Is serum phosphate a useful target in patients with chronic kidney disease and what is the role for dietary phosphate restriction?
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both play an important role in regulating serum phosphate by stimulating urinary phosphate excretion. Phosphate is freely filtered through the glomerulus and reabsorbed via the renal sodium/phosphate type 2 cotransporters NaPi‐2a and NaPi‐2c, which are expressed on the luminal side of the proximal tubular epithelial cells. How, or even if, humans ‘sense’ and control extracellular phosphate remains unclear, and no extracellular phosphate sensor has been described to date.
Phosphate elimination is dependent upon renal function, such that positive phosphate balance occurs relatively early in renal dysfunction but serum phosphate levels rise only late in chronic kidney disease (CKD) and remain elevated in patients on dialysis without treatment. Hyperphosphataemia is recognized as an independent risk factor for accelerated vascular disease in CKD.1 Epidemiological studies show consistently that serum phosphate levels are independently and positively correlated with all‐cause mortality in virtually all populations, including those without CKD, and even where serum phosphate levels are in the upper normal reference range.2 Cardiovascular mortality, vascular calcification, arterial stiffness and progression of renal impairment in patients with CKD are similarly correlated with higher serum phosphate.5 Evidence also suggests that elevated PTH and FGF23 levels in response to a positive phosphate balance contribute to these adverse clinical outcomes.2 Thus, it is plausible that therapeutic strategies aimed at producing a reduction in serum phosphate in patients with CKD might be associated with improved outcomes. Unfortunately, direct evidence for the benefit of such strategies remains elusive.
Most nephrologists routinely measure serum phosphate in patients with CKD and prescribe dietary phosphate restriction, phosphate binders and dialysis in order to achieve a reduction in serum phosphate to prescribed target levels. This is predicated on the assumption that inorganic phosphate is a cellular toxin and may be causally related to adverse cardiovascular outcomes, such as vascular calcification, and mortality. However, much of the data linking phosphate‐lowering interventions to better outcomes do not necessarily involve a reduction in serum phosphate, and data from in vitro and animal experiments may be flawed by the models used.
Potential toxicity of excess phosphate has been linked to vascular calcification, endothelial dysfunction, left ventricular hypertrophy and the development of secondary hyperparathyroidism and bone disease.12 Serum phosphate provides only a crude measure of phosphate balance but recent data looking at calciprotein particles (CPPs) may provide the missing link in the pathogenesis.15 CPPs are soluble colloidal protein‐mineral nanoparticles, comprised of calcium/phosphate and the protein calcification inhibitor fetuin‐A along with other proteins, and these function to prevent ectopic mineral precipitation. Levels of CPPs are positively associated with vascular calcification and aortic stiffness and are potentially a marker of calcification propensity, which begin to rise before the appearance of hyperphosphataemia in individuals with CKD.17 PTH, FGF23 and CPPs may be more appropriate targets for therapeutic interventions than serum phosphate.