systhiperСистемные гипертензииSystemic Hypertension2075-082X2542-2189LLC «ИнтерМедсервис»systhiper-522Research ArticleСТАТЬИARTICLESИнгибиторы кальциневрина и артериальная гипертензия у реципиентов внутренних органовCalcineurin inhibitors and arterial hypertension in recipients of solid organsКосмачеваЕ. Д.KosmachevaE. D.noemail@neicon.ruМартиросянС. М.MartirosyanS. M.noemail@neicon.ruЛепшоковаМ. Х.LepshokovaM. Kh.noemail@neicon.ruБабичА. Э.BabichA. E.anna-babich1@yandex.ruФГБОУ ВО КубГМУ, ГБУЗ «НИИ-ККБ №1 им. проф. С.В.Очаповского»РоссияKuban State Medical University of the Ministry of Health of the Russian Federation; Prof. S.V.Ochapovsky Clinical Hospital №1 of the Ministry of Health of the Krasnodar RegionRussian Federation2017231220221438486Copyright © Космачева Е.Д., Мартиросян С.М., Лепшокова М.Х., Бабич А.Э., 20222022Космачева Е.Д., Мартиросян С.М., Лепшокова М.Х., Бабич А.Э.Kosmacheva E.D., Martirosyan S.M., Lepshokova M.K., Babich A.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.syst-hypertension.ru/jour/article/view/522

Артериальная гипертензия является доказанным фактором риска сердечно-сосудистых осложнений. С введением в схемы лечения ингибиторов кальциневрина артериальная гипертензия регистрируется у 50-80% реципиентов внутренних органов. Мы обобщили основные механизмы, участвующие в генезе индуцированной ингибиторами кальциневрина артериальной гипертензии: нарушение функции почек, эндотелиальная дисфункция, активация симпатической и ренин-ангиотензин-альдостероновой систем, усиление синтеза сосудосуживающих веществ, активация Na+/Cl-котранспортера. Акцентируется внимание на дозозависимости повышения артериального давления и необходимости дальнейшего изучения интенсивности прогипертензивного действия различных ингибиторов кальциневрина.

Arterial hypertension is an established risk factor for cardiovascular complications. Since the introduction of calcineurin inhibitors (CNI), аrterial hypertension is observed in 50-80% of transplanted patients. Arterial hypertension and transplantation are closely linked, and its association may promote impaired graft and overall survival. We summarize the main mechanisms involved in the genesis of CNI-induced hypertension as follows: impaired renal function with the sodium retaining, endothelial dysfunction, renin-angiotensin-aldosterone system and sympathetic activation, production of vasoconstrictor substances, activation the renal Na+/Cl--cotransporter. Attention is focused on the dose-dependent increase in arterial pressure and the need for further study of the intensity of the pro-hypertensive effect of various calcineurin inhibitors.

трансплантацияартериальная гипертензияингибиторы кальциневринаtransplantationarterial hypertensioncalcineurin inhibitorsReferencesMells G, Neuberger J. Reducing the risks of cardiovascular disease in liver allograft recipients. Transplantation 2007; 83 (9): 1141-50.Mells G, Neuberger J. Reducing the risks of cardiovascular disease in liver allograft recipients. Transplantation 2007; 83 (9): 1141-50.Готье С.В., Мойсюк Я.Г. Трансплантология: фармакотерапия без ошибок. М.: E-noto, 2014.Готье С.В., Мойсюк Я.Г. Трансплантология: фармакотерапия без ошибок. М.: E-noto, 2014.Hoorn E.J, Walsh S.B, McCormick J. et al. Pathogenesis of calcineurin inhibitor - induced hypertension. J Nephrol 2012; 25: 269-75. DOI: 10.5301/jn.5000174Hoorn E.J, Walsh S.B, McCormick J. et al. Pathogenesis of calcineurin inhibitor - induced hypertension. J Nephrol 2012; 25: 269-75. DOI: 10.5301/jn.5000174Azancot M.A, Ramos N, Moreso F.J. et al. Hypertension in chronic kidney disease: the influence of renal transplantation. Transplantation 2014; 98 (5): 537-42. DOI: 10.1097/TP.0000000000000103Azancot M.A, Ramos N, Moreso F.J. et al. Hypertension in chronic kidney disease: the influence of renal transplantation. Transplantation 2014; 98 (5): 537-42. DOI: 10.1097/TP.0000000000000103Kassel L.E, Odum L.E. Our own worst enemy: pharmacologic mechanisms of hypertension. Adv Chronic Kidney Dis 2015; 22: 245-52. DOI:10.1053/j.ackd.2014.10.002Kassel L.E, Odum L.E. Our own worst enemy: pharmacologic mechanisms of hypertension. Adv Chronic Kidney Dis 2015; 22: 245-52. DOI:10.1053/j.ackd.2014.10.002Kirilov G, Tomova A, Dakovska L. et al. Elevated plasma endothelin as an additional cardiovascular risk factor in patients with Cushing’s syndrome. Eur J Endocrinol 2003; 149 (6): 549-53. DOI: http://dx.doi.org/ 10.1530%2Feje.0.1490549Kirilov G, Tomova A, Dakovska L. et al. Elevated plasma endothelin as an additional cardiovascular risk factor in patients with Cushing’s syndrome. Eur J Endocrinol 2003; 149 (6): 549-53. DOI: http://dx.doi.org/ 10.1530%2Feje.0.1490549Taler S.J, Textor S.C, Canzanello V.J. et al. Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine. Transplantation 1996; 62 (11): 1588-92.Taler S.J, Textor S.C, Canzanello V.J. et al. Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine. Transplantation 1996; 62 (11): 1588-92.Трансплантация поджелудочной железы. Национальные клинические рекомендации. (Российское трансплантологическое общество). М., 2013. http://transpl.ru/images/cms/data/pdf/nacional_nye_klinicheskie_rekomendacii_po_transplantacii_podzheludochnoj_zhelezy.pdfТрансплантация поджелудочной железы. Национальные клинические рекомендации. (Российское трансплантологическое общество). М., 2013. http://transpl.ru/images/cms/data/pdf/nacional_nye_klinicheskie_rekomendacii_po_transplantacii_podzheludochnoj_zhelezy.pdfТрансплантация печени. Национальные клинические рекомендации. (Российское трансплантологическое общество). М., 2013.Трансплантация печени. Национальные клинические рекомендации. (Российское трансплантологическое общество). М., 2013.Трансплантация почки. Национальные клинические рекомендации. (Российское трансплантологическое общество). М., 2013.Трансплантация почки. Национальные клинические рекомендации. (Российское трансплантологическое общество). М., 2013.Textor S.C, Taler S.J, Canzanello V.J. et al. Posttransplantation hypertension related to calcineurin inhibitors. Liver Transplantation 2000; 5 (6): 521-30.Textor S.C, Taler S.J, Canzanello V.J. et al. Posttransplantation hypertension related to calcineurin inhibitors. Liver Transplantation 2000; 5 (6): 521-30.Shiba N, Chan M.C, Kwok W. et al. Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience. J Heart Lung Transplant 2004; 23 (2): 155-64.Shiba N, Chan M.C, Kwok W. et al. Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience. J Heart Lung Transplant 2004; 23 (2): 155-64.Шумаков В.И. Трансплантология. М.: Мед. информ. агентство, 2006.Шумаков В.И. Трансплантология. М.: Мед. информ. агентство, 2006.Siddharth S, Watt K.D. Long-term medical management of the liver transplant recipient: what the primary care physician needs to know. Mayo Clin Proc 2012; 87 (8): 779-90.Siddharth S, Watt K.D. Long-term medical management of the liver transplant recipient: what the primary care physician needs to know. Mayo Clin Proc 2012; 87 (8): 779-90.Bohlke M, Barcellos FC, Rocha M. et al. Predictors of hypertension following successful renal transplantation: a population-based study. Transplant Proc 2009; 41: 3743-4632.Bohlke M, Barcellos FC, Rocha M. et al. Predictors of hypertension following successful renal transplantation: a population-based study. Transplant Proc 2009; 41: 3743-4632.Hohage H, Bruckner D, Arlt M. et al. Influence of cyclosporine A and FK506 on 24 h blood pressure monitoring in kidney transplant recipients. Clin Nephrol 1996; 45 (5): 342-4.Hohage H, Bruckner D, Arlt M. et al. Influence of cyclosporine A and FK506 on 24 h blood pressure monitoring in kidney transplant recipients. Clin Nephrol 1996; 45 (5): 342-4.Nishi H, Hanafusa N, Kondo Y. et al. Clinical outcome of thrombotic microangiopathy after living-donor liver transplantation treated with plasma exchange therapy. Clin J Am Society Nephrology 2006; 4: 811-9.Nishi H, Hanafusa N, Kondo Y. et al. Clinical outcome of thrombotic microangiopathy after living-donor liver transplantation treated with plasma exchange therapy. Clin J Am Society Nephrology 2006; 4: 811-9.Gerhards U, Rudash M, Hokage U. Blood pressure controls in kidney transplant recipients: influence of immunosuppression. J A Pharmac 1999; 19 (1): 45-54.Gerhards U, Rudash M, Hokage U. Blood pressure controls in kidney transplant recipients: influence of immunosuppression. J A Pharmac 1999; 19 (1): 45-54.Snanoudj R, Kriaa F, Arzouk N. et al. Single-center experience with cyclosporine therapy for kidney transplantation: analysis of a twenty-year period in 1200 patients. Transplant Proc 2004; 36: 83-8. DOI: 10.1016/j. transproceed.2004.01.089Snanoudj R, Kriaa F, Arzouk N. et al. Single-center experience with cyclosporine therapy for kidney transplantation: analysis of a twenty-year period in 1200 patients. Transplant Proc 2004; 36: 83-8. DOI: 10.1016/j. transproceed.2004.01.089Porter G., Bennett W.M, Sheps S.G. Cyclosporine-associated hypertension. National High Blood Pressure Education Program. Arch Intern Med 1990; 150: 280-3.Porter G., Bennett W.M, Sheps S.G. Cyclosporine-associated hypertension. National High Blood Pressure Education Program. Arch Intern Med 1990; 150: 280-3.Van Buren D.H, Burke J.F, Lewis R.M. Renal function in patients receiving long-term cyclosporine therapy. J Am Soc Nephrol 1994; 4 (Suppl. 8): 17-22.Van Buren D.H, Burke J.F, Lewis R.M. Renal function in patients receiving long-term cyclosporine therapy. J Am Soc Nephrol 1994; 4 (Suppl. 8): 17-22.Vercauteren S.B, Bosmans J.L, Elseviers M.M. et al. A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases. Kidney Int 1998; 54: 536-45.Vercauteren S.B, Bosmans J.L, Elseviers M.M. et al. A meta-analysis and morphological review of cyclosporine-induced nephrotoxicity in auto-immune diseases. Kidney Int 1998; 54: 536-45.Molkentin J.D, Lu J.R, Antos C.L et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998; 93: 215-28.Molkentin J.D, Lu J.R, Antos C.L et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998; 93: 215-28.Wadei H.M, Textor S.C. Hypertension in the kidney transplant recipient. Transplant Rev (Orlando) 2010; 24: 105-20.Wadei H.M, Textor S.C. Hypertension in the kidney transplant recipient. Transplant Rev (Orlando) 2010; 24: 105-20.Hoorn E.J, Nelson J.H, McCormick J.A et al. The WNK kinase network regulating sodium, potassium, and blood pressure. J Am Soc Nephrol 2011; 4: 605-14.Hoorn E.J, Nelson J.H, McCormick J.A et al. The WNK kinase network regulating sodium, potassium, and blood pressure. J Am Soc Nephrol 2011; 4: 605-14.Luft F.C. How calcineurin inhibitors cause hypertension. Nephrol Dial Transplant 2012; 2 (27): 473-5.Luft F.C. How calcineurin inhibitors cause hypertension. Nephrol Dial Transplant 2012; 2 (27): 473-5.Hoorn E.J, Walsh S.B, McCormick J.A et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nature Medicine 2011; 10 (17): 1304-9.Hoorn E.J, Walsh S.B, McCormick J.A et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nature Medicine 2011; 10 (17): 1304-9.Melnikov S, Mayan H, Uchida S. et al. Cyclosporine metabolic side effects: association with the WNK4 system. Eur J Clin Inves 2011; 10 (41): 1113-20.Melnikov S, Mayan H, Uchida S. et al. Cyclosporine metabolic side effects: association with the WNK4 system. Eur J Clin Inves 2011; 10 (41): 1113-20.Dbouk H.A, Huang C.L, Cobb M.H. Hypertension: the missing WNKs. Am J Physiol Renal Physiol 2016; 311: 16-27.Dbouk H.A, Huang C.L, Cobb M.H. Hypertension: the missing WNKs. Am J Physiol Renal Physiol 2016; 311: 16-27.Bhavani N. Pediatric endocrine hypertension. Indian J Endocrinol Metab 2011; 15 (Supp. l4): 361-6.Bhavani N. Pediatric endocrine hypertension. Indian J Endocrinol Metab 2011; 15 (Supp. l4): 361-6.Маркель А.Л. Генетика артериальной гипертонии. Вестн. рос. академии наук. 2008; 3 (78): 235-46.]Маркель А.Л. Генетика артериальной гипертонии. Вестн. рос. академии наук. 2008; 3 (78): 235-46.]Morris S.T, McMurray J.J, Rodger R.S. et al. Endothelial dysfunction in renal transplant recipients maintained on cyclosporine. Kidney Int 2000; 3 (57): 1100-6.Morris S.T, McMurray J.J, Rodger R.S. et al. Endothelial dysfunction in renal transplant recipients maintained on cyclosporine. Kidney Int 2000; 3 (57): 1100-6.Roullet J.B, Xue H, McCarron D.A. et al. Vascular mechanisms of cyclosporin-induced hypertension in the rat. J Clin Inves 1994; 5 (93): 2244-50.Roullet J.B, Xue H, McCarron D.A. et al. Vascular mechanisms of cyclosporin-induced hypertension in the rat. J Clin Inves 1994; 5 (93): 2244-50.Richards N.T, Poston L, Hilton P.J. Cyclosporine A inhibits relaxation but does not induce vasoconstriction in human subcutaneous resistance vessels. J Hyperten 1989; 1 (7): 1-3.Richards N.T, Poston L, Hilton P.J. Cyclosporine A inhibits relaxation but does not induce vasoconstriction in human subcutaneous resistance vessels. J Hyperten 1989; 1 (7): 1-3.Cauduro R.L, Costa C, Lhulieretal F. Endothelin-1 plasma levels and hypertension in cyclosporine-treated renal transplant patients. Clin Transplant 2005; 19 (4): 470-4.Cauduro R.L, Costa C, Lhulieretal F. Endothelin-1 plasma levels and hypertension in cyclosporine-treated renal transplant patients. Clin Transplant 2005; 19 (4): 470-4.Forslund T, Hannonen P, Reitamo S. et al. Hypertension in cyclosporin A-treated patients is independent of circulating endothelin levels. J Int Med 1995; 1 (238): 71-5.Forslund T, Hannonen P, Reitamo S. et al. Hypertension in cyclosporin A-treated patients is independent of circulating endothelin levels. J Int Med 1995; 1 (238): 71-5.Karabesheh S, Verma D.R, Jain M. et al. Clinical and hemodynamic effects of renin-angiotensin system blockade in cardiac transplant recipients. Am J Cardiol 2011; 108 (12): 1836-9.Karabesheh S, Verma D.R, Jain M. et al. Clinical and hemodynamic effects of renin-angiotensin system blockade in cardiac transplant recipients. Am J Cardiol 2011; 108 (12): 1836-9.Lee D.B.N. Cyclosporine and the renin-angiotensin axis. Kidney Int 1997; 1 (52): 248-60.Lee D.B.N. Cyclosporine and the renin-angiotensin axis. Kidney Int 1997; 1 (52): 248-60.Textor S.C. Hypertension and transplantation in Hypertension Primer. Lippincott Williams and Wilkins, 2003.Textor S.C. Hypertension and transplantation in Hypertension Primer. Lippincott Williams and Wilkins, 2003.Klein I.H, Abrahams A.C, Van Ede T. Differential effects of acute and sustained cyclosporine and tacrolimus on sympathetic nerve activity. J Hypertens 2010; 28 (9): 1928-34.Klein I.H, Abrahams A.C, Van Ede T. Differential effects of acute and sustained cyclosporine and tacrolimus on sympathetic nerve activity. J Hypertens 2010; 28 (9): 1928-34.Sander M, Lyson T, Thomas G.D. et al. Sympathetic neural mechanisms of cyclosporine-induced hypertension. Am J Hypertens 1996; 9 (11): 121-38.Sander M, Lyson T, Thomas G.D. et al. Sympathetic neural mechanisms of cyclosporine-induced hypertension. Am J Hypertens 1996; 9 (11): 121-38.Victor R.G, Thomas G.D, Marban E. et al. Presynaptic modulation of cortical synaptic activity by calcineurin. Proc Nation Acad Sci USA 1995; 14 (92): 6269-73.Victor R.G, Thomas G.D, Marban E. et al. Presynaptic modulation of cortical synaptic activity by calcineurin. Proc Nation Acad Sci USA 1995; 14 (92): 6269-73.Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension 2009; 4 (54): 690-7.Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension 2009; 4 (54): 690-7.Zbroch E, Małyszko J, Mysliwiec M. Hypertension in solid organ transplant recipients. Ann Transplant 2012; 17: 100-7.Zbroch E, Małyszko J, Mysliwiec M. Hypertension in solid organ transplant recipients. Ann Transplant 2012; 17: 100-7.Schlaich M.P, Grassi G. Sympatho excitation in calcineurin inhibitor-induced hypertension: villain or innocent by stander? J Hypertens 2010; 9 (28): 1809-10.Schlaich M.P, Grassi G. Sympatho excitation in calcineurin inhibitor-induced hypertension: villain or innocent by stander? J Hypertens 2010; 9 (28): 1809-10.Государственный реестр лекарственных средств. http://grls.rosminzdrav.Государственный реестр лекарственных средств. http://grls.rosminzdrav.Robert N, Wong G.W, Wright J.M. Effect of cyclosporine on blood pressure. Cochrane Database Syst Rev 2010: Cd007893. DOI: 10. 1002/14651858.CD007893.pub2Robert N, Wong G.W, Wright J.M. Effect of cyclosporine on blood pressure. Cochrane Database Syst Rev 2010: Cd007893. DOI: 10. 1002/14651858.CD007893.pub2Loughran J.T.P, Deeg H.J, Dahlberg S et al. Incidence of hypertension after marrow transplantation among 112 patients randomized to either cyclosporine or methotrexate as graft-versus-host disease prophylaxis. Br J Haematol 1985; 59: 547-53.Loughran J.T.P, Deeg H.J, Dahlberg S et al. Incidence of hypertension after marrow transplantation among 112 patients randomized to either cyclosporine or methotrexate as graft-versus-host disease prophylaxis. Br J Haematol 1985; 59: 547-53.Grossman E, Messerli F.H. High blood pressure. A side effect of drugs, poisons, and food. Arch Intern Med 1995; 155: 450-60.Grossman E, Messerli F.H. High blood pressure. A side effect of drugs, poisons, and food. Arch Intern Med 1995; 155: 450-60.Jensik S.C. Tacrolimus (FK 506) in kidney transplantation: three-year survival results of the US Multicenter, randomized, comparative trial. Transplantation Proceedings 1998; 4 (30): 1216-8.Jensik S.C. Tacrolimus (FK 506) in kidney transplantation: three-year survival results of the US Multicenter, randomized, comparative trial. Transplantation Proceedings 1998; 4 (30): 1216-8.Bohlke M, Barcellos F.C, Rocha M.et al. Predictors of hypertension following successful renal transplantation: a population-based study. Trans Proceedings 2009; 9 (41): 3743-6.Bohlke M, Barcellos F.C, Rocha M.et al. Predictors of hypertension following successful renal transplantation: a population-based study. Trans Proceedings 2009; 9 (41): 3743-6.Mangray M, Vella J.P. Hypertension after kidney transplant. Am J Kidney Dis 2011; 2 (57): 331-41.Mangray M, Vella J.P. Hypertension after kidney transplant. Am J Kidney Dis 2011; 2 (57): 331-41.Cush J.J, Tugwell P, Weinblatt M. et al. US consensus guidelines for use of cyclosporine A in rheumatoid arthritis. J Rheumatol 1999; 26: 1176-86.Cush J.J, Tugwell P, Weinblatt M. et al. US consensus guidelines for use of cyclosporine A in rheumatoid arthritis. J Rheumatol 1999; 26: 1176-86.Ekberg H, Griny J, Nashan B. et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR study. Am J Transplant 2007; 3 (7): 560-70.Ekberg H, Griny J, Nashan B. et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: the CAESAR study. Am J Transplant 2007; 3 (7): 560-70.Pascual M, Curtis J, Delmonico F.L. et al. A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation. Transplantation 2003; 75 (9): 1501-5.Pascual M, Curtis J, Delmonico F.L. et al. A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation. Transplantation 2003; 75 (9): 1501-5.Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomized multicenter study. Lancet 2002; 359 (9308): 741-6.Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomized multicenter study. Lancet 2002; 359 (9308): 741-6.Gonwa T, Mendez R, Yang H.C. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 2003; 75 (8): 1213-20.Gonwa T, Mendez R, Yang H.C. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 2003; 75 (8): 1213-20.

The authors declare that there are no conflicts of interest present.