24 hr BP control

Renal aspects

Hypertension and Chronic Renal Disease: Hemodynamic Abnormalities

Mean BPTotal Systemic

Vascular Resistance= X

Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity

Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity

IncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane

IncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane

CardiacOutput

DecreasedVasodilation Prostacyclin Nitric oxide EDHF*

DecreasedVasodilation Prostacyclin Nitric oxide EDHF*

Textor SC. Atlas of Diseases of the Kidney, 2001.

*Endothelium-derived Hyperpolarizing Factors

www.hypertensiononline.org

“ The inherent variability of the blood pressure has ledto problems in the diagnosis, treatment, and prognosis

of hypertension. Knowing how the blood pressurefluctuates with the stresses and strains of everyday lifeshould help in assessing the severity of hypertension,

the response to treatment, and the prognosis in individualcases”

Hinman et al; 1962

DIURNAL BLOOD PRESSURE VARIATION IS LONG RECOGNISED !

Diurnal blood pressure variation

Am J Hypertens 2005; 18: 149-151.

Altered Circadian rhythm in CKD

Nephrol Dial Transplant (1997) 12: 2301–2307

Consecutive patients referred for ambulatory blood pressure monitoring, Followed over 1 year

322 patients included:– 137 dippers, 185 non dippers

Mean baseline GFRs– Dippers: 80.5 mL/min per 1.73 m2 – Non dippers: 76.4 mL/min per 1.73 m2

Arch Intern Med. 2006;166:846-852

Dippers vs Non dippers - only significantly different parameters shown

- values in brackets are percentage of total

Arch Intern Med. 2006;166:846-852

Variable Dippers

(n = 137)

Non dippers

(n = 185)

Age, y 61.3 ± 12.6 65.7 ± 12.2

Diabetes mellitus 9 (6.6) 32 (17.3)

Hypertension 92 (67.2) 162 (87.6)

Coronary artery disease 17 (12.4) 47 (25.4)

Antihypertensive drugs ACEI, BB

Dippers vs Non dippers - only significantly different parameters shown

- values in brackets are percentage of total

Arch Intern Med. 2006;166:846-852

Variable Dippers

(n = 137)

Non dippers

(n = 185)

FBG, mg/dL 95.7 ± 19.2 102.4 ± 28.5

GFR at Follow-up 81.0 ± 20.7 64.7 ± 26.6

Triglyceride level, mg/dL 129.4 ± 68.9 163.8 ± 93.7

High-density lipoprotein 55.8 ± 17.3 49.5 ± 15.2

Dippers vs Non dippers

Arch Intern Med. 2006;166:846-852

Non Dipping pattern – Cause or effect ? Fifteen healthy subjects (4 men, 11 women; aged 33 to 65

years;mean age 55±2 years) who underwent unilateral nephrectomy for kidney donation were studied

Hypertens Res 2005; 28: 301–306

Results suggest that unilateral nephrectomy disturbs the circadian rhythm of BP as a function of renal dysfunction without affecting absolute levels of BP

Non dipping of BP seems to be the consequence of the loss of renal function, rather than the cause

Am J Physiol Renal Physiol 2007 293:655-659

ABPM findings in a community

The Spanish Society of Hypertension - 20000 patients - 17 219 analyzed

Remarkable discrepancy between office and ambulatory BP in high-risk hypertensive patients

The prevalence of a non-dipper BP pattern was almost 60%

Journal of Hypertension 2007, 25:977–984

ABPM findings in a community

Journal of Hypertension 2007, 25:977–984

Nocturnal BP Changes and CV Mortality: Ohasama study

0.96 1

2.56

3.69

0

0.5

1

1.5

2

2.5

3

3.5

4

Extreme dippers

Dippers Non-dippers

Risers

Risk of CV Mortality

Ohkubo et al; AJH 1997; 10: 1201

Analysis of The Influence of the Morning Surge of BP on Stroke

Incidence Cox regression analysis for clinical stroke eventsCovariates RR P value

Age (10 yrs) 1.80 (1.21-2.69) 0.004

Male gender 1.42 (0.76-2.67) 0.266

BMI 0.98 (0.90-1.07) 0.663

24 hr SBP 1.37 (1.16-1.63) 0.003

Morning BP surge* 1.29 (1.10-1.51) 0.001

Nocturnal BP fall* 0.88 (0.73-1.06) 0.167

Lowest sleep BP 1.05 (0.65-1.71) 0.837* per 10 mmHg

Kario, Pickering et al, Circ 2003; 107:1401

Cause of Circadian Rhythms - Role of the Autonomic system

212 patients with progressive autonomic failure due to familial amyloid polyneuropathy

Group I – No evidence yet of impairment of their ANS– Circadian BP and HR variations indistinguishable from controls

Group II – Variable parasympathetic, intact sympathetic – 24 hour HR was higher vs Controls but maintained– Circadian BP variation diminished - attenuation of the nocturnal BP

decline

Hypertension 2000;35;892-897

Role of the Autonomic system

Group III – parasympathetic failure and intermediate sympathetic

dysfunction– Blunted diurnal BP variation

Group IV – parasympathetic failure and severe sympathetic

dysfunction– Absent diurnal BP variation

Hypertension 2000;35;892-897

How to tackle the variations

Pharmacodynamic Pharmacokinetic

maintain blood concentration of a drug for longer periods

longer acting drugs

• Sympatholytic drugs

• RAAS system

Diuretics Convert Non-Dippers to Dippers

100

110

120

130

140

150

Systolic pressure mmHg

Day

Night

No Rx HCTZ No Rx HCTZ

Dippers Non-DippersUzu & Kimura Circ 1999; 100:1635

Diuretics Convert Non-Dippers to Dippers

100

110

120

130

140

150

Systolic pressure mmHg

Day

Night

No Rx HCTZ No Rx HCTZ

Dippers Non-DippersUzu & Kimura Circ 1999; 100:1635

Effects of Alpha-Blockade on the Morning Surge of Blood Pressure

Kario, Pickering, et al Am J Hypertens 2004;17; 668

Doxazosin

No Rx

Role of alpha blockers Type 2 DM with hypertension and nephropathy

Effects of antihypertensive therapy of combinations of angiotensin converting enzyme (ACE) inhibitor, calcium antagonists (CCB), diuretics (DU), and α blocker (AB)

At the end of the studySignificant associations among – decline of 24-hr creatinine clearance and the levels of systolic

blood pressure

– levels of systolic blood pressure and the urine excretion of protein-creatinine ratio in the morning

– Analysis of patients who had systolic blood pressure in the morning less than 140 mmHg revealed that 65% of these patients received doxazosin-averaged doses of 4.8 ± 1.5 mg daily

Clinical and Experimental Hypertension, 2005; 27:129 - 138

Pre Tx(n = 30) – CCB/DU + ARB

Tx (n = 27) – Pre Tx + AB at bedtime

Changing the timing of dosing helps Setting & Participants

– 32 CKD patients with CKD , eGFR > 90 mL/min/1.73 m2 and ABP night-day ratio greater than 0.9

– normal daytime ABP (<135/85 mm Hg)

Intervention – Shifting 1 antihypertensive drug from morning to evening

Outcomes – Percentage of patients changing the night-day ratio of mean

ABP from greater than 0.9 to 0.9 or less 8 weeks after the shift

Measurements– Office blood pressure/ABP and proteinuria at baseline and after

the shift

AJKD, 2007;50(6):908-17

Changing the timing of dosing helps

Results After shift:

– ABP N/D ratio decreased in 93.7% of patients, with normal circadian rhythm restored in 87.5%

– Was not associated with an increase in diurnal ABP and was independent from number and class of shifted drug

– Office blood pressure in the morning also decreased (from 136 ± 16/77 ± 10 to 131 ± 13/75 ± 8 mm Hg; P = 0.02)

– Urinary protein excretion decreased from 235 ± 259 to 167 ± 206 mg/dl (P < 0.001)

AJKD, 2007;50(6):908-17

Question: If you were allowed just one reading over 24 hours to predict morbidity,

which would you choose?

Gosse et al, J Hum Hypertens 2001; 15: 413

Awake AwakeSleep

Going to bed Arising

Evening BP

Lowest BP

Preawake BP

Morning BP

Masked hypertension = ↑ risk of ESRD in CKD

White coat hypertension = better outcome

AMBP = Home BP >> Clinic BP

BP obtained in triplicate twice daily for 3 days every 3 months appears appropriate

Alternatively, blood pressure obtained thrice daily for 1 week can be used

Curr Opin Nephrol Hypertens, 2006 15:309–313