Transcript American Society of Nephrology

American Society of Nephrology Presents
RENAL WEEKENDS: HYPERTENSION
Highlights from of the
American Society of Nephrology 41th Annual Meeting
November 4-8, 2008
HEMODIALYSIS
The Growing Problem of Intradialytic
Hypertension
American Society Nephrology
Annual Meeting – November 2008
Jula K. Inrig, MD, MHS
Assistant Professor
UT Southwestern Medical Center
P<0.00
01
P=0.2
6
5
4
3.9 3.8
P=0.00
02
3.7
3.1
2.7 2.6
3
2
IDWG%
SBP fell
SBP
unchanged
SBP
rose
SBP fell
IDWG (kg)
SBP unchanged
SBP rose
Inrig et al. KI, 2007; 71:454
Serum Creatinine (mg/dl)
P=0.0
1
No difference in
serum albumin,
calcium, phos,
PTH, cholesterol
or Hgb
Inrig et al. KI, 2007; 71:454
Adjusted HR Odds ratio
4
3
P=0.01
Every
10 mmHg increase in SBP following HD was
associated
with a 20% increased odds of 2.17
2
1.85
hospitalization or death (OR 1.20,
CI 1.10-1.30,
P=0.002)
1
1
0
SBP fell
SBP unchanged
SBP rose
*Adjusted for age, race, gender, weight, IDWG,
cause of ESRD, comorbid conditions, txt group,
medications, and laboratory variables



Intradialytic hypertension is associated with
increased risk of hospitalization and death
Hemodialysis unit BP parameters can be used
to identify one particular “high-risk” group of
hypertensive HD patients – those with
intradialytic HTN
Further research is needed to determine
whether intradialytic HTN is treatable and if
treatment can improve outcomes
RESISTANT
HYPERTENSION
Resistant Hypertension
3 Big Issues
1. The doctor is not providing the right
treatment
2. The patient is not taking the pills
3. The blood pressure is not properly
measured
Diagnostic and Treatment Recommendations
Confirm Treatment Resistance
Exclude Pseudoresistance
Identify & Reverse Lifestyle Factors
Discontinue Interfering substances
Screen for Secondary HTN
Pharmacological Treatment
Refer to Specialist
Calhoun et al;
Hypertension:
2008; 51; 000
Diagnosis of Treatment Resistance
(Calhoun et al; Hypertension 2008)
• Office blood pressure >140/90 or 130/80 mm Hg in
patients with diabetes or chronic kidney disease
and
• Patient prescribed 3 or more antihypertensive
medications at optimal doses, including if possible a
diuretic
or
• Office blood pressure at goal but patient requiring 4
or more antihypertensive medications
Meta-Analysis of Home Monitoring
for Improving BP Control
(Cappuccio et al, BMJ 2004; 329,145)
Meta-Analysis of Home Monitoring
for Improving BP Control
(Cappuccio et al, BMJ 2004; 329,145)
Modest
increase in
BP control
Improved BP Control with Home BP
Monitoring and Web Control
(Green et al JAMA 2008: 299;2857)
HBPM + webbased pharmacist
% with
BP
control
Usual
Care
Usual Care
+ HBPM
31% 36%
56%
Exclude Pseudoresistance
(Calhoun et al; Hypertension 2008)
• Is patient adherent with prescribed regimen?
• Obtain home, work, or ambulatory BP
readings to exclude white coat effect
• Identify and Reverse Contributing Lifestyle
Factors
Identify and Reverse
Contributing Lifestyle Factors
(Calhoun et al; Hypertension 2008)
• Obesity
• Physical inactivity
• Excessive alcohol ingestion
• High salt, low fiber diet
Identify and Reverse
Contributing Lifestyle Factors
(Calhoun et al; Hypertension 2008)
• Obesity
• Physical inactivity
• Excessive alcohol ingestion
• High salt, low fiber diet
Medications That Can Interfere With
BP Control
(Calhoun et al; Hypertension 2008)
Nonsteroidal antiinflammatory agents, including aspirin
Selective COX-2 inhibitors
Sympathomimetic agents (decongestants, diet pills,
cocaine)
Stimulants (dexmethylphenidate, amphetamine,
modafinil)
Alcohol
Oral contraceptives
Cyclosporine
Erythropoietin
Natural licorice
Herbal compounds (ephedra or ma huang)
Secondary Causes of Resistant
Hypertension
Common
Obstructive sleep apnea
Renal parenchymal disease
Primary aldosteronism
Renal artery stenosis
Uncommon
Pheochromocytoma
Cushing’s disease
Hyperparathyroidism
Aortic coarctation
Intracranial tumor
Calhoun et al; Resistant Hypertension; Scientific Statement from AHA : Hypertension:
2008; 51; 000
Secondary Causes of Resistant
Hypertension
Common
Obstructive sleep apnea
Renal parenchymal disease
Primary aldosteronism
Renal artery stenosis
Uncommon
Pheochromocytoma
Cushing’s disease
Hyperparathyroidism
Aortic coarctation
Intracranial tumor
Calhoun et al; Resistant Hypertension; Scientific Statement from AHA : Hypertension:
2008; 51; 000
When to Suspect Sleep Apnea
High Prevalence of Sleep Apnea in
Resistant Hypertension
(Logan et al J Hypertens 2001:19:2271)
• 41 consecutive patients with 3 drug-resistant
hypertension evaluated with PSG and ABPM
• Clinic BP was 168/94 on 3.6 drugs; most were obese
• 83% had OSA (AHI >10); commoner in men (96%) than
women (65%)
• ABPM showed that 64% were non-dippers; no difference
in dipping between those with and without OSA
Concept of Treatment Resistance
Adequate
Treatment
Prescribed
Have appropriate pills
been prescribed?
Is the patient taking
the pills ?
BP
Remains
High
Is BP measured
appropriately?
Concept of Treatment Resistance
Adequate
Treatment
Prescribed
Have appropriate pills
been prescribed?
Is the patient taking
the pills ?
BP
Remains
High
Blame the Doctor
Pharmacologic Treatment
(Calhoun et al; Hypertension 2008)
• Maximize diuretic therapy, including possible
addition of mineralocorticoid receptor antagonist
• Combine agents with different mechanisms of
action
• Use of loop diuretics in patients with chronic
kidney disease and/or patients receiving potent
vasodilators (e.g., minoxidil)
Concept of Treatment Resistance
Adequate
Treatment
Prescribed
BP
Remains
High
Have appropriate pills
been prescribed?
Is the patient taking
the pills ?
Blame the Patient
Assessment of Compliance in Clinical
Practice
•
•
•
•
•
Talking to Patient
Giving Patient a Questionnaire
Checking Pill Containers
Electronic Pill Containers
Medication Possession Ratio (MPR)
Number of days of medication dispensed
Number of days between prescription refills
Use of Medication Possession Ratio
(MPR)
(Cramer et al Int J Clin Pract 2008: 62: 76)
• Used prescription dates and renewal dates:
Number of days of medication dispensed
= MPR
Number of days between prescription refills
• Reviewed publications on hypertension, diabetes,
dyslipidemia, and CHD
Main finding: 30% of days ‘on therapy’ were not
actually covered by medication
• Also: Only 59% of patients had medications for more
than 80% of days on therapy
Use of Medication Possession Ratio
(MPR)
(Cramer et al Int J Clin Pract 2008: 62: 76)
• Used prescription dates and renewal dates:
Number of days of medication dispensed
= MPR
Number of days between prescription refills
• Reviewed publications on hypertension, diabetes,
dyslipidemia, and CHD
• Main finding: 30% of days ‘on therapy’ were not
actually covered by medication
• Also: Only 59% of patients had medications for more
than 80% of days on therapy
MECHANISMS
Dietary Potassium Deficiency Is Independently
Associated with Increased Blood Pressure in a
Multi-Ethnic Population-Based Cohort
Susan Hedayati, Abu Minhajuddin, Orson Moe, Chou-Long Huang
University of Texas Southwestern Medical Center in Dallas
American Society of Nephrology 41th Annual Meeting
Free Communication Session
November 8, 2008
Hypothesis
■ Low dietary K+ intake, independent of Na+
intake, is associated with increased blood
pressure
■ This association is stronger in African
Americans than non-African American
counterparts
The Dallas Heart Study
Dallas
Heart
Study
■ Cross-sectional observational study
■ Multi-ethnic, population-based cohort
– 50% African American
– 17% Hispanic
– 50% women
■ 3,303 subjects with first void urine samples
■ Urine [K+] and urine [Na+]/[K+] ratio were analyzed
Linear Regression of Urine [K+] on
Systolic Blood Pressure
Systolic Blood Pressure by Urine [K+]
230
Systolic BP (mm Hg)
210
190
Non-African American
(AA)
170
Trend Line (Non-AA)
150
African American
130
Trend Line (AA)
110
90
70
0
100
200
Urine [K+] (meq/l)
300
Linear Regression of Urine [Na+]/[K+] on
Systolic Blood Pressure
Systolic Blood Pressure by U [Na+]/[K+]
230
Systolic BP (mm Hg)
210
190
Non-African American (AA)
170
Trend Line (Non-AA)
150
African American (AA)
130
Trend Line (AA)
110
90
70
0
10
20
Urine [Na +]/[K+]
30
40
Summary
■ Lower urine [K+] and higher urine [Na+]/[K+]
ratio correlated with higher BP
– Association was independent of demographics,
eGFR and cardiovascular risk factors
■ The magnitude of the association between
urine [K+] and BP was greater than between
urine [Na+] and BP
Conclusions
■ This analysis supports the hypothesis that dietary
K+ deficiency plays an important role in the
pathogenesis of HTN, independent of Na+ intake
■ The effect of dietary K+ on HTN may be as
important as other cardiovascular risk factors
■ The association between urine [K+] and BP was
more pronounced in African Americans, suggesting
racial differences in the pathogenesis of HTN
K+ Deficiency Increases WNK1 Expression
Huang CL and Kuo E. Nature Clinical Practice Nephrology 2007; 3(11):623-630
Outcomes in Pre-dialysis
Populations
Objectives
This study was designed to:
1) determine prospectively the relationship of 24 hr
ambulatory systolic blood pressure (24hr SBP), daytime
SBP, nighttime SBP and clinic SBP with progression of
renal disease as defined by the composite of death,
doubling of serum creatinine and dialysis
2) determine the relationship between dipping status and
progression of kidney disease
3) compare 24hr SBP, daytime SBP, nighttime SBP, clinic
SBP and dipping status as predictors of kidney disease
progression.
BP at Start of AASK Cohort Study
24hrSBP
136±18 mmHg
Nighttime SBP
134±21 mmHg
Daytime SBP
138±17 mmHg
Clinic SBP
134±17 mmHg
MAP
Mean ± SDs are presented
97±11 mmHg
Kaplan-Meier survival curves based
on various BP variables
0
10
20
30
1.0
0.8
0.6
0.4
Proportion of Patients w/o Renal Events
0.8
0.6
0.4
0.2
(94,126]
(126,140]
(140,200]
0.0
(84.9,128]
(128,142]
(142,197]
p<0.001
0.2
1.0
Kaplan-Meier Curves by Tertiles of Clinic SBP
p<0.001
0.0
Proportion of Patients w/o Renal Events
Kaplan-Meier Curves by Tertiles of 24-hour SBP
40
Months
50
60
0
10
20
30
40
Months
50
60
Kaplan-Meier survival curves based
on various BP variables
0
10
20
30
0.2
0.4
0.6
0.8
1.0
p<0.001
(77.2,125]
(125,141]
(141,210]
0.0
(92.6,130]
(130,144]
(144,200]
Proportion of Patients w/o Renal Events
1.0
0.2
0.4
0.6
0.8
p<0.001
0.0
Proportion of Patients w/o Renal Events
Kaplan-Meier Curves by Tertiles of Daytime SBP Kaplan-Meier Curves by Tertiles of Nocturnal SB
40
Months
50
60
0
10
20
30
40
Months
50
60
Summary
• In the setting of aggressive BP
management that focused on clinic BP,
our population had markedly elevated
nighttime SBP
• 24 hr, daytime, nighttime and clinic SBP
predict subsequent renal outcomes
• Dipping status at baseline did not predict
renal outcomes
Conclusion
• Continued CKD progression in the setting of
controlled clinic BP yet high nighttime BP
highlights the need for trials to determine
whether reducing nocturnal BP can retard
kidney disease progression.
ESCAPE
Intensified Blood Pressure Control Slows CKD Progression
in Children Undergoing Fixed-Dose ACE Inhibition:
Final Results of the ESCAPE Trial
Franz Schaefer
Division of Pediatric Nephrology
Center for Pediatric and Adolescent Medicine
Heidelberg University
Primary Objective of ESCAPE Trial
To evaluate the renoprotective efficacy of
intensified blood pressure control,
targeting to low- normal 24h BP,
in children with CKD receiving fixed-dose ACE inhibition
ESCAPE
468 patients screened:
Age 3-18 years
GFR 15-80 ml/min/1.73 m²
24h MAP > 50th percentile
6 months ‚run-in‘
≥ 2 months: ACEi wash-out period
Stratification according to baseline progression rate
385 patients: Ramipril 6 mg/m²
Randomisation
Group A (n=189):
‘intensified’ BP control
Target BP < 50th percentile
Group B (n=196):
‘conventional’ BP control
Target BP 50th-95th percentile
Follow-up for 5 years
2-monthly assessment of renal function, proteinuria.
6 monthly 24-hour ABPM, annual echocardiographies
ESCAPE
Patient Characteristics at Randomization
Intensified
N=189
Conventional
N=196
11.5 ± 4.1
11.5 ± 4.0
56.6
62.2
% Glom./ Hypodyspl./ other
14 / 66 / 20
12 / 71 / 17
24h MAP
89.5 ± 10.3
89.5 ± 9.5
1.53 ± 2.15
1.45 ± 1.61
9 / 18 / 24
11 / 15 / 21
46.4 ± 19.1
45.4 ± 19.9
Median GFR loss / yr
-2.4
-3.6
% progressive
48.7
52.0
33/ 18 / 49
41 / 21 / 38
Age
% male
SDS
% on diuretics / CCB / BB
Estimated GFR
% UPCR <0.5/0.5-1.5/ >1.5
2,0
90
conventional
85
*
80
*
*
*
*
*
*
*
intensified
0
6
12
18
24
30
36
42
48
Observation Period [Months]
54
60
Mean Arterial Pressure SDS
Mean Arterial Pressure [mm Hg]
Effect of Interventions on 24h Blood Pressure
1,5
1,0
0,5
*
*
*
0,0
*
*
-0,5
-1,0
0
12
24
36
48
Observation period (months)
ESCAPE
60
Renal Survival: Intention To Treat Analysis
% patients without endpoint
100
intensified
P=0.013
90
80
conventional
70
60
182
50 190
0
165
163
157
154
1
148
142
139
131
2
128
122
118
113
112
108
3
108
97
4
97
85
80
63
5
Observation Period [years]
ESCAPE
Conclusions
In children with CKD receiving a high, fixed dose of an ACE inhibitor,
renal failure progression can be slowed significantly by intensified
blood pressure control targeting to low-normal 24h MAP.
By this intervention, the risk of losing 50% GFR or attaining ESRD
within 5 years is reduced by almost 50 %
(renal survival 70.1  83.6 %).
Although more prominent in glomerulopathies, the renoprotective
benefit from intensified BP control is also significant in children with
hypo/dysplastic kidney disease.
Ongoing or recurrent proteinuria is a risk factor for progressive renal
failure even with excellent BP control.
Systolic Blood Pressure and Carotid
Intima-Media Thickness Progression
in Chronic Kidney Disease Patients
Jessica Kendrick MD1,
Michel Chonchol MD1, Hannes Gnahn MD2,
Dirk Sander MD3
1University
2INVADE
of Colorado at Denver Health Sciences Center, Aurora, CO, U.S.
Study Group, Ebersberg, Germany
3Technical
University of Munich, Munich, Germany
Hypothesis
We tested the hypotheses that participants
with a SBP <120 mmHg with or without
CKD, would have less progression of
carotid IMT and fewer cardiovascular
events than participants with a SBP >120
mmHg
Methods
Intervention Project on Cerebrovascular
Diseases and Dementia in the Community
of Ebersberg, Bavaria
Prospective, population-based study in the
elderly
Established in 2001
Subjects followed for 4 years
Sander D et al. Stroke 2006; 37:351-357
Baseline Carotid IMT According to
Baseline SBP and Kidney Function
Carotid IMT (mm)
*Fully Adjusted, p=0.001 for trend
*Adjusted for age, sex, body mass index, smoking, prevalent ischemic heart disease and stroke, cholesterol, LDL-C, HbA1c, hs-CRP,
homocysteine and usage of anti-hypertension medications, aspirin and statins. The covariate adjusted mean CIMT values (LS mean ) are shown.
Baseline Characteristics
Characteristic
NO CKD
83 ± 18
mL/min/1.73m2
N=2640
CKD
50 ± 9
mL/min/1.73m2
N=724
P-value
Age (years)
65 ± 6.6
74 ± 7.6
<0.001
Diabetes N (%)
266 (18.2)
195 (27.0)
<0.001
Hypertension N(%)
1394 (52.8)
518 (71.6)
<0.001
251 (9.5)
169 (23.3)
<0.001
1375 (52.1)
519 (71.7)
<0.001
137 ± 18
139 ± 18
0.016
Ischemic Heart
Disease N (%)
Use of
antihypertensive
medications N(%)
Baseline SBP
(mmHg)
Carotid IMT Progression According to
Baseline SBP and Kidney Function
Carotid IMT (mm/year)
*Fully Adjusted, p=0.003 for trend
*Adjusted for age, sex, body mass index, smoking, prevalent ischemic heart disease and stroke, cholesterol, LDL-C, HbA1c, hs-CRP, homocysteine,
usage of anti-hypertension medications, aspirin and statins and baseline carotid IMT. The covariate adjusted mean CIMT values (LS mean) are shown.
Vascular Events According to SBP and Kidney Function
SBP≤120mmHg/CKD-
SBP>120mmHg/CKDSBP≤120mmHg/CKD+
SBP>120mmHg/CKD+
Conclusions
A SBP >120 mmHg is associated with greater carotid
IMT progression and an increased risk of vascular
events regardless of the presence or absence of CKD
In subjects with and without CKD a SBP > 130 mmHg
predicts vascular events
In subjects with and without CKD a SBP < 120 mmHg
had similar magnitude in the association with vascular
events although it did not reach statistical significance
Large randomized trials are needed to confirm the
optimal SBP target in CKD patients
Digoxin Immune FAB Ovine
(Digibind®) Administration in
Severe Preeclampsia Reduces
the Decline in Creatinine
Clearance: Results of the DEEP
Trial
V.M. Buckalew MD, Wake Forest University
School of Medicine; T.M. Danoff MD, PhD,
GlaxoSmithKline; C.D. Adair MD, Glenveigh
Research; S.W. Graves PhD, Brigham Young
University; and N. Chauhan PhD, Protherics
PLC; for the DEEP Trial Investigators
Digibind Efficacy Evaluation in
Preeclampsia (DEEP) Trial
• Investigator initiated, industry sponsored,
multicenter pilot trial
• Randomized, double blind, placebo
controlled
• 51 patients enrolled (24 Digibind, 27
placebo) at eight US clinical centers
• ClinicalTrials.gov (Registration
# NCT00158743).
Trial Hypotheses
• Increased EDLF levels in severe PE cause
maternal vasoconstriction contributing to:
– Increased blood pressure
– Decreased renal hemodynamics
• Binding of EDLF by Digibind® would:
– Improve renal function
– Decrease need for antihypertensive drugs
DEEP Trial Design
CrCl
baseline
Primary End Point (2)
• Use of antihypertensive drugs composite*
– Initiation of antihypertensive treatment
– For patients already on antihypertensives:
change in dose, addition of new drug, or
delivery required due to failure to control
hypertension
*2-sided test, P <0.05, & 80% power to detect
difference of 35 percentage points between
groups requires 25 patients/group
Primary Efficacy Variable - Change in CrCl
(6 patients excluded)
Difference: 31mL/min
(95% CI 5 to 58 mL/min)
Summary and Conclusions
• CrCl declined significantly just prior to delivery in
•
•
•
women who received placebo
The decline was prevented by Digibind
administration
Digibind reduced the sodium pump inhibitory
activity of serum from patients with PE
The results support the hypothesis that renal
vasoconstriction in severe PE is due in part to
increased circulating EDLF
DIABETIC NEPHROPATHY
Diabetologia 2004;47(11):1936-9
• Significantly enhanced rate of GFR
decline in breakthroughs compared to
non-breakthroughs
• 5 ml/min/year vs. 2.4 ml/min/year
Change in serum aldosterone during RAAS blockade
Aldosterone Breakthrough
+
Aldosterone
breakthrough
0
-
6 months
Expected decline
in aldosterone on
ACE-I and/or ARB
therapy.
12 months
Twenty-Four Hour Urinary Protein Excretion in
Subjects with Resistant Hypertension
Pimenta, E. et al. Hypertension 2008;51:339-344
Effects on Blood Pressure and GFR
• Blood Pressure
» In 6/15 studies, MRB
therapy significantly
reduced blood pressure
» (+) Brought subjects who
were not at goal blood
pressure for proteinuric
CKD either to goal or
much closer to goal
» (-) Some of the proteinuria
reductions could be
attributed to blood
pressure reduction
• Renal Function
» “Significant” ↓ GFR in 4/15
studies
» Did not change CKD stage
(e.g., eGFR 7467)
» May reflect short-term,
physiologic response to
higher RAAS blockade
» Some of the proteinuria
reductions could be due
to GFR reduction
Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE
inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis. 2008;51(2):199-211
Hypotheses
 Addition of either an ARB or a MRA to a
maximally-dosed ACEi-based regimen will
afford greater renoprotection than the
ACEi-based regimen alone.
 Added value of a MRA is specific for
aldosterone and is not explained solely on
the basis of reduced time-integral blood
pressure burden.

Randomized Double-Blind Placebo-Controlled Trial
Double-Blind
Run-in
W/O
Lisinopril 80 mg daily and SBP goal <130 mmHg
Placebo daily
Two 24-hour urine
UACR > 300 mg/g
at end of run-in
Losartan 100 mg daily
Spironolactone 25 mg daily
*
-4
-2
0
*
12
24
36
*
*
48
52
Weeks
* Inpatient CTRC :
24 hour ABP, creatinine clearance and urine albumin/creatinine ratio
Urine Albumin Creatinine Ratio
(Median % change from baseline)
UACR (% change)
80
60
* P = 0.04 vs baseline
* P < 0.001 vs baseline
† P = 0.007 spironloactone vs placebo
40
20
0
-13.5%
-20
-27%
-40
*
-51% †
*
-60
-80
0
24
48
52
21
21
17
21
18
17
Week
Placebo
Losartan
Spironolactone
27
26
27
22
23
20
24-Hour Systolic Blood Pressure
(Median % change from baseline)
24-hr SBP (% change)
20
15
10
5
0
-5
-10
-15
-20
Placebo
Losartan
Spironolactone
0
24
No. of subjects
Week
27
26
27
22
23
20
48
21
21
17
52
21
18
17
Creatinine Clearance
CrCl (% change)
20
(Median % change from baseline)
0
-20
-40
0
24
48
52
21
21
17
21
18
17
Week
No. of subjects
Placebo
Losartan
Spironolactone
27
26
27
22
23
20
Serum Potassium Concentration
(mean)
Spironolactone vs Placebo, p < 0.001
5.6
Losartan vs Placebo, p = 0.03
Serum K (mEq/L)
Spironolactone vs Losartan, p = 0.05
5.2
Mean serum K
4.8
5.0 (0.51)
4.7 (0.33)
4.4
4.5 (0.38)
Placebo
Losartan
Spironolactone
4.0
0.0
01 4
8
12 16 20 24 28 32 36 40 44 48
Week
Conclusions
• Addition of spironolactone, afforded
greater renoprotection than a maximallydosed ACEi-based regimen.
• Added value of spironolactone is not
explained solely on the basis of reduced
time-integral (24-hour) blood pressure
burden.
Efficacy and Safety of the Endothelin
Receptor Antagonist Avosentan
in Diabetic Nephropathy
Viberti GC,Mann JFE, Jamerson K, Ruilope L,
Marshall SM, Erhardt LR, Ford I, Littke T, Lindhe J,
Kuranoff S for the ASCEND Study Group
King’s College London School of Medicine
King’s College London, UK
ASCEND: Study Design
 Randomised, double-blind, placebo-controlled, parallel
group, multi-centre study, investigating the use of
avosentan on top of RAS blockade in type 2 diabetes
with nephropathy
 Sample size calculation: to detect a risk reduction of
25% for 25mg vs placebo and 30% for 50mg vs
placebo with a 90% power at α=0.01 at 36 months
required 747 events and resulted in a sample size of
788 patients per group
ASCEND: Study Design
Randomization
Double blind treatment phase
Placebo
group
Run in
2 wk
25 mg
avosentan
group
Screening
0
42
Assessments: monthly for safety
2 monthly for efficacy
50 mg
avosentan
months group
ASCEND: Absolute and Percent Median (IQ range)
Albumin/Creatinine Ratio Changes
0
ACR (mg/mmol)
300
250
**
200
150
100
*
173
167
165
167
161
100
*
105
89
89
50
0
-8
-10
50mg
-10
-20
-30
-38
-41
-40
-44
-49
-50
-60
*
*
-70
*
*
25mg
50mg
-80
25mg
*p<0.001
ACR change from baseline (%)
350
placebo
0 Months
3 Months
6 Months
placebo
ASCEND: Frequency of CHF and Fluid Overload
1.0
*
*
46.4
46.9
40
33.8
20
Ratio of patients without CHF/FO
% Patients with CHF/fluid overload
60
0.9
0.8
0.7
0.6
0.5
0.4
0.3
Placebo
Avosentan 25mg
Avosentan 50mg
0.2
0.1
0.0
0
25 mg
50 mg
Placebo
(n=455)
(n=479)
(n=461)
* p<0.01 vs placebo
0.0
No. at risk:
25 mg
455
50 mg
478
Placebo 459
2.0
4.0
Time (months)
6.0
299
325
364
177
179
215
225
230
268
Renal Mechanisms of Fluid Retention Induced
by the Endothelin Receptor Antagonist
Avosentan in healthy subjects
J. Smolander, M. Maillard, B. Vogt, T. Littke, T. Hengelage and M. Burnier
Department of Nephrology and Hypertension
Centre Hospitalier Universitaire Vaudois of Lausanne, Switzerland
Introduction
•
Endothelin-1 (ET-1) is a potent vasoconstrictor agent which affects
renal function
•
ET-1 functions in a paracrine and autocrine manner
- ETA receptors:
a) vasoconstriction and growth-promoting functions
- ETB receptors:
a) vasodilation and inhibition of growth and inflammation
(NO, prostacyclin)
b) natriuresis, diuresis
•
ETA receptor blockade may be useful to lower proteinuria
•
Fluid overload is a known adverse effect of endothelin receptor
antagonists
Objective of the study
To investigate the acute and sustained effects of increasing
doses of the ETA receptor antagonist avosentan on:
– Renal and systemic hemodynamics
– Renal sodium handling and fluid retention
Study design
•
Open-label, placebo-controlled,
randomized two-period cross-over study
•
23 healthy subjects
•
Oral doses of 0.5 mg, 1.5 mg,
5 mg or 50 mg once daily
•
N = 8-9 per dose
Clinical parameters
• Body weight, blood pressure, heart rate
• Clinical chemistry and haematology
• Renal hemodynamics (inulin / PAH, creatinine)
• Urinary electrolytes (Na+, K+, endogenous Li+)
Effect of increasing doses of avosentan (SPP)
on fractional excretion of sodium
Day 1
Day 8
D FENa (6h-baseline)
D FENa (6h-baseline)
1.5
1.5
1
1
0.5
0.5
0
0
Placebo
SPP 0.5
N= 8-9 per group
SPP 1.5
SPP 5
SPP 50
Placebo
p for trend <0.05
SPP 0.5
SPP 1.5
SPP 5
SPP 50
Effect of increasing doses of avosentan (SPP)
on proximal reabsorption of sodium
Day 1
Day 8
D PRNa (6h-baseline) (%)
D PRNa (6h-baseline) (%)
12
12
10
10
8
8
6
6
4
4
2
2
0
0
-2
-4
-2
Placebo
SPP 0.5
SPP 1.5
SPP 5
SPP 50
Placebo
p for trend <0.01
SPP 0.5
SPP 1.5
SPP 5
SPP 50
Effect of increasing doses of avosentan on
body weight
*
2.5
2.0
*
1.5
Delta BW
(kg)
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
Placebo
*
0.5 mg
1.5 mg
5 mg
50 mg
max
Mean and median significantly
different from 0 (one sample t-test
and Wilcoxon signed-rank test)
75% percentile
median
25% percentile
min
Conclusions
• Avosentan causes :
 peripheral vasodilation (decrease in DBP, headache)
 fluid retention and edema by increase in (proximal) salt and
water retention by the kidney in healthy subjects
• This effect is dose-dependent and predominates at higher doses
probably due to a lack of receptor selectivity at these high doses
• Avosentan fluid retention and edema are most likely not cardiac in
origin
• These data support further investigation of the anti-proteinuric
effect of avosentan in diabetic kidney disease at doses of 5 mg/d
and below
LITERATURE REVIEW
- Literature Review Hypertension and CKD
“The Good, The Bad and The Ugly”
Karen A. Griffin, M.D.
Professor of Medicine
Loyola University Medical Center
Renal Section Chief
Edward Hines, Jr. VA
“The Bad”
AASK Cohort Study
Event Rates per
100 Person-Years
(Doubling of Serum Creatinine,
ESRD or Death)
7.2
ACE-I
(40-50%)
136/82 mmHg
Event Rates per
100 Person-Years
(Doubling of Serum Creatinine,
ESRD or Death)
7.8
ACE-I
(85-90%)
133/78 mmHg
Appel LJ, et al. Arch Intern Med 2008; 168(8):832-839
Limitations of the Cohort Study

“AASK trial phase and the cohort study adjusted
antihypertensive therapy based on traditional
office BP readings rather than on ambulatory BP
readings.”

“Sustained nocturnal BP, which cannot be
detected by office measurements, is commonplace
in the setting of CKD and may lead to rapid CKD
progression.”
Appel LJ, et al. JAMA 2008; 168(8): 832-839
CKD PROGRESSION IN AFRICAN-AMERICANS
GENETIC FACTORS
Kopp, et al: MYH9 is a major-effect risk gene for focal
segmental glomerulosclerosis.
Nature Genetics 2008; 40:1175-1184
Kao, et al: MYH9 is associated with nondiabetic end-stage
renal disease in African Americans.
Nature Genetics 2008; 40:1185-1192
Freedman BI, and Sedor JR: Hypertension-associated kidney
disease: Perhaps no more.
J Am Soc Nephrol 2008; 19:2047-2051
Effect of ACEI+ARB vs ACEI Alone on Proteinuria
MacKinnon et al. Am J Kidney Dis 2006; 48:8-20, Doulton T, et al. Hypertension 2005;45:880-886,
Kunz R, et al. Ann Intern Med 2008; 148:30-48, Catapano F, et al. AJKD 2008; 52(3): 475-485
Net Change in Ambulatory SBP and Clinic SBP for
ACE-ARB Combination versus ACE-I Alone
Doulton T, et al. Hypertension 2005;45:880-886, MacKinnon et al. Am J Kidney Dis 2006; 48:8-20,
Kunz R, et al. Ann Intern Med 2008; 148:30-48, Catapano F, et al. AJKD 2008; 52(3): 475-485
Copyright ©2005 American Heart Association
ONTARGET: Key Results
Number of Patients: Ramipril 8,576; Telmisartan 8,542; Combination 8,502
Outcome
Risk ratio (95% CI),
telmisartan vs ramipril
P
Risk ratio (95% CI),
combination therapy vs
ramipril
P
CV death/MI/
stroke/ CHF
hospitalization
CV death/MI/strokea
1.01 (0.94–1.09)
NS
0.99 (0.92–1.07)
NS
0.99 (0.91–1.07)
NS
1.00 (0.93–1.09)
NS
Renal Impairmentb
1.04 (0.96-1.14)
NS
1.33 (1.22-1.44)
0.001
a.
Primary end point in the HOPE trial; b. Secondary Outcome
Yusuf S et al. N Engl J Med 2008: 358:1547-1559.
ONTARGET: Renal Outcomes
All dialysis,
doubling, death
1.00 (0.92-1.09)
NS
1.09 (1.01-1.18)
0.037
All dialysis
and doubling
1.09 (0.89-1.34)
NS
1.24 (1.01-1.51)
0.038
Mann JF et al. Lancet 2008; 372:547-553
ONTARGET: Renal Outcomes
Outcome
Δ BP (mmHg)
Ramipril Telmisartan
-
Combination
P
-2.4
- 0.9
?
eGFR (ml/min/1.73m2)
-2.82 (17)
-4.12 (17)
-6.11 (17)
UACR (mg/mmol)
1.32
1.25
1.22
<0.0001
0.0028
Adverse Effects
Hyperkalemia
Hypotension
283 (3.3)
149 (1.7)
287 (3.4)
480 (5.6)
229 (2.7)
406 (4.8)
ARF
60 (0.7)
68 (0.8)
94 (1.1)
0.001
Acute dialysis
13 (0.15)
20 (0.23)
28 (0.33)
0.02
0.001
0.001
Mann JF et al. Lancet 2008; 372:547-553
Phillips CO et al. Arch Intern Med 2007; 167: 1930-1936
Proteinuria
Grams/24 hour
BP, mmHg
Mean
mmHg
Blunting of Antiproteinuric Efficacy of ACE Inhibition
by High Sodium Intake can be Restored by HCTZ
50 mmol
200 mmol
50 mg
50 mmol 200 mmol
50 mg
Buter H, et al. Nephrol Dial Transplant 1998; 13:1682-1685
Vogt L, et al. J Am Soc Nephrol 2008; 19:999-1007
Preventing Renal Disease Progression
-Therapeutic Principles-
• Achieving BP goals – normotension around the clock
(Home BP monitoring supplemented by ABPM)
 Requires adequate use of diuretics
 RAS Blockade
– Synergistic with diuretics
– Minimize potassium and magnesium losses
– Counteracts pro-hyperglycemic effects of diuretics
– Effective and well-tolerated
 Calcium Channel Blockers
-Ensure normotension
-Monitor proteinuria