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TmP/GFR = maximum reabsorption of PO 4 per unit volume of GFR

TmP/GFR = maximum reabsorption of PO 4 per unit volume of GFR. FE PO4 = U PO4 /P PO4 / U creat /P creat 1 - FE PO4 = TRP Assuming P PO4 = [PO4] GFR TmPO4/GFR = TRP X P PO4. Tubular reabsoption of phosphate (TRP) Tubular maximal reabsoption rate of phosphate to GFR (TmP/GFR) .

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TmP/GFR = maximum reabsorption of PO 4 per unit volume of GFR

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  1. TmP/GFR = maximum reabsorption of PO4 per unit volume of GFR FEPO4 = UPO4 /PPO4 / Ucreat /Pcreat 1 - FEPO4 = TRP Assuming PPO4 = [PO4]GFR TmPO4/GFR = TRP X PPO4

  2. Tubular reabsoption of phosphate (TRP) • Tubular maximal reabsoption rate of phosphate to GFR (TmP/GFR)

  3. 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

  4. Regulation of Phosphate Transport in Proximal Tubule Alexander Usorov, MD 11/25/08

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

  6. 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

  7. Phosphorus Metabolism 1500mg 1100mg 200mg 200mg

  8. 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

  9. Different stoichiometries • NaPi-2a is electrogenic • Stoichiometry is 3:1 Na:P • NaPi-2c is eletroneutral • Stoichiometry is 2:1 • Both cotransporters show similar affinity fo Na (-50mM) and Pi (<0.1mM) • Why is stoichiometry important? • It allows the favorable inward gradient to drive continued phosphate uptake despite a falling tubular fluid phosphate concentration

  10. 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

  11. 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

  12. 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)

  13. 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) <- phenotypically different from TIO • Reduced in Tumoral calcinosis, a disorder characterized by: • Hyperphosphatemia • Reduced fractional excretion of phosphate • Ca phosphate deposits in soft tissues

  14. 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

  15. FGF 23

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