A large-scale clinical trial demonstrating the benefit of phosphate binders in nondialysis CKD is not available, and treatment recommendations are based on observational study findings and expert opinion (Kidney Disease: Improving Global Outcomes [KDIGO], 2009, 2013). Increased serum phosphorus has been associated with increased mortality among nondialysis CKD patients. In a meta-analysis of three studies with 4,651 such patients, there was a 35% increase in mortality per 1-mg/dL increase in serum phosphorus above normal (Palmer et al., 2011). Normalization
of plasma phosphorus (i.e., <4.5 mg/dL [1.45 mmol/L]) is recommended by the KDIGO guidelines.

Increased serum phosphorus is also associated with increased mortality among dialysis patients (Block et al., 1998; Palmer et al., 2011). In a meta-analysis of 12 studies that included 92,345 patients with CKD, over 97% of whom were on dialysis (Palmer et al., 2011), serum phosphate of more than 5.5 mg/dL (1.78 mmol/L) was associated with increased mortality, with an 18% increase in risk for each 1-mg/dL increase in serum phosphorus. Maintaining the serum phosphorus concentration between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L) is recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (National Kidney Foundation, 2003). This, however, differs from the more recent KDIGO guidelines, which recommend lowering levels toward the normal range, but do not specify a specific target. As with nondialysis CKD, no randomized study has evaluated whether achieving these serum phosphate targets with phosphate binders affects clinically important outcomes in dialysis patients.

The treatment with the least risk is restriction of phosphate intake, providing it is done in a manner that does not result in limitation of nutritional intake. Phosphate restriction should therefore focus on avoidance of phosphate additives added to processed foods and drinks, and not high-biologic-value foods such as meat and eggs. The amount of phosphate additives in foods has doubled in the past 25 years, and this is likely the major reason for the continued high prevalence of hyperphosphatemia in end-stage renal disease (ESRD) patients despite improvements in dialysis therapy during this time. The phosphate in highly processed foods and drinks, which have high phosphate content, is not bound
to phytates and is more easily absorbed compared with phosphate in fresh, unprocessed foods (Uribarri and Calvo, 2003). Patients must be instructed to read food labels and to identify phosphate-containing additives (Table 16.1). Limiting the intake of phosphate-containing food additives has been shown to be effective in reducing the serum phosphorus concentration in dialysis patients in a randomized trial (Sullivan et al., 2009).

Phosphate binders are categorized as calcium-containing and non-calcium-containing binders. Calcium-containing binders include calcium carbonate and calcium acetate. Non-calcium-containing binders include aluminum, sevelamer, and lanthanum. In the early days of maintenance dialysis, calcium carbonate was commonly used, but a not-infrequent problem was the development of hypercalcemia. Subsequently, aluminum-containing binders were in vogue, but it turned out that enough aluminum was absorbed to cause aluminum toxicity, which could be fatal, and calcium-containing binders, in particular calcium acetate, were again widely prescribed. More recently, there has been increased use of non-calcium-containing binders, in particular the cationic ion-exchange polymer sevelamer and the rare earth mineral lanthanum.

Because of impaired renal excretion of calcium, administration of calcium in CKD patients is expected to result in a positive calcium balance. A randomized, placebo-controlled crossover study examined the effect of oral calcium carbonate administration on calcium and phosphate balance in eight patients with stage 3 to 4 CKD (mean estimated GFR [eGFR] of 15-59 mL/min/1.73 m²) (Hill et al., 2013). Subjects received a controlled diet with either a calcium carbonate supplement (1,500 mg/day calcium) or placebo and underwent two 3-week balance periods. Patients were in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation had no effect on phosphorus balance, as decreased absorption was balanced by decreased urine phosphorus excretion. However, it caused a positive calcium balance; of note, the amount of calcium that was deposited in bone was less than the overall positive calcium balance, suggesting that some degree of soft-tissue deposition occurred. This study raises the question as to efficacy and safety of calcium-containing phosphate binders in nondialysis CKD patients.