Post on 02-Jun-2018
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Do we still think there is evidence for
RAAS blockade?
Peter Rossing
MD DMScSteno
Diabetes Center
KDIGO Controversies Conference Diabetic Kidney Disease
New Delhi 2012
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Natural history of diabetic nephropathy
FunctionalGFR -
(90-95%)
Microalbuminuria,hypertension
Proteinuria, nephrotic
syndrome, GFR
StructuralRenal
hypertrophy
Mesangial
expansion,glomerular basementmembrane thickening,
arteriolar hyalinosis
Mesangial
nodules(Kimmelstiel-Wilson
lesions)
Tubular-interstitial fibrosis
Urinary protein excretionGFR
Urinary
proteinexcretio
n(mg/d)
Years
Glomer
ularfiltrationra
te(GFR)
(mL/min)
0
150
100
50
5 10 15 20 25
20
200
1000
5000
Incipient diabetic
nephropathyPre Overt diabetic
nephropathyEnd-stage
renal disease
1 2 3 4 5
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J Ingelfinger NEJM 2008
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Progression of Diabetic Renal Disease
in Patients with Type 2 Diabetes2000
20
2
200
A
lbuminuria(g/min)
40%
60%
Normoalbuminuria
Overt nephropathy
Microalbuminuria
Time (Years)
IDNT
RENAAL
IRMA 2
MARVAL
GFR2-20:10
GFR
1-3
GFR
1
BENEDICT
ROADMAP
DIRECT
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0
5
10
15
0 6 12 18 24 30 36 42 48
Cu
mulative
incid
enceof
microalbuminu
ria(%)
Follow-up
(months)
301
300
254
229
237
214
224
203
207
187
198
176
188
164
149
136
104
89
No. at Risk
Trandolapril
Placebo
Placebo
(30 events)
Trandolapril(18 events)
Benedict trial NEJM
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Occurrence of Microalbuminuria
during the 48-Month Follow-up Period
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RAS study, normomtensive
normoalbuminuric Type 1 (n=285)Structural
endpoint
Mauer et al NEJM 2009
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RAS study, normomtensive
normoalbuminuric Type 1 (n=285)
Mauer et al NEJM 2009
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Odds ratio ( 95% CI)
0.8 1 1.2 1.4 1.60.60.40.2
EUCLID 0.75 (0.36;1.58)
DIRECT 1.04 (0.76;1.44)
BENEDICT 0.57 (0.31;1.05)
DIRECT 0.91 (0.70;1.20)
ADVANCE 0.79 (0.72;0.86)
Type 2 diabetes
Type 1 diabetes
HOPE 0.80 (0.67;0.95)
RASS-enalapril 0.66 (0.18;2.42)
RASS-losartan 2.97 (1.11;7.95)
0.1
ODDS RATIO FOR DEVELOPMENT OF MICROALBUMINURIA WITH
RAS BLOCKADE
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0
5
10
15
20
0 3 6 12 18 24
IRMA 2: Primary Endpoint
Time to
Development of Overt Nephropathy
Cumula
tiveeventr
ate(%)
Months of Follow-up
172
160
162
Placebo
Irbesartan 150 mg
Irbesartan 300 mg
69% RRR Irbesartan 300 mg vs
Placebo, p = 0.0013
40% RRR Irbesartan 150 mg vs
Placebo , p = 0.096
172
160
162
142
144
152
136
139
147
122
125
139
31
39
40
No. at Risk
114
120
130
Dataset: Per-protocol analysis
22
Parving H-H, et al. N Engl J Med 2001;345:870-878.
EARLY INTERVENTION
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-10
-8
-6
-4
-2
0
-60
-40
-20
0
EARLY INTERVENTIONResponse to spironolactone 25 mg
21 type 1 diabetic patients with microalbuminuria
-60%
(-21 to -80) %
-3
(-8 to 3)
mm Hg
0
(-3 to 3)
mm Hg
Relativechange(%)
Albuminuria 24hour Blood
Pressure
Baseline:
90 (61-121)mg/d 135 (3) 65 (2) mm Hg
Ch
ange(mm
Hg)
SBP
DBP
S Nielsen Diabetic Medicine 2011
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DETAIL study: ACEi
vs
ARB
AH Barnett NEJM 2004
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Progression
to death,
dialysis or
transplant(%)
Captopril
Placebo
Follow-up (years)
0 1 2 3 4
0
10
20
30
40
p=0.006
Effect of ACE inhibition on diabetic nephropathy in patients with
Type 1 diabetes
Lewis EJ et al. N Engl
J Med.
1993
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0.4 1.4
Comparison of Clinical Studies in OvertComparison of Clinical Studies in OvertType 2 Diabetic NephropathyType 2 Diabetic Nephropathy
Primary compositeendpoint
Doubling of
serum creatinine
ESRD
All-causemortality
Relative risk
IDNTIDNT
Relative risk
RENAALRENAAL
0.7 1.0
0.80
0.67
0.77
0.92
Doubling of serumcreatinine / ESRD
0.74
0.1
0.84
0.75
0.72
1.02
0.79
0.4 1.40.7 1.00.1
Irbesartan vs Placebo Placebo vs Losartan
Brenner BM et al. N Engl J Med 2001;345:861-869. Lewis EJ et al. N Engl J Med 2001;345:851-860
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RENAAL; Losartan
more renoprotective
than placebo intype 2 diabetes;similar blood pressure, different albuminuria
%wi
thevent
p=0.024
Risk Reduction: 16%Placebo
Losartan
0 12 24 36 48
0
10
20
30
40
50
Systolic
Diastolic
MAP
0 12 24 36 48 Mo
60
80
100
120
140
160
Pulse PressureB
loodPressure
(mmHg)
P
L
Brenner et al; New Engl J Med 2001
Album
inuria(Change,%
)
p=
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What
should
we
do in the
normoalbuminuric
patients?
CKD in DEMAND eGFR
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New Renoprotective
Treatment
Modalities
Dual
RAS blockade
High
dose
RAS blockade
Aldosterone
blockade
Renin
inhibition
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Additional effects of irbesartan
900 mg vs. 300 mg
-30
-20
-10
0
24-hrs collections
%
4-hrs collections
-20
p
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CV risk
factor reduction
with
dual
RAAS blockade
in diabetic
nephropathy
BP (mmHg)
8/5
P < 0.01
Albuminuria
(%)
25-43
P < 0.01
LDL-cholesterol
(mmol/l)
0.3
P = 0.01
Side effects
P-potassium
(mmol/l)
0.3
Hb
(mmol/l)
0.3
GFR
reversible
Jacobsen et al. NDT 2002;17:1019-1024
Jacobsen et al. JASN 2003;14:992-959
Jacobsen et al. Kidney International 2003;65:1874-1880
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The ONTARGET Investigators. N Engl J Med 2008;10.1056/NEJMoa0801317
Kaplan-Meier Curves for the Primary Outcome in the Three Study Groups
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Diabetologia 2011,54:2978-86
Time to primary composite renal endpoint in type 2 diabetic patients
with overt proteinuria
and renal insufficiency. Solid line, olmesartan;
dashed line, placebo
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Urinary Proteomics
Technology platform: CE/MS Technologie
Capillary
Electrophoresis
coupled
to Mass
Spectrometry
Urine
Sample
Capillary
Electrophoresis
Mass
Spectrometry
Ionization
Report
Data Storage
and
Evaluation
DiagnosticDisease
specific
Biomarker pattern
Separation and analysis
of proteins
and peptides
(>1,000)
Run time ~60 min
CE
fast
robust
inexpensive
reproducible
MS
resolution
scan
speed
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CE-MS peptidome
profile
300 400 500 600 700 800 900 1000 1100m/z
0
10
20
30
40
50
60
70
80
90
100
Relative
Abundance
y9
y8
y6
y4y3b3 b6 b8
b112++H2O
b112+
300 400 500 600 700 800 900 1000 1100m/z
0
10
20
30
40
50
60
70
80
90
100
Relative
Abundance
y9
y8
y6
y4y3b3 b6 b8
b112++H2O
b112+
Ph G R Ph G E R G P Ph G P
b ions
y ions
3 6 7 8 11
9 8 6 4 3
Ph G R Ph G E R G P Ph G P
b ions
y ions
3 6 7 8 11
9 8 6 4 3
Sequence
information
0 20 40 60 80 100
100
80
60
40
20
0
100-Specificity
Sensitivity
Statistics
Creatinine (micromol/l)
Cholesterole (mmol/l)
Urinary albumin/creatinine
Gender
Ag e
Creatinine (micromol/l)
Cholesterole (mmol/l)
Urinary albumin/creatinine
Gender
Ag e
Clinical
data
Patients
history
controls
cases
controls
cases
Biomarkerselection
Database
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control normo
micro macro
Determination of Biomarkers for Diabetes and Diabetic Nephropathy
Type 1 diabetic patients and healthy controls
Rossing JASN 2008
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Intervention Standard
Patients
with
Type 2 DM and normoalb
TEST
Positive
(at risk)
Evaluation of1) predictive power of test for outcome
2) Effect of intervention in high risk patients
negative
(no risk)
Standard
Follow up
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Kidney int 2006
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0
25
50
75
100
0 5 10 15 20
years since onset of diabetic nephropathy
Cumulativedeathrate(%
Andersen 1983
Knowles 1971
Parving 1996
Rossing 1996
Astrup AS, et al
Cumulative
death
rate in type 1 diabetesafter
onset
of diabetic
nephropathy
Astrup AS. et al. Kidney International 2005;68:1250-1257
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Slide no 32
RAAS Blockade
in DiabetesConclusions
Renoprotective: primary, secondary
and tertiary
prevention
but no
effect
in normoalbuminuric
normotensive
subjects
Postpone
ESRD / death
Discussions
about
optimal blockade
high
dose, dual
blockade, DRI
Cardio-vascular
protection
Role
of
aldosterone
blockade?
How
to treat
normoalbuminuric
patients with
low
eGFR?
Is ACEi
and ARB the
same?