HYPERTENSION

&

THE KIDNEY Prof Pham Van Bui

PNT University of Medicine

NTP Hospital, Viet Nam

Invited Professor, Liège University, Belgium

HYPERTENSION & KIDNEY

8

4 questions in pts with HT

Primary or secondary?

Pathophysiology ?

CV Risk factors& co-morbidities?

Primary or secondary prevention:

Target –organ involvement?

Heart(LVH)

Kidney(proteinuria) Bakris LG (2013). CME. Med Educ

9

Key considerations in pathophysiology of HT

Volume, sodium loading, volume status

Renin-angiotensin-aldosterone system(RAS)

Sympathetic nervous system

Comorbidities

Other vasoactive substances(NO, PGl, endothelin,

EDHF) → endothelial dysfunction

Genetic components

Bakris LG (2013). CME. Med Educ

10

Key considerations in pathophysiology of HT

Volume, sodium loading, volume status

Renin-angiotensin-aldosterone system(RAS)

Sympathetic nervous system

Comorbidities

Other vasoactive substances(NO, PGl, endothelin,

EDHF) → endothelial dysfunction

Genetic components

Bakris LG (2013). CME. Med Educ

• Salt retention along w/ volume overload:

major cause of HT in patients with CKD

• Verdalles et al. used BIS to assess fluid status

and guided the use of diuretics to treat HT in

CKD patients not on dialysis.

• 30 patients w/ ECV expansion treated =

diuretic

• 20 patients w/o ECV expansion receiving

another additional antiHT medication

Verdalles U, et al(2012). Nephrol Dial Transplant 2012; 27 (Suppl 4):iv31–iv35.

At 6 months of follow-up, :

Pts w/ ECV expansion (30

treated=diuretic)

Pts w/o ECV expansion (20

treated =

another antiHT

med. )

P

↓sBlood

Pressure

21 mmHg 09 mmHg < 0.01

Target BP <

140/90 mmHg 09/30 pts 02/20 pts < 0.01

Verdalles U, et al(2012). Nephrol Dial Transplant 2012; 27 (Suppl 4):iv31–iv35.

• Micardis Plus &

Amlodipine/HCTZ

• Old pts w/ isolated sHT

• t = 14 weeks; n=1000

• Results:

Micardis Plus> Amlodipine/HCTZ

- ↓ in sHT/24

- Safety

• Micardis Plus vs Losartan/HCTZ

• t=6 weeks; n=805

• Results:

Micardis Plus

1.Superior to Losartan+HCTZ in lowering

BP over 24h

2.Superior to Losartan+HCTZ in lowering

BP in the early morning

3. Superior to Losartan+HCTZ in

lowering BP in the last 6h of the dosing

interval

Neutel et al. Hypertens Res 2005;28:555–563

Thiazides in CKD

• The traditional teaching has been that

thiazides become ineffective when

GFR< 30ml/min whereas loop

diuretics remain effective in

advanced CKD. Although widely

accepted, this traditional notion has

been called into question by a recent

pilot study

Opie HL.(2013). Diuretics. In Drugs for the Heart

A Pilot Study Comparing Furosemide

and HCTZ in Patients With Hypertension

and Stage 4 or 5 CKD

• RCT, crossover trial of 23 pts w/ HT & CKD

G4/5, 3 months ttt w/ either HCTZ(25mg/d)

or long acting furosemide (60mg/d)

• No differences between furosemide and

HCTZ with respect to natriuresis and BP

control in patients with HT and CKD.

Bertrand Dussol et al(2012). J Clin Hypertens (Greenwich)

In Advanced CKD,

Thiazide May Help Control BP

Dialogue b/w Bakris GL & Agarwal R:

• 7 studies of thiazides in patients with CKD.

We found that there may be some evidence

that Thiazides may work, even for people

with advanced kidney disease

Bakris GL, Agarwal R(2014).lIn Advanced CKD, Thiazide May Help Control BP. Medscape. May 20, 2014.

Chlorthalidone for Poorly Controlled HT in CKD:

An Interventional Pilot Study

• 14 subjects 67.5 years, taking median of 4

antihypertensive drug (incl RAS blockers)

• eGFR :26.8 ± 8.8 ml/min/1.73 m2 (20-45 )

• Chlorthalidone

• 25 mg/day added to existing medications

• dose doubled every 4w if BP still high

• Twelve subjects completed the 12-week

treatment phase

Agarwal R et al(2014).Am J Nephrol (Abst(

Ambulatory BP

Response

Ag

arwal R

et al(20

14

).Am

J Nep

hro

l (Ab

st)

Home BP Response A

garw

al R et al(2

01

4).A

m J N

eph

rol (A

bst)

Albuminuria significantly reduced #40-45%

Agarwal R et al(2014).Am J Nephrol (Abst)

KDIGO Clinical Practice Guideline for the

Management of BP in CKD 2013

• Thiazides: one of the first 2 or 3 drugs used for

BP lowering in CKD, particularly :

• Edema

• Add-on ACE-Is/ARBs

• Potentiate the effect of other

antihypertensive agents, particularly

ACE-Is/ARBs

• ↓ risk of hyperkalemia

• ↓ Albuminuria

25

Key considerations in pathophysiology of HT

Volume, sodium loading, volume status

Renin-angiotensin-aldosterone system(RAS)

Sympathetic nervous system

Comorbidities

Other vasoactive substances(NO, PGl, endothelin,

EDHF) → endothelial dysfunction

Genetic components

Bakris LG (2013). CME. Med Educ

Angiotensin II Plays a Central Role in CV

Pathophysiology

Oxidative Stress Inflammation

Endothelial dysfunction Tissue remodelling

Vascular permeability ↑ Leucocyte infiltration ↑

Activation of signalling pathways

Production of inflammatory mediators

Proliferation of VSMCs

Matrix deposition

MMP activation Platelet aggregation

PAI-1 activation

Vasoconstriction

Nitric oxide ↓

LDL peroxidation ↓

LDL peroxidation ↑

Reactive oxygen species ↑

NAD(P)H oxidase activity ↑

Angiotensin II

Schmieder et al. Lancet. 2007;369:1208-1219

Ag II triggers end-organ damage

directly and by causing atherosclerosis

Adapted from: Chung O. & Unger T., Am J Hypertens 1999;12:150S–156S

Angiotensin II

Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Hypertension

Decreased GFR

Proteinuria/albuminuria

Glomerulosclerosis

Vascular disease

Apoptosis

LVH

Fibrosis

Arrhythmia

Heart failure

MI

Stroke

Cognitive

dysfunction

Renal failure

Death

AT1 Receptor

Where Are We in Diabetic Nephropathy

MicroRNAs and Biomarkers?

McClelland et al. Curr Opin Nephrol Hypertens. 2014

It appears that AngII-induced hypertension

increases miR-132 and miR-212 in organs

associated with blood pressure control, including

the kidney.

Significant decrease in miR-132 and miR-212

were observed in arteries of angiotensin

receptor blocker (ARB)-treated patients, but

treatment with β-blockers had no effect.

McClelland et al. Curr Opin Nephrol Hypertens. 2014

INTERNATIONAL GUIDELINES

R8. In the general

population aged ≥18y w/

CKD, initial(or add-on )

antihypertensive treatment

should include an ACEI

or ARB to improve

kidney outcome. This

applies to all CKD

patients w/ hypertension

regardless of race or

diabetic state (Moderate

Recommendation- Grade

B)

Pharmacological

therapy for patients

w/ diabetes and

hypertension should

comprise a regimen

that includes either

an ACEI or ARB. If

one class is not

tolerated, the other

should be substitued .

C

CKD ND pts w/o DM

ARB /ACEI use in adults

w/ CKD ND and UAE of

30-300mg/24h(S-2D)or

>300mg/24h(R-1B) in

whom treated w/ BP-

lowering drugs is indicated

CKD ND pts w/ DM

ARB /ACEI use in adults

w/ diabetes and CKD ND

w/ UAE of 30-300mg/24h

(S) or UAE > 300mg/24h

(R)

JNC 8, 2014 DIABETIC CARE

2014 KDIGO 2013:

Antihypertensives May Delay

Kidney Disease Progression

Hsu TW et al(2013). JAMA Dec

In advanced stage of CKD + stable HT by RAA

blocking medicines →lower risk of advancing to

long-term dialysis or dying ?

Prospective cohort study: 28,497 predialysis

patients with advanced CKD, HT, and anemia.

B/w January 1, 2000, and June 30, 2009,

20,152 pts (70.7%) requiring long-term

dialysis

5696 (20.0%) died before progressing ESRD

Antihypertensives May Delay Kidney

Disease Progression

• Compared w/ pts not using ACEIs/ARBs Use of

ACEIs/ARBs :

• ↓ 6% risk for long-term dialysis ( HR 0.94;

95% CI, 0.91 - 0.97)

• ↓ 6% risk in the composite outcome of

long-term dialysis or death (HR, 0.94; 95%

CI, 0.92 - 0.97).

Hsu TW et al(2013). JAMA Dec

KDIGO Clinical Practice Guideline for the

Management of BP in CKD 2013

• Albuminuria. The level of

albuminuria in CKD

predicts not only the

prognosis with respect to

kidney function but also

morbidity and mortality

from CVD events including

stroke.

Shaded areas represent 95% CIs.

Models included spline eGFR, categorical

albuminuria, and their interaction terms

as well as adjustment for age, sex, ethnic

origin, history of cardiovascular disease,

systolic blood pressure, diabetes,

smoking, and total cholesterol. The

reference (diamond) was eGFR 95

mL/min/1.73 m² plus ACR less than 3.4

mg/mmol (30 mg/g) or dipstick test result

negative or trace. Circles represent

statistically significant and triangles

represent not significant.

Decline in eGFR and albumin:creatinine ratio are

closely linked to CV mortality

CKDPC Lancet 2010;375:2073-2081.

Guideline 6: Management of Albuminuria

in Normotensive Patients with Diabetes

Treatments that produce a lasting

decrease in urinary albumin

excretion may slow the

progression of DKD even in the

absence of hypertension.

NFK KDOQI CLINICAL PRACTICE GUIDELINE FOR DIABETES AND CKD:

2012 UPDATE

KDIGO Clinical Practice Guideline for the

Management of BP in CKD 2013

• Some BP-lowering agents are particular

effective at reducing albuminuria or

proteinuria, suggesting that BP management

should differ depending on the amount

of albumin or protein in the urine

• ACE-Is and ARBs are valuable BP-

reducing agents in CKD patients, are

indicated if urinary albumin excretion is

elevated and are safe to combine with

most other BP-reducing agents.

• The transition RR to overt

nephropathy ↓ # 66%

(telmisartan 80mg) 55%(

telmisartan 40 mg)/ placebo (a)

• The renoprotective benefit of

telmisartan also apparent in

normotensive patients at

baseline (b), suggesting a BP-

independent effect

(The INcipieNt to OVert: AII receptor blocker,

Telmisartan, Investigation On type 2 diabetic Nephropathy)

Makino et al. Diabetes Care 2007

*P<0.05 vs losartan not attributed

to BP control, as reductions in

systolic and diastolic BP similar in

both treatment arms

Proteinuria reduction at 1 year

-35

-30

-25

-20

-15

-10

-5

0

Telmisartan 40-80 mg Losartan 50-100 mg

Pro

tein

uri

a-a

dju

ste

d m

ea

n c

ha

ng

e (

%)

29%

reduction*

20%

reduction

Bakris et al . Kidney International 2008 74:364-369

• Telmisartan vs. Losartan

• t = 52 weeks

• 1566 Hyertensive diabetic pts w/ overt nephropathy

After a 2-month period in

which both drugs were

stopped: a sustained and

persistent antiproteinuric

effect with the novel

ARB(Telmisartan).

A trial to compare telMisartan 40 mg titrated to 80 mg versus

losArtan 50 mg titrated to 100 mg in hypertensive type 2

DiabEtic patients with Overt nephropathy: 1566 patients

Telmisartan more renoprotective than losartan

Micardis reduces proteinuria

significantly better than losartan

0

2

4

6

8

10

Overall composite CV Composite

Incid

en

ce

(%

)

Telmisartan 40-80 mg

Losartan 50-100 mg

a Doubling of serum creatinine, ESRD or all-cause death;

b Myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary

or peripheral revascularization

a b

Bakris et al . Kidney International 2008 74:364-369

Concept of Metabolic Domino effect

in metabolic syndrome

Hiroshi Ito. Mebio 2005; 22: 125-8

Cardiac

arrest

Hyperlipidemia

Dementia Apoplexia

Cerebri lower limb

amputation

ED No light

perception Dialysis

Nephropathy Retinopathy Neurosis ASO Cerebrovascular

accident

Ischemic

cardiac

disease

Micro angiopathy

Diabetes

Macro angiopathy

Hypertension

Postprandial

Hyperglycemia

Lifestyle habit

Sympathetic nerve system

Renin-angiotensin system

Hypertension

/ARB

, CCB

Samir G Mallat. Cardiovasc Diabetol. 2012;11(32):1-12.; Mancia G . J Hypertens 2009,

27(11):2121–2158 ; K/DOQI. Am J Kidney Dis 2004, 43(5 Suppl 1):S1–S290.

• ASH indicated a preference for RAS

blockers in combination with either a

diuretic or CCB, with selection

dependent on individual patient F*,

including additional CV risk factors &

comorbidities

What is a Preferred ARB-based Combination

Therapy for BP Control in HT Patients With

Diabetic and Non-diabetic Renal Impairment

What is a Preferred ARB-based Combination

Therapy for BP Control in HT Patients With

Diabetic and Non-diabetic Renal Impairment

Samir G Mallat. Cardiovasc Diabetol. 2012;11(32):1-12.; Mancia G . J Hypertens 2009,

27(11):2121–2158 ; K/DOQI. Am J Kidney Dis 2004, 43(5 Suppl 1):S1–S290.

• In pts with evidence of renal disease or in those with a

greater risk of developing renal disease(pts w/ DM & high-

normal BP or overt HT), guidelines clearly recommend

RAS blocker-based combination therapy superior

renoprotective effects

• ARB-based preferred > ACE inhibitors:

• Superior tolerability& adherence

• Delay the progression of DKD

• Delay development of diabetes in at-risk patients

CCB + ARB:

The Synergies of Counter-Regulation (1)

Synergistic

BP reduction

Complementary

clinical benefits

CCB

Arteriodilation

Peripheral oedema

Effective in low-renin patients

Reduces cardiac ischaemia

CCB

RAS activation

No renal or CHF

benefits

BP

Mistry et al. Expert Opin Pharmacother. 2006;7:575–581;

Sica. Drugs. 2002;62:443–462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.

Afferent arteriole Efferent arteriole

CCBs(Amlodipine) Block L-Type

Dilatation

N-Type Ca channel

L-Type Ca channel

α Receptor

AII Receptor

CCBs & renal microcirculation

Sympathetic

nerve endings

Ca2+ Ca2+

N-Type

Ca Channel L-Type

Ca Channel

Sympathetic

nerve endings

Sympathetic

nerves

CCB + ARB:

The Synergies of Counter-Regulation (2)

ARB

Venodilation

Attenuates peripheral oedema

Effective in high-renin patients

No effect on cardiac ischaemia

ARB

RAS blockade

CHF and renal

benefits

Mistry et al. Expert Opin Pharmacother. 2006;7:575–581; Sica. Drugs. 2002;62:443–462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.

Synergistic

BP reduction

Complementary clinical benefits

BP

CCB

Arteriodilation

Peripheral oedema

Effective in low-renin patients

Reduces cardiac ischaemia

CCB

RAS activation

No renal or CHF

benefits

The Two Key Components of BP Regulation

Grassi. J Hypertens. 2001;19:1713–1716; modified.

© Theodore Kurtz, MD

all rights reserved

Combinations of Telmisartan with Other Antihypertensive Drugs Are Also Highly Effective in Reducing BP

▐ Responder rate in 8 week long Japanese Phase III trial)

- Systolic BP Responder Rate -

< 140mmHg

or more than 20 mmHg BP

(243/255）

Telmisartan 40mg + Amlodipine 5mg

95.3％

Afferent arteriole Efferent arteriole

CCBs Block L-Type

Dilatation Dilatation

RAS inhibitors

N-Type Ca channel

L-Type Ca channel

α Receptor

AII Receptor

MOA of CCBs & RASIs on renal microcirculation

Sympathetic

nerve endings

Ca2+ Ca2+

N-Type

Ca Channel

Additive

effect

L-Type

Ca Channel

Sympathetic

nerve endings

Sympathetic

nerves

KDIGO 2013 Clinical Practice Guideline for the

Management of BP in CKD

Information of value in deciding on the optimal BP

lowering regimen: data on drug half-life and dose

adjustments in CKD stage 5D, which may be of

help in guiding the use of BP lowering drugs in

advanced CKD ND.

It is wise to avoid CCBs in CKD patients with

already increased urinary albumin excretion,

particularly if there is not concomitant use of an

ACE-I or ARB

Telmisartan + Amlodipine:

Reduction of Urinary Albumin Excretion

-25.5

-34.1-37.1

-33.2

-25.9

-46.4

-63.8

-75.3

-100

-80

-60

-40

-20

0

* p < 0.03; ** p < 0.01, change from baseline; † p < 0.01; ‡ p < 0.001, between treatment; §p < 0.05 vs 80/2.5 Hypertensive patients with type 2 diabetes (n = 300); microalbuminuria > 30 – < 300 mg/24 h

*

†

**

‡ §

Fogari et al. Am J Hypertens. 2007;20:417–422.

UA

ER c

han

ge f

rom

bas

elin

e (%

)

Telmisartan increasing dose (40–160 mg)

40/2.5 40/5 40/7.5 40/10

4 weeks 48 weeks

40/2.5 80/2.5 120/2.5 160/2.5

Amlodipine increasing dose (2.5–10 mg)

DIABETIC CARE 2014

• Multiple-drug therapy(two or more

agents at maximal doses) is generally

required to achieve BP target. B

• Administer one or more

antihypertensive medications at

bedtime. A

AMAZING KIDNEYS !