Статья
НАРУШЕНИЯ СИСТЕМНОГО ОБМЕНА НЕОРГАНИЧЕСКОГО ФОСФАТА КАК НОВЫЙ КЛАСТЕР КАРДИОВАСКУЛЯРНЫХ РИСКОВ
Исследования последней декады показали отчетливую связь между уровнем неорганического фосфата (Pi) сыворотки крови, а также нарушением баланса эндокринных систем почек, паращитовидных желез и костей, регулирующих обмен Pi, с сердечно-сосудистыми событиями и смертностью. Данные связи продемонстрированы для пациентов с хронической болезнью почек и для общей популяции. В передовой статье обсуждаются клинические и экспериментальные данные, объединяющие патофизиологию нарушений обмена Pi и развитие изменений в сердечно-сосудистой системе.
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group.KDIGO clinical practice guideline for thediagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease — Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1–S130.
2. Смирнов А. В., Шилов Е. М., Добронравов В. А. и др. Национальные рекомендации. хроническая болезнь почек:основные принципы скрининга, диагностики, профилактики и подходы к лечению Национальные рекомендации. Нефрология. 2012;16(1):89–115..
3. Смирнов А. В., Добронравов В. А., Каюков И. Г. Проблема хронической болезни почек в современной медицине. Артериальная гипертензия. 2006;12(3):185–193..
4. Gansevoort RT, Matsushita K, van der Velde M et al. Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80(1):93–104.
5. Perk J, De Backer G, Gohlke H et al. European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33(13):1635–1701.
6. Смирнов А. В., Добронравов В. А., Каюков И. Г. Кардиоренальный континуум: патогенетические основы превентивной нефрологии. Нефрология. 2005;9(3):7–15..
7. Kestenbaum B, Sampson JN, Rudser KD. et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16(2):520–528.
8. McGovern AP, de Lusignan S, van Vlymen J et al. Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study. PLoS One. 2013;8(9): e74996.
9. Kendri ck J, Kest enbaum В, Chonchol М. Phosphat e and cardiovascular disease. Adv Chronic Kidney Dis. 2011;18(2):113–119.
10. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension. 1999;33(5):1111–1117.
11. Hollander M, Hak AE, Koudstaal PJ et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke. 2003;34(10):2367–2372.
12. Detrano R, Guerci AD, Carr JJ et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358(13):1336–1345.
13. Olson JC, Edmundowicz D, Becker DJ, Kuller LH, Orchard TJ. Coronary calcium in adults with type 1 diabetes: a stronger correlate of clinical coronary artery disease in men than in women. Diabetes. 2000;49 (9):1571–1578.
14. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003;18 (9):1731–1740.
15. Klassen PS, Lowrie EG, Reddan DN et al. Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis. J Am Med Assoc. 2002;287(12):1548–1555.
16. Hunt JL, Fairman R, Mitchell ME et al. Bone formation in carotid plaques: a clinicopathological study. Stroke. 2002;33(5):1214–1219.
17. Edmonds ME, Morrison N, Laws JW, Watkins PJ. Medial arterial calcification and diabetic neuropathy. Br Med J (Clin Res Ed). 1982;284(6320):928–930.
18. Micheletti RG, Fishbein GA, Currier JS, Fishbein MC. Monckeberg sclerosis revisited: a clarification of the histologic definition of Monckeberg sclerosis. Arch Pathol Lab Med. 2008;132(1):43–47.
19. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342(20):1478–1483.
20. Ix JH, De Boer IH, Peralta CA et al. Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. Clin J Am Soc Nephrol. 2009;4(3):609–615.
21. Adeney KL, Siscovick DS, Ix JH et al. Association of serum phosphate with vascular and valvular calcification in moderate CKD. J Am Soc Nephrol. 2009;20(2):381–387.
22. . Foley RN. , Collins AJ . , Herzog CA. , Ishani A. , Kalra PA. Serum phosphorus levels associate with coronary atherosclerosis in young adults. J Am Soc Nephrol. 2009;20(2):397–404.
23. Kendrick J, Ix JH, Targher G, Smits G, Chonchol M. Relation of serum phosphorus levels to ankle brachial pressure index (from the Third National Health and Nutrition Examination Survey). Am J Cardiol. 2010;106(4):564–568.
24. Li JW, Xu C, Fan Y, Wang Y, Xiao YB. Can serum levels of alkaline phosphatase and phosphate predict cardiovascular diseases and total mortality in individuals with preserved renal function? A systemic review and meta-analysis. PLoS One. 2014;9(7): e102276.
25. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, Strippoli GF. 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. J Am Med Assoc. 2011;305 (11):1119–1127.
26. Levy D, Garrison RJ, Savage DD, Kannel WB, Cast el l i WP. Pr ognost i c i mpl i cat i ons of echocar di ogr aphi cal l y determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322(22):1561–1566.
27. Park M, Hsu CY, Li Y et al. Chronic Renal Insufficiency Cohort (CRIC) Study Group Associations between kidney function and subclinical cardiac abnormalities in CKD. J Am Soc Nephrol. 2012;23(10):1725–1734.
28. Levi n A. Clincal epi demi ol ogy of car di ovas cul ar disease in chronic kidney disease prior to dialysis. Semin Dial. 2003;16 (2):101–105.
29. Strozecki P, Adamowicz A, Nartowicz E, Odrowaz Sypniewska G, Wiodarczyk Z, Manitius J. Parathormone, calcium, phosphorus, and left ventricular structure and function in normotensive hemodialysis patients. Ren Fail 2001;23(1):115–126.
30. Galetta F, Cupisti A, Franzoni F et al. Changes in heart rate variability in chronic uremic patients during ultrafiltration and hemodialysis. Blood Purif. 2001;19(4):395–400.
31. Culleton BF, Walsh M, Karenbach SW et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. J Am Med Assoc. 2007;298(11):1291–1299.
32. Yamamoto KT, Robinson-Cohen C, de Oliveira MC et al. Dietary phosphorus is associated with greater left ventricular mass. Kidney Int. 2013;83(4):707–714.
33. Slinin Y, Foley RN, Collins AJ. Calcium, phosphorus, parathyroid hormone and cardiovascular disease in hemodialysis patients. The USRDS waves 1,3 and 4 study. J Am Soc Nephrol. 2005;16(6):1788–1793.
34. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in hemodialysis patients. J Am Soc Nephrol. 2004;15(8):2208–2218.
35. Chonchol M, Dale R, Schrier RW, Estacio R. Serum phosphorus and cardiovascular mortality in type 2 diabetes. Am J Med. 2009;122(4):380–386.
36. 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):2627–2633.
37. Dhingra R, Sullivan LM, Fox CS et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007;167(9):879–885.
38. Foley RN, Collins AJ, Ishani A, Kalra PA. Calciumphosphate levels and cardiovascular disease in community-swelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2008;156(3):556–563.
39. Hruska K, Mathew S, Lund R, Fang Y, Sugatani T. Cardiovascular risk factors in chronic kidney disease: does phosphate qualify? Kidney Int Suppl. 2011;79(121): S9-S13.
40. Tentori F, Blayney MJ, Albert JM et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2008;52(3):519–530.
41. Grandi NC, Brenner H, Hahmann H et al. Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease. Heart. 2012;98(12):926–933.
42. . Van Hemelrijck M, Mi c h a e l s s o n K, Li n s e i s e n J , Rohrmann S. Calcium intake and serum concentration in relation to risk of cardiovascular death in NHANES III. PLoS One. 2013;8 (4): e61037.
43. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mo r t a l i t y i n t h e H e i d e l b e r g c o h o r t o f t h e E u r o p e a n Prospective Investigation into Cancer and Nutrition study (EPIC — Heidelberg). Heart. 2012;98(12):920–925.
44. Bolland MJ, Avenell A, Baron JA et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. Br Med J. 2010;341: e3691.
45. Bolland MJ, Barber PA, Doughty RN et al. Vascular events in healthy older women receiving calcium supplementation: randomized controlled trial. Br Med J. 2008;336(7638):262–266.
46. Wang X, Chen H, Ouyang Y et al. Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies. BMC Med. 2014;12 (1):158.
47. Bolland MJ, Grey A, Reid IR. Calcium supplements and cardiovascular risk: 5 years on. Ther Adv Drug Saf. 2013;4 (5):199–210.
48. Sage AP, Lu J, Tintut Y, Demer LL. Hyperphosphatemiai n d u c e d n a n o c r y s t a l s u p r e g u l a t e t h e e x p r e s s i o n o f b o n e morphogenetic protein-2 and osteopontin genes in mouse smooth muscle cells in vitro. Kidney Int. 2011;79(4):414–422.
49. Vi l l a-Bel l ost a R, Sorri bas V. Phosphonoformi cacid prevents vascular smooth muscle cell calcification by inhibiting calcium-phosphate deposition. Arterioscler Thromb Vasc Biol. 2009;29(5):761–766.
50. Ewence AE, Bootman M, Roderick HL et al. Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: a potential mechanism in atherosclerotic plaque destabilization. Circ Res. 2008;103(5): e28-e34.
51. Khoshniat S, Bourgine A, Julien M et al. Phosphatedependent stimulation of MGP and OPN expression in osteoblasts via the ERK1/2 pathway is modulated by calcium. Bone. 2010;48 (4):894–902.
52. Kuro-o M. Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol. 2013;9 (11):650–660.
53. Smi t h ER, For d ML, Toml i nson LA, Raj kumar C, McMahon LP, Holt SG. Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD. Nephrol Dial Transplant. 2012;27(5):1957–1966.
54. Steitz SA, Speer MY, Curinga G et al. Smooth muscle cell phenotypic transition associated with calcification: up-regulation of Cbfa1 and down-regulation of smooth muscle lineage markers. Circ Res. 2001;89(12):1147–1154.
55. Speer MY, Li X, Hiremath PG, Giachelli CM. Runx2/Cbfa1. but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis. J Cell Biochem. 2010;110(4):935–947.
56. Shioi ANY, Jono S, Koyama H, Hosoi M, Morii H. Betaglycerophosphate accelerates calcification in cultured bovine vascular smooth muscle cells. Arterioscler Throm Vasc Biol. 1995;15 (11):2003–2009.
57. Chen NX, O’Neill KD, Duan D, Moe SM. Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int. 2002;62(5):1724–1731.
58. Mathew S, Tustison KS, Sugatani T, Chaudhary LR, Ri f as L, Hr us ka KA. The mechani s m of phos phor us as a cardiovascular risk factor in CKD. J Am Soc Nephrol. 2008;19(6): 1092–1105.
59. Gittenberger-de Groot AC, Winter EM, Bartelings MM et al. The arterial and cardiac epicardium in development, disease and repair. Differentiation. 2012;84(1):41–53.
60. Von Gise A, Pu WT. Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ. Res. 2012;110(12):1628–1645.
61. Mill C, George SJ. Wnt signalling in smooth muscle cells and its role in cardiovascular disorders. Cardiovasc Res. 2012;95 (2):233–240.
62. Liu H, Fergusson MM, Castilho RM et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science. 2007;317(5839):803–806.
63. Kawakami T, Ren S, Duffield JS. Wnt signalling in kidney diseases: dual roles in renal injury and repair. J Pathol. 2013;229 (2):221–231.
64. Kamiya N, Kobayashi T, Mochida Y et al. Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. J Bone Miner Res. 2010;25(2):200–210.
65. Ueland T, Otterdal K, Lekva T et al. Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29(8):1228–1234.
66. Sabbagh Y, Graciolli FG, O’Brien S et al. Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy. J Bone Miner Res. 2012;27 (8):1757–1772.
67. Li X, Yang HY, Giachelli CM. BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. Atherosclerosis. 2008;199(2):271–277.
68. Cheng SL, Shao JS, Behrmann A, Krchma K, Towler DA. Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33(7):1679–1689.
69. Askevold ET, Gullestad L, Aakhus S et al. Secreted Wnt modulators in symptomatic aortic stenosis. J Am Heart Assoc. 2012;1(6): e002261.
70. Garcia-Martín A, Reyes-Garcia R, García-Fontana B et al..Relationship of Dickkopf1 (DKK1) with cardiovascular disease and bone metabolism in caucasian type 2 diabetes mellitus. PLoS One. 2014;9(11): e111703.
71. Wang L, Hu XB, Zhang W et al. Dickkopf –1 as a novel predictor is associated with risk stratification by GRACE risk scores for predictive value in patients with acute coronary syndrome: a retrospective research. PLoS One. 2013;8(1): e54731.
72. Fang Y, Ginsberg C, Seifert M et al. CKD-induced wi ngl ess/ i nt egr at i on1 i nhi bi t or s and phosphor us cause t he CKD-mineral and bone disorder. J Am Soc Nephrol. 2014;25 (8):1760–1773.
73. Добронравов В. А. Современный взгляд на патофизиологию вторичного гиперпаратиреоза: роль фактора роста фибробластов 23 и klotho. Нефрология. 2011;15(4):11–20..
74. Смирнов А. В., Волков М. М., Добронравов В. А. Кардиопротективные эффекты D-гормона у больных с хронической болезнью почек: обзор литературы и собственные данные. Нефрология. 2009;13(1):30–38..
75. Nigwekar SU, Thadhani R. Vitamin D receptor activation: cardiovascular and renal implications. Kidney Int Suppl (2011). 2013;3(5):427–430.
76. Li YC. Vitamin D: roles in renal and cardiovascular protection. Curr Opin Nephrol Hypertens. 2012;21(1):72–79. 77. Weishaar RE, Kim SN, Saunders DE, Simspon RU. Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties. Am J Physiol. 1990;258 (1 Pt. 1): E134-E142.
77. Xiang W, Kong J, Chen S et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am. J. Physiol. Endocrinol Metab. 2005;288(1):125–132.
78. Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol. 2008;19(8):1509–1519.
79. Mizobuchi M, Finch JL, Martin DR, Ststopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72(6):709–715.
80. Kokot F, Pietrek J, Srokowska S et al. 25-hydroxyvitamin D in patients with essential hypertension. Clin Nephrol. 1981;16 (4):188–192.
81. Burga z A, Or s i ni N, La r s s on SC, Wol k A. B ood 25-hydroxyvitamin D concentration and hypertension: a metaanalysis. J Hypertens. 2011;29(4):636–645.
82. Pilz S, Marz W, Wellnitz B et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008;93 (10):3927–3935.
83. Wang TJ, Pencina MJ, Booth SL et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117(4): 503–511.
84. Pilz S, Iodice S, Zittermann A, Grant WB, Grandini S. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am J Kidney Dis. 2011;58(3):374–382.
85. Drechsler C, Verduijn M, Pilz S et al. Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. Nephrol Dial Transplant. 2011;26(3):1024–1032.
86. Abu el Maaty MA, Gad MZ. Vi t ami n D defi ci ency and cardiovascular disease: potential mechanisms and novel perspectives. J Nutr Sci Vitaminol (Tokyo). 2013;59(6):479–488.
87. Clemens TL, Cormier S, Eichinger A et al. Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Br J Pharmacol. 2001;134(6): 1113–1136.
88. Goettsch C, Iwata H, Aikawa E. Parathyroid hormone: critical bridge between bone metabolism and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2014;34(7):1333–1335.
89. Ma c f a r l a ne DP, Yu N, Le e s e GP. Subc l i ni c a l a nd asymptomatic parathyroid disease: implications of emerging data. Lancet Diabetes Endocrinol. 2013;1(4):329–340.
90. Bosworth C, Sachs MC, Duprez D et al. Parathyroid hormone and arterial dysfunction in the multi-ethnic study of atherosclerosis. Clin Endocrinol (Oxf). 2013;79(3):429–436.
91. Hagst r öm E, Hel l man P, Lar sson TE et al . Pl asma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119(21):2765–2771.
92. Нagström E, Michaëlsson K, Melhus H et al. Plasmaparathyroid hormone is associated with subclinical and clinical atherosclerotic disease in 2 community-based cohorts. Arterioscler Thromb Vasc Biol. 2014;34(7):1567–1573.
93. Nakayama K, Nakao K, Takatori Y et al. Long-term effect of cinacalcet hydrochloride on abdominal aortic calcification in patients on hemodialysis with secondary hyperparathyroidism. Int J Nephrol Renovasc Dis. 2013;7:25–33.
94. Tomaschitz A, Ritz E, Pieske B et al. Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease. Metabolism. 2014;63(1):20–31.
95. Gutierrez OM, Wolf M, Taylor EN. Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the Health Professionals Follow-up Study. Clin J Am Soc Nephrol. 2011;6(12):2871–2878.
96. Manghat P, Fraser WD, Wierzbicki AS et al. Fibroblast growth factor-23 is associated with C-reactive protein, serum phosphate and bone mineral density in chronic kidney disease. Osteoporos Int. 2010;21(11):1853–1861.
97. Isakova T, Xie H, Yang W et al. Chronic Renal Insufficiency Cohort (CRIC) Study Group: fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. J Am Med Assoc. 2011;305(23):2432–2439.
98. Fliser D, Kollerits B, Neyer U et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007;18(9):2600–2608.
99. Wolf M, Molnar MZ, Amaral AP et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol. 2011;22(5):956–966.
100. Gutiérrez OM, Mannstadt M, Isakova T et al. Fibroblast growt h fact or 23 and mort al i t y among pat i ent s undergoi ng hemodialysis. N Engl J Med. 2008;359(6):584–592.
101. Lundberg S, Qureshi AR, Olivecrona S, Gunnarsson I, Jacobson SH, Larsson TE. FGF23, albuminuria, and disease progression in patients with chronic IgA nephropathy. Clin J Am Soc Nephrol. 2012;7(5):727–734.
102. Ix JH, Katz R, Kestenbaum BR et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol. 2012;60(3):200–207.
103. Ärnlöv J, Carlsson AC, Sundström J et al. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int. 2013;83(1):160–166.
104. Ärnl öv J, Carl sson AC, Sundst röm J et al . Serum FGF23 and Risk of Cardiovascular Events in Relation to Mineral Metabolism and Cardiovascular Pathology. Clin J Am Soc Nephrol. 2013;8(5):781–786.
105. Jovanovich A, Ix JH, Gottdiener J et al. Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. Atherosclerosis. 2013;231 (1):114–119.
106. Scialla J J , X e H, Rahman M etal . Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol. 2014;25(2):349–360.
107. Faul C, Amaral AP, Oskouei B et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393–4408.
108. Shibata K, Fujita S, Morita H et al.As s oci at i on between circulating fibroblast growth factor 23, α-Klotho, and the left ventricular ejection fraction and left ventricular mass in cardiology inpatients. PLoS One. 2013;8 (9): e73184.
109. Sei f er t ME, de Las Fuent es L, Gi nsberg C et al . Left ventricular mass progression despite stable blood pressure and kidney function in stage 3 chronic kidney disease. Am J Nephrol. 2014;39(5):392–399.
110. Seiler S, Rogacev KS, Roth HJ et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2–4. Clin J Am Soc Nephrol. 2014;9(6): 1049–1058.
111. Molkentin JD, Lu J, Antos C et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998;93(2): 215–228.
112. Komuro I, Yazaki Y. Control of cardiac gene expression by mechanical stress. Annu Rev Physiol. 1993;55:55–75. 114. I t oh N, Oht a H. Pat hophysi ol ogi cal r ol es of FGF signaling in the heart. Front Physiol. 2013;4:247.
113. Kendrick J, Cheung AK, Kaufman JS et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol. 2011;22(10):1913–1922.
114. Seiler S, Reichart B, Roth D, Seibert E., Fliser D., Heine G. H. FGF-23 and future cardiovascular events in patients with chronic kidney disease before initiation of dialysis treatment. Nephrol Dial Transplant. 2010;25(12):3983–3989.
115. Parker BD, Schurgers LJ, Brandenburg VM 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):640–648.
116. Taylor EN, Rimm EB, Stampfer MJ, Curhan GC. Plasma fibroblast growth factor 23, parathyroid hormone, phosphorus, and risk of coronary heart disease. Am Heart J. 2011;161(5): 956–962.
117. Srivaths PR, Goldstein SL, Silverstein DM, Krishnamurthy R., Brewer E. D. Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients. Pediatr Nephrol. 2011;26(6):945–991.
118. Roos M, Lutz J, Salmhofer H et al. Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed t omogr aphy i n pat i ent s wi t h nor mal ki dney f unct i on. Cl i n Endocrinol (Oxf). 2008;68(4):660–665.
119. Mirza MA, Larsson A, Lind L, Larsson TE. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis. 2009;205(2):385–390.
120. Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the
121. mouse Klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51.
122. Kuro-o М. Phosphate and klotho. Kidney Int. 2011;
123. (121):S20-S23.
124. Dai B, Dav d V, Martin A et a l . A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS One. 2012;7(9): e44161.
125. Lim K, Lu T.S, Molostvov G et al. Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation. 2012;125(18):2243–2255.
126. Van Venrooij NA, Pereira RC, Tintut Y et al. FGF23 protein expression in coronary arteries is associated with impaired kidney function. Nephrol Dial Transplant. 2014;29(8):1525–1532.
127. Navarro-González JF, Donate-Correa J et al. Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart. 2014;100(1):34–40.
128. Hu MC, Shi M, Zhang J et al . Kl ot ho defi ci ency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124–136.
129. Zhao Y, Banerjee S, Dey N 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):1907–1916.
130. Hu MC, Kuro-o M, Moe OW. Secreted klotho and chronic kidney disease. Adv Exp Med Biol. 2012;728:126–157.
131. De Oliveira RM, Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett. 2006;580(24):5753–5758.
132. Nakano-Kurimoto R, Ikeda K et al. Replicative senescence of vascul ar smoot h muscl e cel l s enhances t he cal ci fi cat i on through initiating the osteoblastic transition. Am J Physiol Heart Circ Physiol. 2009;297(5):1673–1684.
133. Kuroo M. Klotho as a regulator of oxidative stress and senescence. Biol Chem. 2008;389(3):233–241.
134. Kusaba T, Okigawa M, Matui A et al. Klotho is associated wi t h VEGF r ecept or- 2 and t he t r ansi ent r ecept or pot ent i al canonical-1 Ca 2+ channel to maintain endothelial integrity. Proc Natl Acad Sci USA. 2010;107(45):19308–19313.
135. Na ga i R, Sa i t o Y, Ohya ma Y e t a l . Endot he l i a l dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol Life Sci. 2000;57(5):738–746.
136. Kurosu H, Yamamoto M, Clark JD et al. Suppression of aging in mice by the hormone Klotho. Science. 2005;309 (5742):1829–1833.
137. Doi S, Zou Y, Togao O et al. Klotho inhibits transforming growth factor -beta1 (TGF -beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem. 2011;286(10): 8655–8665.
138. Takeshita K, Fujimori T, Kurotaki Y et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation. 2004;109(14):1776–1782.
139. Nowak A, Friedrich B, Artunc F et al. Prognostic value and link to atrial fibrillation of soluble Klotho and FGF23 in hemodialysis patients. PLoS One. 2014;9(7): e100688.
140. Six I, Okazaki H, Gross P et al. Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium. PLoS One. 2014;9(4): e93423.
141. Богданова Е. О., Береснева О. Н., Семенова Н. Ю. и др. Почечная экспрессия белка αKlotho ассоциирована с гипертрофией миокарда (экспериментальное исследование). Артериальная гипертензия. 2014;20(6):522–530]..
142. Xie J, Cha SK, An SW, Kuro-o M., Birnbaumer L, Huang CL. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat Commun. 2012;3:1238.
143. Hu MC, Shi M, Cho HJ et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol. 2014; pii: ASN.2014050465 .
144. Song S, Gao P, Xiao H, Xu Y, Si LY. Kl o t h o suppresses cardiomyocyte apoptosis in mice with stress-induced cardiac injury via downregulation of endoplasmic reticulum stress. PLoS One. 2013;8(12): e82968.
145. Maekawa Y, Ohishi M, Ikushima M et al. Klotho protein diminishes endothelial apoptosis and senescence via a mitogenactivated kinase pathway. Geriatr Gerontol Int. 2011;11(4):510–516.
146. Liu F, Wu S, Ren H, Gu J. Klotho suppresses RIGI-mediated senescence-associated inflammation. Nat Cell Biol. 2011;13(3):254–262.
147. Fang Y, Ginsberg C, Sugatani T et al. Early chronic kidney disease — mineral bone disorder stimulates vascular calcification. Kidney Int. 2014;85(1):142–150.
148. Kim HR, Nam BY, Kim DW et al. Circulating α-klotho levels in CKD and relationship to progression. Am J Kidney Dis. 2013;61(6):899–909.