Renin Angiotensin Aldosterone System In Progressive Kidney Disease

CONTENTS
Pathogenesis of CKD RAAS and CKD Inhibition of RAAS in CKD

Pathogenesis of CKD

Definition and Causes of CKD

Definition and Causes of CKD

Progression of CKD

Progression of CKD

Development of Primary renal disease regression Progression of renal disease - early renal inflammation - tubulointerstitial fibrosis - tubular atrophy - glomerulosclerosis

RAAS

ESRD

Progression of CKD

Mechanisms in Progression of Chronic Kidney Disease

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

Progression of CKD

Factors involved in the initiation and progression of CKD

Progression of CKD

Six stage of renal progression

1.Persistent glomerular injury local 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

Possible mechanism of progressive renal damage Systemic and glomerular hypertension Proteinuria Various cytokine and growth factors RAAS Podocyte loss Dyslipidemia

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 PDGF AngII basic FGF endothelin Various chemokines PPAR-r PAI-1

Progression of CKD

Podocyte loss
Many glomerular disease Podocyte injury Podocyte dose not proliferative loss of podocyte after injury Key factor resulting in progressive sclerosis

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

Progression of CKD

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

Proteinuria:significance
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

Progression of CKD

Proteinuria:significance

Progression of CKD

Proteinuria:mechanism
Usually due to increased glomerular pressure
Glomerulus

High BP
Afferent A

High efferent Pr
Efferent A

GPr

Proteinuria

Progression of CKD

Proteinuria:mechanism
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

RAAS and Chronic Kidney Disease

RAAS and CKD

How the RASS was seen in the past

aldosterone

RAAS and CKD

Recent overview of RASS : AngII

RAAS and CKD

Angiotensin II

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

RAAS and CKD

Angiotensin II

RAAS 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

Angiotensin II 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

RAAS 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

Angiotensin II Profibrotic action

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

RAAS and CKD

Recent overview of RASS : ATR

RAAS and CKD

ATR

RAAS and CKD

Recent overview of RASS:Aldosterone

RAAS and CKD

Aldosterone

RAAS and CKD

Aldosterone

RAAS and CKD

Aldosterone
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

Inhibition of RAAS in CKD

Similar process in ESRD, CHF

Inhibition of RAAS in CKD

Role of angiotensin II in the CVD,CKD

Remodelling Ventricular dilatation/ cognitive dysfunction

infarction & stroke

Microalbuminuria Atherosclerosis Endothelial and LVH dysfunction

Myocardial

Congestive heart failure/ secondary stroke Macroproteinuria End-stage heart disease, brain damage and dementia

Nephrotic proteinuria

Hypertension risk factors diabetes, obesity, elderly

End-stage Cardio/ renal cerebrova disease scular death

Inhibition of RAAS in CKD

Target in inhibition of RAAS

Inhibition of RAAS in CKD

ACEI

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

Inhibition of RAAS in CKD

First clinical study

ACEI

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 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.

After this, more study in DN

Inhibition of RAAS in CKD

ACEI

Nondiabetic CKD
Effect of the Angiotensin-ConvertingEnzyme 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.

Inhibition of RAAS in CKD

Nondiabetic CKD

ACEI

REIN study( Ramipril Efficacy In Nephropathy study, 1997, Lancet Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis( AASK ): a randomized controlled trial.2001, JAMA Efficacy and safety of benazepril for advanced chronic renal insufficiency 2006, NEJM

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

Inhibition of RAAS in CKD

ACEI Conclusion
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

Inhibition of RAAS in CKD

ARB
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

Inhibition of RAAS in CKD

ARB

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.

Inhibition of RAAS in CKD

ARB

IDTN ( Irbesartan diabetes type 2 nephropathy Trial ) 2001 IRMA(Irbesartan in patient with type 2 diabetes and microalbuminuria) 2001 MARVAL(Microalbuminuria Reduction with Valsartan in type 2 diabetes And microalbuminuria) 2001 similar effect as previous study More reduce proteinuria

Inhibition of RAAS in CKD

ARB

Study Nondiabetic CKD

ARB Monothepy in nondiabetic renal disease is not studied untill recent yrs

Inhibition of RAAS in CKD

ARB
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

Inhibition of RAAS in CKD

ACEI or ARB ?
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 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 But ARB is better tolerated than ACEI ( higher incedence of hyperkalemia, cough, angioedema)

Inhibition of RAAS in CKD

ACEI and ARB Potential benefit of combination

dual

block

additive benefit from increased bradykinin activity preventing ACEI escape phenomenon preventing detrimental effect of AngIV

Inhibition of RAAS in CKD

Nondiabetic CKD

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 lisinopril microalbuminuria (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%) conclusion Combination treatment is well tolerated more effective in reducing BP

Inhibition of RAAS in CKD

Nondiabetic CKD

ACEI and ARB

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.

Inhibition of RAAS in CKD

Nondiabetic CKD

ACEI and ARB

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 in primary proteinuric nephropathies. KI 2002
lisinopril and candesartan combination reduce more proteinuria

Combination treatment of ARB and ACEI in non-diabetic renal disease (COOPERATE): a randomised controlled trial, lancet 2003
losartan and trandolapril Combination treatment safely retards progression of non-diabetic renal disease compared \ with monotherapy

Inhibition of RAAS in CKD

Nondiabetic CKD

ACEI and ARB

Combination therapy with an angiotensin receptor blocker and ACE inhibitor in proteinuric renal disease: systematic review ofthe efficacy and safety data. 2006 AJKD 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.

Inhibition of RAAS in CKD

ACEI and ARB

Nondiabetic CKD

Negative result

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

Inhibition of RAAS in CKD

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.

Inhibition of RAAS in CKD

ACEI and ARB

ONTARGET

Telmisartan 80mg is as protective as ramipril 10mg

Reduction in composite CV risk

NEJM,2008

Inhibition of RAAS in CKD

ACEI and ARB

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

Reduction in composite CV risk

NEJM,2008

Inhibition of RAAS in CKD

ACEI and ARB

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 - 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.

Inhibition of RAAS in CKD

ACEI and ARB Conclusion

In theory, Dual block of RAAS with ACEI and ARB may provide renal benefit beyond therapy with either drug alone combined 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

RAAS and CKD

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

Inhibition of RAAS in CKD

Aldosterone Blocker
Animal experiment
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

Inhibition of RAAS in CKD

Aldosterone Blocker

Inhibition of RAAS in CKD

Aldosterone Blocker
Cardiovascular ourcome - AHA : add aldosterone to clinical guideline of heart failure Renal outcome - further reduction in albuminuria - but caution with hyperkalemia

Inhibition of RAAS in CKD

Aldosterone Blocker

Inhibition of RAAS in CKD

Aldosterone Blocker
Two recent meta- analyses
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.

Inhibition of RAAS in CKD

Aldosterone Blocker
Two recent meta- analyses
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.

Inhibition of RAAS in CKD

Aldosterone Blocker
Summary of two recent meta- analyses
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

Inhibition of RAAS in CKD

Aldosterone Blocker Conclusion

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

Inhibition of RAAS in CKD

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 of low potency, poor bioavailability, short half life Aliskiren ( FDA,2007, approved)

Inhibition of RAAS in CKD

Renin inhibitor
Aliskiren
to assess the BPlowering efficacy and safety of aliskiren aliskiren, through inhibition of renin, is an effective and safe orally active BP-lowering agent

Hypertension. 2003

Inhibition of RAAS in CKD

Renin inhibitor
Clincal trial in nephropathy: Aliskiren

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

Inhibition of RAAS in CKD

Renin inhibitor: Aliskiren

Conclusion
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 ?

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

Start early
To 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 early
Start RAASI in subject with high risk of developing CKD - Diabetes Mellitus - Hypertension - Obesity

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

Optimal dose
Aim of using RAASI in CKD Reduction of blood pressure, Decrease of urinary protein excretion, Retarding the progressive renal function decline

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

Optimal dose
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

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