Phosphorus in kidney disease: Culprit or bystander?

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Phosphorus is essential for life. However, both low and high levels of phosphorus in the body have consequences, and its concentration in the blood is tightly regulated through dietary absorption, bone flux, and renal excretion and is influenced by calcitriol (1,25 hydroxyvitamin D3), parathyroid hormone, and fibroblast growth factor 23 (FGF23).

See related articles by M. Shetty and A. Sekar

Sekar et al,1 in this issue of the Journal, provide an extensive review of the pathophysiology of phosphorus metabolism and strategies to control phosphorus levels in patients with hyperphosphatemia and end-stage kidney disease.


What's in a name? That which we call a rose
By any other word would smell as sweet.
—Shakespeare, Romeo and Juliet

The terms phosphate and phosphorus are often used interchangeably, though most writers still prefer phosphate over phosphorus.

The serum concentrations of phosphate and phosphorus are the same when expressed in millimoles per liter, as every mole of phosphate contains 1 mole of phosphorus, but not the same when expressed in milligrams per deciliter.2 The molecular weight of phosphorus is 30.97, whereas the molecular weight of the phosphate ion (PO43–) is 94.97—more than 3 times higher. Therefore, using these terms interchangeably in this context can lead to numerical error.3

Phosphorus, being highly reactive, does not exist by itself in nature and is typically present as phosphates in biologic systems. When describing phosphorus metabolism, the term phosphates should ideally be used because phosphates are the actual participants in the bodily processes. But in the clinical laboratory, all methods that measure serum phosphorus in fact measure inorganic phosphate and are expressed in terms of milligrams of phosphorus per deciliter rather than milligrams of phosphate per deciliter, and using these 2 terms interchangeably in clinical practice should not be of concern.4


US adults typically ingest 1,200 mg of phosphorus each day, and about 60% to 70% of the ingested phosphorus is absorbed both by passive paracellular diffusion via tight junctions and by active transcellular transport via sodium-phosphate cotransport. The kidneys must excrete the same amount daily to maintain a steady state. As kidney function declines, phosphorus accumulates in the blood, leading to hyperphosphatemia.

Hyperphosphatemia is often asymptomatic, but it can cause generalized itching, red eyes, and adverse effects on the bone and parathyroid glands. Higher serum phosphorus levels have been shown to be associated with vascular calcification,5 cardiovascular events, and higher all-cause mortality rates in the general population,6 in patients with diabetes,7 and in those with chronic kidney disease.8 This association between higher serum phosphorus levels and the all-cause mortality rate led to the assumption that lowering serum phosphorus levels in these patients could reduce the rates of cardiovascular events and death, and to efforts to correct hyperphosphatemia.

Research into FGF23 continues, especially its role in cardiovascular complications of chronic kidney disease, as both phosphorus and FGF23 levels are elevated in chronic kidney disease and are implicated in poor clinical outcomes in these patients. However, both FGF23 and parathyroid hormone levels rise early in the course of kidney disease, long before overt hyperphosphatemia develops. Further, FGF23 rises earlier than parathyroid hormone and has been found to be an independent risk factor for cardiovascular events and death from any cause in end-stage kidney disease.9

Whether hyperphosphatemia is the culprit or merely an epiphenomenon of metabolic complications of chronic kidney disease is still unclear, as more molecules are being identified in the complex process of cardiovascular calcification.10

However, one thing is clear: vascular calcification is not just a simple precipitation of calcium and phosphorus. Instead, it is an active process that involves many regulators of mineral metabolism.10 The complex nature of this process is likely one of the reasons that evidence is conflicting11 about the benefits of phosphorus binders in terms of cardiovascular events or all-cause mortality in these patients.

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