Elevated levels are associated with higher mortality and greater risk of CKD progression.
Phosphorus plays an important role in human life. It is an essential building block of the human body as a component of the bony skeleton, adenosine triphosphate, nucleic acids, phospholipid membranes, and blood and urinary buffers.1
An intricate regulatory system assures the maintenance of normal phosphorus homeostasis under normal circumstances.2 The kidneys play a pivotal role in this system as the main organs responsible for phosphorus excretion. One of the many abnormalities in CKD is a derangement of mineral metabolism,3 with abnormalities affecting phosphorus being one of its centerpieces. Much attention has focused on hyperphosphatemia and its consequences in dialysis patients, even though they represent only a minority of all patients with CKD.4
This review will describe the physiology and pathophysiology of phosphorus metabolism, various adverse outcomes associated with phosphorus deregulation, and potential treatment strategies in patients with CKD who are not yet on dialysis.
The human body contains approximately 700 grams of phosphorus contained in various inorganic and organic molecules.1 The majority of this (85%) is in the bones as hydroxyapatite and about 14% is contained in soft tissues.1 Only 1% is found in the extracellular fluid.2 The main sources of phosphorus intake are meats, dairy products, and particularly food additives. The daily amount of phosphorus consumption in an average Western diet is 800-1500 mg, with approximately 65% of this being absorbed in the small intestine.1
The main regulator of intestinal phosphorus absorption is 1,25-dihydroxy vitamin D (calcitriol) acting through the Na-phosphate co-transporter Npt2b in the intestinal epithelial cells.2 A physiologic plasma phosphorus level of 3.0-4.5 mg/dL is maintained chiefly through renal clearance; about 900 mg of phosphorus is excreted daily in the urine. About 90% of plasma phosphates are filtered in the glomerulus, and 80%-97% of the filtered load is reabsorbed, mostly in the proximal tubule; no phosphorus is secreted by the tubular cells.2
The main regulators of proximal tubular reabsorption are the plasma phosphorus level and various hormones with phosphaturic properties, the main ones being parathyroid hormone (PTH) 2 and fibroblast growth factor 23 (FGF-23).5 Plasma phosphorus level exerts a direct negative feedback effect on proximal tubular phosphate reabsorption.2 PTH blocks phosphate reabsorption in the proximal tubule through its action on the sodium-phosphate transporter Npt2a,6 and concomitantly increases 1-hydroxylation of 25(OH) vitamin D, thus raising levels of calcitriol; the net effect is thus an increase in urinary phosphate excretion but also a concomitant increase in intestinal phosphate (and calcium) absorption. PTH is produced in the parathyroid glands, with lower calcium, higher phosphorus and lower calcitriol levels all stimulating its production.5-7
FGF-23 also lowers phosphate reabsorption in the proximal tubule through Npt2a (independent of PTH), but it blocks 1- hydroxylation of 25(OH) vitamin D, consequently lowering calcitriol levels; its effect is thus net hypophosphatemic, with higher urinary excretion and lower intestinal absorption of phosphorus.5 FGF-23 is produced in the bone; higher phosphorus and higher calcitriol stimulate its production.5