Pharmacological Nephroprotection in a Novel Mouse Model of Hereditary Nephrotic Syndrome
ACE / ARB: renovascular hypertension and nephroprotection
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Transcript of ACE / ARB: renovascular hypertension and nephroprotection
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ACE / ARB: renovascular hypertension and nephroprotection
Johan RosmanRenal Physician and CMOSpecialist in Hypertension
Waitemata DHB, andApollo Centre , Albany
Omapere, October 09
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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
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What maintains our normal BP ?Intravascular volumeAutonomic nervous systemRenin Angiotensin Aldosterone System
(RAAS)Vascular mechanisms
The 2 determinants of BP are Cardiac output Peripheral resistance
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-BlockersACE InhibitorsAT1 Blockers
Direct renin inhibitors1-Blockers2-Agonists
All CCBsDiuretics
SympatholyticsVasodilators
-Blockers
Non-DHPCCBs
Diuretics
BloodPressure = Cardiac
Output
ACE = angiotensin-converting enzyme; AT1 = angiotensin type 1;CCBs = calcium channel blockers; DHP = dihydropyridine
Antihypertensive Drug Classes: Action Sites
Total PeripheralResistance
Ant
ihyp
erte
nsiv
e D
rug
Cla
sses
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“Nobody goes there anymore; it’s too crowded”
Yogi Berra
Future antihypertensive treatment:
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Importance of BP control
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Hypertension - causes90 % ‘essential hypertension’10 % ‘secondary hypertension’ (probably
underestimatedOf these 10% probably 8% renal artery
stenosis (RAS)
Important to make the distinction !
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Suggestive of sec hypertensionSevere 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
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Case studyMrs G is a 54 year old lady with diabetes, moderately
controlled on oral antidiabeticsShe was always normotensive, but recently you find
bloodpressures of 190/105 with a normal pulse rateYou prescribe an ACE inhibitor, as she is also
proteinuric with 3.4 g/L of proteinuriaFor oedema she is treated with frusemide 40 mg ODThree weeks later you get a call that she is in hospital
with acute renal failureWhat happened ?
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MRA Gadolinium-enhanced
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Case studyMr. C, 79 years old, known with prostate
carcinomaSince 6 months worsening hypertension and
proteinuriaMRA and isotope nephrography requested
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Case studyMr. C, 79 years old, known with
prostatecarcinomaSince 6 months worsening hypertension and
proteinuriaMRA and isotope nephrogram: virtually
occluded left renal artery
Would you give this man an ACE inhibitor ?
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ACE Inhibition and RAS
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IT STARTSHERE :
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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)
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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).
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Advantages of blocking RAASPossible by blocking Angiotensin Converting
EnzymePossible by directly blocking the angiotensin
II receptor
Excellent blood pressure loweringCardioprotectiveReduction of strokeRenoprotectiveReducing renal protein lossReduces incidence of diabetes
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Renal haemodymacical consequences of ACE and ARBDraw on board
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Antihypertensive and Antiproteinuric Responses to an Increasing Dose of an Angiotensin-Converting Enzyme Inhibitor*
Palla R, et al. Int J Clin Pharmacol Res. 1994;14:35-43.
-80-70-60-50-40-30-20-10
0
% R
educ
tion
from
Con
trol
Blood PressureUrine Protein
5 mg 10 mg 15 mg 20 mg
Lisinopril Dose
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Relative Risk Reduction With ACEIs in ABCD, CAPPP and FACET
-24
-43
-63
-51
-70
-60
-50
-40
-30
-20
-10
0
% r
elat
ive
risk
red
ucti
on
Pahor M, et al. Diabetes Care. 2000;23:888-892.
Acute Myocardi
al Infarction
Cardiovascular Event Stroke
All-cause Mortality
P<0.001
P<0.001
P=0.01
NS
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Angiotensin II Receptor BlockersNo generalised effects, sits directly on the
receptorIt does not have a systemic effect
(bradykinin/kallikrein), still works as good as ACE
Effects and benefits comparable to ACE inhibitorsSimilar cardio- and renoprotectionLike ACE, reduces risks beyond just BP
reductionHowever significantly less side effects (as
only AH agent comparable to placebo !)ARB’s reduce risk of new onset diabetes
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Antiproteinuric effects of AT 1 RB
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What is better: block ACE or AR ?(here given in same patient)
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The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan Study
RENAAL OverviewRandomized 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
Population1,513 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.
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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.
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“If you don’t know where you are going, be careful. You may not get there”
Yogi Berra
Future antihypertensive treatment:
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Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661 with permission from National Kidney Foundation.
National Kidney Foundation Algorithm for Achieving Target BP Goals in Hypertensive Diabetic Patients
Start ACE inhibitor titrate upwards
If BP still not at goal
(130/80 mm Hg)
BP still not at goal
(130/80 mm Hg)
Baseline pulse <84Add low-dose
beta blocker or alpha/beta blocker
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
BP still not at goal (130/80 mm Hg)
If BP goal achieved, convert to fixed dose combinations (ACE inhibitor + CCB
or ACE inhibitor + diuretic)
Baseline pulse 84Add Thiazide Diuretic or
long-acting CCB*
Blood pressure >130/80 mm Hg
*If proteinuria present (>300 mg per day) non-DHP preferred.
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Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS
StrokeAny Diabetic
EndpointDM
DeathsMicrovascularComplications
-50
-40
-30
-20
-10
0
% R
educ
tion
In R
elat
ive
Ris
k
Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL)
Tight BP Control (Average 144/82 mmHg)
32%
37%
10%
32%
12%
24%
5%
44%
*
*
**
*P <0.05 compared to tight glucose control
Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission from WB Saunders.
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“If you come to a fork in the road: take it !”
Yogi Berra
Is two better than one ??Modern EBM decision making:
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The COOPERATE Trial260 patients with non-diabetic renal diseaseRandomly assigned to 100 mg losartan, or 3
mg trandolapril or combinationEndpoint: doubling of serum creatinine (loss
of renal function)Secondary point: proteinuria
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The COOPERATE trial, con’t
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Interesting recent articleStuart 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 donePotential safety issues (hypothetical): hyper-K, loss of
renal function in advanced stagesStrong individual differences, race differences, dose
finding issuesStrongest 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)
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“Its tough making predictions, especially about the future”
Yogi Berra
Future antihypertensive treatment:
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New drugs classesRenin inhibitors: AliskirenAVOID 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
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The key to good careCommunicationCommunicationCommunication
021- KIDNEY(021-543639)[email protected]
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Are there any questions to my answers ?
(Henry Kissinger, 1976)