arterial hypertension epidemiology, pathofysiologie ... van der niepen.pdfclinical management,...

26/09/2013

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Arterial Hypertension & Renal disease Pathophysiology, Clinical management,

Therapy prescription and Complications

P. Van der Niepen

Nefrologie & Hypertensie

UZ Brussel

Core Curriculum Course Nephrology

Brussel, 28 september 2013

Hypertension Excellence

centre of the ESH

in Brussel

2

Outline

Introduction - Epidemiology,

Pathophysiology,

Clinical management,


3

Introduction

Hypertension (HT) is a major risk factor for

cardiovascular (CV) and renal disease.

Conversely, chronic kidney disease (CKD) is the

most common form of secondary HT and mounting

evidence suggests it is an independent risk factor

for CV morbidity and mortality.

Renal disease is a consequence as well as a cause of

hypertension

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Blood Pressure Predicts Risk of Developing End-

Stage Renal Disease in Men and Women

4

Cumulative incidence of ESRD

in 46 881 men and 51 878

women, according to the 6 BP

categories.

Relative risk (95% CI) of development of

ESRD for BP categories in men and women.

Relative risks, with optimal BP as the reference

category, are adjusted for age and BMI.

Tozawa et al. Hypertension 2003;41:1341-1345

HR of all-cause and CV mortality according to

eGFR/ACR in general population

5 CKD Prognosis Consortium. Lancet 2010; 375: 2073–81

Lower eGFR and higher albuminuria are associated with

mortality and ESRD. A collaborative meta-analysis of KD

population cohorts.

6

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical

Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney intern,

Suppl. 2013; 3: 1–150.

Green: low risk (if

no other markers of

KD, no CKD);

Yellow: moderately

increased risk;

Orange: high risk;

Red, very high risk

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Introduction

Effective treatment ameliorates the harmful effects

of uncontrolled hypertension, as has been clearly

demonstrated by a large number of clinical trials [1].

Unfortunately, most trials have excluded patients

with CKD, and those trials that specifically targeted

CKD patients primarily focused on progression of

renal disease as the primary clinical endpoint.

[1]Turnbull F. Lancet 2003; 362:1527-35.

Prevalence of hypertension in CKD

The prevalence of hypertension is higher among

patients with CKD than in individuals without CKD,

progressively increasing with the severity of CKD.

Based on a national survey of a representative

sample of non-institutionalized adults in the USA, it

is estimated that hypertension occurs in

23.3% of individuals without CKD,

35.8% of stage 1,

48.1% of stage 2,

59.9% of stage 3, and

84.1% of stage 4-5 CKD patients

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U S Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and

End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of

Diabetes and Digestive and Kidney Diseases. Bethesda, Md, USA, 2010.

Prevalence of hypertension in CKD

The incidence and prevalence of hypertension also

varie with the cause, the type of onset (acute and

chronic KD), and the duration of KD (GN and

vasculitis > interstitial disease);

A strong association with hypertension was

especially reported in patients with renal artery

stenosis (93%), diabetic nephropathy (87%), and

polycystic kidney disease (74%)

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N. Ridao et al. “Prevalence of hypertension in renal disease,” NDT 2001; 16(1): 70–73.

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Crews D et al. Hypertension 2010;55:1102-1109

Copyright © American Heart Association

Population prevalence (%) of CKD stages 1 to 4, by

hypertension status, NHANES 1999–2006.

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Outline

Introduction - Epidemiology,

Pathophysiology,



Pathophysiology of hypertension

The genesis of essential hypertension is a complex interplay

of various pathophysiologic factors.

These pathophysiologic factors interact also with genetic,

demographic, and environmental influences

Explaining the heterogeneity of the hypertensive population

Increased vascular stifness, endothelial dysfunction,

inflammation and increased oxidative stress play a role in

increasing BP and CV risk

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Pathophysiologic factors that play a role in

the development and maintenance of

hypertension

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Pathophysiologic factors that play a role in the

development and maintenance of hypertension

Pathophysiologic factor Increased or decreased activity

Neurohumoral mechanisms • SNS activity

• RAAS activity

• Production of sodium-retaining hormones

• Production and expression of vasoconstrictors

• Production and expression of vasodilators

• Kallikrein-kinin system activity

Dietary factors • Sodium intake

• Potassium and calcium intake

Vascular factors • Peripheral resistance

• Vascular stifness

• Endothelial dysfunction

Cellular mechanisms • Cellular ion transport

• Adrenergic receptor activity

or

or

Others • Inflammation

• Oxidative stress

• Psychosocial stress

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Pathophysiology of Hypertension The Sympathetic Nervous System

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Sympathetic nerve activity in normotensive versus hypertensive persons, showing the resting level

of activity of sympathetic postganglionic neurons that innervate muscle resistance arterioles (B).

The intensity and frequency of muscle sympathetic nerve activity (MSNA) bursts are higher in

hypertensive compared with normotensive persons (B and C). A, The level at which MSNA was

measured. (Guyenet PG. The sympathetic control of BP. Nat Rev Neurosci. 2006;7:335-346.)

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The Sympathetic Nervous System: the afferent signals

from peripheral sympathetic and somatic receptors

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Somatic and sympathetic afferent nerves

The Sympathetic Nervous System: the sympathetic

efferent signals to the periphery

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Long-term consequences of increased central sympathetic outflow. pCO2, partial pressure of

carbon dioxide.

Pathophysiology of Hypertension The Renin-Angiotensin-Aldosterone System

18

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Pathophysiology of Hypertension Salt Sensitivity

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Mechanisms of salt-induced BP elevation and target organ damage. Increased dietary salt activates

shear forces and stimulates transforming growth factor-β (TGF-β) and nitric oxide (NO)

production. In the setting of increased tonicity and in the presence of aldosterone, NO production

is suppressed, leading to unopposed TGF-β activity. Ultimately, these changes result in increased

BP and TOD. (Redrawn from Sanders PW. Vascular consequences of dietary salt intake. Am J

Physiol Renal Physiol. 2009;297:F237-243.)

Pathophysiology of Hypertension Arterial Stiffness

20

Neurohumoral, mechanical, and genetic factors regulate extracellular matrix protein expression

and result in increased arterial stiffness, peripheral resistance, and BP. MMPs, matrix

metalloproteinases. (Redrawn from Briones AM, Arribas SM, Salaices M. Role of extracellular

matrix in vascular remodeling of hypertension. Curr Opin Nephrol Hypertens. 2010;19:187-194.)

Pathophysiology of Hypertension in Kidney

Disease

The kidneys play a vital role in long-term BP

regulation[]

Virtually all forms of experimental and human HT

exhibit impaired sodium excretion by the kidneys at

normal BP[2]

Sodium loading increases BP only when renal sodium

excretion is constrained (ablation 2/3 renal mass;

administration of angiotensin or aldosteron) Initial BP rise

is mediated by expansion of extracellular fluid volume and

CO(SBP). Over time, ECF volume and CO normalize and

high BP results from elevated peripheral resistance (DBP)[1]

21

[1]C. Guyton et al. “Salt balance and long-term blood pressure control” Ann Rev Med 1980; 31:15–27. [2]J. E. Hall. Hypertension 2003; 41(3):625–633.

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Disease

Key components of hypertension in KD include:

Inappropriately elevated sympathetic nervous activity

efferent arteriolar vasoconstriction (-receptors) more sodium

retention

Stimulate renin release (-receptors) more AII

efferent arteriolar vc and sodium retention

stimulates PTC to recover filtered sodium (Na+/H+ antiporter)

stimulates aldosteron production and release stimulates distal sodium

reabsorption

Activation of the RAAS

SNS activity

Fall in distal nephron [sodium] is an additional stimulus for renin release

Increased arterial stiffness

Impaired salt and water excretion by the kidneys increase

in extracellular fluid exacerbation of high BP in KD 22


Disease

Other factors that may explain increased vascular

resistance in CKD include:

Increased production of endothelin and endogenous digitalis-

like substance[1,2]

Reduced generation of vasodilators (NO, Kinins)[3,4]

Imbalance between VD and VC prostaglandins[5]

Oxidative stress[6]

23

[1] D. E. Kohan. AJKD 1997;29(1):2–26. [2] M. P. Blaustein et al. Hypertension 2009; 53, (2):291–

298. [3] N. D. Vaziri. AJKD 2001;38(4):S74–S79, [4] J. A. Mitas, et al. NEJM 1978; 299(4):162–165. [5] M. J. Dunn and V. L. Hood. Am J Physiol 1977; 233(3):169–184. [6] N. D. Vaziri. Curr Opin

Nephrol Hypertens 2004; 13(1):93–99,

Subtle renal defects may underlie the pathogenesis of

essential hypertension

This is supported by

Transplant with kidneys from normotensive donors in

patients with ESRD due to hypertensive nephrosclerosis

results in resolution of their HT[]

NT individuals with family history of HT respond to salt

loading with less natriuresis and higher BP than those with

no family history [2]

HT patients have fewer nephrons than NT counterparts[3]

• The exact nature of renal defect(s) for inappropriate

sodium excretion remains unclear

24

[]J.J. Curtis et al. “Remission of essential HT after renal transplantation” NEJM 1983; 309(17):1009–15. [2]B.R. Widgren et al. “Blunted renal Sodium excretion during acute saline loading in normotensive men

with positive family histories of HT” Am J Hypertens 1991; 4:570–578. [3]G. Keller, et al. “Nephron

number in patients with primary hypertension” NEJM 2003; 348(2):101–108

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Proposed pathogenesis of

salt-sensitive

hypertension in the

setting of subtle renal

parenchymal injury.

GFR, glomerular filtration rate. (Adapted from Johnson RJ, Herrera-

Acosta J, Schreiner GF, Rodriguez-

Itrube B. Subtle acquired renal injury

as a mechanism of salt-sensitive

hypertension. N Engl J Med.

2002;346:913-923)

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Outline

Introduction - Epidemiology

Pathophysiology,



Definitions and classification of office blood

pressure levels (mmHg)a

27

aThe (BP) category is defined by the highest level of BP, whether systolic or diastolic.

Isolated systolic HT should be graded 1, 2, or 3 according to systolic BP values in the

ranges indicated.

2013 ESH/ESC guidelines. J Hypertens 2013;31:1281-1357

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Definitions of hypertension by office and out-

of-office blood pressure levels

28 2013 ESH/ESC guidelines. J Hypertens 2013;31:1281-1357

What do we need to know before treating “high BP”

True high BP

Has the patient family history of HT

Does the patient take BP increasing medication

Is there a secondary cause,

Has the patient risk factors for HT

Has the patient other CV risk factors

Is there TOD or symptomatic CV or renal disease

Has the patient already been taken anthypertensive

drugs

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What do we need to know before treating “high BP”

Standardized BP measurement (ev. home and/or 24-

h ABPM)

Carefull physical examination

Blood exam: Hct, sCreatinine, electrolytes, uric acid

glucose, lipids

Urine analysis: microscopic examination, proteïnuria

ECG (echocardiogram)

Additional tests, based on history, physical

examination,and findings from routine lab tests

30

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Clinical indications for out-of-office BP

measurement for diagnostic purposes

31

ABPM, ambulatory

blood pressure

monitoring;

BP, blood pressure;

CKD, chronic kidney

disease;

CV, cardiovascular;

HBPM, home blood

pressure monitoring.


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The relationship between BP and CV morbidity and mortality is

modified by the concomitance of other CV risk factors.

The relationship between BP and CV morbidity and mortality

is modified by the concomitance of other CV risk factors.

Metabolic risk factors are more common when BP is high

than when it is low[1,2,3].

1Lewington S et al. Lancet 2002; 360:1903–1913. 2Kannel WB et al. Am J Hypertens 2000;

13:3S-10S. 3Thomas F et al. Hypertension 2001; 37:1256-61.

Survival probability for CVD mortality in younger (left) and older (right) men according to the

presence of HTN and associated RFs.

Nt = normotensive subjects; Ht 0, HT subjects without RFs; Ht 1-2, HT subjects with 1 or 2 RFs; ...

Assessment of total cardiovascular risk

33

Stratification of total CV risk in categories of low, moderate, high and very high risk according to SBP

and DBP and prevalence of RFs, asymptomatic OD, diabetes, CKD stage or symptomatic CVD. Subjects

with a high normal office but a raised out-of-office BP (masked HT) have a CV risk in the HT range.

Subjects with a high office BP but normal out-of-office BP (white-coat HT), particularly if there is no

diabetes, OD, CVD or CKD, have lower risk than sustained HT for the same office BP.


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When to initiate antihypertensive drug

treatment

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Initiation of lifestyle changes & antihypertensive drug treatment. Targets of treatment are also indicated.

The optimal DBP target in patients with diabetes is between 80 and 85 mmHg. In the high normal BP

range, drug treatment should be considered in the presence of a raised out-of-office BP (masked HT).

Lack of evidence in favour of drug treatment in young individuals with isolated systolic HT. 2013 ESH/ESC guidelines. J Hypertens 2013;31:1281-1357

BP goals in hypertensive patients

35

CHD, coronary heart disease; CKD, chronic kidney disease; CV, cardiovascular; DBP, diastolic

blood pressure; SBP, systolic blood pressure; TIA, transient ischaemic attack.

aClass of recommendation. bLevel of evidence.


TREATMENT STRATEGIES

Lifestyle changes

36 Based on the effect on BP and/or CV risk profile

Based on outcome studies

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TREATMENT STRATEGIES

Pharmacological therapy

Choice of antihypertensive drugs

The main benefits of antihypertensive treatment

are due to lowering of BP per se and are largely

independent of the drugs employed as has been

shown by large meta-analysis[,2,3]

Diuretics, BB, CCB, ACEI and ARBs are all

suitable for the initiation and maintenance of

antihypertensive treatment, either as monotherapy

or in some combinations[1]

37

[] 2013 ESH guidelines. J Hypertens 2013; 31:1281-1357. [2] Law MR et al. BMJ 2009;

338:b1665. [3] BPLTTC. Lancet 2003; 362:1527-35. Arch Intern Med 2005; 165:1410-19.

Relative risk estimates of coronary heart disease

events and stroke (Law meta-analysis; BMJ 2009)

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Relative risk estimates of coronary heart disease (CHD) events and stroke in 46 drug

comparison trials comparing each of the five classes of BP lowering drug with any other class

of drug (excluding CHD events in trials of β blockers in people with a history of CHD)

Drugs to be preferred in specific conditions


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Compelling and possible contra-indications to the use

of antihypertensive drugs


Monotherapy vs. drug combination strategies to achieve target

BP. Moving from a less intensive to a more intensive therapeutic

strategy should be done whenever BP target is not achieved.


Possible combinations of classes of antihypertensive

drugs

42

Green continuous lines: preferred combinations; green dashed line: useful combination (with

some limitations); black dashed lines: possible but less well tested combinations; red continuous

line: not recommended combination. Although verapamil and diltiazem are sometimes used with a

beta-blocker to improve ventricular rate control in permanent atrial fibrillation, only dihydropyridine

calcium antagonists should normally be combined with beta-blockers.

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In patients with CKD—with or without diabetes—

there are two treatment objectives

1. Prevention of CV events (the most frequent

complication of CKD) and

2. Prevention or retardation of further renal

deterioration or failure.

Unfortunately, evidence concerning the BP target to be

achieved in these patients is scanty and confused by the

uncertainty about the respective roles of reduction of

BP and specific effects of RAS blockers

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Therapeutic strategies in hypertensive patients

with nephropathy

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References

Lewis JB. JASN 2010; 21:1086-92

Upadhyay et al. Ann Intern Med 2011; 154:541-48

Sarnak MJ et al. Ann Intern Med 2005; 142:342-51

(MDRD -FU)

Appel EJ et al. NEJM 2010; 363:918-29

Upadhyay et al. Ann Intern Med 2011; 154:541-48

(review)

Schmieder RE et al. Lancet 2007; 369:1208-19

Kunz R et al. Ann Intern Med 2008; 148:30-48

Wald DS et al. Am J Med 2009; 122:290-300

Mann JF et al. Lancet 2008; 372:547-53 (ONTARGET)

Parving HH et al. NEJM 2012; 367:2204-13

(ALTITUDE)

ONTARGET. NEJM 2008; 358:1547-59

/-/


Treatment strategies in patients with diabetes

45

References

HOPE. Lancet 2000; 355:253-59

ADVANCE. Lancet 2007; 370:829-40

HOT. Lancet 1998; 351:1755-62

SHEP. JAMA 1996; 276:1886-92

SYSTEUR. NEJM 1999; 340:677-84

UKPDS 38. BMJ 1998; 317:703-13

FEVER. Eur Heart J 2011; 32:1500-08

HOPE. Lancet 2000; 355:253-59

ADVANCE. Lancet 2007; 370:829-40

ACCORD. NEJM 2010; 362:1575-85

HOT. Lancet 1998; 351:1755-62

UKPDS 38. BMJ 1998; 317:703-13

BPLTT collaboration. Arch Intern Med 2005; 165:1410-19

Schmieder et al. Lancet 2007; 369:1208-19

/-/

ALTITUDE. NEJM 2012; 367:2204-13


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Complications of hypertension

Subclinical target organ damage

Left ventricle hypertrophy

Retinopathy

Microalbuminuria

Carotid intima-media thickness, generalised atheromatosis

Binswanger lesions (asymptomatic white-matter lacunar infarcts)

Cardiovascular and renal events

Coronary heart disease, Heart failure

Stroke

Renal failure

Peripheral artery disease, aortic dissection, aortic aneurysm

Vascular dementia

CV death

46

Complications of (untreated) hypertension

47

Schematic model of the natural history of (untreated)

hypertension, showing the progression from

prehypertension to hypertension, to target organ

damage, to clinical events, and eventually to death.

48

Age-specific relevance of usual BP to vascular mortality: a

meta-analysis of individual data for one million adults in 61

prospective studies.

Lewington S, et al. Lancet

2002; 360:1903–1913.

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49

CV mortality risk

0

2

4

8

115/75 135/85 155/95 175/105

6

2x

4x

8x

SBP/DBP (mm Hg)

* Individuals 40–69 y without CV disease

Lewington S, et al. Lancet 2002;360:1903-13

Continuous relationship between BP and CV risk: The risk on

CV mortality doubles with each 20/10 mmHg increase in BP*

Ischemic heart disease-related mortality

50


2002; 360:1903–1913.

Stroke mortality

51


2002; 360:1903–1913.

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52 Safar et al. J Hypertens 2000; 18:1527-1535

75

80

85

90

95

DBP

(mmHg)

120 140 160 180 200 220 240 SBP (mmHg)

0.28

0.24

0.20

0.16

0.12

0.08

0.04

EWPHE (n = 840)

SYST-EUR (n = 4695)

SYST-CHINA (n = 2394)

2 y

ea

r ris

k o

f en

dp

oin

t The probability of a major CV endpoint increased with greater SBP but, at any

given value of SBP, this probability increased with lower DBP, suggesting that

the wider pulse pressure in the elderly drives the risk of major complications

Relationship between hypertension and coronary

artery disease.

53

DBP, diastolic blood pressure; SBP, systolic blood pressure; SNS, sympathetic nervous system.

Change in aortic pressure profile resulting from age-related

vascular stiffening and increased pulse wave velocity (PWV).

54

1. Increased SBP and decreased DBP

owing to decreased aortic distensibility.

2. Increased PWV as a result of decreased

aortic distensibility and increased distal

(arteriolar) resistance.

3. Return of the reflected primary pulse to

the central aorta in systole rather than

in diastole as a result of faster wave

travel.

4. Change in aortic pulse wave profile

because of early wave reflection. Note

the summation of antegrade and

retrograde pulse waves to produce a

large SBP. This increases LV stroke

work and therefore myocardial oxygen

demand. Note also the reduction in the

diastolic pressure-time (integrated area

under the DBP curve). This reduction in

coronary perfusion pressure increases

the vulnerability of the myocardium to

hypoxia.

Modified from Smulyan H, Safar ME. The diastolic blood pressure in systolic hypertension.

Ann Intern Med. 2000;132:233-237

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Autoregulation of coronary blood flow and myocardial

flow reserve in the presence of LV hypertrophy.

55

A1 represents total coronary blood flow over a range of

perfusion pressures.

P1 is the lower limit of the autoregulatory range.

D1 is the pressure-flow relationship in the maximally

dilated coronary bed.

At any given perfusion pressure, the coronary flow reserve

is R1.

A2, P2, D2, and R2 represent corresponding values in

patients with HTN and LVH. At any given perfusion

pressure, coronary flow reserve is less in the

hypertensive/hypertrophied hearts, thus increasing the

vulnerability of the myocardium to ischemia, especially

during exercise or any other situation requiring increased

coronary flow. Moreover, the lower limit of coronary

autoregulation is shifted to the right (P1 to P2) in the

hypertensive heart, thereby increasing the vulnerability to a

severe drop in perfusion pressure.

Adapted from Hoffman JIE. A critical view of coronary reserve.

Circulation. 1987;75[suppl I]:I6.)

Blood pressure control

In the general population, only a minority of patients

achieve recommended treatment goals.

Reports on CKD patients enrolled in prospective

observational studies have described rates of

awareness and control of HT as similar to current

levels in the general population[1,2]. Rates of

hypertension control were suboptimal in a cohort of

patients with CKD, despite almost universal HT

awareness and treatment[1].

56

[1]P. Muntner et al. (CRIC) study. AJKD 2010; 55(3): 441–51. [2] P. Muntner et al. ”Low

medication adherence and hypertension control among adults with CKD: data from the REGARDS

(Reasons for Geographic and Racial Differences in Stroke) study” AJKD 2010; 56: 447–57.

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Extent of awareness, treatment, and control of high BP

by age (National Health and Nutrition Examination Survey: 2005–2008)

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58

I-inSyst: Blood pressure control (0-6/2004)

SBP (mmHg)

60 80 100 120 140 160 180 200 220 240 260

DB

P (

mm

Hg

)

20

40

60

80

100

120

140

160

21.5%

2.3%

28.5%

47.8%

23.7% 76.3%

50.1%

49.9%

n=11,562 (49%V); 18% DM; 63 yrs; 150 (12)/88 (6) mm Hg

Van der Niepen et al, J Hypertens 2008; 26(10):2057-63

78,5%

NOT at goal

# : 1.6; 50% monotherapy

21.5 %

HT prevalence, awareness, treatment and control in

adults with CKD (CRIC study. AJKD 2010; 55: 441-51)

59

SBP & DBP distribution among participants

in the CRIC study (n=3612).

Overall rates of HT prevalence, awareness,

treatment and control among participants

of the Chronic Renal Insufficiency Cohort

(CRIC) study. HTN Prevalence among all

CRIC participants; Aware and Treated are

the percent among all participants with HT.

HT control rates are calculated for all

CRIC participants with HT.

Conclusions

Hypertension is a frequent CVRF

Hypertension is a cause and a consequence of CKD

The pathophysiology is complex

Total CV risk should be calculated

Treatment and BP control can be ameliorated

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