Phosphate Metabolism in Health and Disease

Phosphorus, a 5A element with atomic weight of 31, comprises just over 0.6% of the composition by weight of plants and animals. Three isotopes are available for studying phosphorus metabolism and kinetics. P-31 is stable, whereas the radioactive isotope P-33 has a half-life of 25 days and P-32 has a half-life of 14 days. Phosphate ester and phosphoanhydride are common chemical linkages and phosphorus is a key element in organic molecules involved in a wide variety of essential cellular functions. These include biochemical energy transfer via adenosine triphosphate (ATP), maintenance of genetic information with nucleotides DNA and RNA, intracellular signaling via cyclic adenosine monophosphate (cAMP), and membrane structural integrity via glycerophospholipids. However, this review focuses on the metabolism of inorganic phosphorus (Pi) acting as a weak acid. Phosphoric acid has all three hydrogens attached to oxygen and is a weak diprotic acid. It has 3 pKa values: pH 2.2, pH 7.2, and pH 12.7. At physiological pH of 7.4, Pi exists as both H2PO4(-) and HPO4(2-) and acts as an extracellular fluid (ECF) buffer. Pi is the form transported across tissue compartments and cells. Measurement of Pi in biological fluids is based on its reaction with ammonium molybdate which does not measure organic phosphorus. In humans, 80% of the body phosphorus is present in the form of calcium phosphate crystals (apatite) that confer hardness to bone and teeth, and function as the major phosphorus reservoir (Fig. 1). The remainder is present in soft tissues and ECF. Dietary phosphorus, comprising both inorganic and organic forms, is digested in the upper gastrointestinal tract. Absorbed Pi is transported to and from bone, skeletal muscle and soft tissues, and kidney at rates determined by ECF Pi concentration, rate of blood flow, and activity of cell Pi transporters (Fig. 2). During growth, there is net accretion of phosphorus, and with aging, net loss of phosphorus occurs. The bone phosphorus reservoir is depleted and repleted by overall phosphorus requirement. Skeletal muscle is rich in phosphorus used in essential biochemical energy transfer. Kidney is the main regulator of ECF Pi concentration by virtue of having a tubular maximum reabsorptive capacity for Pi (TmPi) that is under close endocrine control. It is also the main excretory pathway for Pi surplus which is passed in urine. Transcellular and paracellular Pi transports are performed by a number of transport mechanisms widely distributed in tissues, and particularly important in gut, bone, and kidney. Pi transporters are regulated by a hormonal axis comprising fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25 dihydroxy vitamin D (1,25D). Pi and calcium (Ca) metabolism are intimately interrelated, and clinically neither can be considered in isolation. Diseases of Pi metabolism affect bone as osteomalacia/rickets, soft tissues as ectopic mineralization, skeletal muscle as myopathy, and kidney as nephrocalcinosis and urinary stone formation. Fig. 1 Content of phosphorus in human adult: skeleton, soft tissue, and extracellular fluid (grams, log scale). Corresponding data for calcium are shown for comparison Fig. 2 Phosphate (Pi) transport to and from tissue compartments in mg/24 h. At a dietary phosphorus of 1400 mg, 1120 mg is absorbed in upper intestine to the ECF, 210 mg returned to intestine by endogenous secretion, resulting in 910 mg net Pi absorption and 490 mg fecal excretion. At bone, 180 mg is deposited by bone formation and 180 mg return to the ECF by bone resorption. At kidney, 5040 mg is filtered at the glomerulus and 4130 mg return to the ECF by tubular reabsorption with 910 mg excreted in the urine. In soft tissue, Pi is exchanged between ECF and cells