TmPGFR maximum reabsorption of PO4 per unit volume of GFR

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TmP/GFR maximum reabsorption of PO4 per unit
volume of GFR
FEPO4 UPO4 /PPO4 / Ucreat /Pcreat 1 - FEPO4
TRP Assuming PPO4 PO4GFR TmPO4/GFR TRP
X PPO4
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• Tubular reabsoption of phosphate (TRP)
• Tubular maximal reabsoption rate of phosphate to
  GFR (TmP/GFR)

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• TRP 99.9
• TmP/GFR TRP x Plasma Phos 0.999 x 0.93 mmol/L
  (converted from 2.9 mg/dL) 0.93 mmol/L

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Regulation of Phosphate Transport in Proximal
Tubule

• Alexander Usorov, MD
• 11/25/08

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Overview

• Role of phosphorus
• Proximal nephron transport mechanism
• Sodium-hydrogen exchanger regulatory factor-1
  (NHERF1)
• Fibroblast Growth Factor (FGF 23)

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Importance of Phosphorus

• Component of hydroxyapatite, which is the major
  component of bone mineral
• Present in nucleic acids, bioactive signaling
  proteins, phosophorylated enzymes, and cell
  membranes
• Deficiency in phosphorus leads to
• Impaired bone mineralization (osteomalacia or
  rickets)
• Abnormal RBC, WBC, Plt fxn
• Impaired cell membrane integrity (rhabdo)
• Impaired cardiac output

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Phosphorus Metabolism
1500mg
1100mg
200mg
200mg
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Phosphorus reabsorption

• Up to 95 occurs in the proximal tubule
• Filtered phosphate moves from lumen to cells via
  Na-phosphate cotransporters located in the
  luminal membrane
• Different types of Na/Pi cotransporters
• NaPi-2a (encoded by SLC34A1 gene, mediates 70 of
  filtered phosphate)
• NaPi-2c (encoded by SLC34A3 gene)
• Pit-1/2

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Different stoichiometries

• NaPi-2a is electrogenic
• Stoichiometry is 31 NaP
• NaPi-2c is eletroneutral
• Stoichiometry is 21
• Both cotransporters show similar affinity fo Na
  (-50mM) and Pi (lt0.1mM)
• Why is stoichiometry important?
• It allows the favorable inward gradient to drive
  continued phosphate uptake despite a falling
  tubular fluid phosphate concentration

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The role of NHERF-1

• Sodium-hydrogen exchanger regulatory factor 1
  protein
• Interacts with C-terminal tail of NaPi-2a and
  NaPi-2c
• Plays an important role in the trafficking and
  transciptional regulation

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NHERF-1 Cont

• Recent study by Karim et al in NEJM from
  September 2008
• Gene sequencing of patients with renal stones,
  bone demineralization, or both (usual causes such
  as hyperparathyroidism were excluded)
• Three different NHERF1 mutations in 7 patients,
  which had a significantly lower renal phosphate
  reabsorption capacities than patients with wild
  type NHERF1
• Greater cAMP stimulation and greater inhibition
  of phosphate transport in the presence of PTH

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Phosphatonins

• Term was coined in 1994 to describe a circulating
  phosphaturic factor present in patient with
  oncogenic or Tumor-induced osteomalacia
• Hypophosphatemia
• Renal phosphate wasting
• Reduced 1,25 Vit D
• Osteomalacia
• All resolved after removal of the tumor
• Include
• Fibroblast growth factor 23 (FGF-23)
• FGF-7
• matrix extracellular phosphoglycoprotein (MEPE)
• secreted frizzled-related protein 4 (sFRP-4)
• Phosphatonins downregulate renal phosphate
  reabsorption at least in part by decreasing the
  abundance of apical sodium/phosphate
  co-transporters in the proximal tubule (both
  NaPi-2a and NaPi-2c)

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FGF-23

• Elevated in the following disorders
  (phenotypically similar to TIO)
• X-linked hypophosphatemic rickets (XLH)
• Autosomal dominant hypophosphatemic rickets
  (ADHR)
• Autosomal recessive hypophosphatemia (ARHP)
• Renal failure (correlates with decline in GFR as
  well as elevated phos) lt- phenotypically
  different from TIO
• Reduced in Tumoral calcinosis, a disorder
  characterized by
• Hyperphosphatemia
• Reduced fractional excretion of phosphate
• Ca phosphate deposits in soft tissues

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FGF-23

• Secreted, circulating 32kDa protein
• Predominantly expressed in osteocytes in the bone
  and endothelial cells of bone marrow and thymus
• Interacts with FGF receptors that belong to type
  1 transmembrane phosphotyrosine kinase receptors
  (MAPK/ERK1-2)
• Requires Klotho as a co-factor for receptor
  activation
• Klotho gene encodes a single-pass membrane
  protein, homologous to B-glucosidase
• Klotho-deficient mice have a phenotype similar to
  FGF-23 null mice

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FGF 23