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

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

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

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

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

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

Phosphorus Metabolism 1500mg 1100mg 200mg 200mg

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

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

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

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

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)

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

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

FGF 23