Renin Angiotensin Aldosterone System In Progressive Kidney Disease 조 선 대 병 원 신 장 내 과 정 종 훈

Renin Angiotensin Aldosterone System In Progressive Kidney Disease

조 선 대 병 원 신 장 내 과 정 종 훈

Pathogenesis of CKD

RAAS and CKD

Inhibition of RAAS in CKD

CONTENTS

Pathogenesis of CKD

Definition and Causes of CKD

Definition and Causes of CKD

Progression of CKD

Development of Primary renal disease

Progression of renal disease

- early renal inflammation - tubulointerstitial fibrosis - tubular atrophy - glomerulosclerosis

ESRD

RAAS

regression

Progression of CKD

Abboud H and Henrich W. N Engl J Med 2010;362:56-65

Progression of CKD

Mechanisms in Progression of Chronic Kidney Disease

Factors involved in the initiation and progression of CKD

Progression of CKD

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

Systemic and glomerular hypertension

Proteinuria

Various cytokine and growth factors

RAAS

Podocyte loss

Dyslipidemia

Possible mechanism of progressive renal damage

Progression of CKD

Systemic and glomerular hypertension

Systemic Hypertensin - Progression of CKD : accelerated by HT BP control is key in Tx of CKD

Glomerular Hypertension - key mediator of progressive sclerosis

Progression of CKD

Proteinuria

Is a marker of renal injury

Contribute to progressive renal injury and inflammation

Progression of CKD

RAAS

Progression of CKD

Specific cytokines/growth factors

TGF-beta PDGFAngII basic FGF endothelinVarious chemokines PPAR-r PAI-1

Progression of CKD

Podocyte loss

Many glomerular diseasePodocyte injuryPodocyte dose not proliferativeloss of podocyte after injuryKey factor resulting in progressive sclerosis

Progression of CKD

Oxidative stress leads to podocyte depletion in CKD via AOPPs(advancedOxidation protein products) KI, 2009

Dyslipidemia

Abnormal lipid important in modulating glomerular sclerosis in rat ( human study is evolving )

associated with increased loss of GFR

Statin may not only benefit CVD risk, but also be of benefit for progressive CKD

Progression of CKD

Most important risk factor for progression of renal disease

Hypertension

Proteinuria

RAAS is involved

Progression of CKD

Hypertension: renal damage

direct glomerular damage

indirect glomerular damage by atherosclerosis, heart failure..

RAAS is involved

Progression of CKD

Nephrotoxin : Increased tubular absorption of filtered protien Induce tubulointerstitial inflammation Tubular atrophy, interstitial fibrosis Loss of renal function

Clinical parameter for diagnosing renal damage, especially glomerular hypertension

Risk factor and predictor for cardiovascular event

Proteinuria:significance

Progression of CKD

Proteinuria:significance

Progression of CKD

Proteinuria:mechanism

Usually due to increased glomerular pressure

Afferent A Efferent A

Glomerulus

Proteinuria

GPr

High BP High efferent Pr

Progression of CKD

Reducing glomerular pressure is a principal strategy for reducing proteinuria

To decrease Gloemrular Pressure blood pressure and arteriolar resistance in efferent arteriole must be reduced

Proteinuria:mechanism

Progression of CKD

RAAS and Chronic Kidney Disease

How the RASS was seen in the past

aldosterone

RAAS and CKD

Recent overview of RASS : AngII

RAAS and CKD

Angiotensin IIAngiotensin II (ang II) promotes injury in at least five separate steps in the cycle.

RAAS and CKD

Angiotensin IIRAAS and CKD

Role of AngII 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

Angiotensin II

Glomerular capillary hypertension

Initiating 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 function due to pressure induced capillary stretch and glomerular injury

RAAS and CKD

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)

AngII increase proteinuria through hemodynamic and nonhemodynamic mechanism

RAAS and CKD

Growth effects and apoptosis

AngII

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

Angiotensin II

Inflammation

AngII

activate through AT1 and AT2 the proinflammatory transcription 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

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

Recent overview of RASS : ATR

RAAS and CKD

RAAS and CKD

ATR

Recent overview of RASS:Aldosterone

RAAS and CKD

Aldosterone RAAS and CKD


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 of mitogen activated protein kinase


Inhibition of Renin Angiotensin Aldosterone System in CKD

Similar process in ESRD, CHF


Cardio/ cerebrova

sculardeath

End-stagerenal

disease

Nephroticproteinuria

Macro-proteinuria

Micro-albuminuria

Endothelialdysfunction

Hypertension risk factorsdiabetes, obesity, elderly

Atherosclerosisand LVH

Myocardialinfarction &

stroke

Remodelling Ventricular dilatation/cognitive dysfunction

Congestive heart failure/secondary stroke

End-stageheart disease,brain damageand dementia

Role of angiotensin II in the CVD,CKD



Target in inhibition of RAAS

Inhibition of ACE activity - decrease formation of Ang II and Aldosterone - potentiate the vasodilatory effect of bradykinin

AECI - treat hypertension - reduce proteinuria, delay progression of renal disease in diabetic and nondiabetic kidney disease


ACEI

The Effect of Angiotensin-Converting-Enzyme Inhibition onDiabetic Nephropathy, NEJM , 1993

Captopril, placebo group in type 1 DM

30% reduction in proteinuria43% reduction in risk of doubling of S.cr 50% reduction in percentage of patients who died or required dialysis

Conclusions : Captopril protects against deterioration in renal function , is significantly more effective than blood-pressure control alone.

First clinical study

After this, more study in DN

ACEIInhibition of RAAS in CKD

Effect of the Angiotensin-Converting–Enzyme Inhibitor Benazepril on The Progression of Chronic 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 progression of renal insufficiency in patients with various renal diseases.

Nondiabetic CKDACEIInhibition of RAAS in CKD

REIN study( Ramipril Efficacy In Nephropathy study, 1997, Lancet

Effect of ramipril vs amlodipine on renal outcomes inhypertensive nephrosclerosis( AASK ): a randomized controlled trial.2001, JAMA

Efficacy and safety of benazepril for advanced chronic renal 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


Important renoprotective effect and BP reduction In patient with diabetic and nondiabetic patient with proteinuria and advanced kidney disease First line therapy for patient with type 1 DM

Conclusion


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

Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy(RENAAL), NEJM, 2001

Losartan, placebo in diabetic patient

doubling of the serum cr,Progression of ESRD

Conclusions Losartan conferred significant renal benefits in patients with type 2 DM and nephropathy, and it was generally well tolerated.


IDTN ( Irbesartan diabetes type 2 nephropathy Trial ) 2001

IRMA(Irbesartan in patient with type 2 diabetes andmicroalbuminuria) 2001

MARVAL(Microalbuminuria Reduction with Valsartan in type 2 diabetes And microalbuminuria) 2001

similar effect as previous studyMore reduce proteinuria


ARB Monothepy in nondiabetic renal diseaseis not studied untill recent yrs

Study Nondiabetic CKD


Conclusion

also have renoprotective properties beyond 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


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, lancetTelmisartan’s effect on renal outcome is similar to ramipril But ARB is better tolerated than ACEI ( higher incedence of hyperkalemia, cough, angioedema)

Angiotensin-receptor blockade versus converting-enzyme inhibition 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-term renoprotection in persons with type 2 diabetes


dual block

additive benefit from increased bradykinin activity

preventing ACEI escape phenomenon

preventing detrimental effect of AngIV

Potential benefit of combination

ACEI and ARB


Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-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


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.jpg

Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European Group for the Investigation of 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 combination is safe and well tolerated in patients with moderate chronic renal failure.



Coadministration of losartan and enalapril exerts additive antiproteinuric 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 2002 lisinopril and candesartan combination reduce more proteinuria

Combination treatment of ARB and ACEI in non-diabeticrenal 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

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 blockerand ACE inhibitor in proteinuric renal disease: systematic review ofthe efficacy and safety data. 2006 AJKD

ACEI and ARB Inhibition of RAAS in CKD

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


Conclusions- the use of an ACEi in combination with an ARB does not reduce the primary outcomes compared to single drug therapy.

ACEI and ARB


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

ONTARGET


NEJM,2008

Telmisartan 80mg added to ramipril 10mg: as effective as ramipril alo

Reduction in composite CV risk

ONTARGET


NEJM,2008

- 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


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


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 treatment of metabolic syndrome and diabetes) - PPAR-r activator may improve renal disease, normalize hyperfiltration, and reduce proteinuria

RAAS and CKD

Aldosterone Blocker

Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats, Hypertension 1998

Aldosterone: a mediator of myocardial necrosis and renalarteriopathy. Endocrinology 2000

May also blunt in profibrotic effect of aldosterone

Animal experiment


Aldosterone Blocker


Cardiovascular ourcome

- AHA : add aldosterone to clinical guideline of heart failure

Renal outcome

- further reduction in albuminuria - but caution with hyperkalemia

Aldosterone Blocker


Aldosterone Blocker


Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. 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 proteinuria without 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


Aldosterone antagonists for preventing the progression of chronic kidney 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 ARBs but 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


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 supplenent 3.Undefined longterm effect of combined therapy on renal outcome

Summary of two recent meta- analyses

Aldosterone Blocker


Aldosterone antagonist in CKD - more decrease in proteinuria after spironolactone with longterm ACEI - increased risk of Hyperkalemia

Aldosterone antagonist in ESRD - potential benefit is extrarenal such as BP, vascular function, LVH - but more study is required

At present , not recommened as routine use

Aldosterone Blocker


Conclusion

Renin inhibitor

Why renin inhibitor ?

1. AngII generation by non ACE pathway2. High plasma renin after ACEI,ARB3. Direct profibrotic role of renin

Renin inhibitor necessary

But difficulty because of low potency, poor bioavailability, short half life

Aliskiren ( FDA,2007, approved)


Aliskirento assess the BP-lowering efficacy and safety of aliskiren

aliskiren, through inhibitionof renin, is an effective and safe orally active BP-lowering

agent

Hypertension. 2003

Renin inhibitor


Clincal trial in nephropathy: Aliskiren

Renin inhibitor


Group with L+A 20% reduction in albuminuria compared with placebo( L only)

In human and experimental nephropathy promising result for aliskiren as 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

수고 하셨읍니다

Start earlyTo achieve maximal renal protection treatment with RAASI should be initiated at earlier stage of CKD

BENEDICT

ACEI prevent development of microalbuminuria in type 2 DM and HT without microalbuminuria

In IRMA 2 study Persistent microalbuminuria is indicator for RAASI

How should RAAS blockade be applied in CKD for optimal renal protection?

Start RAASI in subject with high risk of developing CKD

- Diabetes Mellitus

- Hypertension

- Obesity

Start early


Optimal dose

Aim of using RAASI in CKD

Reduction of blood pressure,

Decrease of urinary protein excretion,

Retarding the progressive renal function decline


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


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 stage with monitoring serum Cr, K


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Renin Angiotensin Aldosterone System In Progressive Kidney Disease 조 선 대 병 원 신 장 내 과 정 종 훈