Вторичный метаболический синдром – распространенная патология и фактор неблагоприятного прогноза


DOI: https://dx.doi.org/10.18565/nephrology.2019.3.47-53

А.Ю. Николаев, Н.Н. Филатова

ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ; Москва, Россия
В представленном обзоре анализируются распространенность, особенности клиники и прогноза вторичного метаболического синдрома, включая ятрогенные формы. Вторичный метаболический синдром – частое осложнение при хронической алкогольной интоксикации, инфекции вирусом гепатита С, применении пероральных гормональных контрацептивов, при лечении глюкокортикостероидами, антиретровирусными препаратами, регулярным гемодиализом, постоянным перитонеальным диализом, трансплантацией.
Ключевые слова: метаболический синдром, гепатит С, хроническая алкогольная интоксикация, пероральные контрацептивы, глюкокортикостероиды, антиретровирусные средства, регулярный гемодиализ, постоянный перитонеальный диализ, трансплантация

Литература


  1. Lakka H.M., Laaksonen D.E., Lakka T.A., Niskanen L.K., Kumpusalo E., Tuomilehto J., Salonen J.T. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288(21):2709–2716. Doi: 10.1001/jama.288.21.2709.
  2. Ожирение. Этиология, патогенез, клинические аспекты. Руководство для врачей. Под ред. И.И. Дедова, Г.А. Мельниченко. М., 2004. 350 с.
  3. Labarrere C.A., Zaloga G.P. C-reactive protein: from innocent bystander to pivotal mediator of atherosclerosis. Am. J. Med. 2004;117(7):499–507. Doi: https://doi.org/10.1016/j.amjmed.2004.03.039
  4. Ordovas J.M., Corella D. Metabolic syndrome pathophysiology: the role of adipose tissue. Kidney Int Suppl. 2008;111:10–14. Doi:10.1038/ki.2008.517.
  5. Ninomiya J.K., L’Italien G., Criqui M.H., Whyte J.L., Gamst A., Chen R.S. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109(1):42–46. Doi:10.1161/01.CIR.0000108926.04022.0C.
  6. Леванковская Е.И., Швецов М.И., Зилов А.В., Шилов Е.М. Инсулинорезистентность как ранний предиктор неблагоприятного течения хронической болезни почек недиабетической этиологии (обзор литературы). Нефрология и диализ. 2010;2:74–81.
  7. Shintani Y., Fujie H., Miyoshi H., Tsutsumi T., Tsukamoto K., Kimura S., Moriya K., Koike K. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterol. 2004;126(3):840–848. Doi: https://doi.org/10.1053/j.gastro.2003.11.056.
  8. Harrison S.A. Correlation between insulin resistance and hepatitis C viral load. Hepatology. 2006;43(5):1168–1169. Doi:10.1002/hep.21125.
  9. Knobler H.Y., Schattner A. TNF-α, chronic hepatitis C and diabetes: a novel triad. QJM. 2005;98(1):1–6. Doi: 10.1093/qjmed/hci001.
  10. Petit J.M., Minello A., Jooste V., Bour J.B., Galland F., Duvillard L., Verges B.,Olsson N.O., Gambert P., Hillon P. Decreased plasma adiponectin concentrations are closely related to steatosis in hepatitis C virus-infected patients. J. Clin. Endocrinol. Metab. 2005;90(4):2240–2243. Doi: 10.1210/jc.2004-1266.
  11. Hickman I.J., Powell E.E., Prins J.B., Clouston A.D., Ash S., Purdie D.M.,Jonsson J.R. In overweight patients with chronic hepatitis C, circulating insulin is associated with hepatic fibrosis: implications for therapy. J. Hepatol. 2003;39(6):1042–1048. Doi: https://doi.org/10.1016/S0168-8278(03)00463-X.
  12. Sanyal A.J., Chand N., Comar K., Mirshahi F. Hyperinsulinemia blocks the inhibition of hepatitis C virus replication by interferon: the potential mechanism for failure of interferon therapy in subjects with HCV and nonalcoholic fatty liver disease. Hepatol. 2004;40:39A.
  13. Walsh M.J., Jonsson J.R., Richardson M.M., Lipka G.M., Purdie D.M., Clouston A.D., Powell E.E. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55(4):529–535. Doi: 10.1136/gut.2005.069674.
  14. Kalantar-Zadeh K., Kilpatrick R.D., McAllister C.J., Miller L.G., Daar E.S., Gjertson D.W., Kopple J.D., Greenland S. Hepatitis C virus and death risk in hemodialysis patients. J. Am. Soc. Nephrol. 2007;18(5):1584–1593. Doi: 10.1681/ASN.2006070736.
  15. Corrao G., Bagnardi V., Zambon A., Arico S. Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction. 1999;94(10):1551–1573. Doi: https://doi.org/10.1046/j.1360-0443.1999.9410155111.x.
  16. Николаев А.Ю. Сахарный диабет при алкогольной болезни. В книге: Алкогольная болезнь. Поражение внутренних органов. Под ред. В.С. Моисеева. М., 2014. С. 396–411.
  17. Piano M.R. Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest. 2002;121(5):1638–1650. Doi: 10.1378/chest.121.5.1638.
  18. Моисеев В.С., Шелепин А.А. Алкоголь и болезни сердца. Руководство. Библиотека врача-специалиста. М., 2009. 168 с.
  19. Grove J., Daly A.K., Bassendine M.F., Day C.P. Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis. Hepatology. 1997;26(1):143–146. Doi:10.1002/hep.510260119.
  20. Гармаш И.В., Моисеев В.С. Алкогольная болезнь печени. В книге: Алкогольная болезнь. Поражение внутренних органов. Под ред. В.С. Моисеева. М.,2014. С. 64–117.
  21. Mookerjee R.P., Malaki M., Davies N.A., Hodges S.J., Dalton R.N., Turner C.,Sen S., Williams R., Leiper J., Vallance P., Jalan R. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatol. 2007;45(1):62–71. Doi: 10.1002/hep.21491.
  22. Танащук Е.Л. Особенности течения смешанного (вирусного и алкогольного) варианта поражения печени. Гепатологический форум. Приложение к журн. Клиническая фармакология и терапия. 2005;4:24–27.
  23. Buttgereit F., da Silva J.A., Boers M., Burmester G.R., Cutolo M., Jacobs  J., Kirwan J., Köhler L., Van Riel P., Vischer T., Bijlsma J.W. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann. Rheum. Dis. 2002;61(8):718–722. Doi: 10.1136/ard.61.8.718.
  24. Terzolo M., Pia A., Reimondo G. Subclinical Cushing’s syndrome: definition and management. Clin. Endocrinol. (Oxf). 2012;76(1):12–18. Doi:10.1111/j.1365-2265.2011.04253.x.
  25. De Leo M., Pivonello R., Auriemma R.S., Cozzolino A., Vitale P., Simeoli C., De Martino M.C., Lombardi G., Colao A. Cardiovascular disease in Cushing’s syndrome: heart versus vasculature. Neuroendocrinology. 2010;92(Suppl. 1):50–54. Doi: 10.1159/000318566.
  26. Graversen D., Vestergaard P., Stochholm K., Gravholt C.H., Jørgensen J.O. Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur. J. Intern. Med. 2012;23(3):278–282. Doi: 10.1016/j.ejim.2011.10.013.
  27. Van Everdingen A.A., Jacobs J.W., Siewertsz Van Reesema D.R., Bijlsma J.W. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann. Intern. Med. 2002;136(1):1–12. Doi: 10.7326/0003-4819-136-1-200201010-00006.
  28. Остеопороз. Диагностика, профилактика, лечение. Клинические рекомендации. Под ред. О.М. Лесняк, Л.И. Беневоленской. 2-е издание. М., 2010. 272 с.
  29. Nikkel L.E., Mohan S., Zhang A., McMahon D.J., Boutroy S., Dube G., Tanriover B., Cohen D., Ratner L., Hollenbeak C.S., Leonard M.B., Shane E., Nickolas T.L. Reduced fracture risk with early corticosteroid withdrawal after kidney transplant. Am. J. Transplant. 2012;12(3):649–659. Doi: 10.1111/j.1600-6143.2011.03872.x.
  30. Lake J.E., Currier J.S. Metabolic disease in HIV infection. Lancet. Infect. Dis. 2013;13(11):964–975. Doi: 10.1016/S1473-3099(13)70271-8.
  31. Holmberg S.D., Moorman A.C., Williamson J.M., Tong T.C., Ward D.J., Wood K.C., Greenberg A.E., Janssen R.S. HIV Outpatient Study (HOPS) investigators. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet. 2002;360(9347):1747–1748. Doi: 10.1016/S0140-6736(02)11672-2.
  32. Carr A., Samaras K., Thorisdottir A., Kaufmann G.R., Chisholm D.J., Cooper D.A. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;353(9170):2093–2099. Doi: 10.1016/S0140-6736(98)08468-2.
  33. Nakanishi R., Post W.S., Osawa K., Jayawardena E., Kim M., Sheidaee N., Nezarat N., Rahmani S., Kim N., Hathiramani N., Susarla S., Palella F., Witt M., Blaha M.J., Brown T.T., Kingsley L., Haberlen S.A., Dailing C., Budoff M.J. Multicenter AIDS Cohort Study Quantitative Coronary Plaque Progression Study: rationale and design. Coron. Artery Dis. 2018;29(1):23–29. Doi: 10.1097/MCA.0000000000000546.
  34. Desvarieux M., Boccara F., Meynard J.L., Bastard J.P., Mallat Z., Charbit  B., Demmer R.T., Haddour N., Fellahi S., Tedgui A., Cohen A., Capeau J., Boyd A., Girard P.M. Infection duration and inflammatory imbalance are associated with atherosclerotic risk in HIV-infected never-smokers independent of antiretroviral therapy. AIDS. 2013;27(16):2603–2614. Doi: 10.1097/QAD.0b013e3283634819.
  35. Wyatt C.M., Hoover D.R., Shi Q., Seaberg E., Wei C., Tien P.C., Karim R., Lazar J., Young M.A., Cohen M.H., Klotman P.E, Anastos K. Microalbuminuria is associated with all-cause and AIDS mortality in women with HIV infection. J. Acquir. Immune Defic. Syndr. 2010;55(1):73–77. Doi: 10.1097/QAI.0b013e3181cc1070.
  36. Campbell L.J., Desai M., Hegazi A., Ibrahim F., Melikian N., Hay P., Fox J.M.,Post F.A. Renal impairment is associated with coronary heart disease in HIV-positive men. HIV. Clin. Trials. 2012;13(6):343–349. Doi: 10.1310/hct1306-343.
  37. Gazzaruso C., Bruno R., Garzaniti A., Giordanetti S., Fratino P., Sacchi P., Filice G. Hypertension among HIV patients: prevalence and relationships to insulin resistance and metabolic syndrome. J. Hypertens. 2003;21(7):1377–1382. Doi: 10.1097/01.hjh.0000059071.43904.dc.
  38. De Socio G.V., Ricci E., Maggi P., Parruti G., Pucci G., Di Biagio A., Calza L.,Orofino G., Carenzi L., Cecchini E., Madeddu G., Quirino T., Schillaci G.; CISAI Study Group. Prevalence, awareness, treatment, and control rate of hypertension in HIV-infected patients: the HIV-HY study. Am. J. Hypertens. 2014;27(2):222–228. Doi: 10.1093/ajh/hpt182.
  39. Jung O., Bickel M., Ditting T., Rickerts V., Welk T., Helm E.B., Staszewski S., Geiger H. Hypertension in HIV-1-infected patients and its impact on renal and cardiovascular integrity. Nephrol. Dial. Transplant. 2004;19(9):2250–2258. Doi: 10.1093/ndt/gfh393.
  40. Jick H., Jick S.S., Gurewich V., Myers M.W., Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet. 1995; 46(8990):1589–1593. Doi: 10.1016/s0140-6736(95)91928-7.
  41. Hannaford P.C., Iversen L., Macfarlane T.V., Elliott A.M., Angus V., Lee A.J. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study. BMJ. 2010;340:927. Doi: 10.1136/bmj.c927.
  42. Burkman R., Bell C., Serfaty D. The evolution of combined oral contraception: improving the risk-to-benefit ratio. Contraception. 2011;84(1):19–34. Doi: 10.1016/j.contraception.2010.11.004.
  43. Cagnacci A., Ferrari S., Tirelli A., Zanin R., Volpe A. Insulin sensitivity and lipid metabolism with oral contraceptives containing chlormadinone acetate or desogestrel: a randomized trial. Contraception. 2009;79(2):111–116. Doi: 10.1016/j.contraception.2008.09.002.
  44. Tepper N.K., Curtis K.M., Steenland M.W., Marchbanks P.A. Blood pressure measurement prior to initiating hormonal contraception: a systematic review. Contraception. 2013;87(5):631–638. Doi: 10.1016/j.contraception.2012.08.025.
  45. Lidegaard Ø., Nielsen L.H., Skovlund C.W., Skjeldestad F.E., Løkkegaard E.Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011(25);343. Doi: https://doi.org/10.1136/bmj.d6423.
  46. Cataland S.R., Wu H.M. Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: clinically differentiating the thrombotic microangiopathies. Eur. J. Intern. Med. 2013;24(6):486–491. Doi: 10.1016/j.ejim.2013.05.007.
  47. Shinohara K., Shoji T., Emoto M., Tahara H., Koyama H., Ishimura E., Miki T., Tabata T., Nishizawa Y. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J. Am. Soc. Nephrol. 2002;13(7):1894–1900. Doi: https://doi.org/10.1097/01.ASN.0000019900.87535.43.
  48. Jacobs C., Frei D., Perkins A.C. Results of the European survey on anaemia management 2003 (ESAM 2003): current status of anaemia management in dialysis patients, factors affecting epoetin dosage and changes in anaemia management over the last 5 years. Nephrol. Dial. Transplant. 2005;20 (Suppl. 3):iii3-iii24. Doi: 10.1093/ndt/gfh1074.
  49. Ahmadi F., Damghani S., Lessan-Pezeshki M., Razeghi E., Maziar S., Mahdavi-Mazdeh M. Association of low vitamin D levels with metabolic syndrome in hemodialysis patients. Hemodial. Int. 2016;20(2):261–269. Doi: 10.1111/hdi.12316.
  50. Descamps-Latscha B., Herbelin A., Nguyen A.T., Roux-Lombard P., Zingraff J.,Moynot A., Verger C., Dahmane D., de Groote D., Jungers P., et al. Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes. J. Immunol. 1995;154(2):882–892.
  51. Kovesdy C.P. Malnutrition in dialysis patients – the need for intervention despite uncertain benefits. Semin. Dial. 2016;29(1):28–34. Doi:10.1111/sdi.12410.
  52. Siew E.D., Ikizler T.A. Determinants of insulin resistance and its effects on protein metabolism in patients with advanced chronic kidney disease. Contrib. Nephrol. 2008;161:138–144. Doi: 10.1159/000130659.
  53. Gama-Axelsson T., Heimbürger O., Stenvinkel P., Bárány P., Lindholm B., Qureshi A.R. Serum albumin as predictor of nutritional status in patients with ESRD. Clin. J. Am. Soc. Nephrol. 2012;7(9):1446–1453. Doi:10.2215/CJN.10251011.
  54. Kalantar-Zadeh K., Streja E., Kovesdy C.P., Oreopoulos A., Noori N.,Jing J., Nissenson A.R., Krishnan M., Kopple J.D., Mehrotra R., Anker S.D.The obesity paradox and mortality associated with surrogates of body size and muscle mass in patients receiving hemodialysis. Mayo Clin. Proc. 2010;85(11):991–1001. Doi:10.4065/mcp.2010.0336.
  55. Stenvinkel P., Ketteler M., Johnson R.J., Lindholm B., Pecoits-Filho R., Riella  M., Heimbürger O., Cederholm T., Girndt M. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia – the good, the bad, and the ugly. Kidney Int. 2005;67(4):1216–1233. Doi:https://doi.org/10.1111/j.1523-1755.2005.00200.x.
  56. Szeto C.C., Kwan B.C., Chow K.M., Leung C.B., Cheng M.S., Law M.C., Li P.K.Metabolic syndrome in peritoneal dialysis patients: choice of diagnostic criteria and prognostic implications. Clin. J. Am. Soc. Nephrol. 2014;9(4):779–787. Doi:10.2215/CJN.06620613.
  57. Heaf J.G., Wehberg S. Relative survival of peritoneal dialysis and haemodialysis patients: effect of cohort and mode of dialysis initiation. PLoS One. 2014;9(3):e90119. Doi:10.1371/journal.pone.0090119.
  58. Kim Y.K., Kim S.H., Kim H.W., Kim Y.O., Jin D.C., Song H.C., Choi E.J., Kim Y.L., Kim Y.S., Kang S.W., Kim N.H., Yang C.W. The association between body mass index and mortality on peritoneal dialysis: a prospective cohort study. Perit. Dial. Int. 2014;34(4):383–389. Doi:10.3747/pdi.2013.00008.
  59. Hassan K., Hassan F., Edgem R., Moshe S., Hassan S. The impact of the peritoneal glucose load index on hydration status and inflammation in peritoneal dialysis patients. J. Int. Med. Res. 2015;43(1):42–53. Doi: 10.1177/0300060514550013.
  60. Smyth A., McCann E., Redahan L., Lambert B., Mellotte G.J., Wall C.A. Peritoneal dialysis in an ageing population: a 10-year experience. Int. Urol. Nephrol. 2012;44(1):283–293. Doi: 10.1007/s11255-011-9973-2.
  61. Lambie M., Chess J., Donovan K.L., Kim Y.L., Do J.Y., Lee H.B., Noh H., Williams P.F., Williams A.J., Davison S., Dorval M., Summers A., Williams J.D.,Bankart J., Davies S.J., Topley N; Global Fluid Study Investigators. Independent effects of systemic and peritoneal inflammation on peritoneal dialysis survival. J. Am. Soc. Nephrol. 2013;24(12):2071–2080. Doi:10.1681/ASN.2013030314.
  62. Mizuno M., Ito Y., Tanaka A., Suzuki Y., Hiramatsu H., Watanabe M., Tsuruta Y., Matsuoka T., Ito I., Tamai H., Kasuga H., Shimizu H., Kurata  H., Inaguma D., Hiramatsu T., Horie M., Naruse T., Maruyama S., Imai E., Yuzawa Y., Matsuo S. Peritonitis is still an important factor for withdrawal from peritoneal dialysis therapy in the Tokai area of Japan. Clin. Exp. Nephrol. 2011;15(5):727–737. Doi:10.1007/s10157-011-0471-8.
  63. Мойсюк Я.Г., Столяревич Е.С., Томилина Н.А. Болезнь почечного трансплантата. В книге: Нефрология. Национальное руководство.Под ред. Н.А. Мухина. М., 2009. С. 629–682.
  64. KDIGO clinical practice guideline for the care of kidney transplant recipients. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. Am. J. Transplant. 2009;9(3):1–155. Doi: 10.1111/j.1600-6143.2009.02834.x.
  65. Khalili M., Lim J.W., Bass N., Ascher N.L., Roberts J.P., Terrault N.A. New onset diabetes mellitus after liver transplantation: The critical role of hepatitis C infection. Liver Transpl. 2004;10(3):349–355. Doi: 10.1002/lt.20092.
  66. Иммуносупрессия при трансплантации солидных органов. Под ред. С.В. Готье. М., 2011. 470 c.
  67. Yarlagadda S.G., Coca S.G., Formica R.N. Jr., Poggio E.D., Parikh C.R. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol. Dial. Transplant. 2009;24(3):1039–1047. Doi:10.1093/ndt/gfn667.
  68. Naylor K.L., Li A.H., Lam N.N., Hodsman A.B., Jamal S.A., Garg A.X. Fracture risk in kidney transplant recipients: a systematic review. Transplant. 2013;95(12):1461–1470. Doi: 10.1097/TP.0b013e31828eead8.
  69. Saito M., Ueshima K., Fujioka M., Ishida M., Goto T., Arai Y., Ikoma K., Fujiwara H., Fukushima W., Kubo T. Corticosteroid administration within 2 weeks after renal transplantation affects the incidence of femoral head osteonecrosis. Acta Orthop. 2014;85(3):266–270. Doi: 10.3109/17453674.2014.916490.
  70. Jurewicz W.A. Tacrolimus versus cyclosporin immunosuppression: long-term outcome in renal transplantation. Nephrol. Dial. Transplant. 2003;18(Suppl. 1):7–11. Doi:10.1093/ndt/gfg1028.
  71. Ekberg H., Tedesco-Silva H., Demirbas A., Vítko S., Nashan B., Gürkan A., Margreiter R., Hugo C., Grinyó J.M., Frei U., Vanrenterghem Y., Daloze P., Halloran P.F. ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N. Engl. J. Med. 2007;357(25):2562–2575. Doi: 10.1056/NEJMoa067411.
  72. Pedroso S., Martins L., Fonseca I., Dias L., Henriques A.C., Sarmento A.M., Cabrita A. Impact of hepatitis C virus on renal transplantation: association with poor survival. Transplant. Proc. 2006;38(6):1890–1894. Doi:10.1016/j.transproceed.2006.06.065.
  73. Cosio F.G., Sedmak D.D., Henry M.L., Al Haddad C., Falkenhain M.E., Elkhammas E.A., Davies E.A., Bumgardner G.L., Ferguson R.M. The high prevalence of severe early posttransplant renal allograft pathology in hepatitis C positive recipients. Transplant. 1996;62(8):1054–1059.
  74. Cruzado J.M., Carrera M., Torras J., Grinyó J.M. Hepatitis C virus infection and de novo glomerular lesions in renal allografts. Am. J. Transplant. 2001;1(2):171–178. Doi:https://doi.org/10.1034/j.1600-6143.2001.10212.x.


Об авторах / Для корреспонденции


Николаев Алексей Юрьевич – д.м.н., профессор кафедры нефрологии и гемодиализа ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ; Россия, Москва. Е-mail: nickolaev.aleksei2011@yandex.ru
Филатова Наталья Николаевна – к.м.н, доцент кафедры нефрологии и гемодиализа ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» МЗ РФ; Россия, Москва. Е-mail: natalia.n.filatova@gmail.com


Бионика Медиа