unique features of hypertension in adpkd · unique features of hypertension in adpkd robert w....

Unique Features of Hypertension in ADPKD

Robert W. Schrier, MD Professor of Medicine

University of Colorado Denver School of Medicine

KDIGO

Disclosures Dr. Robert W. Schrier serves as an

Advisor to Novartis, Jannsen, Ikaria, and Otsuka Pharmaceuticals.

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enta

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yper

tens

ion

Age (years)

Prevalence of Hypertension in ADPKD Males, 1985-1994 versus NHANES III,

1988-1994 P < 0.001 P < 0.0001 P < 0.0001

NHANES III ADPKD Kelleher, Schrier, et al., Am J Hypertension, 17:1029-34, 2004.

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Age (years)

Prevalence of Hypertension in ADPKD Females, 1985-1994 versus NHANES III,

1988-1994 P < 0.001 P < 0.0001 P < 0.0001

NHANES III ADPKD Kelleher, Schrier, et al., Am J Hypertension, 17:1029-34, 2004.

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Age (years)

Prevalence of Hypertension in ADPKD Males 1995-2000 versus

NHANES IV 1999-2000

P < 0.0001

P < 0.0001

P < 0.005 NS

NHANES IV ADPKD Kelleher, Schrier, et al., Am J Hypertension, 17:1029-34, 2004.

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Age (years)

Prevalence of Hypertension in ADPKD Females 1995-2000 versus

NHANES IV 1999-2000 P < 0.0001 P < 0.0001 P < 0.005 NS

NHANES IV ADPKD Kelleher, Schrier, et al., Am J Hypertension, 17:1029-34, 2004.

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The Progression of Renal Disease in Hypertensive and Normotensive ADPKD

Patients

Age (years) 15 20 25 30 35 40 45 50 55 60 65 70 75

1.5

1

0.5

0

0.67

1.0

2.0

Normotensive

Hypertensive P<0.001

1/Sc

r Scr (m

g/dl)

Gabow, Schrier, et al. KI,41:1311-1319,1992

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800

600

400

200

0

800

600

400

200

0

Males Females HBP NBP HBP NBP

P < 0.0005

P < 0.002

Gabow, Schrier, et al: KI,38:1177-1180,1990.

Mean Renal Volume is Significantly Higher in Hypertensive versus Normotensive

ADPKD Patients

cm3

cm3

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Relationship between GFR and Renal

Volume in 229 ADPKD Subjects

Fick, Schrier, et al., J Am Soc Nephrol 5:2048-2056, 1995

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Parameter NBP (N=30) BBP (N=27) HBP (N=28) P-value for ANOVA

Male/female 13/17 15/12 17/11 NS

Age (years) 12.0 ± 0.8 11.8 ± 0.8 13.6 ± 0.8 NS

Height (cm) 151 ± 5 151 ± 5 160 ± 4 NS Serum creatinine (mg/100 ml) 0.66 (0.57–0.70) 0.69 (0.62–0.77) 0.74 (0.68–0.81) NS

24-h creatinine clearance (ml/min/1.73 m2)

135 (127–145) 127 (117–138) 130 (120–141) NS

Urine microalbumin excretion (mg/day) 31 (19–51) 22 (14–35) 23 (16–33) NS

Systolic blood pressure (mm Hg) 109 ± 2 119 ± 2 130 ± 3 <0.0001

Diastolic blood pressure (mm Hg) 64 ± 1 68 ± 1 72 ± 2 0.0005

Note. SBP: NBP vs BBP (P=0.0122), NBP vs HBP (P<0.0001), BBP vs HBP (P=0.0022); DBP: NBP vs BBP (P=NS), NBP vs HBP (P=0.0003), BBP vs HBP (P=NS). Data presented as mean ± s.e. or geometric mean (95% CI).

Cadnapaphornchai, Schrier, et al. CJASN, 4;820-829, 2009

Normotensive (NBP), borderline hypertensive (BBP), and hypertensive (HBP) subjects

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Correlation between systolic blood pressure and renal volume in 85 ADPKD children

Cadnapaphornchai, Schrier, et al. Kidney Int 74; 1192-96, 2008

3

4

5

6

7

8

75 100 125 150 175Systolic blood pressure (mm Hg)

Ln[R

enal

Vol

ume]

(ml)

Borderline Hypertensive Normotensive

r = 0.70 P<0.0001 KD

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Correlation between diastolic blood pressure and renal volume in 85 ADPKD children


33.54

4.55

5.56

6.57

7.5

50 60 70 80 90 100Diastolic blood pressure (mm Hg)

Ln[R

enal

Vol

ume]

(ml)

r = 0.52 P<0.0001

Borderline Hypertensive Normotensive

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NORMAL RENAL VASCULATURE

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RENAL VASCULATURE IN ADPKD

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Hypothesis

!  Bilateral cyst enlargement causes compression of adjacent parenchyma and stretch of arterioles lining cyst cavities, leading to intrarenal ischemia and activation of the renin-angiotensin-aldosterone system. KD

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The Effect of the RAAS in the Development of Hypertension and Progression of ADPKD

Hypertension

á Renin

á Angiotensin II

Aldosterone Renal sodium retention

á Vascular resistance

Fibrosis á Mitogenesis

Bilateral renal cysts

Ecder,Schrier: JASN,12:194-200,2001

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Blood Pressure Responses to Saralasin in Hypertensive patients with PKD and Renal

Vascular Hypertension (mean + SEM)

80

100

120

140

160

180

Pre-Saralasin Post-Saralasin

Systolic

Systolic

Diastolic

Diastolic

*

*

* P < 0.05 Pre- vs Post- Saralasin

Blo

od P

ress

ure

(mm

Hg)

Anderson et al. (1979).

ADPKD RVH

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MAP response to AII Inhibitor in 1K1C HBP Rats

Gavras, 1973

Angiotensin II Inhibitor 270 µg (9 µg/min i.v.)

24-hour sodium repletion

Sodium depletion

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Plasma Renin Activity (PRA) Response to Captopril During High Sodium Diet in

ADPKD (300 mEq/day)

0

2

4

6

8

Pre-Captopril Post-Captopril

Normotensive Hypertensive

NS

P<.04

PRA

(ng/

ml/h

r)

Bell, Schrier, et al. KI, 34:683-690,1988

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0

0.5

1

1.5

2

2.5

Supine Upright AfterCaptopril

PKD + HTN Ess. HTN

P<0.03

P=0.05

P<0.0006

PRA

(ng/

L.se

c)

The Renin-Angiotensin-Aldosterone System is Stimulated in ADPKD as Compared to Essential

Hypertension

Chapman, Schrier, et al.: N Engl J Med 323: 1091-96, 1990

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0

200

400

600

800

1000

Supine Upright AfterCaptopril

PKD + HTN Ess. HTN

P<0.055

P=0.006 P<0.02

Ald

oste

rone

(pm

ol/L

)

The Renin-Angiotensin-Aldosterone System is Stimulated in ADPKD as Compared to Essential

Hypertension

Chapman, Schrier, et al.: N Engl J Med 323: 1091-96, 1990

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ANGIOTENSINOGEN (AGT) EXPRESSION BY ADPKD KIDNEY

Loghman-Adham, et al. Am J Physiol Renal Physiol 287:755-788, 2004

Renal Cyst Renal Tubules KDIGO

RENIN EXPRESSION BY ADPKD KIDNEY


ADPKD Kidney Normal Kidney KDIGO

ANGIOTENSIN II EXPRESSION BY ADPKD KIDNEY


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PLASMA CATECHOLAMINES IN ESSENTIAL HYPERTENSIVES (EH) AND IN HYPERTENSIVES

WITH ADPKD DIVIDED IN TWO GROUPS ACCORDING TO RENAL FUNCTION

0

100

200

300

400

500

600

Plasma norepinephrine Plasma epinephrine

EH s ADPKD without renal failure ADPKD with renal failure

*p< 0.001 and **p<0.01 vs. ADPKD

Cerasola et al. Am J Nephrol 18:391-398, 1998

Con

cent

ratio

n (p

g/m

l)

*

**

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Kidney section from a 39-yr-old patient with typical ADPKD (H and E stain)

Immunohistochemical staining using an ET-1 antibody

Hocher et al. J Am Soc Nephrol 9: 1169-77, 1998.

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0

5

10

15

20

25

30

Hypertensive ADPKD Patients

Essential Hypertensive

Patients

Healthy Subjects

Endo

thel

ial-D

epen

dent

D

ilata

tion

(%)

EVIDENCE FOR IMPAIRED ENDOTHELIAL FUNCTION IN ADPKD

Kocaman et al.: Am J Kidney Dis 43:854-860, 2004

P < .01

P < .05

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Hypertensive ADPKD

Patients (n = 15)

Essential Hypertensive

Patients (n = 16)

Healthy Subjects (n = 24)

Age (y) 39.6 ± 7.2 40.8 ± 4.8 38.1 ± 8.8

Sex (M/F) 4/11 7/9 8/16

BMI (kg/m2) 25.5 ± 3.5 26.0 ± 3.2 24.7 ± 3.5

Smokers (n) 2 4 3

Systolic BP (mm Hg) 138 ± 18 * 134 ± 14 * 119 ± 14

Diastolic BP (mm Hg) 85 ± 11 ** 77 ± 13 75 ± 9

CrCl (ml/min/1.73 m2) 91 ± 29 112 ± 14 105 ± 12

Total cholesterol (mg/dl)

195 ± 23 179 ± 29 180 ± 30

Triglycerides (mg/dl) 121 ± 37 115 ± 35 114 ± 37

LVMI (g/m2) 132 ± 23 *** 111 ± 16 **** 95 ± 17

PATIENT CHARACTERISTICS

Kocaman et al.: Am J Kidney Dis 43:854-860, 2004

* P < 0.01 vs. healthy subjects; ** P < 0.005 vs. healthy subjects; *** P = 0.02 vs. essential hypertensive patients, P < 0.0001 vs. healthy subjects; **** P < 0.005 vs. healthy subjects

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Percentage of LVH in ADPKD Patients

020

4060

Hypertensive Normotensive

Perc

ent w

ith L

VH

ADPKD Patients

48

23

Chapman, Schrier, et al.: J Am Soc Nephrol 8:1292-1297, 1997

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Correlation Between Blood Pressure and Left Ventricular Hypertrophy in Polycystic Kidney Disease

Mean Arterial Pressure (mm Hg)

Chapman, Schrier, et al. JASN,8(8):1292-7,1997.

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Renal volume was markedly increased in hypertensive (HBP) as compared to borderline hypertensive (BBP) and

normotensive (NBP) children with ADPKD


300

200

100

P<0.002

P<0.0002

NS

NBP HBP BBP

Ren

al v

olum

e (g

eom

etric

mea

n w

ith 9

5% C

I)

0

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Effect of ACE Inhibitors on Left Ventricular Hypertrophy in ADPKD

020406080

100120140160

Baseline Year 1 Year 7

LVM

I (g/

m2 )

* **

P < 0.05 versus baseline; P < 0.01 versus year 1 and baseline

MAP mmHg 110 94 94

Ecder, Schrier, Nephrol Dial Transplant 14: 1113-16, 1999.

* **

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Introduction !   In a 7-year prospective randomized study, 79

hypertensive ADPKD patients with left ventricular hypertrophy (LVH) were randomized to standard blood pressure control (135-140/85-90 mm Hg) or rigorous blood pressure control (< 120/80 mm Hg).

!  With angiotensin converting enzyme inhibitor

or calcium channel blocker, amlodipine KDIGO

Mean Sitting Systolic BPs from the 4th month through year 7 of ADPKD Patients Randomized

to Rigorous (<120/80 mm Hg) or Standard 135-140/85-90 mm Hg) BP Control

110

115

120

125

130

135

140

4 12 20 28 36 44 52 60 68 76 84 92

Time in Months

Syst

olic

Blo

od P

ress

ure

(mm

Hg)

StandardRigorous

P < 0.0001

Schrier et al. JASN, 2002 July;13(7):1733-9.

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Mean Sitting Diastolic BPs from the 4th month through year 7 of ADPKD Patients Randomized

to Rigorous (<120/80 mm Hg) or Standard 135-140/85-90 mm Hg) BP Control

70

75

80

85

90

95

4 12 20 28 36 44 52 60 68 76 84 92

Time in Months

Dia

stol

ic B

lood

Pre

ssur

e (m

m H

g)

StandardRigorous

P < 0.0001


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Effect of Rigorous versus Standard BP Control on Left Ventricular Mass Index in ADPKD

Patients Over 7 years

8090

100110120130140150160170

0 1 2 3 4 5 6 7 8

Time in Years

Left

Vent

ricul

ar M

ass

(g/m

2 )

Standard

Rigorous

P = 0.006


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Effect of BP Control with Amlodipine versus Enalapril on Left Ventricular Mass Index in

ADPKD Patients Over 7 Years

100

110

120

130

140

150

160

170

0 1 2 3 4 5 6 7 8

Time in Years

Left

Vent

ricul

ar M

ass

(g/m

2)

AmlodipineEnalapril


P < 0.01 KDIGO

unique features of hypertension in adpkd · unique features of hypertension in adpkd robert w....

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