**2.1 Phosphate metabolism in normal physiology**

Phosphorus is essential for multiple and diverse biological functions, including cellular signal transduction, mineral metabolism, and energy exchange. Although more than 80% of total body phosphorus is stored in bone and teeth, intracellular phosphorus exists in the form of organic compounds such as adenosine triphosphate and as free anions like H2PO4-, which are commonly referred to as phosphate. Serum phosphorus primarily occurs in the form of inorganic phosphate, which is maintained within the physiological range by regulation of dietary absorption, bone formation, and renal excretion, as well as equilibration with intracellular stores (Takeda et al., 2000; Bringhurst et al., 2004; Fukagawa et al., 2004; Blumsohn, 2004).

Phosphate absorption in the renal proximal tubule and the small intestine is important for phosphate homeostasis. This is a major regulator of phosphate homeostasis and has the phosphate reabsorptive capacity to accommodate physiologic phosphate requirement. Up to 70% of filtered phosphate is reabsorbed in the proximal tubule where sodium-dependent

vascular calcification (Braun et al., 1996; Block et al., 1998; Ganesh et al., 2001; Wang et al., 2003; Young et al., 2005). Thus, phosphorus has the potential to induce vascular calcification and may be cardiotoxic (Achinger & Ayus, 2006). Hyperphosphatemia is sometimes regarded as a distinct syndrome (Hruska et al., 2008), and its treatment should be

Hyperphosphatemia

Vascular calcification, Arterial stiffness, Endothelial dysfunction

Hyperparathyroidism 1,25(OH)2D FGF23 Klotho

Atherosclerosis, Arteriolosclerosis, Arterial thickening Left ventricular hypertrophy, Cardiac interstitial fibrosis

myocardial infarction, ischemic infarction

High mortality Sudden death

Phosphorus is essential for multiple and diverse biological functions, including cellular signal transduction, mineral metabolism, and energy exchange. Although more than 80% of total body phosphorus is stored in bone and teeth, intracellular phosphorus exists in the form of organic compounds such as adenosine triphosphate and as free anions like H2PO4-, which are commonly referred to as phosphate. Serum phosphorus primarily occurs in the form of inorganic phosphate, which is maintained within the physiological range by regulation of dietary absorption, bone formation, and renal excretion, as well as equilibration with intracellular stores (Takeda et al., 2000; Bringhurst et al., 2004; Fukagawa

Phosphate absorption in the renal proximal tubule and the small intestine is important for phosphate homeostasis. This is a major regulator of phosphate homeostasis and has the phosphate reabsorptive capacity to accommodate physiologic phosphate requirement. Up to 70% of filtered phosphate is reabsorbed in the proximal tubule where sodium-dependent

stroke, peripheral vascular disease

Cardiovascular disease

Fig. 1. Hyperphosphatemia in hemodialysis

**2. Phosphate metabolism in human** 

et al., 2004; Blumsohn, 2004).

**2.1 Phosphate metabolism in normal physiology** 

considered preferentially and even independently of other laboratory values (Fig. 1).

phosphate transport systems in the brush-border membrane mediate the rate limiting step in the overall phosphate reabsorptive process (Murer et al, 2000; Takeda et al, 2000; Miyamoto et al, 2007; Tenenhouse, 2005; Biber et al, 2009). Three different types of sodiumdependent phosphate transporters have been identified till now, types I, II and III. The sodium-dependent phosphate transport system includes the type IIa and type IIc Nadependent phosphate cotransporters, which are localized in the apical membrane of the renal proximal tubular cells, and the type IIb Na-dependent phosphate cotransporter, which is localized in the apical membrane of the intestinal epithelial cells. The type IIa Nadependent phosphate transporter is the major determinant of plasma phosphate level and urinary phosphate excretion (Murer et al, 2000; Takeda et al, 2000; Miyamoto et al, 2007; Tenenhouse, 2005; Biber et al, 2009). This transporter is regulated by physiological stimuli, for example, type IIa transporter levels in the apical membrane are increased in response to dietary restriction of phosphate and 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] and decreased in response to parathyroid hormone, or a high- phosphate diet. In addition, intestinal phosphate transport activity and type IIb Na-dependent phosphate transporter levels are upregulated by 1,25(OH)2D3 (Xu et al., 2002; Segawa et al., 2004).

In addition, fibroblast growth factor 23 (FGF23), a recently identified member of the FGF family, is involved in renal phosphate homeostasis (Yu X & White, 2005; Yu & White, 2005). FGF23 induces urinary phosphate excretion by suppressing the expression of type IIa and IIc Na-dependent phosphate cotransporters in the brush border of renal proximal tubules (Shimada et al., 2004; Shimada et al., 2005). It also suppresses 1,25(OH)2D production by inhibiting 1a-hydroxylase (CYP27B1), which converts 25-hydroxyvitamin D [25(OH)D] to 1,25(OH)2D, and by stimulating 24-hydroxylase (CYP24), which converts 1,25(OH)2D to inactive metabolites in the proximal tubule of the kidney (Shimada et al., 2004; Shimada et al., 2005). Given the fact that FGF23 promotes renal phosphaturia, its secretion should be regulated by serum phosphate levels. Experimental and clinical studies showed that several days of dietary phosphate loading lead to an increase in serum FGF23 in humans (Ferrari et al, 2005; Perwad et al., 2005; Nishida et al., 2006).
