Phosphorus and Mortality: Do We Have the Panacea?

Chapter

Abstract

Epidemiological studies show that serum phosphate concentration is an independent risk factor for cardiovascular morbidity and death in CKD patients. The effects of phosphate on the cardiovascular system have been extensively studied, and concurrent perturbations in the FGF23—Klotho axis have been shown to play a pivotal role in this process. To reduce cardiovascular complications and death, pharmacological as well as dietary interventions to reduce serum phosphate levels are key. On a population basis, an overall restriction of dietary intake of phosphorus is likely to yield promising effects on cardiovascular outcomes, in part by altering FGF 23 and Klotho dynamics.

Keywords

Phosphate FGF-23 Klotho 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, et al. Intestinal npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol. 2009;20(11):2348–58.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Giral H, Caldas Y, Sutherland E, Wilson P, Breusegem S, Barry N, et al. Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Am J Physiol Renal Physiol. 2009;297(5):F1466–75.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lederer E, Miyamoto K. Clinical consequences of mutations in sodium phosphate cotransporters. Clin J Am Soc Nephrol. 2012;7(7):1179–87.CrossRefPubMedGoogle Scholar
  4. 4.
    Forster IC, Hernando N, Biber J, Murer H. Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med. 2013;34(2–3):386–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Evenepoel P, Wolf M. A balanced view of calcium and phosphate homeostasis in chronic kidney disease. Kidney Int. 2013;83(5):789–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Davis GR, Zerwekh JE, Parker TF, Krejs GJ, Pak CY, Fordtran JS. Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency. Gastroenterology. 1983;85(4):908–16.PubMedGoogle Scholar
  7. 7.
    Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism—unique biological characteristics of FGF23. Bone. 2007;40(5):1190–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Investig. 2003;112(5):683–92.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone. 2009;45(6):1161–8.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503–33.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rodriguez-Ortiz ME, Lopez I, Munoz-Castaneda JR, Martinez-Moreno JM, Ramirez AP, Pineda C, et al. Calcium deficiency reduces circulating levels of FGF23. J Am Soc Nephrol. 2012;23(7):1190–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun. 2004;314(2):409–14.CrossRefPubMedGoogle Scholar
  13. 13.
    Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, et al. Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflugers Arch. 2003;446(5):585–92.CrossRefPubMedGoogle Scholar
  14. 14.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Investig. 2004;113(4):561–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Miyamoto K, Ito M, Kuwahata M, Kato S, Segawa H. Inhibition of intestinal sodium-dependent inorganic phosphate transport by fibroblast growth factor 23. Ther Apher Dial. 2005;9(4):331–5.CrossRefPubMedGoogle Scholar
  16. 16.
    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. J Bone Miner Res. 2004;19(3):429–35.CrossRefPubMedGoogle Scholar
  17. 17.
    Vervloet MG, van Ittersum FJ, Buttler RM, Heijboer AC, Blankenstein MA, ter Wee PM. Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clin J Am Soc Nephrol. 2011;6(2):383–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281(10):6120–3.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    Olauson H, Lindberg K, Amin R, Jia T, Wernerson A, Andersson G, et al. Targeted deletion of Klotho in kidney distal tubule disrupts mineral metabolism. J Am Soc Nephrol. 2012;23(10):1641–51.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol. 2009;20(5):955–60.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhao Y, Banerjee S, Dey N, LeJeune WS, Sarkar PS, Brobey R, et al. Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. Diabetes. 2011;60(7):1907–16.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Osuka S, Razzaque MS. Can features of phosphate toxicity appear in normophosphatemia? J Bone Miner Metab. 2012;30(1):10–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pillar R, Lopes MG, Rocha LA, Cuppari L, Carvalho AB, Draibe SA, et al. Severe hypovitaminosis D in chronic kidney disease: association with blood pressure and coronary artery calcification. Hypertens Res. 2013;36(5):428–32.CrossRefPubMedGoogle Scholar
  26. 26.
    Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol. 2004;15(12):2959–64.CrossRefPubMedGoogle Scholar
  27. 27.
    Giachelli CM, Jono S, Shioi A, Nishizawa Y, Mori K, Morii H. Vascular calcification and inorganic phosphate. Am J Kidney Dis. 2001;38(4 Suppl 1):S34–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545–52.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Investig. 2011;121(11):4393–408.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lee YT, Ng HY, Chiu TT, Li LC, Pei SN, Kuo WH, et al. Association of bone-derived biomarkers with vascular calcification in chronic hemodialysis patients. Clin Chim Acta. 2016;15(452):38–43.CrossRefGoogle Scholar
  31. 31.
    Shah NH, Dong C, Elkind MS, Sacco RL, Mendez AJ, Hudson BI, et al. Fibroblast growth factor 23 is associated with carotid plaque presence and area: the Northern Manhattan Study. Arterioscler Thromb Vasc Biol. 2015;35(9):2048–53.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wright CB, Dong C, Stark M, Silverberg S, Rundek T, Elkind MS, et al. Plasma FGF23 and the risk of stroke: the Northern Manhattan Study (NOMAS). Neurology. 2014;82(19):1700–6.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Parker BD, Schurgers LJ, Brandenburg VM, Christenson RH, Vermeer C, Ketteler M, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med. 2010;152(10):640–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Jimbo R, Shimosawa T. Cardiovascular risk factors and chronic kidney disease-FGF23: a key molecule in the cardiovascular disease. Int J Hypertens. 2014;2014:381082.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jimbo R, Kawakami-Mori F, Mu S, Hirohama D, Majtan B, Shimizu Y, et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 2014;85(5):1103–11.CrossRefPubMedGoogle Scholar
  36. 36.
    Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 2004;565(1–3):143–7.CrossRefPubMedGoogle Scholar
  37. 37.
    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 J. 2010;24(9):3438–50.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro OM, Huang CL. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci USA. 2008;105(28):9805–10.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Silswal N, Touchberry CD, Daniel DR, McCarthy DL, Zhang S, Andresen J, et al. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab. 2014;307(5):E426–36.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Six I, Okazaki H, Gross P, Cagnard J, Boudot C, Maizel J, et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS ONE. 2014;9(4):e93423.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Moe SM, Chertow GM, Parfrey PS, Kubo Y, Block GA, Correa-Rotter R, et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the evaluation of Cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial. Circulation. 2015;132(1):27–39.CrossRefPubMedGoogle Scholar
  42. 42.
    Ballinger AE, Palmer SC, Nistor I, Craig JC, Strippoli GF. Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. Cochrane Database Syst Rev. 2014;12:CD006254.Google Scholar
  43. 43.
    Fajol A, Chen H, Umbach AT, Quarles LD, Lang F, Foller M. Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by beta-blocker treatment. FASEB J. 2015 Nov 2.Google Scholar
  44. 44.
    Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16(2):520–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 2011;305(11):1119–27.CrossRefPubMedGoogle Scholar
  46. 46.
    Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;112(17):2627–33.CrossRefPubMedGoogle Scholar
  47. 47.
    Sim JJ, Bhandari SK, Smith N, Chung J, Liu IL, Jacobsen SJ, et al. Phosphorus and risk of renal failure in subjects with normal renal function. Am J Med. 2013;126(4):311–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis. 1998;31(6):954–61.CrossRefPubMedGoogle Scholar
  49. 49.
    Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int. 2002;62(1):220–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Clinical Laboratory, Faculty of MedicineInternational University of Health and WelfareNaritaJapan
  2. 2.Department of Clinical LaboratoryMita Hospital, IUHWMinatokuJapan
  3. 3.Department of Internal MedicineTohto Bunkyo HospitalBunkyo-kuJapan

Personalised recommendations