Hypertension: the Heart Vs the Kidney. George Moturi Physician/Nephrologist Aga Khan Hospital Nairobi

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1 Hypertension: the Heart Vs the Kidney George Moturi Physician/Nephrologist Aga Khan Hospital Nairobi 24 th Feb, 2017

2 Travel facilitation from Novartis Disclaimer

3 Systolic blood pressure (SBP) of at least 110 mm Hg has been related to multiple CV and renal outcomes Eg: Ischemic heart disease Cerebrovascular disease Chronic kidney disease Collins et al Lancet 1990, Wright et al JAMA 2002, Van Gaal et al Nature 2006

4 Sign post History and epidemiology Pathophysiology, genetics and aetiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Conclusion

5 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Nomenclature

6 Treatment of the Hard Pulse disease (2600BC) acupuncture venesection bleeding by leeches Journal of the Royal Society of Medicine Volume 84 October 1991

7 First published measurement of blood pressure in 1733 Stephen Hales, was an English clergyman

8 Worldwide people with HTN: 594M (1975) and 1.13B (2015) Lancet 15 th Nov DOI:

9 Interpretation: During the past four decades, the highest worldwide blood pressure levels have shifted from high-income countries to low-income countries in south Asia and sub-saharan Africa due to opposite trends, while blood pressure has been persistently high in central and eastern Europe

11 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Conclusion

13 Page s mosaic theory of hypertension

14 Guyton Hierarchy of BP control systems Provides both short-term damping and long-term control of arterial pressure. 1. Short-term (cardiovascular reflexes) 2. Intermediate-term (capillary fluid shifts, vascular compliance, and hormones) control mechanisms function primarily as pressure-buffering mechanisms 3. Long-term control of BP is vested almost entirely in the longterm control of body fluid volumes, primarily by the kidney Guyton 1980

15 Guyton s model for the short-term and long-term control of arterial pressure

16 In 1898, Tigerstedt and Bergmann published an account of their research demonstrating the existence of a heat-labile substance in crude extracts of rabbit renal cortex that caused a sustained increase in arterial pressure. Piepho and Beal. J Clin Pharmacol. 2000;40: Pharm. 2007;13(8)(suppl S-b):S9-S20

17 Mechanisms regulating mean arterial blood pressure Mayet, Heart 2003

18 GENETICS OF HYPERTENSION Most relate to renal sodium handling Kidney has an overriding influence on BP regulation

19 Taposh and Singh, J The Assoc of Phys India 2015

20 The discovery of genes responsible for the monogenic syndromes of HTN has highlighted the primacy of the kidneys and the adrenal glands in BP regulation and provided a valuable molecular layer to the expanding BP regulatory model. Giuseppe. Circ Res. 2015;116:

21 Molecular pathways affecting sodium transport involving Cullin 3 (CUL3), Kelchlike 3 (KLHL3), and Uromodulin

23 Understanding hypertension beyond the 21 st century

24 Microparticles released from endothelial cells and platelets were significantly increased in patients with severe arterial hypertension and that Endothelial microparticles correlated strongly with the level of both systolic and diastolic blood pressures. EMPs and PMPs can be used as circulating markers for endothelial injury in arterial hypertension Preston et al. Hypertension. 2003;41:

Background: Hypertensive patients with microalbuminuria have decreased endothelial progenitor cells (EPCs) and increased levels of endothelial apoptotic microparticles (EMP).

25 Background: Hypertensive patients with microalbuminuria have decreased endothelial progenitor cells (EPCs) and increased levels of endothelial apoptotic microparticles (EMP). However, whether these changes are related to a subsequent decline in glomerular filtration rate (GFR) remains unclear. Conclusions: An increased circulating EMP to EPC ratio is associated with subsequent decline in GFR in hypertensive patients, which suggests endothelial damage with reduced vascular repair capacity may contribute to further deterioration of renal function in patients with hypertension. Hsu et al. PLoS ONE2013; 8(7):e68644

27 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Nomenclature

28 How do we make diagnosis of hypertension?

29 Assess TOD Heart: ECG, ECHO Kidney: Urinalysis, Renal Ultrasound Novel Biomarkers

30 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Nomenclature

33 Heart Vs Kidney When to start treatment Treatment BP targets Outcomes

34 Is lower and lower Bp target desirable?

35 Achieved BP 120/64

36 HOPE 3 trial HOPE 3 Lipids: Showered cardiovascular protection About 2.8% participants had mild renal dysfunction at baseline

38 Weiss et al. Ann Intern Med 2017 Article: 8 benefits

39 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Nomenclature

40 Salt, salt and salt; I just need to add a little!

41 Average daily salt intake of population samples and prevalence of high BP Samler Am J Cli,, Nutr 1997

42 Blood pressure control: salt gets under your skin Marvar et al Nat Med 2009

43 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Nomenclature

44 Dates of Discovery of Antihypertensive Drugs or Drug Classes

45 Diuretic targets along the renal tubule

46 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Conclusion

47 How about resistant HTN? Who is the culprit? How about the winner

48 Hypertension Resistant Secondary Secondary and Resistant Hypertension

49 Secondary forms of hypertension (disease categories) Faselis et al Internl J Hypertens 2011

50 Initial therapy in R HTN Background Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure Spironolactone was the most effective add on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. William et al. Lancet 2015; 386:

51 Catheter based radiofrequency ablation of renal sympathetic nerves ( RDN Therapy)

Resistance Sleep Disturbances Renal Afferent Nerves Hypertrophy

53 Renal Sympathetic Activation: Afferent Nerves Kidney as Origin of Central Sympathetic Drive Vasoconstriction Atherosclerosis Insulin Resistance Sleep Disturbances Renal Afferent Nerves Hypertrophy Arrhythmia Oxygen Consumption Renin Release RAAS activation Sodium Reten on Renal Blood Flow

54 Renal Nerve Anatomy Nerves arise from T10 L2 Follow the renal artery to the kidney Primarily lie within the adventitia. Vessel Lumen Medi a Adventitia Renal Nerves

55 N Engl J Med 2014 In a prospective, multicenter, randomized, blinded, sham controlled trial of patients with uncontrolled resistant hypertension, percutaneous renal denervation was safe but not associated with significant additional reductions in office or ambulatory blood pressure.

57 The ROX Coupler Novel treatment of R THN

Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial Arteriovenous anastomosis was associated with

58 Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension. Lobo et al. Lancet 385(9978), (2015).

59 Sign post History and epidemiology Pathophysiology, genetics and etiology Diagnosis Treatment considerations Non pharmacological interventions Pharmacological interventions Autonomic denervation Conclusion

60 The future. Formation of hypertension society of Kenya/Eastern Africa Formation of hypertension clinics in teaching hospitals Encourage team work in management of hypertension Foster hypertension research locally Cardiac and renal Polypill in HTN

61 Indeed, primary or essential hypertension is perhaps better not considered a disease at all, rather a level of blood pressure above which treatment does more good than harm Sir Geoffrey Rose

62 Thank You For Listening

RISE, FALL AND RESURRECTION OF RENAL DENERVATION. Michael A. Weber, MD State University of New York Downstate College of Medicine

RISE, FALL AND RESURRECTION OF RENAL DENERVATION Michael A. Weber, MD State University of New York Downstate College of Medicine Michael Weber, Disclosures Research/Trial Commitments and Consulting: Boston