Renin Angiotensin Aldosterone System

1
Renin Angiotensin Aldosterone System In
Progressive Kidney Disease
? ? ? ? ? ? ? ? ? ? ? ?
2
CONTENTS
? Pathogenesis of CKD ? RAAS and CKD ?
Inhibition of RAAS in CKD
3
Pathogenesis of CKD
4
Definition and Causes of CKD
5
Definition and Causes of CKD
6
Progression of CKD
7
Progression of CKD
Development of Primary renal disease Progressio
n of renal disease - early renal
inflammation - tubulointerstitial fibrosis
- tubular atrophy - glomerulosclerosis
ESRD
regression
RAAS
8
Progression of CKD
Mechanisms in Progression of Chronic Kidney
Disease
Abboud H and Henrich W. N Engl J Med
201036256-65
9
Progression of CKD
Factors involved in the initiation and
progression of CKD
10
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
11
Progression of CKD
Possible mechanism of progressive renal damage

• ? Systemic and glomerular hypertension
• ? Proteinuria
• ? Various cytokine and growth factors
• ? RAAS
• ? Podocyte loss
• ? Dyslipidemia

12
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
13
Progression of CKD
Proteinuria

• ? Is a marker of renal injury
• ? Contribute to progressive renal injury and
• 
  inflammation

14
Progression of CKD
RAAS
15
Progression of CKD
Specific cytokines/growth factors
TGF-beta PDGF AngII basic FGF
endothelin Various chemokines PPAR-r PAI-1
16
Podocyte loss
Progression of CKD

• 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
17
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
18
Progression of CKD
Most important risk factor for progression
of renal disease
Hypertension Proteinuria
?
?
? RAAS is involved
19
Progression of CKD
Hypertension renal damage
? direct glomerular damage ? indirect glomerular
damage by atherosclerosis, heart
failure..
? RAAS is involved
20
Progression of CKD
Proteinuriasignificance

• ? 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

21
Progression of CKD
Proteinuriasignificance
22
Progression of CKD
Proteinuriamechanism
Usually due to increased glomerular pressure
Glomerulus
High BP
High efferent Pr
Efferent A
GPr
Afferent A
Proteinuria
23
Progression of CKD
Proteinuriamechanism
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
24
RAAS and Chronic Kidney Disease
25
RAAS and CKD
How the RASS was seen in the past
aldosterone
26
RAAS and CKD
Recent overview of RASS AngII
27
RAAS and CKD
Angiotensin II
Angiotensin II (ang II) promotes injury in at
least five separate steps in the cycle.
28
RAAS and CKD
Angiotensin II
29
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
30
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
31
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

32
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

33
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
34
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

35
RAAS and CKD
Recent overview of RASS ATR
36
RAAS and CKD
ATR
37
RAAS and CKD
Recent overview of RASSAldosterone
38
RAAS and CKD
Aldosterone
39
RAAS and CKD
Aldosterone
40
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
41
Inhibition of Renin Angiotensin Aldosterone
System in CKD
42
Inhibition of RAAS in CKD
Similar process in ESRD, CHF
43
Inhibition of RAAS in CKD
Role of angiotensin II in the CVD,CKD
Ventricular dilatation/cognitive dysfunction
Remodelling
Myocardialinfarction stroke
Congestive heart failure/secondary stroke
Macro-proteinuria
Micro-albuminuria
End-stageheart disease,brain damage and dementia
Atherosclerosis and LVH
Endothelialdysfunction
Nephrotic proteinuria
End-stagerenal disease
Cardio/ cerebrovascular death
Hypertension risk factors diabetes, obesity,
elderly
ANGIOTENSIN II
44
Inhibition of RAAS in CKD
Target in inhibition of RAAS
45
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
46
ACEI
Inhibition of RAAS in CKD
First clinical study
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
47
ACEI
Inhibition of RAAS in CKD
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.
48
ACEI
Inhibition of RAAS in CKD
Nondiabetic CKD
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
49
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
50
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
51
ARB
Inhibition 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.
52
ARB
Inhibition of RAAS in CKD
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
53
ARB
Inhibition of RAAS in CKD
Study Nondiabetic CKD
ARB Monothepy in nondiabetic renal disease is not
studied untill recent yrs
54
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
55
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)
56
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
57
Inhibition of RAAS in CKD
ACEI and ARB
Nondiabetic CKD
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 albcr 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

58
Inhibition of RAAS in CKD
ACEI and ARB
Nondiabetic CKD
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.

59
Inhibition of RAAS in CKD
ACEI and ARB
Nondiabetic CKD

• 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

60
Inhibition of RAAS in CKD
ACEI and ARB
Nondiabetic CKD
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.
61
Inhibition of RAAS in CKD
ACEI and ARB
Negative result
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
62
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.
63
Inhibition of RAAS in CKD
ACEI and ARB
ONTARGET
Telmisartan 80mg is as protective as ramipril 10mg
Reduction in composite CV risk
NEJM,2008
64
Telmisartan 80mg added to ramipril 10mg as
effective as ramipril alo
Inhibition of RAAS in CKD
ACEI and ARB
ONTARGET
Reduction in composite CV risk
NEJM,2008
65
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.

66
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

67
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

68
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
69
Inhibition of RAAS in CKD
Aldosterone Blocker
70
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
71
Inhibition of RAAS in CKD
Aldosterone Blocker
72
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.

73
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.
74
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 lt 30
ml/min/1.73m2, K increased
drug, oral K supplenent
3.Undefined longterm effect of combined therapy

on renal outcome
75
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 Aldosteron
e 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
76
Inhibition of RAAS in CKD
Renin inhibitor

• Why renin inhibitor ?
• 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)

77
Inhibition of RAAS in CKD
Renin inhibitor
Aliskiren
to assess the BP- lowering efficacy and safety
of aliskiren aliskiren, through inhibition of
renin, is an effective and safe orally active
BP-lowering agent
Hypertension. 2003
78
Inhibition of RAAS in CKD
Renin inhibitor
Clincal trial in nephropathy Aliskiren
79
Group with LA? 20 reduction in albuminuria
compared with placebo( L only)
80
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 gt or losartan
? aliskiren losartan gt or lt ACEI ARB ?
imcomplete aldosterone suppression ? more
expensive ?
81
?? ?????
82
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

83
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
84
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

85
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

86
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