unique features of hypertension in adpkd · unique features of hypertension in adpkd robert w....
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![Page 1: Unique Features of Hypertension in ADPKD · Unique Features of Hypertension in ADPKD Robert W. Schrier, MD Professor of Medicine University of Colorado Denver School of Medicine .',*2](https://reader030.vdocuments.net/reader030/viewer/2022041112/5f17dff676e03677de37dba4/html5/thumbnails/1.jpg)
Unique Features of Hypertension in ADPKD
Robert W. Schrier, MD Professor of Medicine
University of Colorado Denver School of Medicine
KDIGO
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Disclosures Dr. Robert W. Schrier serves as an
Advisor to Novartis, Jannsen, Ikaria, and Otsuka Pharmaceuticals.
KDIGO
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0102030405060708090100
20-34 35-44 45-54
Perc
enta
ge w
ith h
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.
KDIGO
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0
10
20
30
40
50
60
70
80
20-34 35-44 45-54
Perc
enta
ge w
ith h
yper
tens
ion
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.
KDIGO
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0102030405060708090100
0-19 20-34 35-44 45-54
Perc
enta
ge w
ith h
yper
tens
ion
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.
KDIGO
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0
10
20
30
40
50
60
70
80
0-19 20-34 35-44 45-54
Perc
enta
ge w
ith h
yper
tens
ion
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.
KDIGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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
IGO
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Correlation between diastolic blood pressure and renal volume in 85 ADPKD children
Cadnapaphornchai, Schrier, et al. Kidney Int 74; 1192-96, 2008
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
KDIGO
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NORMAL RENAL VASCULATURE
KDIGO
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RENAL VASCULATURE IN ADPKD
KDIGO
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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
IGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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
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RENIN EXPRESSION BY ADPKD KIDNEY
Loghman-Adham, et al. Am J Physiol Renal Physiol 287:755-788, 2004
ADPKD Kidney Normal Kidney KDIGO
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ANGIOTENSIN II EXPRESSION BY ADPKD KIDNEY
Loghman-Adham, et al. Am J Physiol Renal Physiol 287:755-788, 2004
KDIGO
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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)
*
**
KDIGO
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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.
KDIGO
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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
KDIGO
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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
KDIGO
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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
KDIGO
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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.
KDIGO
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Renal volume was markedly increased in hypertensive (HBP) as compared to borderline hypertensive (BBP) and
normotensive (NBP) children with ADPKD
Cadnapaphornchai, Schrier, et al. Kidney Int 74; 1192-96, 2008
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
KDIGO
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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.
* **
KDIGO
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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
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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.
KDIGO
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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
Schrier et al. JASN, 2002 July;13(7):1733-9.
KDIGO
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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
Schrier et al. JASN, 2002 July;13(7):1733-9.
KDIGO
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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
Schrier et al. JASN, 2002 July;13(7):1733-9.
P < 0.01 KDIGO