Низкий сывороточный уровень Klotho как предиктор кальцификации сердца и сосудов у больных хронической болезнью почек 2–5D стадий
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Milovanova L.Yu., Lysenko (Kozlovskaya) L.V., Milovanova S.Yu., et al. Low serum Klotho level as a predictor of calcification of the heart and blood vessels in patients with CKD stages 2–5D. Therapeutic Archive. 2020; 92 (6): 37–45.
DOI: 10.26442/00403660.2020.06.000670
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Цель. Изучить ранние маркеры КВК с целью оптимизации кардиоренопротективной стратегии. Проведен проспективный сравнительный анализ следующих факторов: фактора роста фибробластов 23, a-Klotho, склеростина, фосфата, паратиреоидного гормона, расчетной скорости клубочковой фильтрации (рСКФ), центрального систолического давления – как независимых детерминант КВК.
Материалы и методы. В исследование включен 131 пациент с ХБП 2–5D стадий. Сывороточные уровни FGF-23, Klotho и склеростина оценивались с помощью ELISA-метода. Исследованы также индексы аугментации (жесткости) сосудов, центральное артериальное давление (с помощью прибора SphygmoCor), кальцификация клапанов сердца и степень кальциноза аорты (рентгенография аорты). Период наблюдения составил 2 года.
Результаты. Согласно корреляционному анализу Спирмена в наибольшей степени связаны процент повышения кальцификации и изменение уровня Klotho. Согласно ROC-анализу снижение сывороточного уровня Klotho на 50 ЕД и более является существенным предиктором увеличения кальцификации аорты на 50% и более с чувствительностью 86% и специфичностью 77%. С помощью логистического регрессионного анализа выявлено, что сывороточный уровень Klotho ниже 632 пг/л предсказывает рСКФ ниже медианного уровня 48 мл/мин/1,73 м2 с чувствительностью 85,5% и специфичностью 78,5%. При этом OШ 17,477 (ДИ 95% 8,046–37,962; p<0,001).
Заключение. Фактором, наиболее ассоциированным с КВК, является Klotho. Снижение сывороточного уровня Klotho – предиктор аортальной кальцификации. Кроме того, исходный сывороточный уровень Klotho является предиктором рСКФ через 2 года.
Ключевые слова: хроническая болезнь почек, фактор роста фибробластов 23, Klotho, склеростин, кардиоваскулярная кальцификация, ремоделирование сердца.
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Cardiovascular calcification (CVC) makes a significant contribution to the manifestation of cardiovascular complications in patients with chronic kidney disease. Early CVC markers are currently being actively studied to optimize cardio-renoprotective strategies. We performed a prospective comparative analysis of the following factors: FGF-23, a-Klotho, sclecrostin, phosphate, parathyroid hormone, the estimated glomerular filtration rate (eGFR), central systolic pressure as an independent determinant of CVC.
Materials and methods. The study included 131 patients with chronic kidney disease 2–5D st. Serum levels of FGF-23, Klotho, and sclerostin were evaluated using the ELISA method. Vascular augmentation (stiffness) indices, central arterial pressure (using the SphygmoCor device), calcification of heart valves and the degree of aortic calcification (aortic radiography) were also investigated. The observation period was 2 years.
Results. According to the Spearman correlation analysis, the percent of calcification increase and the change in Klotho level are most related. According to ROC analysis, a decrease in serum levels of Klotho by 50 units or more is a significant predictor of an increase in aortic calcification of 50% or more with a sensitivity of 86% and a specificity of 77%. Using logistic regression analysis, it was found that a serum Klotho level <632 pg/L predicts an eGFR below a median level of 48 ml/min/1.73 m2 with a sensitivity of 85.5% and a specificity of 78.5%. Wherein OR 17.477 (CI 95% 8.046–37.962; p<0.001).
Conclusion. The factor most associated with CVC is Klotho. Decreased serum level of Klotho is a predictor of aortic calcification. In addition, the initial serum level of Klotho is a predictor of eGFR after 2 years.
Keywords: chronic kidney disease, fibroblast growth factor 23, Klotho, sclerostin, cardiovascular calcification, heart remodeling.
For citation:
2. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. doi: 10.1056/NEJMoa041031
3. Kumar S, Bogle R, Banerjee D. Why do young people with chronic kidney disease die early? World J Nephrol. 2014;3(4):143-55. doi: 10.5527/wjn.v3.i4.143
4. Garland JS, Holden RM, Groome PA, et al. Prevalence and associations of coronary artery calcification in patients with stages 3 to 5 CKD without cardiovascular disease. Am J Kidney Dis. 2008;52(5):849-58. doi: 10.1053/j.ajkd.2008.04.012. Epub 2008 Jun 17.
5. Memmos E, Sarafidis P, Pateinakis P, et al. Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol. 2019;20:217. doi: 10.1186/s12882-019
6. Lu X, Hu MC. Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. Kidney Dis. 2016;17:1-9.
7. Milovanova LY, Fomin VV, Lysenko (Kozlovskaya) LV, et al. Disorders in the system of mineral and bone metabolism regulators – FGF-23, Klotho and Sclerostin – in chronic kidney disease: clinical significance and possibilities for correction. In Rath T, editor. Chronic Kidney Disease. From Pathophysiology to Clinical Improvements. London: IntechOpen Limited; 2018; p. 43-60. doi: 10.5772/intechopen.69298
8. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79:1370-8. doi: 10.1038/ki.2011.47. Epub 2011 Mar 9
9. Milovanova L, Kozlovskaya L, Markina M, et al. Morphogenetic proteins – fibroblast growth factor-23 (FGF-23) and Klotho in serum of patients with chronic kidney disease, as the markers of cardiovascular risk. Clin Med. 2016;12:34-40.
10. Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor-23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545-52. doi: 10.1161/CIRCULATIONAHA.108.844506
11. Sharaf UA, Din El, Salem MM, Abdulazim DO. Is Fibroblast growth factor 23 the leading cause of increased mortality among chronic kidney disease patients? A narrative review. J Adv Res. 2017;8(3):271-8. doi: 10.1016/j.jare.2017.02.003
12. Donate-Correa J, Martín-Núñez E, Mora-Fernández C, et al. Klotho in cardiovascular disease: Current and future perspectives. World J Biol Chem. 2015;6(4):351-7. doi: 10.4331/wjbc.v6.i4.351
13. Милованова Л.Ю., Мухин Н.А., Козловская Л.В. и др. Снижение сывороточного уровня морфогенетического белка Klotho у больных хронической болезнью почек: клиническое значение. Вестн. РАМН. 2016;71:288-96 [Milovanova LY, Mukhin NA, Kozlovskaya LV, et al. Decreased serum levels of klotho protein in chronic kidney disease patients: Clinical importance. Vestn. Ross. Akad. Meditsinskikh Nauk. 2016;71:288-96 (In Russ.)]. doi: 10.15690/vramn581
14. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45-51. doi: 10.1038/36285
15. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770-4. doi: 10.1038/nature05315
16. Saito Y, Yamagishi T, Nakamura T, et al. Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun. 1998;248:324-9. doi: 10.1006/bbrc.1998.8943
17. Kusaba T, Okigaki M, Matui A, et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci USA. 2010;107:19308-13. doi: 10.1073/pnas.1008544107
18. Semba RD, Cappola AR, Sun K, et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci. 2011;66:794-800. doi: 10.1093/gerona/glr058
19. Cejka D, Herberth J, Branscum AJ, et al. Sclerostin and Dickkopf-1 in renal osteodystrophy. Clin J Am Soc Nephrol. 2011;6:877-82. doi: 10.2215/CJN.06550810
20. Bruzzese A, Lacquaniti A, Cernaro V, et al. Sclerostin levels in uremic patients: a link between bone and vascular disease. J Renal Failure. 2016;38(5):123-9. doi: 10.3109/0886022X.2016.1160207
21. Kanbay M, Solak Y, Siriopol D, et al. A. Sclerostin, cardiovascular disease and mortality: a systematic review and meta-analysis. Int Urol Nephrol. 2016;48(12):2029-42. doi: 10.1007/s11255-016-1387-8
22. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3 (Suppl. 1). http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf
23. Cheng H-M, Chuang S-Y, Sung S-H, et al. Derivation and validation of diagnostic thresholds for central blood pressure measurements based on long-term cardiovascular risks. J Am Coll Cardiol. 2013;92(19):1780-87. doi: 10.1016/j.jacc.2013.06.029
24. Ermolenko VM, Volgina GV, Dobronravov VA, et al. National recommendations on mineral and bone disorders in chronic kidney disease. Russian Dialysis Society (May 2010). Nephrologia I Dialis. 2011;13(1):33-51.
25. Mancia G, Fagard R, et al. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159-219. doi: 10.1097/01.hjh.0000431740.32696.cc
26. Heine GH, Nangaku M, Fliser D. Calcium and phosphate impact cardiovascular risk. Eur Heart J. 2013;34:1112-21. doi: 10.1093/eurheartj/ehs353
27. Milovanova L, Milovanov Y, Plotnikova A. Phosphorus and calcium metabolism disorders associated with chronic kidney disease stage III-IV (Systematic Review and Meta-Analysis). In Sahay M, editor. Chronic Kidney Disease and Renal Transplantation. London: IntechOpen Limited; 2012; p. 95-118. doi: 10.5772/25689
28. Chertow GM, Block GA, Correa-Rotter R, et al. EVOLVE Trial Investigators: Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367:2482-94. doi: 10.1056/NEJMoa1205624
29. Block GA, Wheeler DC, Persky MS, et al Effects of Phosphate Binders in Moderate CKD. J Am Soc Nephrol. 2012;23(8):1407-15. doi: 10.1681/ASN.2012030223
30. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307(7):674-84. doi: 10.1001/jama.2012.120
31. Jimbo R, Kawakami-Mori F, Mu S, et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 2014;85(5):1103-11. doi: 10.1038/ki.2013.332
32. Zhou L, Li Y, Zhou D, et al. Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. J Am Soc Nephrol. 2013;24:771-85. doi: 10.1681/ASN.2012080865
33. Maekawa Y, Ishikawa K, Yasuda O, et al. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine. 2009;35:341-6. doi: 10.1007/s12020-009-9181-3
34. Munoz Mendoza J, Isakova T, Ricardo AC, et al. Fibroblast growth factor 23 and Inflammation in CKD. Clin J Am Soc Nephrol. 2012;7(7):1155-62. doi: 10.2215/CJN.13281211
35. NasrAllah MM, El-Shehaby AR, Osman NA, et al. The Association between Fibroblast growth factor-23 and vascular calcification is mitigated by inflammation markers. Nephron Extra. 2013;3(1):106-12.
36. Milovanova LY, Kozlovskaya LV, Milovanova SY, et al. Associations of fibroblast growth factor 23, soluble Klotho, troponin i in CKD patients. Int Res J. 2016;9(51):65-9.
37. Claes KJ, Viaene L, Heye S, et al. Sclerostin: Another vascular calcification inhibitor? J Clin Endocrinol Metab. 2013;98(8):3221-8. doi: 10.1210/jc.2013-1521
38. Register TC, Hruska KA, Divers J, et al. Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study. J Clin Endocrinol Metab. 2014;99(1):315-21. doi: 10.1210/jc.2013-3168
39. Monroe DG, McGee-Lawrence ME, Oursler MJ, et al. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012;492(1):1-18. doi: 10.1016/j.gene.2011.10.044
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1. Couser WG, Remuzzi G, Mendis S, et al. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int. 2011;80(12):1258-70. doi: 10.1038/ki.2011.368. Epub 2011 Oct 12.
2. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. doi: 10.1056/NEJMoa041031
3. Kumar S, Bogle R, Banerjee D. Why do young people with chronic kidney disease die early? World J Nephrol. 2014;3(4):143-55. doi: 10.5527/wjn.v3.i4.143
4. Garland JS, Holden RM, Groome PA, et al. Prevalence and associations of coronary artery calcification in patients with stages 3 to 5 CKD without cardiovascular disease. Am J Kidney Dis. 2008;52(5):849-58. doi: 10.1053/j.ajkd.2008.04.012. Epub 2008 Jun 17.
5. Memmos E, Sarafidis P, Pateinakis P, et al. Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol. 2019;20:217. doi: 10.1186/s12882-019
6. Lu X, Hu MC. Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. Kidney Dis. 2016;17:1-9.
7. Milovanova LY, Fomin VV, Lysenko (Kozlovskaya) LV, et al. Disorders in the system of mineral and bone metabolism regulators – FGF-23, Klotho and Sclerostin – in chronic kidney disease: clinical significance and possibilities for correction. In Rath T, editor. Chronic Kidney Disease. From Pathophysiology to Clinical Improvements. London: IntechOpen Limited; 2018; p. 43-60. doi: 10.5772/intechopen.69298
8. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79:1370-8. doi: 10.1038/ki.2011.47. Epub 2011 Mar 9
9. Milovanova L, Kozlovskaya L, Markina M, et al. Morphogenetic proteins – fibroblast growth factor-23 (FGF-23) and Klotho in serum of patients with chronic kidney disease, as the markers of cardiovascular risk. Clin Med. 2016;12:34-40.
10. Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor-23 and left ventricular hypertrophy in chronic kidney disease. Circulation. 2009;119(19):2545-52. doi: 10.1161/CIRCULATIONAHA.108.844506
11. Sharaf UA, Din El, Salem MM, Abdulazim DO. Is Fibroblast growth factor 23 the leading cause of increased mortality among chronic kidney disease patients? A narrative review. J Adv Res. 2017;8(3):271-8. doi: 10.1016/j.jare.2017.02.003
12. Donate-Correa J, Martín-Núñez E, Mora-Fernández C, et al. Klotho in cardiovascular disease: Current and future perspectives. World J Biol Chem. 2015;6(4):351-7. doi: 10.4331/wjbc.v6.i4.351
13. Milovanova LY, Mukhin NA, Kozlovskaya LV, et al. Decreased serum levels of klotho protein in chronic kidney disease patients: Clinical importance. Vestn. Ross. Akad. Meditsinskikh Nauk. 2016;71:288-96 (In Russ.). doi: 10.15690/vramn581
14. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45-51. doi: 10.1038/36285
15. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770-4. doi: 10.1038/nature05315
16. Saito Y, Yamagishi T, Nakamura T, et al. Klotho protein protects against endothelial dysfunction. Biochem Biophys Res Commun. 1998;248:324-9. doi: 10.1006/bbrc.1998.8943
17. Kusaba T, Okigaki M, Matui A, et al. Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2+ channel to maintain endothelial integrity. Proc Natl Acad Sci USA. 2010;107:19308-13. doi: 10.1073/pnas.1008544107
18. Semba RD, Cappola AR, Sun K, et al. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci. 2011;66:794-800. doi: 10.1093/gerona/glr058
19. Cejka D, Herberth J, Branscum AJ, et al. Sclerostin and Dickkopf-1 in renal osteodystrophy. Clin J Am Soc Nephrol. 2011;6:877-82. doi: 10.2215/CJN.06550810
20. Bruzzese A, Lacquaniti A, Cernaro V, et al. Sclerostin levels in uremic patients: a link between bone and vascular disease. J Renal Failure. 2016;38(5):123-9. doi: 10.3109/0886022X.2016.1160207
21. Kanbay M, Solak Y, Siriopol D, et al. A. Sclerostin, cardiovascular disease and mortality: a systematic review and meta-analysis. Int Urol Nephrol. 2016;48(12):2029-42. doi: 10.1007/s11255-016-1387-8
22. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3 (Suppl. 1). http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf
23. Cheng H-M, Chuang S-Y, Sung S-H, et al. Derivation and validation of diagnostic thresholds for central blood pressure measurements based on long-term cardiovascular risks. J Am Coll Cardiol. 2013;92(19):1780-87. doi: 10.1016/j.jacc.2013.06.029
24. Ermolenko VM, Volgina GV, Dobronravov VA, et al. National recommendations on mineral and bone disorders in chronic kidney disease. Russian Dialysis Society (May 2010). Nephrologia I Dialis. 2011;13(1):33-51.
25. Mancia G, Fagard R, et al. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159-219. doi: 10.1097/01.hjh.0000431740.32696.cc
26. Heine GH, Nangaku M, Fliser D. Calcium and phosphate impact cardiovascular risk. Eur Heart J. 2013;34:1112-21. doi: 10.1093/eurheartj/ehs353
27. Milovanova L, Milovanov Y, Plotnikova A. Phosphorus and calcium metabolism disorders associated with chronic kidney disease stage III-IV (Systematic Review and Meta-Analysis). In Sahay M, editor. Chronic Kidney Disease and Renal Transplantation. London: IntechOpen Limited; 2012; p. 95-118. doi: 10.5772/25689
28. Chertow GM, Block GA, Correa-Rotter R, et al. EVOLVE Trial Investigators: Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367:2482-94. doi: 10.1056/NEJMoa1205624
29. Block GA, Wheeler DC, Persky MS, et al Effects of Phosphate Binders in Moderate CKD. J Am Soc Nephrol. 2012;23(8):1407-15. doi: 10.1681/ASN.2012030223
30. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307(7):674-84. doi: 10.1001/jama.2012.120
31. Jimbo R, Kawakami-Mori F, Mu S, et al. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 2014;85(5):1103-11. doi: 10.1038/ki.2013.332
32. Zhou L, Li Y, Zhou D, et al. Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. J Am Soc Nephrol. 2013;24:771-85. doi: 10.1681/ASN.2012080865
33. Maekawa Y, Ishikawa K, Yasuda O, et al. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine. 2009;35:341-6. doi: 10.1007/s12020-009-9181-3
34. Munoz Mendoza J, Isakova T, Ricardo AC, et al. Fibroblast growth factor 23 and Inflammation in CKD. Clin J Am Soc Nephrol. 2012;7(7):1155-62. doi: 10.2215/CJN.13281211
35. NasrAllah MM, El-Shehaby AR, Osman NA, et al. The Association between Fibroblast growth factor-23 and vascular calcification is mitigated by inflammation markers. Nephron Extra. 2013;3(1):106-12.
36. Milovanova LY, Kozlovskaya LV, Milovanova SY, et al. Associations of fibroblast growth factor 23, soluble Klotho, troponin i in CKD patients. Int Res J. 2016;9(51):65-9.
37. Claes KJ, Viaene L, Heye S, et al. Sclerostin: Another vascular calcification inhibitor? J Clin Endocrinol Metab. 2013;98(8):3221-8. doi: 10.1210/jc.2013-1521
38. Register TC, Hruska KA, Divers J, et al. Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study. J Clin Endocrinol Metab. 2014;99(1):315-21. doi: 10.1210/jc.2013-3168
39. Monroe DG, McGee-Lawrence ME, Oursler MJ, et al. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012;492(1):1-18. doi: 10.1016/j.gene.2011.10.044
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
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L.Yu. Milovanova, L.V. Lysenko (Kozlovskaya), S.Yu. Milovanova, M.V. Taranova, V.V. Kozlov, V.A. Reshetnikov, M.V. Lebedeva, T.V. Androsova, D.O. Zubacheva, N.V. Сhebotareva
Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia