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 = x 0.93 mmol/L (converted from 2.9 mg/dL) = 0.93 mmol/L

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

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

7. 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

8. Phosphorus Metabolism
1500mg
1100mg
200mg
200mg

10. 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

12. 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

15. 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

16. 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

18. 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)

19. 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

20. 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

21. FGF 23