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Phosphorus binders: The new and the old, and how to choose

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ABSTRACT

In caring for patients with chronic kidney disease, it is important to prevent and treat hyperphosphatemia with a combination of dietary restrictions and phosphorus binders. This review describes the pathophysiology and control of hyperphosphatemia and the different classes of phosphorus binders with respect to their availability, cost, side effects, and scenarios in which one class of binder may be more beneficial than another.

KEY POINTS

  • Serum phosphorus is maintained within normal levels in a tightly regulated system involving interplay between organs, hormones, diet, and other factors.
  • Dietary phosphorus comes mainly from protein, so restricting phosphorus without introducing protein deficiency is difficult. Food with a low phosphorus-to-protein ratio and plant-based sources of protein may be preferable.
  • Although dialysis removes phosphorus, it usually does not remove enough, and many patients require phosphorus-binding drugs.
  • Selection of an appropriate binder should consider serum calcium levels, pill burden, serum iron stores, and cost.


 

References

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,1 nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

  • Phosphorus balance
  • The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
  • The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

Daily intake and output of phosphorus
Net phosphorus balance depends on dietary phosphorus intake, gastrointestinal absorption, renal function, and flux between extracellular and intracellular (skeletal) pools (Table 1).

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.2

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D3, also called calcitriol).3

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.4 Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.5

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.6

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.7

Hormonal regulation of calcium and phosphorus

Figure 1. Hormonal regulation of calcium and phosphorus. Serum calcium and phosphorus balance is maintained by a tight interplay between parathyroid hormone (PTH), vitamin D, and fibroblast growth factor 23 (FGF23).

Parathyroid hormone, in contrast, has a mixed effect. It increases renal excretion of phosphorus on one hand but increases phosphorus release from bone into the serum on the other. The latter is accomplished by increasing both bone resorption (directly) and intestinal absorption (indirectly, via stimulation of calcitriol) of phosphorus.8
Factors that affect the serum phosphorus level
FGF23 inhibits parathyroid hormone and calcitriol. Parathyroid hormone stimulates both FGF23 and calcitriol, whereas calcitriol inhibits parathyroid hormone. The complex interplay between these hormones is shown in Figure 1 and Table 2.

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

  • Decreased calcitriol due to its inhibition by FGF239
  • Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
  • Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).
Chronic renal failure and hyperphosphatemia

Figure 2. Pathophysiologic processes of hyperphosphatemia. As the glomerular filtration rate (GFR) drops, the serum inorganic phosphorus (Pi) level spikes and prompts a series of responses that include stepwise increases in fibroblast growth factor 23 (FGF23), decreases in calcitriol (1,25 D), and increases in parathyroid hormone (PTH).

As chronic kidney disease progresses, the glomerular filtration rate falls, the phosphorus level rises, and the above sequence of events is repeated and accentuated, which leads to correction of the phosphorus levels. However, once the glomerular filtration rate falls below 25 to 40 mL/min/1.73 m2, these response mechanisms no longer suffice and the phosphorus level stays elevated.10 This is illustrated in Figure 2.

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

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Phosphorus in kidney disease: Culprit or bystander?

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