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


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




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Target in inhibition of RAAS



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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


ACEI



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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



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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




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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




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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




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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



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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.


ARB



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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


ARB



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ARB Monothepy in nondiabetic renal disease

is not studied untill recent yrs

Study Nondiabetic 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




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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




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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




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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


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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




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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



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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



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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



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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



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Reduction in composite CV riskTelmisartan 80mg is as protective as ramipril 10mg

ONTARGET

ACEI and ARB

NEJM,2008



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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



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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



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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



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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



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Aldosterone Blocker



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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



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Aldosterone Blocker



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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



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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



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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



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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



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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)



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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



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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)



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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


for optimal renal protection?



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Start RAASI in subject with high risk of developing CKD

- Diabetes Mellitus

- Hypertension

- Obesity

Start early




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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




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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



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


raas ckd progression

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