Regulation of calcium and phosphate balance
- Jonathan Hogan, MD
Jonathan Hogan, MD
- Assistant Professor of Medicine
- Perelman School of Medicine at the University of Pennsylvania
- Stanley Goldfarb, MD
Stanley Goldfarb, MD
- Editor-in-Chief — Nephrology
- Section Editor — Mineral and Bone Metabolism; Renal Ureteral Stones
- Professor of Medicine
- University of Pennsylvania School of Medicine
The maintenance of calcium and phosphate homeostasis involves intestinal, bone, and renal handling of these ions.
Within the plasma, calcium circulates in different forms. Of the plasma calcium, roughly 40 percent is bound to albumin, 15 percent is complexed with citrate, sulfate, or phosphate, and 45 percent exists as the physiologically important ionized (or free) calcium. As routinely measured in the laboratory, the plasma calcium concentration includes all of the calcium in the plasma (free and bound). In general, measuring the total plasma calcium concentration is sufficient since changes in this parameter are usually associated with parallel changes in the ionized concentration. Exceptions to this commonly occur in patients with hypoalbuminemia, acid-base disorders, and chronic kidney disease. Issues surrounding the measurement of total and ionized calcium are presented elsewhere in detail. (See "Relation between total and ionized serum calcium concentrations".)
In comparison to calcium, plasma phosphorus exists in both organic and inorganic forms, including phospholipids, ester phosphates, and inorganic phosphates. Inorganic phosphates are completely ionized, circulating primarily as HPO42- or H2PO4- in a ratio of 4:1 at a plasma pH of 7.40.
Only a small fraction of the total body calcium and phosphate is located in the plasma. However, it is the plasma concentrations of ionized calcium and inorganic phosphate that are under hormonal control. Calcium balance is mediated primarily by parathyroid hormone (PTH) and calcitriol (1,25-dihydroxyvitamin D), which affect intestinal absorption, bone formation and resorption, and urinary excretion [1-4]. Phosphorous balance is also primarily regulated by PTH but may also respond to fibroblast growth factor 23 (FGF-23) and its cofactor, Klotho, which together and separately promote renal excretion of phosphorous [5,6]. The physiologic roles of other hormones (such as calcitonin and estrogens) in the regulation of calcium and phosphate balance are incompletely understood .
Gastrointestinal calcium handling — Dietary calcium is absorbed by two mechanisms :
- Kumar R. Vitamin D and calcium transport. Kidney Int 1991; 40:1177.
- Brown EM. PTH secretion in vivo and in vitro. Regulation by calcium and other secretagogues. Miner Electrolyte Metab 1982; 8:130.
- Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone 1997; 20:303.
- Lambers TT, Bindels RJ, Hoenderop JG. Coordinated control of renal Ca2+ handling. Kidney Int 2006; 69:650.
- Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007; 18:1637.
- Lederer E. Regulation of serum phosphate. J Physiol 2014; 592:3985.
- Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption across epithelia. Physiol Rev 2005; 85:373.
- Bronner F, Pansu D, Stein WD. An analysis of intestinal calcium transport across the rat intestine. Am J Physiol 1986; 250:G561.
- Moor MB, Bonny O. Ways of calcium reabsorption in the kidney. Am J Physiol Renal Physiol 2016; 310:F1337.
- Yu AS. Claudins and the kidney. J Am Soc Nephrol 2015; 26:11.
- Gkika D, Hsu YJ, van der Kemp AW, et al. Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice. J Am Soc Nephrol 2006; 17:3020.
- Mensenkamp AR, Hoenderop JG, Bindels RJ. TRPV5, the gateway to Ca2+ homeostasis. Handb Exp Pharmacol 2007; :207.
- Brown EM, Hebert SC. A cloned extracellular Ca(2+)-sensing receptor: molecular mediator of the actions of extracellular Ca2+ on parathyroid and kidney cells? Kidney Int 1996; 49:1042.
- Cole DE, Peltekova VD, Rubin LA, et al. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 1999; 353:112.
- Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
- Pollak MR, Chou YH, Marx SJ, et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 1994; 93:1108.
- Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1.
- de Groot T, Lee K, Langeslag M, et al. Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation. J Am Soc Nephrol 2009; 20:1693.
- Zehnder D, Bland R, Walker EA, et al. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in the human kidney. J Am Soc Nephrol 1999; 10:2465.
- Kumar R, Tebben PJ, Thompson JR. Vitamin D and the kidney. Arch Biochem Biophys 2012; 523:77.
- Dusso AS, Kamimura S, Gallieni M, et al. gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses. J Clin Endocrinol Metab 1997; 82:2222.
- Lieben L, Carmeliet G. Vitamin D signaling in osteocytes: effects on bone and mineral homeostasis. Bone 2013; 54:237.
- Slatopolsky E, Brown A, Dusso A. Pathogenesis of secondary hyperparathyroidism. Kidney Int Suppl 1999; 73:S14.
- Takeyama K, Kitanaka S, Sato T, et al. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 1997; 277:1827.
- Kurokawa K. Calcium-regulating hormones and the kidney. Kidney Int 1987; 32:760.
- Martin A, David V, Quarles LD. Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 2012; 92:131.
- Boros S, Bindels RJ, Hoenderop JG. Active Ca(2+) reabsorption in the connecting tubule. Pflugers Arch 2009; 458:99.
- Vezzoli G, Soldati L, Gambaro G. Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport. Curr Pharm Biotechnol 2009; 10:302.
- Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol 2010; 298:F485.
- Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 2015; 10:1257.
- Marks J, Debnam ES, Unwin RJ. The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease. Curr Opin Nephrol Hypertens 2013; 22:481.
- Lederer E. Renal phosphate transporters. Curr Opin Nephrol Hypertens 2014; 23:502.
- Wagner CA, Rubio-Aliaga I, Biber J, Hernando N. Genetic diseases of renal phosphate handling. Nephrol Dial Transplant 2014; 29 Suppl 4:iv45.
- Paleologos M, Stone E, Braude S. Persistent, progressive hypophosphataemia after voluntary hyperventilation. Clin Sci (Lond) 2000; 98:619.
- Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 2014; 466:139.
- Bergwitz C, Jüppner H. Phosphate sensing. Adv Chronic Kidney Dis 2011; 18:132.
- Weinman EJ, Lederer ED. NHERF-1 and the regulation of renal phosphate reabsoption: a tale of three hormones. Am J Physiol Renal Physiol 2012; 303:F321.
- CALCIUM HANDLING
- Gastrointestinal calcium handling
- Bone calcium handling
- Renal calcium handling
- REGULATION OF PLASMA CALCIUM CONCENTRATIONS
- Parathyroid hormone
- Vitamin D
- - Effect of vitamin D on calcium
- - Regulation of vitamin D
- Direct effects of the plasma calcium
- PHOSPHATE HANDLING AND REGULATION
- Phosphate handling
- Regulation of plasma phosphate concentrations