SRAA y Nefropatía Diabetica

8/11/2019 SRAA y Nefropata Diabetica

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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


6/32Haller et al. N Engl J Med 2011;364:907-17

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?

SRAA y Nefropatía Diabetica

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