Значение малобелковой диеты и препаратов кетоаналогов незаменимых аминокислот в контроле над карбамилированием белков и токсическими эффектами мочевины при хронической болезни почек
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Mikhailova NA. The value of a low-protein diet and ketoanalogues of essential amino acids in the сontrol of protein carbamylation and toxic effects of urea in chronic kidney disease. Terapevticheskii Arkhiv (Ter. Arkh). 2021; 93 (6): 729–735. DOI: 10.26442/00403660.2021.06.200915
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К числу таких факторов относятся уремические токсины, для которых установлена причинно-следственная взаимосвязь с конкретными патологическими процессами у пациентов с ХБП, в том числе с формированием сосудистой дисфункции и ускоренным прогрессированием атеросклероза. Мочевина долгое время рассматривалась не в качестве уремического токсина, а как маркер метаболического дисбаланса или эффективности диализа (Kt/V) у пациентов с ХБП. В последние годы появляется все больше публикаций, посвященных изучению токсических эффектов мочевины с развитием токсико-уремических осложнений и фенотипа преждевременного старения, распространенного при ХБП. Установлено, что повышение уровней мочевины при уремическом синдроме вызывает повреждение эпителиального барьера кишечника с транслокацией бактериальных токсинов в кровоток и развитием системного воспаления, провоцирует апоптоз клеток гладкой мускулатуры сосудов, а также эндотелиальную дисфункцию, что напрямую способствует развитию сердечно-сосудистых осложнений.
Опосредованные эффекты повышенного содержания мочевины связаны с реакциями карбамилирования, когда изоциановая кислота (продукт катаболизма мочевины) изменяет структуру и функцию белков в организме. Карбамилирование белков у пациентов с ХБП связано с развитием фиброза почек, атеросклероза и анемии. Таким образом, мочевина сегодня рассматривается в качестве важного негативного агента в патогенезе осложнений при ХБП. Исследования, посвященные изучению малобелковой диеты с назначением препаратов кетоаналогов незаменимых аминокислот в целях минимизации накопления мочевины и других уремических токсинов, демонстрируют клиническую пользу такого вмешательства в плане замедления прогрессирования ХБП и развития сердечно-сосудистых осложнений.
Ключевые слова: уремические токсины, мочевина, карбамилирование белков, малобелковая диета, кетоаналоги аминокислот, хроническая болезнь почек
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Chronic kidney disease (CKD) is characterized by high mortality from cardiovascular diseases, the development of which is facilitated by traditional risk factors (typical for the general population) and by nontraditional ones (specific to patients with CKD) as well. These factors include also uremic toxins, for which a causal relationship has been established with specific pathological processes in patients with CKD, comprising the development of vascular dysfunction and accelerated progression of atherosclerosis. Urea has long been considered not as a uremic toxin, but as a marker of metabolic imbalance or dialysis efficiency (Kt/V) in CKD patients. In recent years, more and more publications have appeared on the study of the toxic effects of urea with the development of toxic-uremic complications and the phenotype of premature aging, common in CKD. It was found that an increase in urea levels in uremic syndrome causes damage to the intestinal epithelial barrier with translocation of bacterial toxins into the bloodstream and the development of systemic inflammation, provokes apoptosis of vascular smooth muscle cells, as well as endothelial dysfunction, which directly contributes to the development of cardiovascular complications. The indirect effects of increased urea levels are associated with carbamylation reactions, when isocyanic acid (a product of urea catabolism) changes the structure and function of proteins in the body. Carbamylation of proteins in CKD patients is associated with the development of renal fibrosis, atherosclerosis and anemia. Thus, urea is now regarded as an important negative agent in the pathogenesis of complications in CKD. Studies on a low-protein diet with using ketoanalogues of essential amino acids to minimize the accumulation of urea and other uremic toxins demonstrate the clinical benefit of such an intervention in slowing the progression of CKD and the development of cardiovascular complications.
Keywords: uremic toxins, urea, protein carbamylation, low protein diet, ketoanalogues of amino acids, chronic kidney disease
2. Kalantar-Zadeh K, Ikizler TA, Block G, et al. Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis. 2003;42:864-81. DOI: 10.1016/j.ajkd.2003.07.016
3. Kendrick J, Chonchol MB. Nontraditional risk factors for cardiovascular disease in patients with chronic kidney disease. Nat Clin Pract Nephrol. 2008;4:672-81. DOI: 10.1038/ncpneph0954
4. Lau WL, Ix JH. Clinical detection, risk factors, and cardiovascular consequences of medial arterial calcification:a pattern of vascular injury associated with aberrant mineral metabolism. Semin Nephrol. 2013;33:93-105. DOI: 10.1016/j.semnephrol.2012.12.011
5. Gotch FA. The current place of urea kinetic modelling with respect to different dialysis modalities. Nephrol Dial Transplant. 1998;13(Suppl. 6):10-4. DOI: 10.1093/ndt/13.suppl_6.10
6. Herter CA. On Urea in Some of its Physiological and Pathological Relations: The Johns Hopkins Hospital Reports: Contributions to the Science of Medicine, Johns Hopkins Press, 1900.
7. Johnson WJ, Hagge WW, Wagoner RD, et al. Effects of urea loading in patients with far-advanced renal failure. Mayo Clin Proc. 1972;47:21-9
8. Massy ZA, Pietrement C, Tour´e F. Reconsidering the lack of urea toxicity in dialysis patients. Semin Dial. 2016;29:333-7. DOI: 10.1111/sdi.12515
9. Wei LL, Vaziri ND. Urea, a true uremic toxin: the empire strikes back. Clin Sci (Lond). 2017;131(1):3-12. DOI:10.1042/CS20160203
10. White WE, Yaqoob MM, Harwood SM. Aging and uremia:is there cellular and molecular crossover? World J Nephrol. 2015;4:19-30. DOI: 10.5527/wjn.v4.i1.19
11. Bossola M, Sanguinetti M, Scribano D, et al. Circulating bacterial-derived DNA fragments and markers of inflammation in chronic hemodialysis patients. Clin J Am Soc Nephrol. 2009;4:379-85. DOI: 10.2215/CJN.03490708
12. Feroze U, Kalantar-Zadeh K, Sterling KA, et al. Examining associations of circulating endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients. J Ren Nutr. 2012;22:317-26. DOI: 10.1053/j.jrn.2011.05.004
13. D’Apolito M, Du X, Zong H, et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest. 2010;120:203-13. DOI: 10.1172/JCI37672
14. Tr´echerel E, Godin C, Louandre C, et al. Upregulation of BAD,
a pro-apoptotic protein of the BCL2 family, in vascularsmooth muscle cells exposed to uremic conditions. Biochem Biophys Res Commun. 2012;417:479-83. DOI:10.1016/j.bbrc.2011.11.144
15. Shroff R, McNair R, Figg N, et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation. 2008;118:1748-57.
DOI: 10.1161/CIRCULATIONAHA.108.783738
16. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109:23(Suppl. 1):III27-III32. DOI: 10.1161/01.CIR.0000131515.03336.f8
17. Annuk M, Zilmer M, Lind L, et al. Oxidative stress and endothelial function in chronic renal failure. J Am Soc Nephrol. 2001;12:2747-52. DOI: 10.1681/ASN.V12122747
18. Apostolov EO, Ray D, Savenka AV, et al. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J Am Soc Nephrol. 2010;21:1852-7. DOI:10.1681/ASN.2010040365
19. Kalim S, Karumanchi SA, Thadhani RI, Berg AH. Protein carbamylation in kidney disease:pathogenesis and clinical implications. Am J Kidney Dis. 2014;64:793-803. DOI: 10.1053/j.ajkd.2014.04.034
20. Nilsson L, Lundquist P, Kågedal B, Larsson R. Plasma cyanate concentrations in chronic renal failure. Clin Chem. 1996;42:482-3. PMID: 8598126
21. Beswick HT, Harding JJ. Conformational changes induced in bovine lens alpha-crystallin by carbamylation. Relevance to cataract. Biochem J. 1984;223:221-7. DOI: 10.1042/bj2230221
22. Park KD, Mun KC, Chang EJ, et al. Inhibition of erythropoietin activity by cyanate. Scand J Urol Nephrol. 2004;38:69-72. DOI: 10.1080/00365590310006291
23. Oimomi M, Hatanaka H, Yoshimura Y, et al. Carbamylation of insulin and its biological activity. Nephron. 1987;46:63-6. DOI: 10.1159/000184303
24. Bose C, Shah SV, Karaduta OK, Gur P. Kaushal Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury. PLoS One. 2016;11(12):e0165576. DOI:10.1371/journal.pone.0165576
25. Jaisson S, Larreta-Garde V, Bellon G, et al. Carbamylation differentially alters type I collagen sensitivity to various collagenases. Matrix Biol, 2007 26(3):p. 190–6. DOI: 10.1016/j.matbio.2006.10.008
26. Binder V, et al., Impact of fibrinogen carbamylation on fibrin clot formation and stability. Thromb Haemost. 2017;17(5):899-910. DOI:10.1016/j.matbio.2006.10.008
27. Mori D, Matsui I, Shimomura A, et al. Protein carbamylation exacerbates vascular calcification. Kidney Int. 2018;94(1):72-90. DOI:10.1016/j.kint.2018.01.033
28. Jaisson S, Kerkeni M, Santos-Weiss IC, et al. Increased serum homocitrulline concentrations are associated with the severity of coronary artery disease. Clin Chem Lab Med. 2015;53(1):103-10. DOI:10.1515/cclm-2014-0642
29. Sun JT, Yang K, Mao JY, et al. Cyanate-impaired angiogenesis: association with poor coronary collateral growth in patients with stable angina and chronic total occlusion. J Am Heart Assoc. 2016;5(12). DOI:10.1161/JAHA.116.004700
30. Drechsler C, Kalim S, Wenger JB, et al. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015;87:1201-8. DOI: 10.1038/ki.2014.429
31. Gorisse L, Pietrement C, Vuiblet V, et al. Protein carbamylation is a hallmark of aging. Proc Natl Acad Sci U.S.A. 2016;113:1191-6. DOI: 10.1073/pnas.1517096113
32. Berg AH, Drechsler C, Wenger J, et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med. 2013;5(175):175ra29. DOI:10.1126/scitranslmed.3005218
33. Koeth RA, Kalantar-Zadeh K, Wang Z, et al. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol. 2013;24(5):853-61. DOI:10.1681/ASN.2012030254
34. Pietrement C, Gorisse L, Jaisson S, Gillery P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One. 2013;8:e82506. DOI: 10.1371/journal.pone.0082506
35. Gross ML, Piecha G, Bierhaus A, et al. Glycated and carbamylated albumin are more "nephrotoxic" than unmodified albumin in the amphibian kidney. Am J Physiol Renal Physiol. 2011;301. DOI:10.1152/ajprenal.00342.2010
36. Hörkkö S, Huttunen K, Kervinen K, Kesäniemi YA. Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein. Eur J Clin Invest. 1994;24:105-13. DOI: 10.1111/j.1365-2362.1994.tb00974.x
37. Ok E, Basnakian AG, Apostolov EO, et al. Carbamylated low-density lipoprotein induces death of endothelial cells:a link to atherosclerosis in patients with kidney disease. Kidney Int. 2005;68:173-8. DOI: 10.1111/j.1523-1755.2005.00391.x
38. Apostolov EO, Shah SV, Ok E, Basnakian AG. Carbamylated low-density lipoprotein induces monocyte adhesion to endothelial cells through intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Arterioscler Thromb Vasc Biol. 2007;27:826-32.
DOI: 10.1161/01.ATV.0000258795.75121.8a
39. Kalim S, Tamez H, Wenger J, et al. Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease. Clin J Am Soc Nephrol. 2013;8:1927-34. DOI: 10.2215/CJN.04310413
40. Raj DS, Oladipo A, Lim VS. Amino acid and protein kinetics in renal failure:an integrated approach. Semin. Nephrol. 2006;26:158-66. DOI: 10.1016/j.semnephrol.2005.09.006
41. Carrero JJ, Stenvinkel P, Cuppari L, et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease:a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM). J Ren Nutr 2013;2:77-90. DOI: 10.1053/j.jrn.2013.01.001
42. Lau WL, Vaziri ND. Urea, a true uremic toxin:the empire strikes back. Clin Sci (Lond). 2017;131(1):3-12. DOI:10.1042/CS20160203
43. Ramezzani A, Raj DS. The Gut Microbiome, Kidney Disease, and Targeted Interventions. J Am Soc Nephrol. 2014;25:657-70. DOI: 10.1681/ASN.2013080905
44. Vaziri ND, Zhao YY, Pahl MV. Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment. Nephrol Dial Transplant. 2016;31:737-46. DOI: 10.1093/ndt/gfv095
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1. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol. 1998;9:S16-S23
2. Kalantar-Zadeh K, Ikizler TA, Block G, et al. Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis. 2003;42:864-81. DOI: 10.1016/j.ajkd.2003.07.016
3. Kendrick J, Chonchol MB. Nontraditional risk factors for cardiovascular disease in patients with chronic kidney disease. Nat Clin Pract Nephrol. 2008;4:672-81. DOI: 10.1038/ncpneph0954
4. Lau WL, Ix JH. Clinical detection, risk factors, and cardiovascular consequences of medial arterial calcification:a pattern of vascular injury associated with aberrant mineral metabolism. Semin Nephrol. 2013;33:93-105. DOI: 10.1016/j.semnephrol.2012.12.011
5. Gotch FA. The current place of urea kinetic modelling with respect to different dialysis modalities. Nephrol Dial Transplant. 1998;13(Suppl. 6):10-4. DOI: 10.1093/ndt/13.suppl_6.10
6. Herter CA. On Urea in Some of its Physiological and Pathological Relations: The Johns Hopkins Hospital Reports: Contributions to the Science of Medicine, Johns Hopkins Press, 1900.
7. Johnson WJ, Hagge WW, Wagoner RD, et al. Effects of urea loading in patients with far-advanced renal failure. Mayo Clin Proc. 1972;47:21-9
8. Massy ZA, Pietrement C, Tour´e F. Reconsidering the lack of urea toxicity in dialysis patients. Semin Dial. 2016;29:333-7. DOI: 10.1111/sdi.12515
9. Wei LL, Vaziri ND. Urea, a true uremic toxin: the empire strikes back. Clin Sci (Lond). 2017;131(1):3-12. DOI:10.1042/CS20160203
10. White WE, Yaqoob MM, Harwood SM. Aging and uremia:is there cellular and molecular crossover? World J Nephrol. 2015;4:19-30. DOI: 10.5527/wjn.v4.i1.19
11. Bossola M, Sanguinetti M, Scribano D, et al. Circulating bacterial-derived DNA fragments and markers of inflammation in chronic hemodialysis patients. Clin J Am Soc Nephrol. 2009;4:379-85. DOI: 10.2215/CJN.03490708
12. Feroze U, Kalantar-Zadeh K, Sterling KA, et al. Examining associations of circulating endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients. J Ren Nutr. 2012;22:317-26. DOI: 10.1053/j.jrn.2011.05.004
13. D’Apolito M, Du X, Zong H, et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest. 2010;120:203-13. DOI: 10.1172/JCI37672
14. Tr´echerel E, Godin C, Louandre C, et al. Upregulation of BAD,
a pro-apoptotic protein of the BCL2 family, in vascularsmooth muscle cells exposed to uremic conditions. Biochem Biophys Res Commun. 2012;417:479-83. DOI:10.1016/j.bbrc.2011.11.144
15. Shroff R, McNair R, Figg N, et al. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation. 2008;118:1748-57.
DOI: 10.1161/CIRCULATIONAHA.108.783738
16. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109:23(Suppl. 1):III27-III32. DOI: 10.1161/01.CIR.0000131515.03336.f8
17. Annuk M, Zilmer M, Lind L, et al. Oxidative stress and endothelial function in chronic renal failure. J Am Soc Nephrol. 2001;12:2747-52. DOI: 10.1681/ASN.V12122747
18. Apostolov EO, Ray D, Savenka AV, et al. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J Am Soc Nephrol. 2010;21:1852-7. DOI:10.1681/ASN.2010040365
19. Kalim S, Karumanchi SA, Thadhani RI, Berg AH. Protein carbamylation in kidney disease:pathogenesis and clinical implications. Am J Kidney Dis. 2014;64:793-803. DOI: 10.1053/j.ajkd.2014.04.034
20. Nilsson L, Lundquist P, Kågedal B, Larsson R. Plasma cyanate concentrations in chronic renal failure. Clin Chem. 1996;42:482-3. PMID: 8598126
21. Beswick HT, Harding JJ. Conformational changes induced in bovine lens alpha-crystallin by carbamylation. Relevance to cataract. Biochem J. 1984;223:221-7. DOI: 10.1042/bj2230221
22. Park KD, Mun KC, Chang EJ, et al. Inhibition of erythropoietin activity by cyanate. Scand J Urol Nephrol. 2004;38:69-72. DOI: 10.1080/00365590310006291
23. Oimomi M, Hatanaka H, Yoshimura Y, et al. Carbamylation of insulin and its biological activity. Nephron. 1987;46:63-6. DOI: 10.1159/000184303
24. Bose C, Shah SV, Karaduta OK, Gur P. Kaushal Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury. PLoS One. 2016;11(12):e0165576. DOI:10.1371/journal.pone.0165576
25. Jaisson S, Larreta-Garde V, Bellon G, et al. Carbamylation differentially alters type I collagen sensitivity to various collagenases. Matrix Biol, 2007 26(3):p. 190–6. DOI: 10.1016/j.matbio.2006.10.008
26. Binder V, et al., Impact of fibrinogen carbamylation on fibrin clot formation and stability. Thromb Haemost. 2017;17(5):899-910. DOI:10.1016/j.matbio.2006.10.008
27. Mori D, Matsui I, Shimomura A, et al. Protein carbamylation exacerbates vascular calcification. Kidney Int. 2018;94(1):72-90. DOI:10.1016/j.kint.2018.01.033
28. Jaisson S, Kerkeni M, Santos-Weiss IC, et al. Increased serum homocitrulline concentrations are associated with the severity of coronary artery disease. Clin Chem Lab Med. 2015;53(1):103-10. DOI:10.1515/cclm-2014-0642
29. Sun JT, Yang K, Mao JY, et al. Cyanate-impaired angiogenesis: association with poor coronary collateral growth in patients with stable angina and chronic total occlusion. J Am Heart Assoc. 2016;5(12). DOI:10.1161/JAHA.116.004700
30. Drechsler C, Kalim S, Wenger JB, et al. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015;87:1201-8. DOI: 10.1038/ki.2014.429
31. Gorisse L, Pietrement C, Vuiblet V, et al. Protein carbamylation is a hallmark of aging. Proc Natl Acad Sci U.S.A. 2016;113:1191-6. DOI: 10.1073/pnas.1517096113
32. Berg AH, Drechsler C, Wenger J, et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med. 2013;5(175):175ra29. DOI:10.1126/scitranslmed.3005218
33. Koeth RA, Kalantar-Zadeh K, Wang Z, et al. Protein carbamylation predicts mortality in ESRD. J Am Soc Nephrol. 2013;24(5):853-61. DOI:10.1681/ASN.2012030254
34. Pietrement C, Gorisse L, Jaisson S, Gillery P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One. 2013;8:e82506. DOI: 10.1371/journal.pone.0082506
35. Gross ML, Piecha G, Bierhaus A, et al. Glycated and carbamylated albumin are more "nephrotoxic" than unmodified albumin in the amphibian kidney. Am J Physiol Renal Physiol. 2011;301. DOI:10.1152/ajprenal.00342.2010
36. Hörkkö S, Huttunen K, Kervinen K, Kesäniemi YA. Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein. Eur J Clin Invest. 1994;24:105-13. DOI: 10.1111/j.1365-2362.1994.tb00974.x
37. Ok E, Basnakian AG, Apostolov EO, et al. Carbamylated low-density lipoprotein induces death of endothelial cells:a link to atherosclerosis in patients with kidney disease. Kidney Int. 2005;68:173-8. DOI: 10.1111/j.1523-1755.2005.00391.x
38. Apostolov EO, Shah SV, Ok E, Basnakian AG. Carbamylated low-density lipoprotein induces monocyte adhesion to endothelial cells through intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Arterioscler Thromb Vasc Biol. 2007;27:826-32.
DOI: 10.1161/01.ATV.0000258795.75121.8a
39. Kalim S, Tamez H, Wenger J, et al. Carbamylation of serum albumin and erythropoietin resistance in end stage kidney disease. Clin J Am Soc Nephrol. 2013;8:1927-34. DOI: 10.2215/CJN.04310413
40. Raj DS, Oladipo A, Lim VS. Amino acid and protein kinetics in renal failure:an integrated approach. Semin. Nephrol. 2006;26:158-66. DOI: 10.1016/j.semnephrol.2005.09.006
41. Carrero JJ, Stenvinkel P, Cuppari L, et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease:a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM). J Ren Nutr 2013;2:77-90. DOI: 10.1053/j.jrn.2013.01.001
42. Lau WL, Vaziri ND. Urea, a true uremic toxin:the empire strikes back. Clin Sci (Lond). 2017;131(1):3-12. DOI:10.1042/CS20160203
43. Ramezzani A, Raj DS. The Gut Microbiome, Kidney Disease, and Targeted Interventions. J Am Soc Nephrol. 2014;25:657-70. DOI: 10.1681/ASN.2013080905
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ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*natmikhailova@mail.ru
________________________________________________
Nataliia A. Mikhailova*
Russian Medical Academy of Continuous Professional Education, Moscow, Russia
*natmikhailova@mail.ru