Phosphate Disorders Physiology Flashcards
What is the central concept of phosphate disorders?
Phosphate Homeostasis
What is the body distribution of phosphate?
- Bones & Teeth (85%)
- Soft Tissues (14%)
- Extracellular Fluid (1%)
What are the forms of phosphate in plasma?
- Organic (70%)
- Inorganic (30%, physiologically active)
- Bound to albumin (10%)
- Free: HPO₄²⁻ (80%) vs. H₂PO₄⁻ (20%) at pH 7.4
Which organ is primarily responsible for phosphate absorption?
Intestine
Where in the intestine does phosphate absorption mainly occur?
Duodenum/jejunum
What stimulates phosphate absorption in the intestine?
1,25(OH)₂D₃
What are the inhibitors of phosphate absorption in the intestine?
- Ca²⁺
- Mg²⁺
- Aluminum (used clinically for hyperphosphatemia)
In the kidney, what percentage of phosphate is reabsorbed?
80–90%
What transporters are involved in phosphate reabsorption in the proximal tubule of the kidney?
- Na/Pi-IIa (SLC34A1, electrogenic)
- Na/Pi-IIc (SLC34A3, electroneutral)
- PiT-2 (SLC20A2, monovalent phosphate)
What is the excretion adjustment of phosphate in the kidney based on?
Dietary intake (10–20% filtered load)
What hormone decreases phosphate reabsorption in the kidney?
Parathyroid Hormone (PTH)
What are the actions of Fibroblast Growth Factor-23 (FGF-23)?
- ↓ Na/Pi cotransporters (kidney)
- ↓ 1,25(OH)₂D₃ (inhibits 1α-hydroxylase)
- ↓ PTH secretion
What is required as a cofactor for FGF-23?
Klotho
What are the effects of Vitamin D (Calcitriol) on phosphate absorption?
↑ Intestinal/kidney phosphate absorption
What causes hypophosphatemia?
- Poor intake
- Vitamin D deficiency
- Renal wasting (PTH excess, FGF-23 excess, Fanconi syndrome)
What are the effects of hypophosphatemia?
- Muscle weakness
- Rhabdomyolysis
- Osteomalacia/rickets
What causes hyperphosphatemia?
- CKD (↓ excretion, ↑ FGF-23 resistance)
- Tumor lysis
- Rhabdomyolysis
What are the effects of hyperphosphatemia?
- Hypocalcemia (precipitates as CaPO₄)
- Vascular calcification
What lab tests are used in the diagnostic approach for phosphate disorders?
- Serum phosphate
- Ca²⁺
- PTH
- FGF-23
- 1,25(OH)₂D₃
What imaging techniques are used to diagnose phosphate disorders?
- Bone X-rays (osteomalacia, rickets)
- Vascular calcification (advanced CKD)
What is a treatment strategy for hypophosphatemia?
- Oral phosphate supplements
- Vitamin D (if deficient)
What is a treatment strategy for hyperphosphatemia?
- Dietary restriction
- Phosphate binders (Ca²⁺/Mg²⁺/Al-based, sevelamer)
- Dialysis (CKD)
What percentage of dietary phosphate is absorbed by the intestine?
65%
This corresponds to an intake of 1,000–1,400 mg/day.
What are the primary sites of phosphate absorption in the intestine?
Duodenum/jejunum (active transport), jejunum/ileum (passive)
These sites utilize different mechanisms for phosphate absorption.
Which transporter in the intestine is stimulated by 1,25(OH)₂D₃?
Na/Pi-IIb
This transporter is inhibited by arsenate, mercury, and calcitonin.
What are the inhibitors of phosphate absorption in the intestine?
- Ca²⁺
- Mg²⁺
- Aluminum
Aluminum is commonly used as a phosphate binder.
How much phosphate does the kidney excrete daily?
700–900 mg/day
This amount adjusts according to dietary intake.
What key transporters are involved in phosphate reabsorption in the proximal tubule of the kidney?
- Na/Pi-IIa (SLC34A1)
- Na/Pi-IIc (SLC34A3)
- PiT-2 (SLC20A2)
These transporters play a crucial role in phosphate homeostasis.
What is the role of PTH in phosphate homeostasis?
↓ Kidney reabsorption, ↑ Bone resorption
This leads to the release of phosphate and Ca²⁺ from bones.
What hormone is secreted by osteocytes and decreases kidney reabsorption of phosphate?
FGF-23
FGF-23 also decreases levels of 1,25(OH)₂D₃ and PTH.
What effect does Vitamin D (1,25(OH)₂D₃) have on phosphate absorption?
↑ Intestinal absorption and ↑ Kidney reabsorption
It increases phosphate absorption in the gut via Na/Pi-IIb.
What happens to phosphate balance during low dietary phosphate intake?
↑ 1,25(OH)₂D₃, ↓ PTH
This leads to increased gut and kidney absorption and decreased renal excretion.
What is a clinical consequence of hypophosphatemia?
Renal wasting
This condition can be caused by excess PTH or FGF-23 and malnutrition.
What is hyperphosphatemia often associated with?
CKD (↓ excretion), tumor lysis
Chronic kidney disease leads to decreased phosphate excretion.
What are the targets for drugs in managing phosphate levels?
- Phosphate binders (Ca²⁺/Mg²⁺/Al)
- Anti-FGF-23 therapies
These drugs help in managing phosphate levels in different clinical conditions.
What is the primary process involved in the handling of phosphate by the kidney?
Filtration and reabsorption
What percentage of filtered phosphate is typically reabsorbed by the proximal tubule?
80–90%
What is the typical percentage of filtered phosphate that appears in urine?
10%
In conditions of high phosphate intake, what percentage of phosphate may be excreted in urine?
Up to 20%
What type of transport occurs for phosphate across the luminal membrane of the proximal tubule?
Transcellular and active
What are the three types of Na/Pi cotransporters identified?
- Type I
- Type II
- Type III
Which isoforms are part of the type II cotransporter?
- Type II(_a)
- Type II(_b)
- Type IIc
Which type II isoforms are involved in the transport of phosphate in the kidney?
- Type II(_a)
- Type II(_c)
How many Na(^+) ions are transported with one phosphate ion by the type II(_a) cotransporter?
3 Na(^+)
How many Na(^+) ions are transported with one phosphate ion by the type II(_c) cotransporter?
2 Na(^+)
What is the function of the Na/K-ATPase in the proximal tubule?
Drives the cotransport system by supplying energy
What gene is associated with the type II(_a) cotransporter?
SLC34A1
What gene is associated with the type II(_b) cotransporter?
SLC34A2
What gene is associated with the type II(_c) cotransporter?
SLC34A3
What is the role of PiT-2 in phosphate transport?
Transports monovalent phosphate
What is the proposed mechanism for phosphate exit across the basolateral membrane?
Na(^+)-independent mechanism involving anion exchange
What physiological factors influence the reabsorption and excretion of phosphate?
- PTH
- FGF-23
- Diet
What effect does calcitriol have on phosphate reabsorption?
Increases phosphate reabsorption directly and decreases it indirectly
What is the response of type II(_a) and type II(_c) cotransporters to PTH?
Rapid response
What is the response of type II(_b) cotransporter to dietary phosphate changes?
Slow response
At what pH level does Na/Pi transport double for type II transporters?
From pH 6.5 to 8.0
What is the effect of pH on PiT-2 activity?
Higher activity at acidic pH and inhibition at alkaline pH
What effect does Parathyroid Hormone (PTH) have on phosphate reabsorption?
PTH decreases phosphate reabsorption and increases its urinary excretion
How does PTH decrease phosphate reabsorption?
By decreasing the abundance of Na/Pi-IIa, Na/Pi-IIc, and PiT-2 cotransporters
What happens to Na/Pi-IIa and PiT-2 cotransporters after parathyroidectomy?
Their protein content increases by two- to threefold
Where are PTH receptors located?
At the apical and basolateral membranes
What pathway is activated when PTH binds to its receptor at the apical membrane?
Phospholipase C/protein kinase C (PKC) pathway
What pathway is activated by PTH binding with the basolateral membrane receptor?
cAMP/PKA pathway
What is the result of both PTH signaling pathways?
Internalization and endocytosis of Na/Pi-IIa followed by its degradation in lysosomes
How quickly does the degradation of Na/Pi-IIa occur?
Rapidly
What is the difference in degradation rate between Na/Pi-IIa and Na/Pi-IIc?
Na/Pi-IIc degradation is rather slow and does not occur in lysosomes
What factors inhibit phosphate reabsorption and increase excretion?
- PTH
- FGF-23
- Dopamine
- Glucocorticoids
- Volume expansion
- Chronic metabolic acidosis
- High phosphate intake
- Diuretics
- Chronic hypercalcemia
- Hypokalemia
What factors promote phosphate reabsorption and decrease excretion?
- Parathyroidectomy
- Calcitriol
- Insulin
- Growth hormone
- Volume contraction
- Metabolic alkalosis
- Low phosphate intake
- Hypocalcemia
- Hypermagnesemia
What role does Na/Pi-IIa play in the apical membrane?
It interacts with several proteins to maintain its expression
What kind of interactions does Na/Pi-IIa have to maintain its stability?
PDZ-based interactions with NHERF1
What happens when the binding of Na/Pi-IIa with NHERF1 is disrupted?
Reduced expression of Na/Pi-IIa at the apical membrane
What is the effect of PTH stimulation on NHERF1?
It phosphorylates NHERF1, reducing its binding to Na/Pi-IIa
What family of proteins is involved in linking plasma membrane proteins to the actin cytoskeleton?
Ezrin, radixin, and moesin family
How does PTH affect the ezrin-NHERF1 interaction?
PTH disrupts this link, diminishing Na/Pi-IIa expression
What is the consequence of lacking ezrin in mice?
Reduced expression of Na/Pi-IIa and NHERF1, leading to urinary loss of phosphate and hypophosphatemia
Fill in the blank: PTH regulates phosphate reabsorption in the _______.
proximal tubule
What is Fibroblast Growth Factor-23 (FGF-23)?
FGF-23 is an important regulator of phosphate transport and excretion.
What conditions is FGF-23 associated with?
Hypophosphatemia, kidney phosphate wasting, reduced 1,25(OH)₂D₃ in tumor-induced osteomalacia.
Which cells secrete FGF-23?
Osteoblasts and osteocytes of the bone.
What is one function of FGF-23 related to phosphate metabolism?
Inhibits Na⁺-dependent phosphate cotransporter in the proximal tubule.
How does FGF-23 affect 1,25(OH)₂D₃ levels?
Inhibits 1α-hydroxylase activity, leading to reduced levels of 1,25(OH)₂D₃.
What is the effect of reduced 1,25(OH)₂D₃ on phosphate reabsorption?
Causes increased phosphate excretion.
How does FGF-23 influence parathyroid hormone (PTH) secretion?
Inhibits synthesis and secretion of PTH, indirectly causing hypocalcemia.
What are the overall effects of FGF-23 on serum levels?
Lowers serum phosphate and Ca²⁺ levels.
What mechanism does FGF-23 use to inhibit phosphate reabsorption?
Mediated by activation of ERK1/2 and SGK1.
What happens to Na/Pi-IIa due to FGF-23 signaling?
Leads to internalization and degradation of Na/Pi-IIa.
How does FGF-23 inhibit 1α-hydroxylase?
Involves ERK1/2 activation, but the exact pathway is unknown.
Which receptors does FGF-23 interact with?
FGFR1c, FGFR3c, FGFR4c.
What is required for FGF-23-mediated receptor activation?
A cofactor called Klotho.
What role does Klotho play in aging?
It is an aging-suppressor gene; deficiency causes premature aging.
What happens when Klotho is absent?
FGF-23 fails to exert its effects.
What independent effect does Klotho have in the kidney?
Promotes phosphate excretion.
How does Klotho affect calcium levels?
Promotes Ca²⁺ reabsorption in the distal tubule.
What regulates FGF-23 secretion?
Phosphate, vitamin D₃, and PTH.
What effect does a high phosphate diet have on FGF-23?
Induces FGF-23 secretion.
What is the effect of exogenous administration of 1,25(OH)₂D₃ on FGF-23?
Increases FGF-23 expression and secretion.
What are the two forms of Klotho?
Transmembrane form and secreted form.
What is the function of the transmembrane form of Klotho?
Acts as a cofactor for FGF-23.
What does the soluble form of Klotho promote?
Phosphate excretion independent of FGF-23.
Fill in the blank: FGF-23 is secreted by _______.
osteoblasts and osteocytes.
True or False: Klotho is essential for the phosphaturic effects of FGF-23.
True.
What is the normal range for serum phosphate levels?
2.5 to 4.5 mg/dL
What physiological changes occur when serum phosphate levels are low?
Increases ionized Ca²⁺ and stimulates production of 1,25(OH)₂D₃
What effect does low phosphate level have on PTH?
Inhibits PTH
How does hypophosphatemia affect kidney reabsorption of phosphate?
Increases kidney reabsorption of phosphate
What happens to intestinal phosphate reabsorption when serum phosphate levels are low?
Increases intestinal phosphate reabsorption
Fill in the blank: When serum phosphate levels are high, serum Ca²⁺ levels ______.
decrease
What hormone is stimulated by high serum phosphate levels?
FGF-23
What effect does high phosphate level have on PTH?
Increases PTH
How does high serum phosphate affect kidney phosphate excretion?
Increases kidney phosphate excretion
What is the role of FGF-23 in phosphate homeostasis?
Inhibits phosphate absorption
What is the relationship between calcitriol and FGF-23?
Calcitriol stimulates FGF-23 synthesis
True or False: Low serum phosphate increases kidney phosphate excretion.
False
What does 1,25(OH)₂D₃ do in response to low phosphate levels?
Increases intestinal and kidney reabsorption of phosphate
Fill in the blank: The interrelationship among PTH, FGF-23, and calcitriol is crucial for maintaining ______.
phosphate homeostasis
What is the effect of calcitriol on phosphate absorption?
Increases phosphate absorption
What happens to phosphate absorption in the GI tract when FGF-23 is present?
Inhibition of phosphate absorption
When serum phosphate levels are normal, what happens to PTH secretion?
Maintained at normal levels
What physiological changes occur in response to high serum phosphate levels?
Decreases intestinal & kidney phosphate reabsorption
What is the normal range for serum phosphate levels?
2.5 to 4.5 mg/dL
What physiological changes occur when serum phosphate levels are low?
Increases ionized Ca²⁺ and stimulates production of 1,25(OH)₂D₃
What effect does low phosphate level have on PTH?
Inhibits PTH
How does hypophosphatemia affect kidney reabsorption of phosphate?
Increases kidney reabsorption of phosphate
What happens to intestinal phosphate reabsorption when serum phosphate levels are low?
Increases intestinal phosphate reabsorption
Fill in the blank: When serum phosphate levels are high, serum Ca²⁺ levels ______.
decrease
What hormone is stimulated by high serum phosphate levels?
FGF-23
What effect does high phosphate level have on PTH?
Increases PTH
How does high serum phosphate affect kidney phosphate excretion?
Increases kidney phosphate excretion
What is the role of FGF-23 in phosphate homeostasis?
Inhibits phosphate absorption
What is the relationship between calcitriol and FGF-23?
Calcitriol stimulates FGF-23 synthesis
True or False: Low serum phosphate increases kidney phosphate excretion.
False
What does 1,25(OH)₂D₃ do in response to low phosphate levels?
Increases intestinal and kidney reabsorption of phosphate
Fill in the blank: The interrelationship among PTH, FGF-23, and calcitriol is crucial for maintaining ______.
phosphate homeostasis
What is the effect of calcitriol on phosphate absorption?
Increases phosphate absorption
What happens to phosphate absorption in the GI tract when FGF-23 is present?
Inhibition of phosphate absorption
When serum phosphate levels are normal, what happens to PTH secretion?
Maintained at normal levels
What physiological changes occur in response to high serum phosphate levels?
Decreases intestinal & kidney phosphate reabsorption
