Download The Renin-Angiotensin

Omapere, October 09
Johan Rosman
Renal Physician and CMO
Specialist in Hypertension
Waitemata DHB, and
Apollo Centre , Albany
[email protected]
A fascinating animal for BP research
Why does a giraffe not faint ?
•Has a heart of 15 kilo’s
•Has twice the human blood
pressure
•Has a very interesting
autonomic nerve system
•Has a large number of pressure
sensors in his carotid arteries
•Has a different R A A System,
poorly understood
What maintains our normal BP ?
 Intravascular volume
 Autonomic nervous system
 Renin Angiotensin Aldosterone System (RAAS)
 Vascular mechanisms
 The 2 determinants of BP are


Cardiac output
Peripheral resistance
Antihypertensive Drug Classes: Action Sites
Blood
Pressure
=
Cardiac
Output

Antihypertensive Drug
Classes
-Blockers
Total Peripheral
Resistance
-Blockers
ACE Inhibitors
AT1 Blockers
Direct renin inhibitors
1-Blockers
2-Agonists
Non-DHP
CCBs
All CCBs
Diuretics
Sympatholytics
Diuretics
Vasodilators
ACE = angiotensin-converting enzyme; AT1 = angiotensin type 1;
CCBs = calcium channel blockers; DHP = dihydropyridine
Future antihypertensive treatment:
Yogi Berra
Importance of BP control
Hypertension - causes
 90 % ‘essential hypertension’
 10 % ‘secondary hypertension’ (probably
underestimated
 Of these 10% probably 8% renal artery stenosis (RAS)
 Important to make the distinction !
Suggestive of sec hypertension
 Severe or refractory hypertension.
 An acute rise in blood pressure over a previously stable
value.
 Proven age of onset before puberty.
 Age less than 30 years in non-obese, non-black
patients with a confirmed negative family history of
hypertension
Case study
 Mrs G is a 54 year old lady with diabetes, moderately controlled





on oral antidiabetics
She was always normotensive, but recently you find
bloodpressures of 190/105 with a normal pulse rate
You prescribe an ACE inhibitor, as she is also proteinuric with 3.4
g/L of proteinuria
For oedema she is treated with frusemide 40 mg OD
Three weeks later you get a call that she is in hospital with acute
renal failure
What happened ?
MRA Gadolinium-enhanced
Case study
 Mr. C, 79 years old, known with prostate carcinoma
 Since 6 months worsening hypertension and
proteinuria
 MRA and isotope nephrography requested
Case study
 Mr. C, 79 years old, known with prostatecarcinoma
 Since 6 months worsening hypertension and
proteinuria
 MRA and isotope nephrogram: virtually occluded left
renal artery
 Would you give this man an ACE inhibitor ?
ACE Inhibition and RAS
IT STARTS
HERE :
Who should be screened for RAS ? (1)
 Onset of hypertension before the age of 30 years,




particularly if there is a negative family history and no
other risk factors for hypertension (eg, obesity).
Onset of severe hypertension ( ≥160/100 mmHg) after the
age of 55 years.
Refractory or resistant hypertension, in a patient adhering
to therapeutic doses of three appropriate antihypertensive
agents (including a diuretic)
Acute rise in blood pressure over a previously stable
baseline in patients with previously well-controlled
hypertension (and includes patients with known renal
artery stenosis who may have worsening stenosis)
Malignant hypertension (eg, patients with severe
hypertension and signs of end-organ damage)
Who should be screened for RAS ? (2)
 Moderate to severe hypertension in a patient with an
unexplained atrophic kidney or asymmetry in renal sizes of
>1.5 cm.
 Moderate to severe hypertension in patients with diffuse
atherosclerosis, particularly those over age 50.
 Moderate to severe hypertension in patients with recurrent
episodes of acute (flash) pulmonary edema or otherwise
unexplained heart failure.
 An acute elevation in the plasma creatinine concentration
that occurs after the institution of therapy with an
angiotensin converting enzyme (ACE) inhibitor or
angiotensin II receptor blocker (ARB).
Advantages of blocking RAAS
 Possible by blocking Angiotensin Converting Enzyme
 Possible by directly blocking the angiotensin II
receptor
 Excellent blood pressure lowering
 Cardioprotective
 Reduction of stroke
 Renoprotective
 Reducing renal protein loss
 Reduces incidence of diabetes
Renal haemodymacical
consequences of ACE and ARB
 Draw on board
Antihypertensive and Antiproteinuric Responses to an Increasing
Dose of an Angiotensin-Converting Enzyme Inhibitor*
Lisinopril Dose
5 mg
10 mg
0
% Reduction
from Control
-10
-20
-30
-40
-50
-60
-70
-80
Blood Pressure
Urine Protein
Palla R, et al. Int J Clin Pharmacol Res. 1994;14:35-43.
15 mg
20 mg
Relative Risk Reduction With ACEIs
in ABCD, CAPPP and FACET
0
Acute
Myocardial
Infarction
Cardiovascular
Event
All-cause
Mortality
Stroke
-10
-24
-20
NS
-30
-43
-40
-51
-50
-60
-70
-63
P<0.001
P<0.001
Pahor M, et al. Diabetes Care. 2000;23:888-892.
P=0.01
Angiotensin II Receptor Blockers
 No generalised effects, sits directly on the receptor
 It does not have a systemic effect
(bradykinin/kallikrein), still works as good as ACE
 Effects and benefits comparable to ACE inhibitors
 Similar cardio- and renoprotection
 Like ACE, reduces risks beyond just BP reduction
 However significantly less side effects (as only AH
agent comparable to placebo !)
 ARB’s reduce risk of new onset diabetes
Antiproteinuric effects of AT 1 RB
What is better: block ACE or AR ?
(here given in same patient)
The Reduction of Endpoints in NIDDM With the Angiotensin II
Antagonist Losartan Study
RENAAL Overview
 Randomized multicentre, double-blind, placebo-controlled study
to evaluate the renal protective effects of the angiotensin II receptor
antagonist losartan in patients with type 2 diabetes and
nephropathy
Population
 1,513 patients (31 to 70 years old)
 Diagnosed type 2 diabetes and nephropathy


albumin/creatinine ratio 300 mg/g
serum creatinine between 1.3–3.0 mg/dL (1.5–3.0 mg/dL for
men >60 kg)
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
RENAAL
Summary of Important Findings
In patients with type 2 diabetes and nephropathy:
 Losartan, in combination with other antihypertensive therapy (non-
ACE or ARB), delayed the onset of the primary composite endpoint*
(P=0.02) and delayed progression to end stage renal disease (P=0.002)
 Losartan reduced proteinuria (P<0.001) and the rate of decline in renal
function (P=0.01)
 Losartan reduced the incidence of first hospitalization for heart
failure (P=0.005)
 These benefits were above and beyond those attributable to blood
pressure reduction alone
*Composite of a doubling of serum creatinine, end stage renal disease, or death
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
Future antihypertensive treatment:
Yogi Berra
Blood pressure
>130/80 mm Hg
Baseline pulse 84
Add low-dose
beta blocker or
alpha/beta blocker
Start ACE inhibitor
titrate upwards
BP still not
at goal
(130/80 mm Hg)
If BP still not
at goal
(130/80 mm Hg)
Add Thiazide
Diuretic or
long-acting CCB*
Baseline pulse <84
BP still not at goal
(130/80 mm Hg)
*If proteinuria present
(>300 mg per day) nonDHP preferred.
If BP goal achieved, convert to fixed
dose combinations (ACE inhibitor +
CCB or ACE inhibitor + diuretic)
Add other subgroup of CCB
(ie, amlodipine-like agent if verapamil
or diltiazem already being used and
the converse)
Refer to a
clinical hypertension specialist
Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661
with permission from National Kidney Foundation.
Diabetes: Tight Glucose vs Tight BP Control and CV
Outcomes in UKPDS
0
Stroke
Any Diabetic
Endpoint
DM
Deaths
Microvascular
Complications
% Reduction In Relative Risk
5%
-10
10%
12%
-20
24%
*
-30
32%
32%
*
*P <0.05 compared to tight glucose control
-40
37%
*
44%
*
Tight Glucose Control
Tight BP Control
(Goal <6.0 mmol/l or 108 mg/dL)
(Average 144/82 mmHg)
-50
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
Reprinted by permission from WB Saunders.
Is two better than one ??
Modern EBM decision making:
Yogi Berra
The COOPERATE Trial
 260 patients with non-diabetic renal disease
 Randomly assigned to 100 mg losartan, or 3 mg
trandolapril or combination
 Endpoint: doubling of serum creatinine (loss of renal
function)
 Secondary point: proteinuria
The COOPERATE trial, con’t
Interesting recent article
 Stuart L. Linas: Are two better than one? ACE Inhibitors plus
ARB for reducing blood pressure and proteinuria in kidney
disease. Clin J Am Soc Nephrol 3: S17-S23, 2008
 Concluded:
 Many smaller combo trials now done
 Potential safety issues (hypothetical): hyper-K, loss of renal
function in advanced stages
 Strong individual differences, race differences, dose finding issues
 Strongest effect on proteinuria, how this translates to slowing the
progression of renal function loss still unclear, despite
COOPERATE (COOPERATE had many design flaws) and
ONTARGET
 No benefit on other outcomes (cardiovascular, stroke etc)
Future antihypertensive treatment:
Yogi Berra
New drugs classes
 Renin inhibitors: Aliskiren
 AVOID trial:
 600 patients with proteinuriac diabetic nephropathy
 Randomly assigned to Losartan monotherapy and
Aliskiren plus Losartan
 The combination treatment gave an additional 20%
reduction in proteinuria
 No additional serious side effects
The key to good care
 Communication
 Communication
 Communication
 021- KIDNEY
 (021-543639)
 [email protected]
(Henry Kissinger, 1976)