Fosfat Metabolizması

Serum fosfatın fizyolojik aralıkta korunması birçok biyolojik işlem için kritiktir. Fosfat, kemiklerin, nükleik asitlerin, hücre zarlarının önemli bir bileşenidir ve hücresel enerji metabolizmasında, proteinlerin fosforilasyonuyla hücre içi sinyalizasyonda ve hemoglobinden oksijen salınmasında önemli bir rol oynar. Fosfat önemli bir idrar ve kan asidi baz tamponudur 1 . Serum fosfor seviyesi, bağırsak emilimi, hücre içi ve kemik depo havuzlarının değişimi ve renal tübüler yeniden emilim arasındaki karmaşık bir etkileşimle sağlanır. Böbrek, tübüler yeniden emilim ile fosfor homeostazının düzenlenmesinde önemli bir rol oynar. Tip IIa ve tip IIc Na taşıyıcıları, proksimal tübüler hücrelerin fırça sınır membranında ifade edilen önemli renal Na bağımlı inorganik fosfat taşıyıcılardır. Her ikisi de diyet ile inorganik fosfat alımı, D vitamini, fibroblast büyüme faktörü 23 FGF23 ve paratiroid hormonu PTH tarafından düzenlenir 2 .

Anahtar Kelimeler:

Hipofosfatemi, hiperfosfatemi, FGF23, Klotho

Phosphate Metabolism

Maintenance of serum phosphate in the physiological range is critical for many biological processes. Phosphate is an essential component of bones, nucleic acids, and cell membranes, and it plays a crucial role in cellular energy metabolism, intracellular signaling by phosphorylation of proteins, and release of oxygen from hemoglobin. Phosphate is an important urinary and blood acid base buffer 1 . The serum phosphorus level is maintained through a complex interplay between intestinal absorption, exchange intracellular and bone storage pools, and renal tubular reabsorption. The kidney plays a major role in regulation of phosphorus homeostasis by renal tubular reabsorption. Type IIa and type IIc Na transporters are important renal Na dependent inorganic phosphate transporters, which are expressed in the brush border membrane of proximal tubular cells. Both are regulated by dietary inorganic phosphate intake, vitamin D, fibroblast growth factor 23 FGF23 and parathyroid hormone 2 .

Keywords:

Hypophosphatemia, hyperphosphatemia, FGF23, Klotho,

PDF

___

1. Gattineni J, Baum M. Genetic disorders of phosphate regulation. Pediatric Nephrology (Berlin, Germany). 2012;27(9):1477-87.
2. Choi NW. Kidney and phosphate metabolism. Electrolyte & Blood Pressure, 2008;6(2):77-85.
3. Amanzadeh J, Reilly RF, Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nature Clinical Practice Nephrology. 2006;2(3):136-48.
4. Alizadeh Naderi AS, Reilly RF. Hereditary disorders of renal phosphate wasting. Nature reviews Nephrology. 2010;6(11):657-65.
5. Farrow EG, White KE. Recent advances in renal phosphate handling. Nature reviews Nephrology. 2010;6(4):207-17.
6. Berndt TJ, Schiavi S, Kumar R. “Phosphatonins” and the regulation of phosphorus homeostasis. American journal of physiology. Renal physiology. 2005;289(6):F1170- 82.
7. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annual review of medicine. 2010;61:91-104.
8. Alon US. Clinical practice. Fibroblast growth factor (FGF)23: a new hormone. European journal of pediatrics. 2011;170(5):545-54.
9. Jubiz W, Canterbury JM, Reiss E, Tyler FH. Circadian rhythm in serum parathyroid hormone concentration in human subjects: correlation with serum calcium, phosphate, albumin, and growth hormone levels. The Journal of clinical investigation. 1972;51(8):2040-6.
10. Lichtman MA, Miller DR, Cohen J, Waterhouse C. Reduced red cell glycolysis, 2, 3-diphosphoglycerate and adenosine triphosphate concentration, and increased hemoglobin-oxygen affinity caused by hypophosphatemia. Annals of internal medicine. 1971;74(4):562-8.
11. Schubert L, DeLuca HF. Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency. Archives of biochemistry and biophysics. 2010;500(2):157-61.
12. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Archives of Internal Medicine. 1977;137(2):203-20.
13. Knochel JP. Hypophosphatemia and rhabdomyolysis. The American Journal of Medicine. 1992;92(5):455-7.
14. Newman JH, Neff TA, Ziporin P. Acute respiratory failure associated with hypophosphatemia. The New England Journal of Medicine. 1977;296(19):1101-3.
15. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. The New England journal of medicine. 1977;297(17):901-3.
16. Kalantar-Zadeh K, Gutekunst L, Mehrotra R, Kovesdy CP, Bross R, Shinaberger CS, et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease. Clinical Journal of the American Society of Nephrology : CJASN. 2010;5(3):519- 30.
17. Ramirez JA, Emmett M, White MG, Fathi N, Santa Ana CA, Morawski SG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney international. 1986;30(5):753-9.
18. Gupta RK, Gangoliya SS, Singh NK. Reduction of phytic acid and enhancement of bioavailable micronutrients in food grains. Journal of food science and technology. 2015;52(2):676-84.
19. Moe SM, Zidehsarai MP, Chambers MA, Jackman LA, Radcliffe JS, Trevino LL, et al. Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease. Clinical journal of the American Society of Nephrology : CJASN. 2011;6(2):257-64.
20. McCutcheon J, Campbell K, Ferguson M, Day S, Rossi M. Prevalence of Phosphorus-Based Additives in the Australian Food Supply: A Challenge for Dietary Education? Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2015;25(5):440-4.
21. Uribarri J, Calvo MS. Hidden sources of phosphorus in the typical American diet: does it matter in nephrology? Seminars in dialysis. 2003;16(3):186-8.
22. Leon JB, Sullivan CM, Sehgal AR. The prevalence of phosphorus-containing food additives in top-selling foods in grocery stores. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2013;23(4):265-70.e2.
23. Wesseling-Perry K. FGF-23 in bone biology. Pediatric nephrology (Berlin, Germany). 2010;25(4):603-8.
24. Xu H, Collins JF, Bai L, Kiela PR, Ghishan FK. Regulation of the human sodium-phosphate cotransporter NaP(i)- IIb gene promoter by epidermal growth factor. American Journal of Physiology Cell physiology. 2001;280(3):C628-36.
25. Arima K, Hines ER, Kiela PR, Drees JB, Collins JF, Ghishan FK. Glucocorticoid regulation and glycosylation of mouse intestinal type IIb Na-P(i) cotransporter during ontogeny. American journal of physiology Gastrointestinal and liver physiology. 2002;283(2):G426- 34.
26. Xu H, Uno JK, Inouye M, Xu L, Drees JB, Collins JF, et al. Regulation of intestinal NaPi-IIb cotransporter gene expression by estrogen. American journal of physiology Gastrointestinal and liver physiology. 2003;285(6):G1317-24.
27. Stauber A, Radanovic T, Stange G, Murer H, Wagner CA, Biber J. Regulation of intestinal phosphate transport. II. Metabolic acidosis stimulates Na(+)-dependent phosphate absorption and expression of the Na(+)-P(i) cotransporter NaPi-IIb in small intestine. American journal of physiology Gastrointestinal and liver physiology. 2005;288(3):G501-6.
28. Danisi G, Bonjour JP, Straub RW. Regulation of Na-dependent phosphate influx across the mucosal border of duodenum by 1,25-dihydroxycholecalciferol. Pflugers Archiv: European journal of physiology. 1980;388(3):227-32.
29. Hattenhauer O, Traebert M, Murer H, Biber J. Regulation of small intestinal Na-P(i) type IIb cotransporter by dietary phosphate intake. The American journal of physiology. 1999;277(4):G756-62.
30. Hilfiker H, Hattenhauer O, Traebert M, Forster I, Murer H, Biber J. Characterization of a murine type II sodiumphosphate cotransporter expressed in mammalian small intestine. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(24):14564-9.
31. Virkki LV, Biber J, Murer H, Forster IC. Phosphate transporters: a tale of two solute carrier families. American journal of physiology Renal physiology. 2007;293(3):F643-54.
32. Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, et al. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. American journal of physiology Renal physiology. 2009;296(4):F691-9.
33. Villa-Bellosta R, Sorribas V. Compensatory regulation of the sodium/phosphate cotransporters NaPi-IIc (SCL34A3) and Pit-2 (SLC20A2) during Pi deprivation and acidosis. Pflugers Archiv : European journal of physiology. 2010;459(3):499-508.
34. Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R, et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. American journal of physiology Renal physiology. 2009;297(2):F282-91.
35. Ma Y, Samaraweera M, Cooke-Hubley S, Kirby BJ, Karaplis AC, Lanske B, et al. Neither absence nor excess of FGF23 disturbs murine fetal-placental phosphorus homeostasis or prenatal skeletal development and mineralization. Endocrinology. 2014;155(5):1596-605.
36. Ohata Y, Yamazaki M, Kawai M, Tsugawa N, Tachikawa K, Koinuma T, et al. Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(7):1627-38.
37. Takaiwa M, Aya K, Miyai T, Hasegawa K, Yokoyama M, Kondo Y, et al. Fibroblast growth factor 23 concentrations in healthy term infants during the early postpartum period. Bone. 2010;47(2):256-62.
38. Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM. Fetal parathyroids are not required to maintain placental calcium transport. The Journal of Clinical Investigation. 2001;107(8):1007-15.
39. Saggese G, Baroncelli GI, Bertelloni S, Cipolloni C. Intact parathyroid hormone levels during pregnancy, in healthy term neonates and in hypocalcemic preterm infants. Acta paediatrica Scandinavica. 1991;80(1):36- 41.
40. Loughead JL, Mimouni F, Ross R, Tsang RC. Postnatal changes in serum osteocalcin and parathyroid hormone concentrations. Journal of the American College of Nutrition. 1990;9(4):358-62.
41. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. American journal of physiology Renal physiology. 2005;289(1):F8- 28.
42. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. The Journal of biological chemistry. 2006;281(10):6120-3.
43. Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2010;24(9):3438-50.
44. Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. The Journal of Clinical Investigation. 2007;117(9):2684- 91.
45. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, et al. Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003;17(1):50-2.
46. Kamemori M, Ohyama Y, Kurabayashi M, Takahashi K, Nagai R, Furuya N. Expression of Klotho protein in the inner ear. Hearing research. 2002;171(1-2):103-10.
47. Toyama R, Fujimori T, Nabeshima Y, Itoh Y, Tsuji Y, Osamura RY, et al. Impaired regulation of gonadotropins leads to the atrophy of the female reproductive system in klotho-deficient mice. Endocrinology. 2006;147(1):120-9.
48. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. The Journal of Clinical Investigation. 2011;121(11): 4393-408.
49. Suga T, Kurabayashi M, Sando Y, Ohyama Y, Maeno T, Maeno Y, et al. Disruption of the klotho gene causes pulmonary emphysema in mice. Defect in maintenance of pulmonary integrity during postnatal life. American Journal of Respiratory Cell and Molecular Biology. 2000;22(1):26-33.
50. Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M. Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia. The Journal of clinical investigation. 1999;104(3):229-37.
51. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45-51.
52. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. The Journal of clinical investigation. 2007;117(12):4003-8.
53. Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. Rickets. Nature Reviews Disease Primers. 2017;3:17101.
54. Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. American journal of human genetics. 2006;78(2):193-201.
55. Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodiumphosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. American Journal of Human Genetics. 2006;78(2):179-92.
56. Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, et al. Hereditary hypophosphatemic rickets with hypercalciuria. The New England Journal of Medicine. 1985;312(10):611-7.
57. Tencza AL, Ichikawa S, Dang A, Kenagy D, McCarthy E, Econs MJ, et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodiumphosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. The Journal of Clinical Endocrinology and Metabolism. 2009;94(11):4433-8.
58. Kremke B, Bergwitz C, Ahrens W, Schutt S, Schumacher M, Wagner V, et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/NaPi-IIc can be masked by vitamin D deficiency and can be associated with renal calcifications. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2009;117(2):49-56.
59. Page K, Bergwitz C, Jaureguiberry G, Harinarayan CV, Insogna K. A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2008;14(7):869-74.
60. Winters RW, Graham JB, Williams TF, Mc FV, Burnett CH. A genetic study of familial hypophosphatemia and vitamin D resistant rickets with a review of the literatu re. Medicine. 1958;37(2):97-142.
61. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nature Genetics. 1995;11(2):130-6.
62. Strom TM, Juppner H. PHEX, FGF23, DMP1 and beyond. Current opinion in nephrology and hypertension. 2008;17(4):357-62.
63. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nature Genetics. 2000;26(3):345-8.
64. Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004;145(7):3087-94.
65. Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. The Journal of Clinical Endocrinology and Metabolism. 1997;82(2):674-81.
66. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nature Genetics. 2006;38(11):1310-5.
67. Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, Muller-Barth U, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nature Genetics. 2006;38(11):1248-50.
68. George A, Sabsay B, Simonian PA, Veis A. Characterization of a novel dentin matrix acidic phosphoprotein. Implications for induction of biomineralization. The Journal of Biological Chemistry. 1993;268(17):12624- 30.
69. George A, Ramachandran A, Albazzaz M, Ravindran S. DMP1--a key regulator in mineralized matrix formation. Journal of Musculoskeletal & Neuronal Interactions. 2007;7(4):308.
70. Narayanan K, Ramachandran A, Hao J, He G, Park KW, Cho M, et al. Dual functional roles of dentin matrix protein 1. Implications in biomineralization and gene transcription by activation of intracellular Ca2+ store. The Journal of Biological Chemistry. 2003;278(19): 17500-8.
71. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A. 2001;98(11):6500-5.
72. Inclan A, Leon P, Camejo MG. Tumoral calcinosis. JAMA. 1943;121(7):490-5.
73. Garringer HJ, Fisher C, Larsson TE, Davis SI, Koller DL, Cullen MJ, et al. The role of mutant UDP-N-acetylalpha-D-galactosamine-polypeptide N-acetylgalactosa minyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis. The Journal of Clinical Endocrinology and Metabolism. 2006; 91(10):4037-42.
74. Frishberg Y, Topaz O, Bergman R, Behar D, Fisher D, Gordon D, et al. Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosishyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders. Journal of Molecular Medicine (Berlin, Germany). 2005;83(1):33-8.
75. Silver J, Kilav R, Sela-Brown A, Naveh-Many T. Molecular mechanisms of secondary hyperparathyroidism. Pediatric Nephrology (Berlin, Germany). 2000;14(7): 626-8.
76. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney International. 2003;64(6):2272-9.
77. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. The New England Journal of Medicine. 2008;359(6): 584-92.
78. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2004;19(3):429-35.
79. Stenvinkel P, Larsson TE. Chronic kidney disease: A clinical model of premature aging. American Journal of Kidney Diseases. 2013;62(2):339-51.