The Role of RAS Blockade in

Hypertension management

PRINGGODIGDO NUGROHO

Division of Kidney and Hypertension

Departement of Internal Medicine
Faculty of Medicine University of Indonesia Dr Cipto Mangunkusumo National General Hospital
 Control of Blood Pressure

Blood Pressure = C.O. X Peripheral Resistance

Preload Contractility
Heart Rate Vasoconstriction

Renal Sympathetic Renin

Sodium Nerve Angiotensin
Retention Activity Aldosterone
System
 The Renin-Angiotensin-System

Angiotensinogen
Angiotensinogen

Renin
Angiotensin
AngiotensinII Ang-(1-9)

ACE ACE2 NEP

Angiotensin
AngiotensinIIII Ang-(1-7) Mas-R

ACE

Ang-(1-5)
ANG II ANG II

AT1 AT2
 Angiotensin effects on the nephron

Angiotensin II
+ + +
+
-
Pglom

Aldosterone

+
Proximal Na+-
reabsorption Na+-reabsorption
 RAS in cardiovascular pathology
Risk factors: diabetes, obesity, smoking, age
Angiotensin II via AT1
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
Atherosclerosis Apoptosis Arrhythmia
LVH Heart failure
Fibrosis MI

Death
Stroke
Hypertension Vascular
Cognitive
disease
dysfunction

Pro-thrombotic state Decreased GFR

Proteinuria/albuminuria Renal failure
Glomerulosclerosis

Adapted from: Chung O. & Unger T., Am J Hypertens 1999;12:150S156S

Drugs inhibiting the renin-angiotensin-aldosterone system

Angiotensinogen
Renin
inhibitors Renin
Bradykinin
ACE ANG I ACE
inhibitors ACE inhibitors ACE
Aldosterone
Aldosterone + rag m
en
antagonists ANG II F ts

AT1 Receptor Blockers ANG II ANG II

AT1 AT2
 ACE I / ARBs
Preferred agent in Diabetic HTN
Offer Reno protection
AT II ACEI / ARB

Increase Intra-renal Pr & Constricts Decreases

Efferent Arteriole

Thickening of Glomerular basement Corrects

membrane : Stimulates Renal fibrosis &
Stimulates TGF beta (Hypertrophy ,
collagen syn.) ; Stimulates MCP
( Inflammation)

Endothelial dysfn Improvement in Endothelial fn

KONTRA INDIKASI ARBs
EFEK SAMPING ARBs
The Effect of Angiotensin-Converting Enzyme
Inhibition on Diabetic Nephropathy
409 Type I diabetics ages 18-49 with nephropathy (U protein>500 mg and S
Cr <2.5)
Prospective, double-blinded multicenter (30) trial randomized to captopril vs.
placebo for 3 years

Lewis EJ et al , New Engl J Med

329:1456-62, 1993
ACE Inhibition and Type I DM Nephropathy
If S Cr > 1.5 mg/dl:
1) Captopril reduced doubling of S
Cr by 48% over 4 years.

2) Captopril reduced
ESRD(dialysis or transplant)
or death by 50% over 4 years.

3) These effects were

independent of effects on
blood pressure.
Lewis EJ et al, New Engl J Med
329:1456, 1993
ACE Inhibitors and CKD Progression
Meta-analysis -Jafar T, Ann Intern Med 135:73-87, 2001

11 randomized controlled trials comparing ACE

inhibitors vs. other medications in treatment of
hypertension in 1860 nondiabetic patients with CKD
(S Cr=2.3).
Results: ACE Inhibitors lowered BP and proteinuria.
Results: ACE inhibitors decreased risk of ESRD
by 31%, combined risk of progression of renal
insufficiency and development of ESRD by 30%
independent of BP lowering effects.
Reduction of Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan RENAAL
1513 Type II diabetics with nephropathy
(U alb/Cr ratio >300 or U prot >500 mg and S Cr 1.3-3.0 mg/dl)
Prospective, randomized, double-blinded multicenter (250) trial
Two arms Losartan (50-100 mg) to keep BP<140/90 vs. placebo for
3.4 years

Brenner BM et al, New Engl J Med 345:861-

869, 2001
RENAAL ARB Reduction of Renal Failure

16% 25%

28% 20%

Brenner BM et al, N Eng J Med 345:861, 2001

Irbesarten Diabetic Nephropathy Trial
(IDNT)
1715 Type II diabetics with hypertension (BP >135/85) and
nephropathy (proteinuria >900 mg, S Cr 1.0-3.0 mg/dl)
Prospective, randomized, double-blinded, multicenter (210) trial
Three arms: Irbesarten, amlodipine, and placebo

Lewis EJ et al, New Engl J Med 345:851, 2001

IDNT ARB Reduction of Renal Failure

23%
20%

33%

Lewis EJ et al, N Eng J Med 345:851, 2001

 ARB Effects of Type II DM Nephropathy
- RENAAL and IDNT
Endpoints RENAAL IDNT

Composite 16% 20%

S Cr Doubling 25% 33%

ESRD 28% 23%

 Aliskiren
Direct Renin Inibitor

Molecular Formula
C30 H53 N3 O6
Molecular Weight
551.758g/mol

(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methyl-
propyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)
phenyl]methyl}-8-methyl-2-propan-2-yl-nonanamide

National Center for Biotechnology Information. PubChem.

Combination of RAS Blockade
Evidence of Benefits: Clinical
Outcomes
Similar long-term blood pressure-lowering effects were seen with ACEIs and ARBs. (high
strength of evidence)
There were no significant differences between ACEIs and ARBs for these outcomes:
Mortality and major cardiovascular events (low strength of evidence)
Rate of monotherapy success (high strength of evidence)
Quality of life measures (low strength of evidence)
Progression of renal disease (moderate strength of evidence)
Effects on LVMI or LVEF (low strength of evidence)
ACEI and ARBs are similar in their lack of effect on serum lipid levels, blood glucose
levels, and HbA1c.
(moderate strength of evidence)
There was insufficient evidence for the DRI aliskiren.
Evidence on Adverse Effects
Cough is more prevalent in patients on ACEIs than ARBs (About 9%
of patients treated with an ACEI and about 2% of patients treated
with an ARB report a cough).
(high strength of evidence)
ACEIswere associated with lower rates of persistence and higher
rates of withdrawals due to adverse events when compared with
ARBs. (moderate strength of evidence)
Lowerpersistence with ACEIs versus ARBs may be explained largely
by the differential rates of cough.
Excludingcough, there were no significant between-class
differences in any other specific adverse events.
Evidence on Adverse Effects:
Angioedema
Angioedema was uncommon and most frequently associated with ACEIs.
In one study, the DRI was associated with angioedema in one patient, but
overall the evidence was insufficient.
Take Home Points

Hypertension occurs in a large proportion of CKD

patients.
Angiotensin blockade slows progression of CKD
independent from BP effects.
Combination of Angiotensin Blockade should be
avoided