RAAS CKD Progression
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Transcript of RAAS CKD Progression
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Renin Angiotensin Aldosterone System
In Progressive Kidney Disease
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Pathogenesis of CKD RAAS and CKD Inhibition of RAAS in CKD
CONTENTS
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Pathogenesis of CKD
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Definition and Causes of CKD
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Definition and Causes of CKD
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Progression of CKD
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Development of Primary renal disease
Progression of renal disease
- early renal inflammation
- tubulointerstitial fibrosis
- tubular atrophy
- glomerulosclerosis
ESRD
RAAS
regression
Progression of CKD
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8/86 Abboud H and Henrich W. N Engl J Med 2010;362:56-65
Progression of CKD
Mechanisms in Progression of Chronic Kidney Disease
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Factors involved in the initiation and progression of CKD
Progression of CKD
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Six stage of renal progression
1.Persistent glomerular injurylocal hypertension in capillary tuft, increase single nephron GFR, protein leak
2.Proteinuria,
Increased Agn II
3.facilitate cytokine bath ( incude accumulation of IMNC)4.interstitial neutrophi is replaced by macrophage/Tcell
produce interstitial nephritis
5.new interstitial fibroblast by
epithelial mesenchymal transition
6.surviving fibroblast induce acellular scar
Progression of CKD
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Systemic and glomerular hypertension Proteinuria Various cytokine and growth factors RAAS Podocyte loss Dyslipidemia
Possible mechanism of progressive renal damage
Progression of CKD
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Systemic and glomerular hypertension
Systemic Hypertensin
- Progression of CKD
: accelerated by HT
BP control is keyin Tx of CKD
Glomerular Hypertension- key mediator of
progressive sclerosis
Progression of CKD
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Proteinuria
Is a marker of renal injury
Contribute to progressive renal injury andinflammation
Progression of CKD
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RAAS
Progression of CKD
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Specific cytokines/growth factors
TGF-beta
PDGF
AngII
basic FGF
endothelin
Various chemokines
PPAR-rPAI-1
Progression of CKD
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Podocyte loss
Many glomerular diseasePodocyte injury
Podocyte dose not proliferative
loss of podocyte after injuryKey factor resulting in
progressive sclerosis
Progression of CKD
Oxidative stress leads to podocyte
depletion in CKD via AOPPs(advanced
Oxidation protein products) KI, 2009
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Dyslipidemia
Abnormal lipidimportant in modulating glomerular sclerosisin rat
( human study is evolving )
associated with increased loss of GFR
Statin
may not only benefit CVD risk,
but also be ofbenefit for progressive CKD
Progression of CKD
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Most important risk factor
for progression of renal disease
Hypertension
Proteinuria
RAAS is involved
Progression of CKD
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Hypertension: renal damage
direct glomerular damage
indirect glomerular damage by
atherosclerosis, heart failure..
RAAS is involved
Progression of CKD
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Nephrotoxin: Increased tubular absorption of filtered protien
Induce tubulointerstitial inflammation Tubular atrophy, interstitial fibrosis Loss of renal function
Clinical parameterfor diagnosing renal damage,
especially glomerular hypertension
Risk factorand predictor for cardiovascular event
Proteinuria:significance
Progression of CKD
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Proteinuria:significance
Progression of CKD
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Proteinuria:mechanism
Usually due to increased glomerular pressure
Afferent A Efferent A
Glomerulus
Proteinuria
GPr
High BP High efferent Pr
Progression of CKD
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Reducing glomerular pressure
is a principal strategy for reducing proteinuria
To decrease Gloemrular Pressure
blood pressure andarteriolar resistance in efferent arteriolemust be reduced
Proteinuria:mechanism
Progression of CKD
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RAAS and Chronic Kidney Disease
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How the RASS was seen in the past
aldosterone
RAAS and CKD
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Recent overview of RASS : AngII
RAAS and CKD
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Angiotensin II
Angiotensin II (ang II) promotes injury in at least
five separate steps in the cycle.
RAAS and CKD
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Angiotensin IIRAAS and CKD
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Role ofAngII in progressive renal injury
Hemodynamic effect
- intraglomerular hypertension
( vasoconstriction of efferent arteriole)
- systemic hypertension
Nonhemodymic effect(remodeling)
- increased connective tissue production and
deposition of extracellular matrix
- stimulation of apoptosis and
chemoattractive activity
infiltration of macropahge and other inflammatory cell
RAAS and CKD
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Angiotensin II
Glomerular capillary hypertensionInitiating event in the kidney disease
: any pathologic process that produce nephron injury and
loss of functioning unit
Result in hyperfiltration and glomerular capillary HT
This adaptive change is deleterious to renal functiondue to pressure induced capillary stretch and
glomerular injury
RAAS and CKD
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Angiotensin II
Proteinuria
RAAS is important role in pathophysiology of proteinuria
1.enhance capillary filtration pressure
by directly efferent vasoconstriction
indirectly TGF-b1-mediated afferent a.autoregulation
2.exhibit direct effect on integrity of the ultrafiltration barrier
( suppression of nephrin),
increase VEGF expression(increased UF permeability)
AngIIincrease proteinuria through hemodynamic and
nonhemodynamic mechanism
RAAS and CKD
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Growth effects and apoptosisAngII
Stimulate proliferation of mesangial cell,
glomerular endothelial cell, fibroblast Enhance structural renal damage and fibrosis
Tubular hypertrophy
Progress tubular atrophy and interstitial fibrosis
induce apoptosis
Angiotensin IIRAAS and CKD
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Angiotensin II
InflammationAngII
activate through AT1 and AT2 the proinflammatorytranscription factor NF-kB
stimulate trascription factor Ets
Ets is a critical regulator of vascular inflammation
Inflammatory cell into glomerulus and tubulointerstitium
Pivotal role in progression of CKD
RAAS and CKD
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Ang II and aldosterone
Proinflammatory and profibrotic effect
cause Renal fibrosis
by toxic oxygen radical formation,
enhanced cellular proliferation,collagen deposition in kidney
TGF-beta , CTGF are involved
Angiotensin II
Profibrotic action
RAAS and CKD
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Recent overview of RASS : ATR
RAAS and CKD
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RAAS and CKD
ATR
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Recent overview of RASS:Aldosterone
RAAS and CKD
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Aldosterone
RAAS and CKD
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AldosteroneRAAS and CKD
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Aldosterone involved in
- endothelial dysfunction
- inflammation
- proteinuria and fibrosis
- increased the effect of AngII
- induce generation of reactive oxygen species
- acceleration of AngII induced activation ofmitogen activated protein kinase
AldosteroneRAAS and CKD
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Inhibition of Renin Angiotensin
Aldosterone System in CKD
f S C
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Similar process in ESRD, CHF
Inhibition of RAAS in CKD
I hibiti f RAAS i CKD
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Cardio/
cerebrovascular
death
End-stage
renaldisease
Nephroticproteinuria
Macro-
proteinuria
Micro-
albuminuria
Endothelialdysfunction
Hypertension risk factors
diabetes, obesity, elderly
Atherosclerosisand LVH
Myocardial
infarction &stroke
Remodelling Ventricular dilatation/cognitive dysfunction
Congestive heart failure/secondary stroke
End-stageheart disease,brain damageand dementia
Role ofangiotensin II in the CVD,CKD
Inhibition of RAAS in CKD
I hibiti f RAAS i CKD
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Inhibition of RAAS in CKD
Target in inhibition of RAAS
I hibiti f RAAS i CKD
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Inhibition of ACE activity
- decrease formation ofAng II andAldosterone
- potentiate the vasodilatory effect ofbradykinin
AECI
- treat hypertension
- reduce proteinuria,
delay progression of renal diseasein diabetic and nondiabetic kidney disease
Inhibition of RAAS in CKD
ACEI
I hibiti f RAAS i CKD
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The Effect of Angiotensin-Converting-Enzyme Inhibition on
Diabetic Nephropathy, NEJM , 1993
Captopril,placebo group in type 1 DM
30% reduction in proteinuria
43% reduction in risk ofdoubling of S.cr
50% reduction in percentage of patients
who died or required dialysis
Conclusions
: Captopril protects against deterioration
in renalfunction ,
is significantlymore effective than
blood-pressure control alone.
First clinical study
After this, more study in DN
ACEIInhibition of RAAS in CKD
Inhibition of RAAS in CKD
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Effect of the Angiotensin-ConvertingEnzyme InhibitorBenazepril on
The Progression ofChronic Renal Insufficiency(AIPRI) ,NEJM , 1996
Benazepril, placebo
in nondiabetic CKD
a doubling of Scr,
percentage of patients who
required dialysis
53 % reduction
Conclusions: Benazepril provides protection
against the progressionof renal
insufficiency in patients with
various renal diseases.
Nondiabetic CKD
ACEIInhibition of RAAS in CKD
Inhibition of RAAS in CKD
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REIN study( Ramipril Efficacy In Nephropathy study, 1997, Lancet
Effect oframipril vs amlodipine on renal outcomes in
hypertensive nephrosclerosis( AASK ):
a randomized controlled trial.2001, JAMA
Efficacy and safety ofbenazepril for advanced chronicrenal insufficiency 2006, NEJM
Nondiabetic CKD
Ramipril
: reduced poteinuria, slow GFR decline
: reduce risk of doubling Scr or progression to ESRD: more effective compared with amlodipine
Benazepril
: renal benefits in patients
without diabetes who had advanced renal insufficiency
ACEIInhibition of RAAS in CKD
Inhibition of RAAS in CKD
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Important renoprotective effect and BPreduction
In patient with diabetic and nondiabetic patient
with proteinuria and
advanced kidney disease
First line therapy for patient with type 1 DM
Conclusion
ACEI
Inhibition of RAAS in CKD
Inhibition of RAAS in CKD
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AT1RB- leave AT2 receptor active,
lead to augmented AT2 effect by unbounded AngII
: AT2 receptor counteract classic AT1 receptor action
ex, vasodilating, mediate apoptosis and growth inhibition
ARB: do not inhibit breakdown of bradykinin
ARBInhibition of RAAS in CKD
ARBInhibition of RAAS in CKD
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Effects ofLosartan on Renal and Cardiovascular Outcomes in Patients
with Type 2 Diabetes and Nephropathy(RENAAL), NEJM, 2001
Losartan, placebo in diabetic patient
doubling ofthe serum cr,
Progression of ESRD
Conclusions
Losartan conferred significant renal
benefits in
patients with type 2 DMand nephropathy, and
it was generallywell tolerated.
ARBInhibition of RAAS in CKD
ARB
Inhibition of RAAS in CKD
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IDTN ( Irbesartandiabetes type 2 nephropathy Trial ) 2001
IRMA(Irbesartan in patient with type 2 diabetes and
microalbuminuria) 2001
MARVAL(Microalbuminuria Reduction with Valsartanin type 2 diabetes And microalbuminuria) 2001
similar effect as previous study
More reduce proteinuria
ARBInhibition of RAAS in CKD
ARB
Inhibition of RAAS in CKD
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ARB Monothepy in nondiabetic renal disease
is not studied untill recent yrs
Study Nondiabetic CKD
ARBInhibition of RAAS in CKD
Inhibition of RAAS in CKD
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Conclusion
also have renoprotective propertiesbeyond their effect on BP
similar cardiovascular and renal protection as ACEI
some favor ARB
better tolerated, lower incidence of hyperkalemia,
not associated with angioedema
should be considered in all patient at risk of
cardiovascular disease or
type 2 DM
ARBInhibition of RAAS in CKD
Inhibition of RAAS in CKD
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ACEI or ARB ?
Renal outcomes with telmisartan, ramipril, or both,
in people at high vascular risk (the ONTARGET study):
a multicentre, randomised, double-blind, controlled trial.2008, lancet
Telmisartans effect on renal outcome is similar to ramipril
ButARB is better tolerated than ACEI ( higher incedence
of hyperkalemia, cough, angioedema)
Angiotensin-receptor blockade versus converting-enzymeinhibition in type 2 diabetes and nephropathy. 2004 NEJM
Telmisartan or enalapril
similar effect in longterm renoprotection
Telmisartan is not inferior to enalapril in providing long-termrenoprotection in persons with type 2 diabetes
Inhibition of RAAS in CKD
Inhibition of RAAS in CKD
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dual block
additive benefit from increased bradykinin activity
preventing ACEI escape phenomenon
preventing detrimental effect of AngIV
Potential benefit of combination
ACEI and ARB
Inhibition of RAAS in CKD
Inhibition of RAAS in CKD
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Randomised controlled trial of dual blockade of renin-angiotensin
system in patients with hypertension, microalbuminuria, andnon-insulin dependent diabetes: the candesartan and lisinoprilmicroalbuminuria (CALM) study. BMJ 2000
candesartan or lisinopril, or both group ,
the reduction in U alb:cr ratio
with combination treatment (50%)
was greater than with candesartan (24%)
and lisinopril (39%)
conclusionCombination treatment is well tolerated
more effective in reducing BP
Nondiabetic CKDACEI and ARB
Inhibition of RAAS in CKD
Inhibition of RAAS in CKD
http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=%20%5BObject%20name%20is%20mogc1832.f2.jpg%5D&p=PMC3&id=27545_mogc1832.f2.jpghttp://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=%20%5BObject%20name%20is%20mogc1832.f2.jpg%5D&p=PMC3&id=27545_mogc1832.f2.jpg -
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Safety of the combination ofvalsartan and benazepril in patients
with chronic renal disease. European Group for the Investigationof Valsartan in Chronic Renal Disease. J Hypertens 2000
Valsartan and benazepri group,
valsartan group
Dual block group
reduce proteinurai 59%
ARB alone 45%
short-term combinationis safe and well tolerated
in patients with moderate
chronic renal failure.
Nondiabetic CKDACEI and ARB
Inhibition of RAAS in CKD
Inhibition of RAAS in CKD
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Coadministration oflosartan and enalapril exerts additiveantiproteinuric effect in IgA nephropathy,AJKD 2001 combination therapy with E and LOS has
an additive dose-dependent antiproteinuric effect
Effects of dual blockade of the renin-angiotensin system inprimary proteinuric nephropathies. KI 2002lisinopril and candesartan combination reduce more proteinuria
Combination treatment of ARB and ACEI in non-diabetic
renal disease (COOPERATE): a randomised controlled trial,
lancet 2003losartan and trandolapril Combination treatment
safely retards progression of non-diabetic renal disease compared \
with monotherapy
Nondiabetic CKD
ACEI and ARBb t o o S C
Inhibition of RAAS in CKD
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Nondiabetic CKD
systematic review and meta-analysis
conclusion
- the combination of ACEI and ARB therapy
in patient with chronic proteinuric renal disease
is safe, without clinically meaningful changes
in serum K levels or GFR.associated with a significant decrease in proteinuria,
at least in the short term.
- Additional trials with longer follow-up
are needed to determine preservation of renal function.
Combination therapy with an angiotensin receptor blocker
and ACE inhibitor in proteinuric renal disease: systematicreview ofthe efficacy and safety data. 2006 AJKD
ACEI and ARB
Inhibition of RAAS in CKD
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Nondiabetic CKD
Add-on angiotensin receptor blockade with
maximized ACE inhibition. KI, 2001
combination therapy
was not superior to maximal dose ACEI therapy
in decreasing proteinuria in patient with renal disease
question of whether combination therapy
is superior to maximal dose monotherapy
Negative result
ACEI and ARB
Inhibition of RAAS in CKD
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Conclusions- the use of anACEi in combination with an ARB
does not reduce the primary outcomes compared to
single drug therapy.
ACEI and ARB
Inhibition of RAAS in CKD
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Reduction in composite CV riskTelmisartan 80mg is as protective as ramipril 10mg
ONTARGET
ACEI and ARB
NEJM,2008
Inhibition of RAAS in CKD
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Telmisartan 80mg added to ramipril 10mg:as effective as ramipril alo
Reduction in composite CV risk
ONTARGET
ACEI and ARB
NEJM,2008
Inhibition of RAAS in CKD
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- renal effects of ramipril, telmisartan and combination
- telmisartan's effects on major renal outcomes
are similar to ramipril.combination therapy reduces proteinuria to
a greater extent than monotherapy,
overall it worsens major renal outcomes.
Renal outcomes with telmisartan, ramipril, or both,in
people at high vascular risk (the ONTARGET study):
a multicentre, randomised, double-blind, controlled
trial. Lancet 2008
ACEI and ARB
Inhibition of RAAS in CKD
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In theory,
Dual block of RAAS with ACEI and ARB
may provide renal benefit beyond therapy
with either drug alonecombined use
more study is needed in different type and severity of CKD
But up to date finding is controversal
Still Ongoing discussion
is premature to draw firm conclusion
about combination therapy in renal disease
Conclusion
ACEI and ARB
RAAS and CKD
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ACEI and AT1RB effect independent of the RAAS
ACEI
block hydrolysis of Ac-SDKP- inhibition of fibrosis
- reduction of inflammatory cell infiltration
AT1RB( especialy in Telmisartan)
Activate PPAR-r ( target for treatmentof metabolic syndrome and diabetes)
- PPAR-r activator
may improve renal disease,
normalize hyperfiltration,
and reduce proteinuria
Inhibition of RAAS in CKD
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Aldosterone Blocker
Mineralocorticoid blockade reduces vascular injury in
stroke-prone hypertensive rats, Hypertension 1998
Aldosterone: a mediator of myocardial necrosis and renal
arteriopathy. Endocrinology 2000
May also blunt in profibrotic effect of aldosterone
Animal experiment
Inhibition of RAAS in CKD
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Aldosterone Blocker
Inhibition of RAAS in CKD
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Cardiovascular ourcome
- AHA : add aldosterone
to clinical guideline of heart failure
Renal outcome
- further reduction in albuminuria- but caution with hyperkalemia
Aldosterone Blocker
Inhibition of RAAS in CKD
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Aldosterone Blocker
Inhibition of RAAS in CKD
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Change in proteinuria after adding aldosterone blockers to ACEinhibitors or angiotensin receptor blockers in CKD: a systematicreview. AJKD 2008
- use of MRBs added to long-term ACEI and/or ARB therapy
in adult patients with proteinuric kidney disease-proteinuria decreases from baseline ranged from 15% to 54%
Conclusion
- adding MRBs to ACE-inhibitor and/or ARB yields significant decreases in proteinuriawithout
adverse effects of hyperkalemia and impaired renal function,
- but routine use of MRBs as additive therapy in patients with
CKD cannot be recommended yet.
Two recent meta- analyses
Aldosterone Blocker
Inhibition of RAAS in CKD
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Aldosterone antagonists for preventing the progression of chronickidney disease: a systematic review and meta-analysis.Clin J Am Nephro, 2009
- evaluated the benefits and harms of adding MB
Conclusion
: Aldosterone antagonists reduce proteinuria in CKD patients
already on ACEis and ARBsbut increase the risk of hyperkalemia.
: Long-term effects of these agents on renal outcomes, mortality,and safety need to be established.
Two recent meta- analyses
Aldosterone Blocker
Inhibition of RAAS in CKD
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Add MRBs to ACEI or ARB
1.Reduce proteinuria
2.Hyperkalemia can be significant
in GFR < 30 ml/min/1.73m2,
K increased drug,
oral K supplenent3.Undefined longterm effect of combined therapy
on renal outcome
Summary of two recent meta- analyses
Aldosterone Blocker
Inhibition of RAAS in CKD
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Aldosterone antagonist in CKD
- more decrease in proteinuria after spironolactone
with longterm ACEI- increased risk of Hyperkalemia
Aldosterone antagonist in ESRD
- potential benefit is extrarenalsuch as BP, vascular function, LVH
- but more study is required
At present , not recommened as routine use
Aldosterone Blocker
Conclusion
Inhibition of RAAS in CKD
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Renin inhibitor
Why renin inhibitor ?
1. AngII generation by non ACE pathway
2. High plasma renin after ACEI,ARB
3. Direct profibrotic role of renin
Renin inhibitor necessary
But difficulty because oflow potency, poor bioavailability, short half life
Aliskiren ( FDA,2007, approved)
Inhibition of RAAS in CKD
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Aliskirento assess the BP-
lowering efficacyand
safety of aliskiren
aliskiren, through inhibition
of renin,
is an effective and safe
orally active BP-lowering
agent
Hypertension. 2003
Renin inhibitor
Inhibition of RAAS in CKD
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Clincal trial in nephropathy: Aliskiren
Renin inhibitor
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Group with L+A 20% reduction in albuminuria compared with placebo( L only)
Inhibition of RAAS in CKD
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In human and experimental nephropathy
promising result for aliskirenas a treatment for nephropathy
Further problem
end point study ( progression to ESRD or doubling of Scr)
aliskiren > or = losartan ?
aliskiren + losartan > or < ACEI + ARB ?imcomplete aldosterone suppression ?
more expensive ?
Renin inhibitor: Aliskiren
Conclusion
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How should RAAS blockade be applied in CKD
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Start earlyTo achieve maximal renal protection
treatment with RAASI should be initiatedat earlier stage of CKD
BENEDICT
ACEI prevent development of microalbuminuria
in type 2 DM and HT without microalbuminuria
In IRMA 2 studyPersistent microalbuminuria is indicator for RAASI
How should RAAS blockade be applied in CKD
for optimal renal protection?
How should RAAS blockade be applied in CKD
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Start RAASI in subject with high risk of developing CKD
- Diabetes Mellitus
- Hypertension
- Obesity
Start early
for optimal renal protection?
How should RAAS blockade be applied in CKD
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Optimal doseAim of using RAASI in CKD
Reduction of blood pressure,
Decrease of urinary protein excretion,
Retarding the progressive renal function decline
for optimal renal protection?
How should RAAS blockade be applied in CKD
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Recommended SBP
- 120 mmHg in type 2 DM
- 110 mmHg in non diabetics
Maximal renal benefit from RAASI Require higher dose than are needed to normalized BP
With multidrug regimen,
optimal titration of RAASI aimed at optimal reduction of
proteinuria
Optimal dose
for optimal renal protection?
How should RAAS blockade be applied in CKD
f
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How long
Longterm treatment with RAASI
might provide more benefit for renoprotection for decreasing progression of renal function
With CKD especially in proteinuria
administer the RAAIS to all stagewith monitoring serum Cr, K
for optimal renal protection?