**1.2 High mortality rate and hyperphosphatemia**

Inorganic phosphate (phosphate) retention, or hyperphosphatemia, has been identified as playing a major role in the progression of renal failure and in the generation of secondary hyperparathyroidism and uremic bone disease (Slatopolsky et al., 2002). Further observational data have also shown a significant association of hyperphosphatemia with increased mortality among patients who have end-stage kidney disease and are on hemodialysis (Block et al., 1998; Owen & Lowrie, 1998; Ganesh et al., 2001). Moreover, elevated serum phosphorus has been associated with an increased risk for cardiovascular mortality and hospitalization (all-cause, cardiovascular, and fracture) among dialysis patients (Block et al., 2004). Elevated phosphorus and Ca × P are also independent risk factors for all-cause and cardiovascular mortality in CKD stage 5, and increased levels of parathyroid hormone may be associated with both cardiovascular disease and increased

Complications and Managements of Hyperphosphatemia in Dialysis 317

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

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

Several studies have measured circulating FGF23 levels in predialysis and dialysis patients and reported progressively elevated FGF23 levels as serum creatinine or phosphate levels increase (Larsson et al., 2003; Imanishi et al., 2004). Thus, it appears that in patients with CKD, FGF23 production increases to counteract chronic phosphate retention by promoting urinary phosphate excretion in the face of reduced nephron mass. Notably, in this setting, a previous study showed that FGF23 was a strong independent predictor of diminished 1,25(OH)2D levels, even after adjustment for renal function, serum phosphorus levels and 25(OH)D levels (Gutierrez et al., 2005). This finding suggests that in patients with CKD, increases in FGF23 intended to maintain neutral phosphate balance result in suppression of renal 1,25(OH)2D production, thereby triggering the early development of secondary

Cardiomyopathy and ischemic heart disease including acute myocardial infarctions, which are both common conditions in dialysis patients, likely play a role in the development of

levels are upregulated by 1,25(OH)2D3 (Xu et al., 2002; Segawa et al., 2004).

al, 2005; Perwad et al., 2005; Nishida et al., 2006).

hyperparathyroidism (Fig. 1).

**2.2 Phosphate metabolism in hemodialysis patients** 

**3. Cardiovascular disease in hemodyalysis** 

**3.1 Hyperphosphatemia and cardiovascular disease** 

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

Fig. 1. Hyperphosphatemia in hemodialysis
