American Society of Nephrology Presents
RENAL WEEKENDS: HYPERTENSION
Highlights from of the American Society of Nephrology 41th Annual Meeting
November 4-8, 2008
HEMODIALYSIS
Jula K. Inrig, MD, MHSAssistant Professor
UT Southwestern Medical Center
The Growing Problem of Intradialytic Hypertension
American Society NephrologyAnnual Meeting – November 2008
P<0.0001 P=0.2
6 P=0.0002
Inrig et al. KI, 2007; 71:454
SBP fell SBP unchanged
SBP rose
P=0.01
No difference in serum albumin, calcium, phos, PTH, cholesterol or Hgb
Inrig et al. KI, 2007; 71:454
Seru
m C
reati
nin
e
(mg
/dl)
P=0.01
*Adjusted for age, race, gender, weight, IDWG, cause of ESRD, comorbid conditions, txt group, medications, and laboratory variables
Every Every 10 mmHg10 mmHg increase in SBP following HD was increase in SBP following HD was associated with a associated with a 20%20% increased odds of increased odds of hospitalization or death (hospitalization or death (OR 1.20OR 1.20, CI 1.10-1.30, , CI 1.10-1.30, P=0.002)P=0.002)
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 Hypertension3 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 SpecialistCalhoun 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)
% with BP control
Usual Care
Usual Care + HBPM
HBPM + web-based pharmacist
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 aspirinSelective COX-2 inhibitorsSympathomimetic agents (decongestants, diet pills, cocaine)Stimulants (dexmethylphenidate, amphetamine, modafinil)AlcoholOral contraceptivesCyclosporineErythropoietinNatural licoriceHerbal compounds (ephedra or ma huang)
Secondary Causes of Resistant Hypertension
CommonObstructive sleep apneaRenal parenchymal diseasePrimary aldosteronismRenal artery stenosisUncommonPheochromocytomaCushing’s diseaseHyperparathyroidismAortic coarctationIntracranial tumor
Calhoun et al; Resistant Hypertension; Scientific Statement from AHA : Hypertension: 2008; 51; 000
Secondary Causes of Resistant Hypertension
CommonObstructive sleep apneaRenal parenchymal diseasePrimary aldosteronismRenal artery stenosisUncommonPheochromocytomaCushing’s diseaseHyperparathyroidismAortic coarctationIntracranial 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
BP Remains High
Have appropriate pills been prescribed?
Is the patient taking the pills ?
Is BP measured appropriately?
Concept of Treatment Resistance
Adequate Treatment Prescribed
BP Remains High
Have appropriate pills been prescribed?
Is the patient taking the pills ?
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 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
= MPR
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 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
= MPR
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 HuangUniversity of Texas Southwestern Medical Center in Dallas
American Society of Nephrology 41th Annual MeetingFree 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
■ 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
DallasDallasHeart Heart StudyStudy
Linear Regression of Urine [K+] on Systolic Blood Pressure
Systolic Blood Pressure by Urine [K+]
70
90
110
130
150
170
190
210
230
0 100 200 300
Urine [K+] (meq/l)
Sys
toli
c B
P (
mm
Hg
) Non-African American(AA)
Trend Line (Non-AA)
African American
Trend Line (AA)
Linear Regression of Urine [Na+]/[K+] on Systolic Blood Pressure
Systolic Blood Pressure by U [Na+]/[K+]
70
90
110
130
150
170
190
210
230
0 10 20 30 40
Urine [Na+]/[K+]
Sys
toli
c B
P (
mm
Hg
)
Non-African American (AA)
Trend Line (Non-AA)
African American (AA)
Trend Line (AA)
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 97±11 mmHg
Mean ± SDs are presented
Kaplan-Meier survival curves based on various BP variables
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Kaplan-Meier Curves by Tertiles of 24-hour SBP
Months
Pro
por
tion
of P
atie
nts
w/o
Ren
al E
vent
s
(84.9,128](128,142](142,197]
p<0.001
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Kaplan-Meier Curves by Tertiles of Clinic SBP
Months
Pro
por
tion
of P
atie
nts
w/o
Ren
al E
vent
s
(94,126](126,140](140,200]
p<0.001
Kaplan-Meier survival curves based on various BP variables
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Kaplan-Meier Curves by Tertiles of Daytime SBP
Months
Pro
por
tion
of P
atie
nts
w/o
Ren
al E
vent
s
(92.6,130](130,144](144,200]
p<0.001
0 10 20 30 40 50 60
0.0
0.2
0.4
0.6
0.8
1.0
Kaplan-Meier Curves by Tertiles of Nocturnal SBP
Months
Pro
por
tion
of P
atie
nts
w/o
Ren
al E
vent
s
(77.2,125](125,141](141,210]
p<0.001
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 NephrologyCenter for Pediatric and Adolescent Medicine
Heidelberg University
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
Primary Objective of ESCAPE Trial
ESCAPE
468 patients screened:Age 3-18 years
GFR 15-80 ml/min/1.73 m²24h MAP > 50th percentile
6 months ‚run-in‘≥ 2 months: ACEi wash-out period
385 patients: Ramipril 6 mg/m²
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
Randomisation
Stratification according to baseline progression rate
ESCAPE
IntensifiedN=189
ConventionalN=196
Age 11.5 ± 4.1 11.5 ± 4.0
% male 56.6 62.2
% Glom./ Hypodyspl./ other 14 / 66 / 20 12 / 71 / 17
24h MAP 89.5 ± 10.3 89.5 ± 9.5
SDS 1.53 ± 2.15 1.45 ± 1.61
% on diuretics / CCB / BB 9 / 18 / 24 11 / 15 / 21
Estimated GFR 46.4 ± 19.1 45.4 ± 19.9
Median GFR loss / yr -2.4 -3.6
% progressive 48.7 52.0
% UPCR <0.5/0.5-1.5/ >1.5 33/ 18 / 49 41 / 21 / 38
Patient Characteristics at Randomization
Effect of Interventions on 24h Blood Pressure
ESCAPE
Observation Period [Months]
0 6 12 18 24 30 36 42 48 54 60
Mea
n A
rter
ial P
ress
ure
[m
m H
g]
80
85
90
* * ** * * *
*
intensified
conventional
* * * **
ESCAPE
Renal Survival: Intention To Treat Analysis
P=0.013
100
90
80
70
60
50
% p
atie
nts
wit
ho
ut
end
po
int
intensified
conventional
Observation Period [years]
0 1 2 3 4 5
182 165 157 148 139 128 118 112 108 97 80 190 163 154 142 131 122 113 108 97 85 63
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.
Conclusions
Systolic Blood Pressure and Carotid Systolic Blood Pressure and Carotid Intima-Media Thickness Progression Intima-Media Thickness Progression in Chronic Kidney Disease Patientsin Chronic Kidney Disease Patients
Jessica Kendrick MDJessica Kendrick MD11,,
Michel Chonchol MDMichel Chonchol MD11, Hannes Gnahn MD, Hannes Gnahn MD22, , Dirk Sander MDDirk Sander MD33
11University of Colorado at Denver Health Sciences Center, Aurora, CO, U.S.University of Colorado at Denver Health Sciences Center, Aurora, CO, U.S.
22INVADE Study Group, Ebersberg, GermanyINVADE Study Group, Ebersberg, Germany
33Technical University of Munich, Munich, GermanyTechnical University of Munich, Munich, Germany
HypothesisHypothesis
We tested the hypotheses that participants We tested the hypotheses that participants with a SBP <120 mmHg with or without with a SBP <120 mmHg with or without CKD, would have less progression of CKD, would have less progression of carotid IMT and fewer cardiovascular carotid IMT and fewer cardiovascular events than participants with a SBP >120 events than participants with a SBP >120 mmHgmmHg
MethodsMethods
Intervention Project on Cerebrovascular Intervention Project on Cerebrovascular Diseases and Dementia in the Community Diseases and Dementia in the Community of Ebersberg, Bavariaof Ebersberg, Bavaria
Prospective, population-based study in the Prospective, population-based study in the elderly elderly
Established in 2001Established in 2001
Subjects followed for 4 yearsSubjects followed for 4 years
Sander D et al. Stroke 2006; 37:351-357
*Adjusted for age, sex, body mass index, smoking, prevalent ischemic heart disease and stroke, cholesterol, LDL-C, HbA1c, hs-CRP, 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.homocysteine and usage of anti-hypertension medications, aspirin and statins. The covariate adjusted mean CIMT values (LS mean ) are shown.
Car
oti
d IM
T (
mm
)
Baseline Carotid IMT According to Baseline Carotid IMT According to Baseline SBP and Kidney FunctionBaseline SBP and Kidney Function
0.78
0.81
0.84
0.87
0.9
SBP >120m
mHg/CKD-
SBP >120m
mHg/CKD+
*Fully Adjusted, p=0.001 for trend
Baseline CharacteristicsBaseline Characteristics
CharacteristicCharacteristic NO CKDNO CKD
83 ± 18 83 ± 18 mL/min/1.73mmL/min/1.73m22
N=2640N=2640
CKDCKD
50 ± 9 50 ± 9 mL/min/1.73mmL/min/1.73m22
N=724N=724
P-valueP-value
Age (years)Age (years) 65 ± 6.665 ± 6.6 74 ± 7.674 ± 7.6 <0.001<0.001
Diabetes N (%)Diabetes N (%) 266 (18.2)266 (18.2) 195 (27.0)195 (27.0) <0.001<0.001
Hypertension N(%)Hypertension N(%) 1394 (52.8)1394 (52.8) 518 (71.6)518 (71.6) <0.001<0.001
Ischemic Heart Ischemic Heart Disease N (%)Disease N (%) 251 (9.5)251 (9.5) 169 (23.3)169 (23.3) <0.001<0.001
Use of Use of antihypertensive antihypertensive medications N(%)medications N(%)
1375 (52.1)1375 (52.1) 519 (71.7)519 (71.7) <0.001<0.001
Baseline SBP Baseline SBP (mmHg)(mmHg)
137 ± 18137 ± 18 139 ± 18139 ± 18 0.0160.016
0
0.005
0.01
0.015
0.02
SBP > 120m
mHg/C
KD -
SBP >120mmHg/C
KD +
Carotid IMT Progression According to Carotid IMT Progression According to Baseline SBP and Kidney FunctionBaseline SBP and Kidney Function
Car
oti
d IM
T (
mm
/yea
r)
*Adjusted for age, sex, body mass index, smoking, prevalent ischemic heart disease and stroke, cholesterol, LDL-C, HbA1c, hs-CRP, homocysteine, 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.usage of anti-hypertension medications, aspirin and statins and baseline carotid IMT. The covariate adjusted mean CIMT values (LS mean) are shown.
*Fully Adjusted, p=0.003 for trend
Vascular Events According to SBP and Kidney FunctionVascular Events According to SBP and Kidney Function
SBP>120mmHg/CKD+
SBP≤120mmHg/CKD+
SBP>120mmHg/CKD-
SBP≤120mmHg/CKD-
ConclusionsConclusionsA SBP >120 mmHg is associated with greater carotid A SBP >120 mmHg is associated with greater carotid IMT progression and an increased risk of vascular IMT progression and an increased risk of vascular events regardless of the presence or absence of CKDevents regardless of the presence or absence of CKD
In subjects with and without CKD a SBP > 130 mmHg In subjects with and without CKD a SBP > 130 mmHg predicts vascular eventspredicts vascular events
In subjects with and without CKD a SBP < 120 mmHg In subjects with and without CKD a SBP < 120 mmHg had similar magnitude in the association with vascular had similar magnitude in the association with vascular events although it did not reach statistical significanceevents although it did not reach statistical significance
Large randomized trials are needed to confirm the Large randomized trials are needed to confirm the optimal SBP target in CKD patientsoptimal SBP target in CKD patients
Digoxin Immune FAB Ovine Digoxin Immune FAB Ovine (Digibind(Digibind®) Administration ®) Administration
in Severe Preeclampsia in Severe Preeclampsia Reduces the Decline in Reduces the Decline in Creatinine Clearance: Creatinine Clearance:
Results of the DEEP TrialResults of the DEEP TrialV.M. Buckalew MD, Wake Forest University V.M. Buckalew MD, Wake Forest University School of Medicine; T.M. Danoff MD, PhD, School of Medicine; T.M. Danoff MD, PhD, GlaxoSmithKline; C.D. Adair MD, Glenveigh GlaxoSmithKline; C.D. Adair MD, Glenveigh Research; S.W. Graves PhD, Brigham Young Research; S.W. Graves PhD, Brigham Young University; and N. Chauhan PhD, Protherics University; and N. Chauhan PhD, Protherics PLC; for the DEEP Trial Investigators PLC; for the DEEP Trial Investigators
Digibind Efficacy Evaluation in Digibind Efficacy Evaluation in Preeclampsia (DEEP) TrialPreeclampsia (DEEP) Trial
• Investigator initiated, industry Investigator initiated, industry sponsored, multicenter pilot trialsponsored, multicenter pilot trial
• Randomized, double blind, placebo Randomized, double blind, placebo controlledcontrolled
• 51 patients enrolled (24 Digibind, 27 51 patients enrolled (24 Digibind, 27 placebo) at eight US clinical centersplacebo) at eight US clinical centers
• ClinicalTrials.gov (Registration ClinicalTrials.gov (Registration
# NCT00158743).# NCT00158743).
Trial HypothesesTrial Hypotheses
• Increased EDLF levels in severe PE cause Increased EDLF levels in severe PE cause maternal vasoconstriction contributing to:maternal vasoconstriction contributing to:– Increased blood pressureIncreased blood pressure– Decreased renal hemodynamicsDecreased renal hemodynamics
• Binding of EDLF by DigibindBinding of EDLF by Digibind®® would: would:– Improve renal functionImprove renal function– Decrease need for antihypertensive drugsDecrease need for antihypertensive drugs
DEEP Trial DesignDEEP Trial Design
CrCl baseline
Primary End Point (2)Primary End Point (2)
• Use of antihypertensive drugs compositeUse of antihypertensive drugs composite**– Initiation of antihypertensive treatmentInitiation of antihypertensive treatment– For patients already onFor patients already on
antihypertensives: change in dose, antihypertensives: change in dose, addition of new drug, oraddition of new drug, or delivery delivery required due to failure to control required due to failure to control hypertensionhypertension
**2-sided test, P <0.05, & 80% power to 2-sided test, P <0.05, & 80% power to detect difference of 35 percentage points detect difference of 35 percentage points between groups requires 25 patients/groupbetween groups requires 25 patients/group
Primary Efficacy Variable - Change in Primary Efficacy Variable - Change in CrCl CrCl (6 patients excluded)(6 patients excluded)
Difference: 31mL/min (95% CI 5 to 58 mL/min)
Summary and ConclusionsSummary and Conclusions
• CrCl declined significantly just prior to CrCl declined significantly just prior to delivery in women who received placebo delivery in women who received placebo
• The decline was prevented by Digibind The decline was prevented by Digibind administrationadministration
• Digibind reduced the sodium pump Digibind reduced the sodium pump inhibitory activity of serum from patients inhibitory activity of serum from patients with PEwith PE
• The results support the hypothesis that The results support the hypothesis that renal vasoconstriction in severe PE is due renal vasoconstriction in severe PE is due in part to increased circulating EDLFin part to increased circulating EDLF
DIABETIC NEPHROPATHY
• Significantly enhanced rate of GFR decline in breakthroughs compared to non-breakthroughs
• 5 ml/min/year vs. 2.4 ml/min/year
Diabetologia 2004;47(11):1936-9
Aldosterone BreakthroughAldosterone Breakthrough
Cha
nge
in s
erum
ald
oste
rone
dur
ing
RA
AS
blo
ckad
e
0
+
-
6 months 12 months
Expected decline in aldosterone on ACE-I and/or ARB therapy.
Aldosterone breakthrough
Pimenta, E. et al. Hypertension 2008;51:339-344
Twenty-Four Hour Urinary Protein Twenty-Four Hour Urinary Protein Excretion in Subjects with Resistant Excretion in Subjects with Resistant
HypertensionHypertension
Effects on Blood Pressure and GFREffects 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 7467)» 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
* * *
Weeks
- 4 -2
Double-Blind
0 12 24 36 48 52
Run-in W/O
Placebo daily
Spironolactone 25 mg daily
Losartan 100 mg daily
Lisinopril 80 mg daily and SBP goal <130 mmHg
Two 24-hour urine UACR > 300 mg/gat end of run-in
* Inpatient CTRC : 24 hour ABP, creatinine clearance and urine albumin/creatinine ratio
*
Week
0 24 48 52
UA
CR
(%
cha
nge)
-80
-60
-40
-20
0
20
40
60
80
Urine Albumin Creatinine Ratio (Median % change from baseline)
*†
Placebo Losartan Spironolactone
222320
212117
-13.5%
-27%
-51%
*
272627
211817
* P = 0.04 vs baseline* P < 0.001 vs baseline† P = 0.007 spironloactone vs placebo
Placebo Losartan Spironolactone
No. of subjects
272627
222320
212117
211817
24-Hour Systolic Blood Pressure (Median % change from baseline)
Week
0 24 4848 52
24-h
r S
BP
(%
cha
nge)
-20
-15
-10
-5
0
5
10
15
20
Creatinine Clearance
(Median % change from baseline)
No. of subjects
Placebo Losartan Spironolactone
272627
222320
212117
211817
Week
0 24 48 52
CrC
l (%
cha
nge)
-40
-20
0
20
Spironolactone vs Placebo, p < 0.001
Losartan vs Placebo, p = 0.03
Spironolactone vs Losartan, p = 0.05
Serum Potassium Concentration (mean)
Mean serum K
5.0 (0.51)
4.7 (0.33)
4.5 (0.38)
Week
01 4 8 12 16 20 24 28 32 36 40 44 48
Se
rum
K (
mE
q/L
)
0.0
4.0
4.4
4.8
5.2
5.6
Placebo Losartan Spironolactone
Conclusions
• Addition of spironolactone, afforded greater renoprotection than a maximally-dosed 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
Double blind treatment phase
Assessments: monthly for safety 2 monthly for efficacy
Screening
Randomization
Placebogroup
25 mgavosentan
group
50 mgavosentan
group
Run in2 wk
0 42 months
ASCEND: Absolute and Percent Median (IQ range) Albumin/Creatinine Ratio Changes
0
50
100
150
200
250
300
350
-80
-70
-60
-50
-40
-30
-20
-10
0
0 Months3 Months6 Months
25mg 50mg placebo 25mg 50mg placebo
* *
* *
*p<0.001
AC
R (
mg
/mm
ol)
AC
R c
han
ge
fro
m b
asel
ine
(%)
161
10089
167
10589
173167
165
-38
-44-41
-49
-8-10
* **
*
ASCEND: Frequency of CHF and Fluid Overload
Placebo
Avosentan 25mg
Avosentan 50mg Rat
io o
f p
atie
nts
wit
ho
ut
CH
F/F
O
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0.0 2.0 4.0 6.0
46.4 46.9
33.8
0
20
40
60
25 mg 50 mg Placebo
% P
atie
nts
wit
h C
HF
/flu
id o
verl
oad
(n=455) (n=479) (n=461)299325364
25 mg50 mgPlacebo
225230268
177179215
455478459
No. at risk:
* p<0.01 vs placebo
* *
Renal Mechanisms of Fluid Retention Induced by the Endothelin Receptor
Antagonist Avosentan in healthy subjects
Department of Nephrology and HypertensionCentre Hospitalier Universitaire Vaudois of Lausanne, Switzerland
J. Smolander, M. Maillard, B. Vogt, T. Littke, T. Hengelage and M. Burnier
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
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
Objective of the study
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
• Body weight, blood pressure, heart rate
• Clinical chemistry and haematology
• Renal hemodynamics (inulin / PAH, creatinine)
• Urinary electrolytes (Na+, K+, endogenous Li+)
Clinical parameters
0
0.5
1
1.5
Placebo SPP 0.5 SPP 1.5 SPP 5 SPP 50
0
0.5
1
1.5
Placebo SPP 0.5 SPP 1.5 SPP 5 SPP 50
FENa (6h-baseline)
N= 8-9 per group
Day 1 Day 8
FENa (6h-baseline)
Effect of increasing doses of avosentan (SPP) on fractional excretion of sodium
p for trend <0.05
-4
-2
0
2
4
6
8
10
12
Placebo SPP 0.5 SPP 1.5 SPP 5 SPP 50 -2
0
2
4
6
8
10
12
Placebo SPP 0.5 SPP 1.5 SPP 5 SPP 50
Day 1 Day 8
PRNa (6h-baseline) (%) PRNa (6h-baseline) (%)
Effect of increasing doses of avosentan (SPP) on proximal reabsorption of sodium
p for trend <0.01
Effect of increasing doses of avosentan on body weight
max
min
median
75% percentile
25% percentile
Mean and median significantly different from 0 (one sample t-test and Wilcoxon signed-rank test)
*
Delta BW(kg)
Placebo 0.5 mg 1.5 mg 5 mg 50 mg-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
*
*
• 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
Conclusions
LITERATURE REVIEW
- Literature Review -- Literature Review -Hypertension and CKDHypertension and CKD
“The Good, The Bad and The Ugly“The Good, The Bad and The Ugly””
Karen A. Griffin, M.D.Professor of Medicine
Loyola University Medical CenterRenal Section Chief
Edward Hines, Jr. VA
AASK Cohort Study
Appel LJ, et al. Arch Intern Med 2008; 168(8):832-839
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
“The Bad”
Limitations of the Cohort StudyLimitations 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
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
Effect of ACEI+ARB vs ACEI Alone on Proteinuria
Copyright ©2005 American Heart Association
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
Yusuf S et al. N Engl J Med 2008: 358:1547-1559.
ONTARGET: Key ResultsONTARGET: Key Results
Outcome Risk ratio (95% CI), telmisartan vs ramipril P
Risk ratio (95% CI), combination therapy vs ramipril P
CV death/MI/stroke/ CHF hospitalization
1.01 (0.94–1.09) NS 0.99 (0.92–1.07) NS
CV death/MI/strokea
Renal Impairmentb
0.99 (0.91–1.07) NS
1.04 (0.96-1.14) NS
1.00 (0.93–1.09) NS
1.33 (1.22-1.44) 0.001
a. Primary end point in the HOPE trial; b. Secondary Outcome
ONTARGET: Renal OutcomesONTARGET: Renal OutcomesAll dialysis, 1.00 (0.92-1.09) NS 1.09 (1.01-1.18) 0.037doubling, death
All dialysis 1.09 (0.89-1.34) NS 1.24 (1.01-1.51) 0.038and doubling
Mann JF et al. Lancet 2008; 372:547-553
Number of Patients: Ramipril 8,576; Telmisartan 8,542; Combination 8,502
ONTARGET: Renal OutcomesONTARGET: Renal Outcomes Outcome
Δ BP (mmHg)
eGFR (ml/min/1.73m2)
UACR (mg/mmol)
Ramipril Telmisartan
- - 0.9
-2.82 (17) -4.12 (17)
1.32 1.25
Adverse EffectsAdverse Effects
Combination P
-2.4 ?
-6.11 (17) <0.0001
1.22 0.0028
Hyperkalemia 283 (3.3) 287 (3.4) 480 (5.6) 0.001
Hypotension 149 (1.7) 229 (2.7) 406 (4.8) 0.001
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 Mann JF et al. Lancet 2008; 372:547-553
Phillips CO et al. Arch Intern Med 2007; 167: 1930-1936
Buter H, et al. Nephrol Dial Transplant 1998; 13:1682-1685
Vogt L, et al. J Am Soc Nephrol 2008; 19:999-1007
Blunting of Antiproteinuric Efficacy of ACE Inhibition by High Sodium Intake can be Restored by HCTZ
Pro
tein
uri
aG
ram
s/24
hou
r
mm
Hg
50 mmol 200 mmol 50 mmol 200 mmol50 mg 50 mg
Mea
n B
P, m
mH
g
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