american society of nephrology presents renal weekends: hypertension highlights from of the american...

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

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

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?



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)



BP Remains High



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


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


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


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


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


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

american society of nephrology presents renal weekends: hypertension highlights from of the american...

Documents