Phosphate Frustration: Treatment Options to Complement Current Therapies

Abstract

Hyperphosphatemia eventually develops in almost all patients with advanced chronic kidney disease and is associated with negative clinical outcomes. Thus, guidelines recommend targeting treatment to normal phosphate levels in patients with chronic kidney disease. Despite low phosphorus diets, clearance by dialysis, and phosphate binder use, many patients with chronic kidney disease on dialysis are unable to consistently achieve and maintain serum phosphate concentrations <5.5 mg/dL. A chart audit of patients on dialysis receiving phosphate binders showed that 74 to 86% were unable to consistently achieve serum phosphate ≤5.5 mg/dL over 6 months. Furthermore, although there is evidence that serum phosphate concentrations <4.5 mg/dL are associated with improved survival and cardiovascular outcomes, real-world phosphate control data suggest achieving and maintaining this goal for most patients would be extremely challenging, if not near impossible, using current therapies. As phosphate binders can only remove approximately 300 mg of the 2,500 mg or more daily dietary phosphate intake, therapeutic innovations are necessary to improve phosphate management. We present treatment options to complement current therapies including tenapanor, a novel sodium/hydrogen exchanger isoform 3 inhibitor that blocks the dominant paracellular phosphate absorption pathway and has been shown to reduce phosphate levels in several clinical trials.

Figure 1

Percent of patients with CKD unable to achieve phosphate control [15, 22]. Many patients on dialysis are unable to consistently achieve and maintain target phosphate concentrations, let alone more normal levels of <4.5 mg/dL. Almost all patients on dialysis cannot consistently achieve and maintain phosphate concentrations <4.5 mg/dL over 6 months.

Figure 2

Current therapies fail to lower phosphate to target levels [42]. A comparative study of calcium acetate, calcium carbonate, sevelamer hydrochloride, and lanthanum carbonate was conducted in 120 patients with ESRD on dialysis [42]. A total of 30 patients were randomly assigned to each binder type [42]. Reductions in serum phosphorus were observed for all phosphate binders but on average did not get below 5.5 mg/dL.

Figure 3

Only a small proportion of dietary phosphate is addressed by binders and dialysis [, , , –, –55]. Phosphate binders and dialysis can address ∼730 mg of phosphate per day (for example, an average of 300 mg/day of phosphorus binding was used for binders and not the potential maximum of 400 mg/day). However, this is far less than the mean daily dietary phosphate consumption in the US (∼1400 mg), particularly for diets high in phosphate additives, which can add ∼1,100 mg phosphate. Therefore, over 1,000 mg phosphate per day may not be addressed by binders and dialysis, increasing the risk of hyperphosphatemia and associated negative clinical outcomes. A net neutral phosphate balance can be achieved if patients strictly follow the guideline-recommended restricted phosphate intake and avoid most phosphate additives.