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Disorders of Calcium, Phosphate, and Magnesium Metabolism

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Book cover Core Concepts in the Disorders of Fluid, Electrolytes and Acid-Base Balance

Abstract

There have been substantial recent advances in the pathophysiology of calcium, phosphate, and magnesium disorders. These include the identification of novel transport pathways for magnesium, characterization of the many genetic causes of hypomagnesemia, and the discovery of FGF23, a potent phosphaturic hormone with pleiotropic effects on calcium and phosphate homeostasis. These advances are incorporated in a comprehensive review of the pathophysiology, clinical presentation, and management of these important disorders.

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References

  1. Brown EM. Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab. 2007;3:122–33.

    PubMed  CAS  Google Scholar 

  2. Hruska KA, Korkor A, Martin K, Slatopolsky E. Peripheral metabolism of intact parathyroid hormone. Role of liver and kidney and the effect of chronic renal failure. J Clin Invest. 1981;67:885–92.

    PubMed  CAS  Google Scholar 

  3. Deftos LJ. Calcitonin. In: Favus M et al., editors. Primer on the metabolic bone diseases and disorders of mineral metabolism. 2nd ed. New York: Raven; 1993. p. 70–6.

    Google Scholar 

  4. The ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.

    Google Scholar 

  5. Alon US. Clinical practice: fibroblast growth factor (FGF)23: a new hormone. Eur J Pediatr. 2010; 170(5):545–54.

    PubMed  Google Scholar 

  6. Barger-Lux MJ, Heaney RP, Recker RR. Time course of calcium absorption in humans: evidence for a colonic component. Calcif Tissue Int. 1989;44:308–11.

    PubMed  CAS  Google Scholar 

  7. Bell NH. Vitamin D-endocrine system. J Clin Invest. 1985;76:1–6.

    PubMed  CAS  Google Scholar 

  8. Dimke H, Hoenderop JG, Bindels RJ. Molecular basis of epithelial Ca2+ and Mg2+ transport: insights from the TRP channel family. J Physiol. 2010;589 (Pt 7):1535–42.

    PubMed  Google Scholar 

  9. Hebert SC. Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again. Kidney Int Suppl. 2004;91:S28–33.

    PubMed  CAS  Google Scholar 

  10. Bindels RJ. Homer W. Smith Award: Minerals in motion: from new ion transporters to new concepts. J Am Soc Nephrol. 2010;21:1263–9.

    PubMed  CAS  Google Scholar 

  11. Kantham L, Quinn SJ, Egbuna OI, et al. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion. Am J Physiol Endocrinol Metab. 2009;297:E915–23.

    PubMed  CAS  Google Scholar 

  12. Silverberg SJ, Bilezikian JP. The diagnosis and management of asymptomatic primary hyperparathyroidism. Nat Clin Pract Endocrinol Metab. 2006;2: 494–503.

    PubMed  Google Scholar 

  13. Silverberg SJ, Bilezikian JP. Clinical presentation of primary hyperparathyroidism in the United States. In: Bilezikian JP, editor. The parathyroids. 2nd ed. New York: Academic; 2001. p. 349–60.

    Google Scholar 

  14. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–71.

    PubMed  CAS  Google Scholar 

  15. Shane E, Bilezikian JP. Parathyroid carcinoma: a review of 62 patients. Endocr Rev. 1982;3:218–26.

    PubMed  CAS  Google Scholar 

  16. Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94:351–65.

    PubMed  CAS  Google Scholar 

  17. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341:1249–55.

    PubMed  CAS  Google Scholar 

  18. Bilezikian JP, Khan AA, Potts Jr JT. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94:335–9.

    PubMed  CAS  Google Scholar 

  19. Khosla S, Ebeling PR, Firek AF, Burritt MM, Kao PC, Heath 3rd H. Calcium infusion suggests a “set-point” abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol Metab. 1993;76:715–20.

    PubMed  CAS  Google Scholar 

  20. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab. 1983;56:572–81.

    PubMed  CAS  Google Scholar 

  21. Simonds WF, James-Newton LA, Agarwal SK, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore). 2002;81:1–26.

    Google Scholar 

  22. Udelsman R, Pasieka JL, Sturgeon C, Young JE, Clark OH. Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94:366–72.

    PubMed  CAS  Google Scholar 

  23. Khan A, Grey A, Shoback D. Medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94:373–81.

    PubMed  CAS  Google Scholar 

  24. Peacock M, Bilezikian JP, Bolognese MA, et al. Cinacalcet HCl reduces hypercalcemia in primary hyperparathyroidism across a wide spectrum of disease severity. J Clin Endocrinol Metab. 2011;96:E9–18.

    PubMed  CAS  Google Scholar 

  25. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373–9.

    PubMed  CAS  Google Scholar 

  26. Abou-Samra AB, Juppner H, Force T, et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci U S A. 1992;89:2732–6.

    PubMed  CAS  Google Scholar 

  27. Wysolmerski JJ, Stewart AF. The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol. 1998;60:431–60.

    PubMed  CAS  Google Scholar 

  28. Asa SL, Henderson J, Goltzman D, Drucker DJ. Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues. J Clin Endocrinol Metab. 1990;71:1112–8.

    PubMed  CAS  Google Scholar 

  29. Yates AJ, Gutierrez GE, Smolens P, et al. Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents. J Clin Invest. 1988;81:932–8.

    PubMed  CAS  Google Scholar 

  30. Pandian MR, Morgan CH, Carlton E, Segre GV. Modified immunoradiometric assay of parathyroid hormone-related protein: clinical application in the differential diagnosis of hypercalcemia. Clin Chem. 1992;38:282–8.

    PubMed  CAS  Google Scholar 

  31. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med. 1990;323: 1324–8.

    PubMed  CAS  Google Scholar 

  32. Shaker JL, Krawczyk KW, Findling JW. Primary hyperparathyroidism and severe hypercalcemia with low circulating 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 1990;71:1305–9.

    PubMed  CAS  Google Scholar 

  33. Guise TA, Mundy GR. Cancer and bone. Endocr Rev. 1998;19:18–54.

    PubMed  CAS  Google Scholar 

  34. Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood. 1993;82:1383–94.

    PubMed  CAS  Google Scholar 

  35. Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: a historical review and description of the modern version of the syndrome. Am J Med Sci. 2006;331:233–42.

    PubMed  Google Scholar 

  36. Picolos MK, Lavis VR, Orlander PR. Milk-alkali syndrome is a major cause of hypercalcaemia among non-end-stage renal disease (non-ESRD) inpatients. Clin Endocrinol (Oxf). 2005;63:566–76.

    Google Scholar 

  37. Patel AM, Goldfarb S. Got calcium? Welcome to the calcium-alkali syndrome. J Am Soc Nephrol. 2010;21:1440–3.

    PubMed  CAS  Google Scholar 

  38. Kapsner P, Langsdorf L, Marcus R, Kraemer FB, Hoffman AR. Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation. Arch Intern Med. 1986;146:1965–8.

    PubMed  CAS  Google Scholar 

  39. Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med. 2000;6:442–7.

    PubMed  CAS  Google Scholar 

  40. Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab. 2010;95:3111–7.

    PubMed  CAS  Google Scholar 

  41. Berliner AR, Haas M, Choi MJ. Sarcoidosis: the nephrologist’s perspective. Am J Kidney Dis. 2006;48:856–70.

    PubMed  Google Scholar 

  42. Ferrand RA, Elgalib A, Newsholme W, Childerhouse A, Edwards SG, Miller RF. Hypercalcaemia complicating immune reconstitution in an HIV-infected patient with disseminated tuberculosis. Int J STD AIDS. 2006;17:349–50.

    PubMed  CAS  Google Scholar 

  43. Adams JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia with short-course chloroquine therapy. Ann Intern Med. 1989;111:437–8.

    PubMed  CAS  Google Scholar 

  44. Taylor RL, Lynch Jr HJ, Wysor Jr WG. Seasonal influence of sunlight on the hypercalcemia of sarcoidosis. Am J Med. 1963;34:221–7.

    PubMed  CAS  Google Scholar 

  45. Subramanian P, Chinthalapalli H, Krishnan M, et al. Pregnancy and sarcoidosis: an insight into the ­pathogenesis of hypercalciuria. Chest. 2004;126: 995–8.

    PubMed  Google Scholar 

  46. Sandler LM, Winearls CG, Fraher LJ, Clemens TL, Smith R, O’Riordan JL. Studies of the hypercalcaemia of sarcoidosis: effect of steroids and exogenous vitamin D3 on the circulating concentrations of 1,25-dihydroxy vitamin D3. Q J Med. 1984;53: 165–80.

    PubMed  CAS  Google Scholar 

  47. Kimberg DV, Baerg RD, Gershon E, Graudusius RT. Effect of cortisone treatment on the active transport of calcium by the small intestine. J Clin Invest. 1971;50:1309–21.

    PubMed  CAS  Google Scholar 

  48. Gibbs CJ, Peacock M. Hypercalcaemia due to sarcoidosis corrects with bisphosphonate treatment. Postgrad Med J. 1986;62:937–8.

    PubMed  CAS  Google Scholar 

  49. Barre PE, Gascon-Barre M, Meakins JL, Goltzman D. Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis. Am J Med. 1987;82:1259–62.

    PubMed  CAS  Google Scholar 

  50. Adams JS, Sharma OP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab. 1990;70:1090–5.

    PubMed  CAS  Google Scholar 

  51. Marx SJ, Attie MF, Levine MA, Spiegel AM, Downs Jr RW, Lasker RD. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore). 1981;60:397–412.

    CAS  Google Scholar 

  52. 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;75:1297–303.

    PubMed  CAS  Google Scholar 

  53. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet. 1994;8:303–7.

    PubMed  CAS  Google Scholar 

  54. Guarnieri V, Canaff L, Yun FH, et al. Calcium-sensing receptor (CASR) mutations in hypercalcemic states: studies from a single endocrine clinic over three years. J Clin Endocrinol Metab. 2010;95:1819–29.

    PubMed  CAS  Google Scholar 

  55. Mosekilde L, Eriksen EF, Charles P. Effects of ­thyroid hormones on bone and mineral metabolism. Endocrinol Metab Clin North Am. 1990;19:35–63.

    PubMed  CAS  Google Scholar 

  56. Mundy GR, Shapiro JL, Bandelin JG, Canalis EM, Raisz LG. Direct stimulation of bone resorption by thyroid hormones. J Clin Invest. 1976;58:529–34.

    PubMed  CAS  Google Scholar 

  57. Montoli A, Colussi G, Minetti L. Hypercalcaemia in Addison’s disease: calciotropic hormone profile and bone histology. J Intern Med. 1992;232:535–40.

    PubMed  CAS  Google Scholar 

  58. Stewart AF, Adler M, Byers CM, Segre GV, Broadus AE. Calcium homeostasis in immobilization: an example of resorptive hypercalciuria. N Engl J Med. 1982;306:1136–40.

    PubMed  CAS  Google Scholar 

  59. Kim GH, Martin SW, Fernandez-Llama P, Masilamani S, Packer RK, Knepper MA. Long-term regulation of renal Na-dependent cotransporters and ENaC: response to altered acid-base intake. Am J Physiol Renal Physiol. 2000;279:F459–67.

    PubMed  CAS  Google Scholar 

  60. Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest. 2005;115:1651–8.

    PubMed  CAS  Google Scholar 

  61. Christensson T, Hellstrom K, Wengle B. Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen. Arch Intern Med. 1977;137: 1138–42.

    PubMed  CAS  Google Scholar 

  62. Mallette LE, Eichhorn E. Effects of lithium carbonate on human calcium metabolism. Arch Intern Med. 1986;146:770–6.

    PubMed  CAS  Google Scholar 

  63. Spiegel AM, Rudorfer MV, Marx SJ, Linnoila M. The effect of short term lithium administration on suppressibility of parathyroid hormone secretion by calcium in vivo. J Clin Endocrinol Metab. 1984;59: 354–7.

    PubMed  CAS  Google Scholar 

  64. Sloand JA, Shelly MA. Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride. Am J Kidney Dis. 2006;48:832–7.

    PubMed  Google Scholar 

  65. Suki WN, Yium JJ, Von Minden M, Saller-Hebert C, Eknoyan G, Martinez-Maldonado M. Acute treatment of hypercalcemia with furosemide. N Engl J Med. 1970;283:836–40.

    PubMed  CAS  Google Scholar 

  66. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74:1385–93.

    PubMed  CAS  Google Scholar 

  67. Cvitkovic F, Armand JP, Tubiana-Hulin M, Rossi JF, Warrell Jr RP. Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J. 2006;12:47–53.

    PubMed  CAS  Google Scholar 

  68. Suzuki T, Ikeda U, Fujikawa H, Saito K, Shimada K. Hypocalcemic heart failure: a reversible form of heart muscle disease. Clin Cardiol. 1998;21:227–8.

    PubMed  CAS  Google Scholar 

  69. Brunet A, Gabau E, Perich RM, et al. Microdeletion and microduplication 22q11.2 screening in 295 patients with clinical features of DiGeorge/velocardiofacial syndrome. Am J Med Genet A. 2006;140:2426–32.

    PubMed  Google Scholar 

  70. Rizzi M, Ferrera F, Filaci G, Indiveri F. Disruption of immunological tolerance: role of AIRE gene in autoimmunity. Autoimmun Rev. 2006;5:145–7.

    PubMed  CAS  Google Scholar 

  71. Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322: 1829–36.

    PubMed  CAS  Google Scholar 

  72. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843–50.

    PubMed  CAS  Google Scholar 

  73. Goswami R, Brown EM, Kochupillai N, et al. Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism. Eur J Endocrinol. 2004;150:9–18.

    PubMed  CAS  Google Scholar 

  74. Brasier AR, Nussbaum SR. Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. Am J Med. 1988;84:654–60.

    PubMed  CAS  Google Scholar 

  75. Stewart ZA, Blackford A, Somervell H, et al. 25-Hydroxyvitamin D deficiency is a risk factor for symptoms of postoperative hypocalcemia and secondary hyperparathyroidism after minimally invasive parathyroidectomy. Surgery. 2005;138:1018–25. discussion 25–6.

    PubMed  Google Scholar 

  76. Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med. 1984;310:1221–5.

    PubMed  CAS  Google Scholar 

  77. Burch WM, Posillico JT. Hypoparathyroidism after I-131 therapy with subsequent return of parathyroid function. J Clin Endocrinol Metab. 1983;57: 398–401.

    PubMed  CAS  Google Scholar 

  78. Levine MA. Clinical spectrum and pathogenesis of pseudohypoparathyroidism. Rev Endocr Metab Disord. 2000;1:265–74.

    PubMed  CAS  Google Scholar 

  79. Quack I, Zwernemann C, Weiner SM, et al. Dihydrotachysterol therapy for hypoparathyroidism: consequences of inadequate monitoring. Five cases and a review. Exp Clin Endocrinol Diabetes. 2005;113:376–80.

    PubMed  CAS  Google Scholar 

  80. Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1–34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003;88:4214–20.

    PubMed  CAS  Google Scholar 

  81. Watanabe S, Fukumoto S, Chang H, et al. Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet. 2002;360: 692–4.

    PubMed  CAS  Google Scholar 

  82. Shiohara M, Shiozawa R, Kurata K, et al. Effect of parathyroid hormone administration in a patient with severe hypoparathyroidism caused by gain-of-function mutation of calcium-sensing receptor. Endocr J. 2006;53:797–802.

    PubMed  CAS  Google Scholar 

  83. Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications. CNS Drugs. 2001;15:633–42.

    PubMed  CAS  Google Scholar 

  84. Fraser D, Kooh SW, Kind HP, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med. 1973;289:817–22.

    PubMed  CAS  Google Scholar 

  85. Stewart AF, Longo W, Kreutter D, Jacob R, Burtis WJ. Hypocalcemia associated with calcium-soap formation in a patient with a pancreatic fistula. N Engl J Med. 1986;315:496–8.

    PubMed  CAS  Google Scholar 

  86. Lind L, Carlstedt F, Rastad J, et al. Hypocalcemia and parathyroid hormone secretion in critically ill patients. Crit Care Med. 2000;28:93–9.

    PubMed  CAS  Google Scholar 

  87. Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am. 1993;22:363–75.

    PubMed  CAS  Google Scholar 

  88. Gaasbeek A, Meinders AE. Hypophosphatemia: an update on its etiology and treatment. Am J Med. 2005;118:1094–101.

    PubMed  CAS  Google Scholar 

  89. Portale AA, Halloran BP, Morris Jr RC. Dietary intake of phosphorus modulates the circadian rhythm in serum concentration of phosphorus. Implications for the renal production of 1,25-dihydroxyvitamin D. J Clin Invest. 1987;80:1147–54.

    PubMed  CAS  Google Scholar 

  90. Murer H, Forster I, Biber J. The sodium phosphate cotransporter family SLC34. Pflugers Arch. 2004;447:763–7.

    PubMed  CAS  Google Scholar 

  91. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev. 2000;80:1373–409.

    PubMed  CAS  Google Scholar 

  92. Bacic D, Lehir M, Biber J, Kaissling B, Murer H, Wagner CA. The renal Na+/phosphate cotransporter NaPi-IIa is internalized via the receptor-mediated endocytic route in response to parathyroid hormone. Kidney Int. 2006;69:495–503.

    PubMed  CAS  Google Scholar 

  93. Gloor HJ, Bonjour JP, Caverzasio J, Fleisch H. Resistance to the phosphaturic and calcemic actions of parathyroid hormone during phosphate depletion. Prevention by 1,25-dihydroxyvitamin D3. J Clin Invest. 1979;63:371–7.

    PubMed  CAS  Google Scholar 

  94. Cai Q, Hodgson SF, Kao PC, et al. Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia. N Engl J Med. 1994;330:1645–9.

    PubMed  CAS  Google Scholar 

  95. Berndt T, Kumar R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda). 2009;24:17–25.

    CAS  Google Scholar 

  96. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol. 2010;21:1427–35.

    PubMed  CAS  Google Scholar 

  97. De Marchi S, Cecchin E, Basile A, Bertotti A, Nardini R, Bartoli E. Renal tubular dysfunction in chronic alcohol abuse—effects of abstinence. N Engl J Med. 1993;329:1927–34.

    PubMed  Google Scholar 

  98. Larsson L, Rebel K, Sorbo B. Severe hypophosphatemia—a hospital survey. Acta Med Scand. 1983;214:221–3.

    PubMed  CAS  Google Scholar 

  99. Camp MA, Allon M. Severe hypophosphatemia in hospitalized patients. Miner Electrolyte Metab. 1990;16:365–8.

    PubMed  CAS  Google Scholar 

  100. Singhal PC, Kumar A, Desroches L, Gibbons N, Mattana J. Prevalence and predictors of rhabdomyolysis in patients with hypophosphatemia. Am J Med. 1992;92:458–64.

    PubMed  CAS  Google Scholar 

  101. Amanzadeh J, Reilly Jr RF. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol. 2006;2:136–48.

    PubMed  CAS  Google Scholar 

  102. Dastur DK, Gagrat BM, Wadia NH, Desai M, Bharucha EP. Nature of muscular change in osteomalacia: light- and electron-microscope observations. J Pathol. 1975;117:211–28.

    PubMed  CAS  Google Scholar 

  103. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. N Engl J Med. 1977;297:901–3.

    PubMed  Google Scholar 

  104. Vered Z, Battler A, Motro M, Frank M, Inbar R, Neufeld HN. Left ventricular function in patients with chronic hypophosphatemia. Am Heart J. 1984;107:796–8.

    PubMed  CAS  Google Scholar 

  105. Davis SV, Olichwier KK, Chakko SC. Reversible depression of myocardial performance in hypophosphatemia. Am J Med Sci. 1988;295:183–7.

    PubMed  CAS  Google Scholar 

  106. Vered I, Vered Z, Perez JE, Jaffe AS, Whyte MP. Normal left ventricular performance in children with X-linked hypophosphatemic rickets: a Doppler echocardiography study. J Bone Miner Res. 1990;5: 469–74.

    PubMed  CAS  Google Scholar 

  107. Venditti FJ, Marotta C, Panezai FR, Oldewurtel HA, Regan TJ. Hypophosphatemia and cardiac arrhythmias. Miner Electrolyte Metab. 1987;13:19–25.

    PubMed  CAS  Google Scholar 

  108. Gravelyn TR, Brophy N, Siegert C, Peters-Golden M. Hypophosphatemia-associated respiratory muscle weakness in a general inpatient population. Am J Med. 1988;84:870–6.

    PubMed  CAS  Google Scholar 

  109. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med. 1985;313:420–4.

    PubMed  CAS  Google Scholar 

  110. Fiaccadori E, Coffrini E, Ronda N, et al. Hypophosphatemia in course of chronic obstructive pulmonary disease. Prevalence, mechanisms, and relationships with skeletal muscle phosphorus content. Chest. 1990;97:857–68.

    PubMed  CAS  Google Scholar 

  111. Michell AW, Burn DJ, Reading PJ. Central pontine myelinolysis temporally related to hypophosphataemia. J Neurol Neurosurg Psychiatry. 2003;74:820.

    PubMed  CAS  Google Scholar 

  112. Yagnik P, Singh N, Burns R. Peripheral neuropathy with hypophosphatemia in a patient receiving intravenous hyperalimentation. South Med J. 1985;78: 1381–4.

    PubMed  CAS  Google Scholar 

  113. Jacob HS, Amsden T. Acute hemolytic anemia with rigid red cells in hypophosphatemia. N Engl J Med. 1971;285:1446–50.

    PubMed  CAS  Google Scholar 

  114. Lau K, Agus ZS, Goldberg M, Goldfarb S. Renal tubular sites of altered calcium transport in phosphate-depleted rats. J Clin Invest. 1979;64:1681–7.

    PubMed  CAS  Google Scholar 

  115. Steele TH, Stromberg BA, Underwood JL, Larmore CA. Renal resistance to parathyroid hormone during phosphorus deprivation. J Clin Invest. 1976;58: 1461–4.

    PubMed  CAS  Google Scholar 

  116. Annino JS, Relman AS. The effect of eating on some of the clinically important chemical constituents of the blood. Am J Clin Pathol. 1959;31:155–9.

    PubMed  CAS  Google Scholar 

  117. Body JJ, Cryer PE, Offord KP, Heath 3rd H. Epinephrine is a hypophosphatemic hormone in man. Physiological effects of circulating epinephrine on plasma calcium, magnesium, phosphorus, parathyroid hormone, and calcitonin. J Clin Invest. 1983;71:572–8.

    PubMed  CAS  Google Scholar 

  118. Ljunghall S, Joborn H, Rastad J, Akerstrom G. Plasma potassium and phosphate concentrations—influence by adrenaline infusion, beta-blockade and physical exercise. Acta Med Scand. 1987;221:83–93.

    PubMed  CAS  Google Scholar 

  119. Trivedi B, Danforth WH. Effect of pH on the kinetics of frog muscle phosphofructokinase. J Biol Chem. 1966;241:4110–2.

    PubMed  CAS  Google Scholar 

  120. Mostellar ME, Tuttle Jr EP. Effects of alkalosis on plasma concentration and urinary excretion of inorganic phosphate in man. J Clin Invest. 1964;43:138–49.

    PubMed  CAS  Google Scholar 

  121. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin Pract. 2005;20: 625–33.

    PubMed  Google Scholar 

  122. De Cock A, Mana F, Velkeniers B, Urbain D. Hypophosphatemia and refeeding: a corrective or a preventive attitude? Acta Clin Belg. 2006;61: 134–7.

    PubMed  Google Scholar 

  123. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Drug-induced Fanconi’s syndrome. Am J Kidney Dis. 2003;41:292–309.

    PubMed  CAS  Google Scholar 

  124. Skinner R, Pearson AD, English MW, et al. Risk factors for ifosfamide nephrotoxicity in children. Lancet. 1996;348:578–80.

    PubMed  CAS  Google Scholar 

  125. Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;348:1656–63.

    PubMed  CAS  Google Scholar 

  126. Pomposelli JJ, Pomfret EA, Burns DL, et al. Life-threatening hypophosphatemia after right hepatic lobectomy for live donor adult liver transplantation. Liver Transpl. 2001;7:637–42.

    PubMed  CAS  Google Scholar 

  127. Salem RR, Tray K. Hepatic resection-related hypophosphatemia is of renal origin as manifested by isolated hyperphosphaturia. Ann Surg. 2005;241: 343–8.

    PubMed  Google Scholar 

  128. Suki WN, Martinez-Maldonado M, Rouse D, Terry A. Effect of expansion of extracellular fluid volume on renal phosphate handling. J Clin Invest. 1969;48:1888–94.

    PubMed  CAS  Google Scholar 

  129. Rauchenzauner M, Kountchev J, Ulmer H, et al. Disturbances of electrolytes and blood chemistry in acute alcohol intoxication. Wien Klin Wochenschr. 2005;117:83–91.

    PubMed  CAS  Google Scholar 

  130. Kebler R, McDonald FD, Cadnapaphornchai P. Dynamic changes in serum phosphorus levels in diabetic ketoacidosis. Am J Med. 1985;79:571–6.

    PubMed  CAS  Google Scholar 

  131. Moorhead JF, Wills MR, Ahmed KY, Baillod RA, Varghese Z, Tatler GL. Hypophosphataemic osteomalacia after cadaveric renal transplantation. Lancet. 1974;1:694–7.

    PubMed  CAS  Google Scholar 

  132. Ward HN, Pabico RC, McKenna BA, Freeman RB. The renal handling of phosphate by renal transplant patients: correlation with serum parathyroid hormone (SPTH), cyclic 3′,5′-adenosine monophosphate (cAMP) urinary excretion, and allograft function. Adv Exp Med Biol. 1977;81: 173–81.

    PubMed  CAS  Google Scholar 

  133. Vannatta JB, Whang R, Papper S. Efficacy of intravenous phosphorus therapy in the severely hypophosphatemic patient. Arch Intern Med. 1981;141:885–7.

    PubMed  CAS  Google Scholar 

  134. Gumurdulu Y, Serin E, Ozer B, Gokcel A, Boyacioglu S. Age as a predictor of hyperphosphatemia after oral phosphosoda administration for colon preparation. J Gastroenterol Hepatol. 2004;19: 68–72.

    PubMed  CAS  Google Scholar 

  135. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol. 2005;16:3389–96.

    PubMed  CAS  Google Scholar 

  136. Heher EC, Thier SO, Rennke H, Humphreys BD. Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation. Clin J Am Soc Nephrol. 2008;3:1494–503.

    PubMed  Google Scholar 

  137. Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004;116:546–54.

    PubMed  CAS  Google Scholar 

  138. Cohen LF, Balow JE, Magrath IT, Poplack DG, Ziegler JL. Acute tumor lysis syndrome. A review of 37 patients with Burkitt’s lymphoma. Am J Med. 1980;68:486–91.

    PubMed  CAS  Google Scholar 

  139. Brannan PG, Vergne-Marini P, Pak CY, Hull AR, Fordtran JS. Magnesium absorption in the human small intestine. Results in normal subjects, patients with chronic renal disease, and patients with absorptive hypercalciuria. J Clin Invest. 1976;57: 1412–8.

    PubMed  CAS  Google Scholar 

  140. Voets T, Nilius B, Hoefs S, et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem. 2004;279:19–25.

    PubMed  CAS  Google Scholar 

  141. Hodgkinson A, Marshall DH, Nordin BE. Vitamin D and magnesium absorption in man. Clin Sci (Lond). 1979;57:121–3.

    CAS  Google Scholar 

  142. Wilz DR, Gray RW, Dominguez JH, Lemann Jr J. Plasma 1,25-(OH)2-vitamin D concentrations and net intestinal calcium, phosphate, and magnesium absorption in humans. Am J Clin Nutr. 1979;32:2052–60.

    PubMed  CAS  Google Scholar 

  143. Simon DB, Lu Y, Choate KA, et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science. 1999;285:103–6.

    PubMed  CAS  Google Scholar 

  144. Hou J, Renigunta A, Konrad M, et al. Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. J Clin Invest. 2008;118:619–28.

    PubMed  CAS  Google Scholar 

  145. Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet. 2002;31:166–70.

    PubMed  CAS  Google Scholar 

  146. Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 1996;335:1115–22.

    PubMed  CAS  Google Scholar 

  147. Groenestege WM, Thebault S, van der Wijst J, et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;117:2260–7.

    PubMed  CAS  Google Scholar 

  148. Thebault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. EGF increases TRPM6 activity and surface expression. J Am Soc Nephrol. 2009;20:78–85.

    PubMed  CAS  Google Scholar 

  149. Kobrin SM, Goldfarb S. Magnesium deficiency. Semin Nephrol. 1990;10:525–35.

    PubMed  CAS  Google Scholar 

  150. Schimatschek HF, Rempis R. Prevalence of hypomagnesemia in an unselected German population of 16,000 individuals. Magnes Res. 2001;14: 283–90.

    PubMed  CAS  Google Scholar 

  151. Lewis RV, Tregaskis B, McLay J, Service E, McDevitt DG. Oral magnesium reduces ventricular ectopy in digitalised patients with chronic atrial fibrillation. Eur J Clin Pharmacol. 1990;38: 107–10.

    PubMed  CAS  Google Scholar 

  152. Ma J, Folsom AR, Melnick SL, et al. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis risk in communities study. J Clin Epidemiol. 1995;48:927–40.

    PubMed  CAS  Google Scholar 

  153. Dyckner T. Relation of cardiovascular disease to potassium and magnesium deficiencies. Am J Cardiol. 1990;65:44K–6.

    PubMed  CAS  Google Scholar 

  154. Brodsky MA, Orlov MV, Capparelli EV, et al. Magnesium therapy in new-onset atrial fibrillation. Am J Cardiol. 1994;73:1227–9.

    PubMed  CAS  Google Scholar 

  155. Rubeiz GJ, Thill-Baharozian M, Hardie D, Carlson RW. Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med. 1993;21:203–9.

    PubMed  CAS  Google Scholar 

  156. Gennari FJ. Hypokalemia. N Engl J Med. 1998;339:451–8.

    PubMed  CAS  Google Scholar 

  157. Rodriguez M, Solanki DL, Whang R. Refractory potassium repletion due to cisplatin-induced magnesium depletion. Arch Intern Med. 1989;149:2592–4.

    PubMed  CAS  Google Scholar 

  158. Whang R, Flink EB, Dyckner T, Wester PO, Aikawa JK, Ryan MP. Magnesium depletion as a cause of refractory potassium repletion. Arch Intern Med. 1985;145:1686–9.

    PubMed  CAS  Google Scholar 

  159. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol. 2007;18:2649–52.

    PubMed  Google Scholar 

  160. Yang L, Frindt G, Palmer LG. Magnesium modulates ROMK channel-mediated potassium secretion. J Am Soc Nephrol. 2010;21:2109–16.

    PubMed  CAS  Google Scholar 

  161. Whang R, Whang DD, Ryan MP. Refractory potassium repletion. A consequence of magnesium deficiency. Arch Intern Med. 1992;152:40–5.

    PubMed  CAS  Google Scholar 

  162. Vandenberg CA. Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc Natl Acad Sci U S A. 1987;84:2560–4.

    PubMed  CAS  Google Scholar 

  163. Abbott LG, Rude RK. Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab. 1993;19:314–22.

    PubMed  CAS  Google Scholar 

  164. Whang R, Ryder KW. Frequency of hypomagnesemia and hypermagnesemia. Requested vs routine. JAMA. 1990;263:3063–4.

    PubMed  CAS  Google Scholar 

  165. Hoorn EJ, van der Hoek J, de Man RA, Kuipers EJ, Bolwerk C, Zietse R. A case series of proton pump inhibitor-induced hypomagnesemia. Am J Kidney Dis. 2010;56:112–6.

    PubMed  Google Scholar 

  166. Scoble JE, Screaton GR, Havard CW. Renal magnesium wasting in Bartter’s syndrome. Nephrol Dial Transplant. 1990;5:388–90.

    PubMed  CAS  Google Scholar 

  167. Bockenhauer D, Feather S, Stanescu HC, et al. Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med. 2009;360:1960–70.

    PubMed  CAS  Google Scholar 

  168. Scholl UI, Choi M, Liu T, et al. Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci U S A. 2009;106:5842–7.

    PubMed  CAS  Google Scholar 

  169. Meij IC, Koenderink JB, van Bokhoven H, et al. Dominant isolated renal magnesium loss is caused by misrouting of the Na(+), K(+)-ATPase gamma-subunit. Nat Genet. 2000;26:265–6.

    PubMed  CAS  Google Scholar 

  170. Glaudemans B, van der Wijst J, Scola RH, et al. A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J Clin Invest. 2009;119:936–42.

    PubMed  CAS  Google Scholar 

  171. Wilson FH, Hariri A, Farhi A, et al. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science. 2004;306:1190–4.

    PubMed  CAS  Google Scholar 

  172. Ryan MP. Diuretics and potassium/magnesium depletion. Directions for treatment. Am J Med. 1987;82:38–47.

    PubMed  CAS  Google Scholar 

  173. Ryan MP. Magnesium and potassium-sparing diuretics. Magnesium. 1986;5:282–92.

    PubMed  CAS  Google Scholar 

  174. Shah GM, Kirschenbaum MA. Renal magnesium wasting associated with therapeutic agents. Miner Electrolyte Metab. 1991;17:58–64.

    PubMed  CAS  Google Scholar 

  175. Craven JL. Cyclosporine-associated organic mental disorders in liver transplant recipients. Psychosomatics. 1991;32:94–102.

    PubMed  CAS  Google Scholar 

  176. Chang CT, Hung CC, Tian YC, Yang CW, Wu MS. Cyclosporin reduces paracellin-1 expression and magnesium transport in thick ascending limb cells. Nephrol Dial Transplant. 2007;22:1033–40.

    PubMed  CAS  Google Scholar 

  177. Ikari A, Okude C, Sawada H, Takahashi T, Sugatani J, Miwa M. Down-regulation of TRPM6-mediated magnesium influx by cyclosporin A. Naunyn Schmiedebergs Arch Pharmacol. 2008;377:333–43.

    PubMed  CAS  Google Scholar 

  178. Brock PR, Koliouskas DE, Barratt TM, Yeomans E, Pritchard J. Partial reversibility of cisplatin nephrotoxicity in children. J Pediatr. 1991;118:531–4.

    PubMed  CAS  Google Scholar 

  179. Markmann M, Rothman R, Reichman B, et al. Persistent hypomagnesemia following cisplatin chemotherapy in patients with ovarian cancer. J Cancer Res Clin Oncol. 1991;117:89–90.

    PubMed  CAS  Google Scholar 

  180. Panichpisal K, Angulo-Pernett F, Selhi S, Nugent KM. Gitelman-like syndrome after cisplatin therapy: a case report and literature review. BMC Nephrol. 2006;7:10.

    PubMed  Google Scholar 

  181. Palestine AG, Polis MA, De Smet MD, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med. 1991;115:665–73.

    PubMed  CAS  Google Scholar 

  182. Mercan D, Bastin G, Lambermont M, Dupont E. Importance of ionized magnesium measurement for monitoring of citrate-anticoagulated plateletpheresis. Transfusion. 1997;37:418–22.

    PubMed  CAS  Google Scholar 

  183. Aglio LS, Stanford GG, Maddi R, Boyd 3rd JL, Nussbaum S, Chernow B. Hypomagnesemia is common following cardiac surgery. J Cardiothorac Vasc Anesth. 1991;5:201–8.

    PubMed  CAS  Google Scholar 

  184. Robertie PG, Butterworth 4th JF, Royster RL, et al. Normal parathyroid hormone responses to hypocalcemia during cardiopulmonary bypass. Anesthesiology. 1991;75:43–8.

    PubMed  CAS  Google Scholar 

  185. Mimouni F, Miodovnik M, Tsang RC, Holroyde J, Dignan PS, Siddiqi TA. Decreased maternal serum magnesium concentration and adverse fetal outcome in insulin-dependent diabetic women. Obstet Gynecol. 1987;70:85–8.

    PubMed  CAS  Google Scholar 

  186. McNair P, Christensen MS, Christiansen C, Madsbad S, Transbol I. Renal hypomagnesaemia in human diabetes mellitus: its relation to glucose homeostasis. Eur J Clin Invest. 1982;12:81–5.

    PubMed  CAS  Google Scholar 

  187. Ryan MP, Ryan MF, Counihan TB. The effect of diuretics on lymphocyte magnesium and potassium. Acta Med Scand Suppl. 1981;647:153–61.

    PubMed  CAS  Google Scholar 

  188. Gao X, Peng L, Adhikari CM, Lin J, Zuo Z. Spironolactone reduced arrhythmia and maintained magnesium homeostasis in patients with congestive heart failure. J Card Fail. 2007;13: 170–7.

    PubMed  CAS  Google Scholar 

  189. Colussi G, Rombola G, De Ferrari ME, Macaluso M, Minetti L. Correction of hypokalemia with antialdosterone therapy in Gitelman’s syndrome. Am J Nephrol. 1994;14:127–35.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Section of Nephrology, Department of Medicine, Yale School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA

    Ali Hariri M.D. & Ashghar Rastegar M.D.

  2. Renal Division, VA Boston Healthcare System, and, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    David B. Mount M.D.

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  1. Ali Hariri M.D.
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Correspondence to David B. Mount M.D. .

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  1. Brigham and Women's Hospital, Harvard Medical School, VA Boston Healthcare System, Blackfan Circle 4, Boston, 02115, Massachusetts, USA

    David B. Mount

  2. Harvard Medical School, Renal Division, Brigham and Women's Hospital, Francis Street 75, Boston, 02115, Massachusetts, USA

    Mohamed H. Sayegh

  3. Harvard Medical School, Renal Division, Brigham and Women's Hospital, Francis Street 75, Boston, 02115, Massachusetts, USA

    Ajay K. Singh

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Hariri, A., Mount, D.B., Rastegar, A. (2013). Disorders of Calcium, Phosphate, and Magnesium Metabolism. In: Mount, D., Sayegh, M., Singh, A. (eds) Core Concepts in the Disorders of Fluid, Electrolytes and Acid-Base Balance. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-3770-3_4

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