Hyperphosphatemia

Phosphate is an abundant mineral found in the body. The body store of phosphate is 500 to 800 g, with 85% of the total body phosphate present in crystals of hydroxyapatite in the bone — about 10% found in muscles and bones in association with proteins, carbohydrates, and lipids. The rest gets distributed in various compounds in the extracellular fluid (ECF) and intracellular fluid (ICF). Phosphate is predominantly an intracellular anion.

The normal plasma inorganic phosphate (Pi )concentration in an adult is 2.5 to 4.5 mg/dl, and men have a slightly higher concentration than women. In children, the normal range is 4 to 7 mg/dl. A plasma phosphate level higher than 4.5 mg/dL is hyperphosphatemia. Phosphate plays an essential role in many biological functions such as the formation of ATP, cyclic AMP, phosphorylation of proteins, etc. Phosphate is also present in nucleic acids and acts as an important intracellular buffer.

Normal adult dietary phosphate intake is around 1000 mg/day. 90% of this is absorbed primarily in the jejunum. In the small intestine, phosphate is absorbed both actively and by passive paracellular diffusion. Active absorption is through sodium-dependent phosphate co-transporter type IIb (NPT2b).

Kidneys excrete ninety percent of the daily phosphate load while the gastrointestinal tract excretes the remainder. As phosphorus is not significantly bound to albumin, most of it gets filtered at the glomerulus. Therefore, the number of functional nephrons plays a significant role in phosphorus homeostasis; 75% of filtered phosphorus is reabsorbed in the proximal tubule, approximately 10% in the distal tubule, and 15% is lost in the urine. In the luminal side of the proximal tubule, the primary phosphorus transporter is the Type II Na/Pi co-transporter (NPT-2a). The activity of this transporter is increased by low serum phosphorus and 1,25(OH)2 vitamin D, increasing reabsorption of phosphorus. Renal tubular phosphorus reabsorption also increases by volume depletion, chronic hypocalcemia, metabolic alkalosis, insulin, estrogen, thyroid hormone, and growth hormone. Tubular reabsorption of phosphorus decreases by parathyroid hormone, phosphatonins, acidosis, hyperphosphatemia, chronic hypercalcemia, and volume expansion.

Phosphorus is transported out of the renal cell by a phosphate-anion exchanger located in the basolateral membrane.

Phosphate homeostasis is under direct hormonal influence of calcitriol, PTH, and phosphatonins, including fibroblast growth factor 23 (FGF-23). Receptors for vitamin D, FGF-23, PTH, and calcium-sensing receptor (CaSR) also play an important role in phosphate homeostasis. Serum phosphate level is maintained through a complex interaction between intestinal phosphate absorption, renal phosphate handling, and the transcellular movement of phosphate that occurs between intracellular fluid and bone storage pool. A transient shift of phosphate into the cells is also stimulated by insulin and respiratory alkalosis.

Sodium-dependent Pi co-transporters

Absorption of phosphate is mediated by the brush border sodium-dependent Pi co-transporters (NPT), which depend on the Na/K-dependent ATPase. There are three classes of these co-transporters:

Type I Na/Pi co-transporter (NPT1): It gets expressed on the renal brush border membrane of the proximal tubule.

Type II Na/Pi co-transporters: These include three closely related isoforms, namely NPT2a, NPT2c, and NPT2b. NPT2a and NPT2c are both exclusively expressed on the brush border membrane of the renal proximal tubules, while NPT2b is expressed in several tissues, including lung and small intestine, but not the kidney.

Type III Na/Pi co-transporters: These are cell surface retroviral receptors that are ubiquitously expressed and are localized to every segment of the nephron at the basolateral membrane and mediate cellular Pi balance.

Parathyroid hormone (PTH)

Parathyroid hormone (PTH) is an important hormone that controls calcium and phosphate concentration through stimulation of renal tubular calcium reabsorption and bone resorption. PTH also stimulates the conversion of 25- hydroxyvitamin D to 1,25 dihydroxy vitamin D in renal tubular cells, which promotes intestinal calcium absorption as well as bone turnover.

Parathyroid hormone is synthesized, processed, and stored in parathyroid cells. Parathyroid hormone is secreted by exocytosis within seconds after induction of hypocalcemia. In circulation, parathyroid hormone is rapidly taken up by the liver and kidney, where it is cleaved into active amino- and inactive carboxyl-terminal fragments that are then cleared by the kidney. Intact parathyroid hormone has a plasma half-life of two to four minutes.

Any change in ionized calcium concentration gets sensed by calcium-sensing receptor (CaSR) on the surface of parathyroid cells, Increase in calcium activates these receptors, which inhibit parathyroid hormone secretion and decreases renal tubular reabsorption of calcium through second messengers.

Hypocalcemia, induced by increased phosphate levels, can also produce these effects. However, changes in phosphate concentration should be significant to produce substantial changes in serum calcium. Hyperphosphatemia can also directly stimulate parathyroid hormone synthesis as well as parathyroid cellular proliferation

Several drugs, such as penicillin, corticosteroids, some diuretics, furosemide, and thiazides, can induce hyperphosphatemia as an adverse reaction.

1, 25 dihydroxycholecalciferol (1, 25 DHCC)

1, 25 dihydroxycholecalciferol is the activated form of Vitamin D. It increases intestinal phosphate absorption by enhancing the expression of NPT2b transporter and stimulates renal phosphate absorption by increasing expression of NPT2a and NPT2c in the proximal tubule. 1,25 DHCC also enhances FGF23 production. The 1,25(OH)2D also suppresses the synthesis of PTH and enhances FGF23 production.

Fibroblast growth factor 23 (FGF23)

FGF23 is a phosphatonin that is produced primarily by osteocytes and to a lesser extent, by osteoblasts. It is a hormone that consists of 251 amino acid residues, including a signal peptide comprising 24 amino acids.

It inhibits renal tubular reabsorption of phosphate. FGF23 exerts its effects by binding to the FGFR1-Klotho complex. Alpha Klotho serves as a co-receptor. FGF23 suppresses NPT2a and NPT2c expression at the proximal renal tubules, thereby inhibiting renal phosphate reabsorption. FGF23 also reduces the circulatory level of 1,25(OH)2D by decreasing the expression of 1-alpha-hydroxylase and increasing the expression of 24-hydroxylase.