Неконтролируемая артериальная гипертензия: почка, нейрогормональный дисбаланс и подходы к антигипертензивной лекарственной терапии

Резистентная и рефрактерная артериальная гипертензии (АГ) представляют собой два разных клинических фенотипа неконтролируемой АГ, которые отличаются по чувствительности к антигипертензивной лекарственной терапии. В обзоре представлены данные, полученные в клинических исследованиях, посвященных выяснению участия нарушения нейрогормонального статуса и функции почек в формировании резистентной и рефрактерной АГ, и новые подходы к повышению эффективности антигипертензивной терапии (АГТ) в этих популяциях пациентов. Результаты этих исследований показывают, что у больных с неконтролируемой АГ, несмотря на длительный прием ≥3 антигипертензивных препаратов с разными механизмами действия, включая диуретик, сохраняется избыточная реабсорбция натрия в дистальных сегментах нефрона, причиной которой являются повышенная активность альдостерона и гиперактивность симпатической части вегетативной нервной системы. В связи с этим в обзоре особое внимание уделено данным, полученным в исследованиях PATHWAY-2, PATHWAY-3 и ReHOT при изучении у пациентов с резистентной АГ клинической эффективности спиронолактона, амилорида и антиадренергических препаратов бисопролола, доксазозина и клонидина, подавляющих активность симпатической части вегетативной нервной системы.

1. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269–324. DOI: 10.1161/HYP.0000000000000066

2. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. European Heart Journal. 2018;39(33):3021–104. DOI: 10.1093/eurheartj/ehy339

3. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. 2018;72(5):e53–90. DOI: 10.1161/HYP.0000000000000084

4. Кузьмин О.Б., Жежа В.В., Ландарь Л.Н., Салова О.А. Резистентная артериальная гипертония у пациентов с хронической болезнью почек: распространенность, прогностическое значение, причины и подходы к антигипертензивной терапии. Нефрология. 2019;23(1):37–44. DOI: 10.24884/1561-6274-2019-23-1-37-44

5. Sim JJ, Bhandari SK, Shi J, Liu ILA, Calhoun DA, McGlynn EA et al. Characteristics of Resistant Hypertension in a Large, Ethnically Diverse Hypertension Population of an Integrated Health System. Mayo Clinic Proceedings. 2013;88(10):1099–107. DOI: 10.1016/j.mayocp.2013.06.017

6. Calhoun DA, Booth JN, Oparil S, Irvin MR, Shimbo D, Lackland DT et al. Refractory Hypertension: Determination of Prevalence, Risk Factors, and Comorbidities in a Large, Population-Based Cohort. Hypertension. 2014;63(3):451–8. DOI: 10.1161/HYPERTENSIONAHA.113.02026

7. Armario P, Calhoun DA, Oliveras A, Blanch P, Vinyoles E, Banegas JR et al. Prevalence and Clinical Characteristics of Refractory Hypertension. Journal of the American Heart Association. 2017;6(12):e007365. DOI: 10.1161/JAHA.117.007365

8. Tsioufis C, Kasiakogias A, Kordalis A, Dimitriadis K, Thomopoulos C, Tsiachris D et al. Dynamic resistant hypertension patterns as predictors of cardiovascular morbidity: a 4-year prospective study. Journal of Hypertension. 2014;32(2):415–22. DOI: 10.1097/HJH.0000000000000023

9. Kasiakogias A, Tsioufis C, Dimitriadis K, Konstantinidis D, Koumelli A, Leontsinis I et al. Cardiovascular morbidity of severe resistant hypertension among treated uncontrolled hypertensives: a 4-year follow-up study. Journal of Human Hypertension. 2018;32(7):487–93. DOI: 10.1038/s41371-018-0065-y

10. Tanner RM, Calhoun DA, Bell EK, Bowling CB, Gutiérrez OM, Irvin MR et al. Incident ESRD and Treatment-Resistant Hypertension: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. American Journal of Kidney Diseases. 2014;63(5):781–8. DOI: 10.1053/j.ajkd.2013.11.016

11. Weinberger MH. Salt Sensitivity of Blood Pressure in Humans. Hypertension. 1996;27(3):481–90. DOI: 10.1161/01.HYP.27.3.481

12. Guyton AC. Renal function curves and control of body fluids and arterial pressure. Acta Physiologica Scandinavica. Supplementum. 1990;591:107–13. PMID: 2220403

13. Ivy JR, Bailey MA. Pressure natriuresis and the renal control of arterial blood pressure: Hypertension and the kidney. The Journal of Physiology. 2014;592(18):3955–67. DOI: 10.1113/jphysiol.2014.271676

14. Hall JE. Renal Dysfunction, Rather Than Nonrenal Vascular Dysfunction, Mediates Salt-Induced Hypertension. Circulation. 2016;133(9):894–906. DOI: 10.1161/CIRCUL ATIO - NAHA.115.018526

15. Кузьмин О.Б., Пугаева М.О., Бучнева Н.В. Почечные механизмы нефрогенной артериальной гипертонии. Нефрология. 2008;12(2):39-46

16. Graham LA, Dominiczak AF, Ferreri NR. Role of renal transporters and novel regulatory interactions in the TAL that control blood pressure. Physiological Genomics. 2017;49(5):261–76. DOI: 10.1152/physiolgenomics.00017.2017

17. Pavlov TS, Staruschenko A. Involvement of ENaC in the development of salt-sensitive hypertension. American Journal of PhysiologyRenal Physiology. 2017;313(2):F135–40. DOI: 10.1152/ajprenal.00427.2016

18. Gaddam KK. Characterization of Resistant Hypertension Association Between Resistant Hypertension, Aldosterone, and Persistent Intravascular Volume Expansion. Archives of Internal Medicine. 2008;168(11):1159–64. DOI: 10.1001/archinte.168.11.1159

19. Judd EK, Calhoun DA, Warnock DG. Pathophysiology and Treatment of Resistant Hypertension: The Role of Aldosterone and Amiloride-Sensitive Sodium Channels. Seminars in Nephrology. 2014;34(5):532–9. DOI: 10.1016/j.semnephrol.2014.08.007

20. Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. The Lancet Diabetes & Endocrinology. 2018;6(6):464–75. DOI: 10.1016/S2213-8587(18)30071-8

21. Calhoun DA. Fluid retention, aldosterone excess, and treatment of resistant hypertension. The Lancet Diabetes & Endocrinology. 2018;6(6):431–3. DOI: 10.1016/S2213-8587(18)30080-9

22. Grassi G, Ram VS. Evidence for a critical role of the sympathetic nervous system in hypertension. Journal of the American Society of Hypertension. 2016;10(5):457–66. DOI: 10.1016/j.jash.2016.02.015

23. Grassi G, Bombelli M, Buzzi S, Volpe M, Brambilla G. Neuroadrenergic disarray in pseudo-resistant and resistant hypertension. Hypertension Research. 2014;37(6):479–83. DOI: 10.1038/hr.2014.25

24. Eikelis N, Marques FZ, Hering D, Marusic P, Head GA, Walton AS et al. A polymorphism in the noradrenaline transporter gene is associated with increased blood pressure in patients with resistant hypertension: Journal of Hypertension. 2018;36(7):1571–7. DOI: 10.1097/HJH.0000000000001736

25. Oki K, Gomez-Sanchez EP, Gomez-Sanchez CE. Role of mineralocorticoid action in the brain in salt-sensitive hypertension: Brain mineralocorticoids in hypertension. Clinical and Experimental Pharmacology and Physiology. 2012;39(1):90–5. DOI: 10.1111/j.1440-1681.2011.05538.x

26. Wray DW, Supiano MA. Impact of Aldosterone Receptor Blockade Compared With Thiazide Therapy on Sympathetic Nervous System Function in Geriatric Hypertension. Hypertension. 2010;55(5):1217–23. DOI: 10.1161/HYPERTENSIONAHA.109.147058

27. Menon DV, Arbique D, Wang Z, Adams-Huet B, Auchus RJ, Vongpatanasin W. Differential Effects of Chlorthalidone Versus Spironolactone on Muscle Sympathetic Nerve Activity in Hypertensive Patients. The Journal of Clinical Endocrinology & Metabolism. 2009;94(4):1361–6. DOI: 10.1210/jc.2008-2660

28. Raheja P, Price A, Wang Z, Arbique D, Adams-Huet B, Auchus RJ et al. Spironolactone Prevents Chlorthalidone-Induced Sympathetic Activation and Insulin Resistance in Hypertensive Patients. Hypertension. 2012;60(2):319–25. DOI: 10.1161/HYPERTENSIONAHA.112.194787

29. Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, KawakamiMori F et al. Epigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension. Nature Medicine. 2011;17(5):573–80. DOI: 10.1038/nm.2337

30. Walsh KR, Kuwabara JT, Shim JW, Wainford RD. Norepinephrineevoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2016;310(2):R115–24. DOI: 10.1152/ajpregu.00514.2014

31. Cooney D, Milfred-Laforest S, Rahman M. Diuretics for hypertension: Hydrochlorothiazide or chlorthalidone? Cleveland Clinic Journal of Medicine. 2015;82(8):527–33. DOI: 10.3949/ccjm.82a.14091

32. Kountz DS, Goldman A, Mikhail J, Ezer M. Chlorthalidone: The Forgotten Diuretic. Postgraduate Medicine. 2012;124(1):60–6. DOI: 10.3810/pgm.2012.01.2518

33. Roush GC, Ernst ME, Kostis JB, Tandon S, Sica DA. Head-toHead Comparisons of Hydrochlorothiazide With Indapamide and Chlorthalidone: Antihypertensive and Metabolic Effects. Hypertension. 2015;65(5):1041–6. DOI: 10.1161/HYPERTENSIONAHA.114.05021

34. Liang W, Ma H, Cao L, Yan W, Yang J. Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta-analysis. Journal of Cellular and Molecular Medicine. 2017;21(11):2634–42. DOI: 10.1111/jcmm.13205

35. Bangalore S, Davis BR, Cushman WC, Pressel SL, Muntner PM, Calhoun DA et al. Treatment-Resistant Hypertension and Outcomes Based on Randomized Treatment Group in ALLHAT. The American Journal of Medicine. 2017;130(4):439-448.e9. DOI: 10.1016/j.amjmed.2016.10.002

36. Brown MJ, Williams B, Morant SV, Webb DJ, Caulfield MJ, Cruickshank JK et al. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. The Lancet Diabetes & Endocrinology. 2016;4(2):136–47. DOI: 10.1016/S2213-8587(15)00377-0

37. Bobrie G, Frank M, Azizi M, Peyrard S, Boutouyrie P, Chatellier G et al. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. Journal of Hypertension. 2012;30(8):1656–64. DOI: 10.1097/HJH.0b013e3283551e98

38. Cestário E do ES, Fernandes LAB, Giollo-Júnior LT, Uyemura JRR, Matarucco CSS, Landim MIP et al. Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension – study protocol for a randomized controlled trial. Trials. 2018;19(1):101. DOI: 10.1186/s13063-017-2343-3

39. Wang C, Xiong B, Huang J. Efficacy and Safety of Spironolactone in Patients with Resistant Hypertension: A Meta-analysis of Randomised Controlled Trials. Heart, Lung and Circulation. 2016;25(10):1021–30. DOI: 10.1016/j.hlc.2016.02.016

40. Zhao D, Liu H, Dong P, Zhao J. A meta-analysis of add-on use of spironolactone in patients with resistant hypertension. International Journal of Cardiology. 2017;233:113–7. DOI: 10.1016/j.ijcard.2016.12.158

41. Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: A meta-analysis of randomized controlled trials. Clinical and Experimental Hypertension. 2017;39(3):257–63. DOI: 10.1080/10641963.2016.1246564

42. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. The Lancet. 2015;386(10008):2059–68. DOI: 10.1016/S0140-6736(15)00257-3

43. Krieger EM, Drager LF, Giorgi DMA, Pereira AC, BarretoFilho JAS, Nogueira AR et al. Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment). Hypertension. 2018;71(4):681–90. DOI: 10.1161/HYPERTENSIONAHA.117.10662

44. Constantine GR, Ranasinghe P, Weeratunga P, Weeraratne C, Galappatthy P, Rajapakse S et al. Addition of Propranolol in Resistant Arterial hypertension Treatment (APROPRIATE study): study protocol for a randomized double-blind placebo-controlled trial. Trials. 2017;18(1):124. DOI: 10.1186/s13063-017-1863-1

45. Siddiqui M, Calhoun DA. Refractory versus resistant hypertension: Current Opinion in Nephrology and Hypertension. 2017;26(1):14–9. DOI: 10.1097/MNH.0000000000000286

46. Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure. Hypertension. 2015;66(1):126–33. DOI: 10.1161/HYPERTENSIONAHA.115.05449

47. Velasco A, Siddiqui M, Kreps E, Kolakalapudi P, Dudenbostel T, Arora G et al. Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes. Hypertension. 2018;72(2):343–9. DOI: 10.1161/HYPERTENSIONAHA.118.10965

48. Аксенова А.В., Есаулова Т.Е., Сивакова О.А., Чазова И.Е. Резистентная и рефрактерная артериальные гипертензии: сходства и различия, новые подходы к диагностике и лечению. Системные гипертензии. 2018;15(3):11-13. DOI: 10.26442/2075-082X_2018.3.11-13