Do we still think there is evidence for

RAAS blockade?
Peter Rossing

MD DMSc
Steno

Diabetes Center
KDIGO Controversies Conference Diabetic Kidney Disease
New Delhi 2012
Natural history of diabetic nephropathy
Functional
GFR -
(90-95%)
Microalbuminuria,
hypertension
Proteinuria, nephrotic

syndrome, GFR
Structural
Renal

hypertrophy
Mesangial

expansion,
glomerular basement
membrane thickening,
arteriolar hyalinosis
Mesangial

nodules
(Kimmelstiel-Wilson
lesions)
Tubular-interstitial fibrosis
Urinary protein excretion GFR
U
r
i
n
a
r
y

p
r
o
t
e
i
n

e
x
c
r
e
t
i
o
n

(
m
g
/
d
)
Years
G
l
o
m
e
r
u
l
a
r

f
i
l
t
r
a
t
i
o
n

r
a
t
e

(
G
F
R
)

(
m
L
/
m
i
n
)
0
150
100
50
5 10 15 20 25
20
200
1000
5000
Incipient diabetic

nephropathy
Pre Overt diabetic

nephropathy
End-stage

renal disease
1 2 3 4 5
J Ingelfinger

NEJM 2008
Progression of Diabetic Renal Disease

in Patients with Type 2 Diabetes
2000
20
2
200
A
l
b
u
m
i
n
u
r
i
a

(

g
/
m
i
n
)
40%
60%
Normoalbuminuria
Overt nephropathy
Microalbuminuria
Time (Years)
IDNT
RENAAL
IRMA 2
MARVAL

GFR
2-20:10

GFR
1-3

GFR
1
BENEDICT
ROADMAP
DIRECT
0
5
10
15
0 6 12 18 24 30 36 42 48
C
u
m
u
l
a
t
i
v
e


i
n
c
i
d
e
n
c
e

o
f
m
i
c
r
o
a
l
b
u
m
i
n
u
r
i
a

(
%
)
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

NEJ M
Haller et al. N Engl J Med 2011;364:907-17
Occurrence of Microalbuminuria

during the 48-Month Follow-up Period
RAS study, normomtensive

normoalbuminuric Type 1 (n=285)

Structural

endpoint
Mauer

et al NEJ M 2009
RAS study, normomtensive

normoalbuminuric Type 1 (n=285)
Mauer

et al NEJ M 2009
Odds ratio (

95% CI)
0.8 1 1.2 1.4 1.6 0.6 0.4 0.2
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 RATI O FOR DEVELOPMENT OF MI CROALBUMI NURI A WI TH
RAS BLOCKADE
Should all type 1 diabetic microalbuminuric

patients receive ACE inhibitors? A meta
regression analysis (n=698)

62% reduction in progression to nephropathy

Regression to normoalbuminuria was 3 times
greater

50% reduction in urinary albumin excretion at 2
years

Preservation of GFR
Nish Chaturvedi

et al. Ann Intern Med -

2001
0
5
10
15
20
0 3 6 12 18 24
IRMA 2: Primary Endpoint

Time to

Development of Overt Nephropathy
C
u
m
u
l
a
t
i
v
e

e
v
e
n
t

r
a
t
e

(
%
)
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.
-10
-8
-6
-4
-2
0
-60
-40
-20
0
EARLY INTERVENTION
Response 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
R
e
l
a
t
i
v
e

c
h
a
n
g
e
(
%
)
Albuminuria 24hour Blood

Pressure
Baseline:

90 (61-121)mg/d 135 (3) 65 (2) mm Hg
C
h
a
n
g
e
(
m
m

H
g
)
SBP

DBP
S Nielsen Diabetic

Medicine

2011
Progression in microalbuminuria in type
1 diabetic

patients without

AHT
-10
0
10
20
30
40
50
60
70
B
a
n
g
s
t
a
d
,

*
*
*
D
i
a
b
e
t
o
l
o
g
i
a
,

1
9
9
4
M
a
t
h
i
e
s
e
n
,

D
i
a
b
e
t
o
l
o
g
i
a
,

1
9
8
4
C
r
e
p
a
l
d
i
,

D
i
a
b
e
t
e
s

C
a
r
e
,

1
9
9
8
M
a
t
h
i
e
s
e
n
,

B
M
J
,

1
9
9
1
T
h
e
M
i
c
r
o
a
l
b
u
m
i
n
u
r
i
a
C
a
p
t
o
p
r
i
l
s
t
u
d
y
g
r
o
u
p
,

D
i
a
b
e
t
o
l
o
g
i
a
,

1
9
9
6
F
e
l
d
t
-
R
a
s
m
u
s
s
e
n
,

L
a
n
c
e
t
,

1
9
8
6
P
r
e
s
e
n
t

s
t
u
d
y
Microalbuminuria defined

as UAER 20-200 g/min or 30-300 mg/24-h except in
***(15-200 g/min)
C
h
a
n
g
e
i
n

U
A
E
R

%
/
y
e
a
r
Schjdt: Diabetologia

2008
DETAIL study: ACEi

vs

ARB
AH Barnett NEJ M 2004
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
0.4 1.4
Comparison of Clinical Studies in Overt
Comparison of Clinical Studies in Overt
Type 2 Diabetic Nephropathy
Type 2 Diabetic Nephropathy
Primary composite
endpoint
Doubling of

serum creatinine
ESRD
All-cause
mortality
Relative risk
IDNT IDNT
Relative risk
RENAAL RENAAL
0.7 1.0
0.80
0.67
0.77
0.92
Doubling of serum
creatinine / ESRD
0.74
0.1
0.84
0.75
0.72
1.02
0.79
0.4 1.4 0.7 1.0 0.1
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
RENAAL; Losartan

more renoprotective

than placebo in
type 2 diabetes;
similar blood pressure, different albuminuria
%

w
i
t
h

e
v
e
n
t
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 Pressure B
l
o
o
d

P
r
e
s
s
u
r
e

(
m
m
H
g
)
P
L
Brenner et al; New Engl

J Med 2001
A
l
b
u
m
i
n
u
r
i
a

(
C
h
a
n
g
e
,
%
)
p=<0.001
40
0 12 24 36 48Mo
-60
-40
-20
0
20
P
L
35% Overall Reduction
What

should

we

do in the

normoalbuminuric

patients?
CKD in DEMAND eGFR<60 ml/min/1.73m
2
17,0%
27,5%
30,7%
0%
10%
20%
30%
40%
Normal Micro Macro
Fraction of patients
DEMAND
NKF GFR stage 3 or

worse
Parving

et al. Kidney

International 2006
New Renoprotective

Treatment

Modalities

Dual

RAS blockade

High

dose

RAS blockade

Aldosterone

blockade

Renin

inhibition
Additional effects of irbesartan
900 mg vs. 300 mg
-30
-20
-10
0
24-hrs collections
%
4-hrs collections
-20
p<0.01
-14
p<0.05
Urinary albumin excretion
2005 K Rossing

Kidney Int
Fractional clearance
of albumin
-15
p<0.05
DROP (n=391)
49% 51%
25%
0%
10%
20%
30%
40%
50%
60%
160 mg 320 mg 640 mg
C
h
a
n
g
e

i
n

a
l
b
u
m
i
n
u
r
i
a
Valsartan
Hollenberg

et al J Hypertension

2007
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
J acobsen et al. NDT 2002;17:1019-1024
J acobsen et al. J ASN 2003;14:992-959
J acobsen et al. Kidney

International 2003;65:1874-1880
The ONTARGET Investigators. N Engl J Med 2008;10.1056/NEJMoa0801317
Kaplan-Meier Curves for the Primary Outcome in the Three Study Groups
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
-10
-8
-6
-4
-2
0
-40
-30
-20
-10
0
Response to spironolactone 25 mg
20 type 2 diabetic patients with nephropathy treated with
maximally recommended doses of ACE-I and/or ARB
- 33
(-41 to -25) %
- 6
(-10 to -2)
mm Hg
- 4
(-2 to -6)
mm Hg
R
e
l
a
t
i
v
e

c
h
a
n
g
e
(
%
)
Albuminuria
Systolic BP Diastolic

BP
ACE-I/ARB:

1566 (655 to 7762) mg/d

24-hrs BP 138 (3) mm Hg / 71 (2) mm Hg
C
h
a
n
g
e
(
m
m

H
g
)
Rossing

K. et al. Diabetes Care 2005;28:2106-2112
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
Diagnostic
Disease

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
CE-MS peptidome
profile
300 400 500 600 700 800 900 1000 1100
m/z
0
10
20
30
40
50
60
70
80
90
100
R
e
l
a
t
i
v
e

A
b
u
n
d
a
n
c
e
y
9
y
8
y
6
y
4
y
3
b
3
b
6
b
8
b
11
2+
+H
2
O
b
11
2+
300 400 500 600 700 800 900 1000 1100
m/z
0
10
20
30
40
50
60
70
80
90
100
R
e
l
a
t
i
v
e

A
b
u
n
d
a
n
c
e
y
9
y
8
y
6
y
4
y
3
b
3
b
6
b
8
b
11
2+
+H
2
O
b
11
2+
P
h
G R P
h
G E R G P P
h
G P
b ions
y ions
3 6 7 8 11
9 8 6 4 3
P
h
G R P
h
G E R G P P
h
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
S
e
n
s
i
t
i
v
i
t
y
Statistics
Creatinine (micromol/l)
Cholesterole (mmol/l)
Urinary albumin/creatinine
Gender
Age
Creatinine (micromol/l)
Cholesterole (mmol/l)
Urinary albumin/creatinine
Gender
Age
Clinical

data
Patients

history
controls
cases
controls
cases
Biomarker
selection
Database
control normo
micro macro
Determination of Biomarkers for Diabetes and Diabetic Nephropathy
Type 1 diabetic patients and healthy controls
Rossing

J ASN 2008
Intervention Standard
Patients

with

Type 2 DM and normoalb
TEST
Positive

(at risk)
Evaluation of
1) predictive power of test for outcome
2) Effect of intervention in high risk patients
negative

(no risk)
Standard
Follow up
Kidney

int

2006
0
25
50
75
100
0 5 10 15 20
years since onset of diabetic nephropathy
C
u
m
u
l
a
t
i
v
e

d
e
a
t
h

r
a
t
e

(
%
)
Andersen 1983
Knowles 1971
Parving 1996
Rossing 1996
Astrup AS, et al
Cumulative

death

rate in type 1 diabetes
after

onset

of diabetic

nephropathy
Astrup AS. et al. Kidney

International 2005;68:1250-1257
Slide no 32
RAAS Blockade

in Diabetes

Conclusions

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?