital
By 48 hours, the serum phosphate can drop to 0 if one is not careful to watch out for hypophosphatemia (which is most likely further exacerbated by glucose infusion given in hospital

41
Q

What are the hyperphosphatemia?

A
  1. massive phosphate load
    i. tumor lysis syndrome
    ii. rhabdomyolysis
    iii. exogenous phosphate administration
    iv. laxatives (phosphate in the laxative)
  2. Renal Failure
  3. Increased tubular reabsorption
    i. hypoparathyroidism
    ii. tumoral calcinosis
  4. Lack of FGF-23 (which leads to insufficient phosphate excretion)
42
Q

What is familial tumoral calcinosis? Mechanism?

A

Mechanism = mutation in GALNT3, a gene that encodes a glycosyltransferase that is key in activating FGF-23
No FGF-23 = no phosphate excretion = phosphorus accumulation in blood that can increase calcification in soft tissue
-think of the man with “calcium shoulder pads”…the nice man from venzuela

43
Q

What are the effects of chronic hyperphosphatemia in renal disease?

A

Calcium-phosphate deposits in the soft tissue (of foot)
Deposits in coronary artery (for patients with ESRD)
Deposits in the conjutivae
Deposits in the skin (uremic pruritis)
Deposits in the joints (tumoral calcinosis)

44
Q

What does tumoral calcinosis mean?

A

Deposition of calcium phosphate in the joints

Renal Week 2 (12 decks)

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