Microalbuminuria; a cardiovascular or a renal risk factor ... · cardiac events in hypertension with LVH; (n=8206) 3.5 mg/mmol = 30 mg/day Microalbuminuria. Baseline Albumin concentration

Dick de ZeeuwDepartment of Clinical Pharmacology

University Medical CenterGroningen

The Netherlands

Microalbuminuria; a cardiovascular or a

renal risk factor or both?

Common and Novel Risk factors for Cardiovascular and Renal Disease progression

• Age

• Gender

• Body Weight

• Smoking the Framingham Risk Score

• Blood pressure

• Cholesterol

• Diabetes

• CRP, pro-BNP etc

• Hemoglobin

• GFR Novel Risk markers or FACTORS?

• Albuminuria!

Wilson PWF et al. Circulation 1998; 97: 1837-47

de Zeeuw; Oct 2004

Albuminuria; a target for renal and cardiovascular protection?

• Albuminuria is related to renal and CV risk:■ The higher albuminuria, the more risk (for early patients as well as

healthy individuals)■ Independent of other risk markers■ Preceeding other risk markers

• Lowering albuminuria is related to renal and CV risk reduction:■ The more albuminuria reduction, the more risk reduction■ Independent of other risk marker reduction

• Common origin for albuminuria and CV and renal disease?

Addenbrooke’s Nephropathy Cohort: Albuminuria predicts CV outcome in diabetes with albuminuria >30mg/d

Yuyun et al; Diabet Med 2003

CVD

eve

nt ra

te /1

000p

y

0

20

40

60

80

1 3 4 52Albuminuria quintile

type1 diabetes; n=161

type2 diabetes; n=266

total

Wachtell et al; Ann Intern Med 2003

0

10

20

30

40

50

60

<0.26 0.26-0.43

0.43-0.63

0.63-0.89

0.89-1.28

1.28-1.88

1.88-2.95

2.95-5.26

5.26-12.22

>12.22 mg/mmol

CV

end

poin

t rat

e / 1

000

patie

nt-y

ears

of f

ollo

w-u

p

Primary composite endpoint rate

LIFELIFE; Baseline a; Baseline albuminuria associated with lbuminuria associated with cardiaccardiac events events in hin hypertensionypertension with LVH; with LVH; (n=8206)(n=8206)

3.5 mg/mmol = 30 mg/day

Microalbuminuria

Baseline Albumin concentration (mg/L)

12

34

5

2 10 100 1000

Normo

Hillege et al; Circulation 2002

PREVEND; Albuminuria predicts CV mortality in the general population (4 yr follow-up)

Ris

k fo

r CV

mor

talit

y du

ring

follo

w-u

p (R

R)

Micro Macro

Framingham; Albuminuria determines survival free CVD the non-diabetic, non-hypertensive subjects (n=1568)

Arnlov et al, Circulation 2005

00

229090

CVD

free

sur

viva

l(%

)

Years44 66 88

100100

9595

Alb > sex specific median

Alb < sex specific median

PREVEND; Albuminuria predicts moderate CKD in the general population (4 jr)

>30030 - 30015 – 290 - 14

Stag

e 3

CK

D (%

)30

25

20

15

10

5

0

Albuminuria (mg/day)

4493833

650

46

Verhave et al. Kidney Int 2004


• Albuminuria is related to renal and CV risk:■ The higher albuminuria, the more risk (for early patients as well

as healthy individuals)■ Independent of other risk markers■ Preceeding other risk markers



* Adjusted for ECG LV mass, Framingham Risk Score, and study treatment allocation

n=8,206

Wachtell et al; Ann Intern Med 2003

0

10

20

30

40

50

60

<0.26 0.26-0.43

0.43-0.63

0.63-0.89

0.89-1.28

1.28-1.88

1.88-2.95

2.95-5.26

5.26-12.22

>12.22 mg/mmol

CV

end

poin

t rat

e / 1

000

patie

nt-y

ears

of f

ollo

w-u

p

Primary composite endpoint rate

Adjusted composite endpoint rate*

LIFELIFE; Baseline a; Baseline albuminurialbuminuria as determinant of as determinant of cardiac events in cardiac events in hhypertensionypertension with LVHwith LVH

3.5 mg/mmol = 30 mg/day

Microalbuminuria

Framingham; Albuminuria determines survival free CVD the non-diabetic, non-hypertensive subjects (n=1568)

Arnlov et al, Circulation 2005

00

229090

CVD

free

sur

viva

l(%

)

Years44 66 88

100100

9595

Alb > sex specific median

Alb < sex specific median

89IFG (%)

1717Smoking (%)

1.11.1Screat (mg/dL)

4.14.3Total/HDL chol ratio

119118SBP (mmHg)

26.427.3BMI (kg/m2)

5654Age (yr)

785783N

UACR > median

UACR < median






PREVEND; Albuminuria predicts new onset diabetes (n= 5654; follow-up 4,2 jr)

>30030 - 30015 – 290 - 14

New

ons

et D

iabe

tes

(%)

14

12

10

8

6

4

2

0


Brantsma et al; Diabetes Care 2005

2.2

4.3

7.9

11.8

4162 789 642 55

PREVEND; Albuminuria predicts new onset hypertension (n=4635; follow-up 4,2 jr)

>3015 – 290 - 14

7,9

12,3

15,5

0,0

2,0

4,0

6,0

8,0

10,0

12,0

14,0

16,0

18,0

3353776 521

New

ons

et H

yper

tens

ion

(%)


Brantsma et al; JASN 2006






Drugs Reducing Albuminuria

• RAAS-intervention, ACEi and AII-A (end point trials)

• Low Protein Diet (end point trials)

• Non-Steroidal-Antiinflammatory Drugs (no prospective endpoint trials)

• Glucosamino Glycans eg Sulodexide (trial stopped)

• Endothelin Antagonists (trial stopped)

• Statins (trials ongoing)

• Vitamine D analogues (trial ongoing)

• Renin-inhibitors (trial ongoing)

LIFE; Treatment (ARB, losartan) associated with lowering albuminuria is cardioprotective in hypertension with LVH

Time (Months)

Frac

tion

free

of C

EP

Ibsen et al; Hypertension 2005

12 24 36 48 600.80

0.85

0.90

0.95

1.00

High UACR0 – High UACR1

High UACR0 – Low UACR1

Low UACR0 – High UACR1

Low UACR0 – Low UACR1

Asselbergs et al; Circulation 2004

PREVEND-IT; Treatment associated with lowering of albuminuria reduces CV morbidity/mortality in “healthy” microalbuminurics (n=800).

00 1010 2020 3030 4040

0.100.10

0.050.05

00

Placebo

ACEi (fosinopril)C

V M

orb/

mor

t (%

)

Months

RiskRiskReductionReduction

44%44%

Del

ta A

lbum

inur

ia (%

)D

elta

Alb

umin

uria

(%)

0

- 10

- 20

- 30

3 Months 4 Years

ACEiACEiEffect on albuminuriaEffect on albuminuria

- 29.5 *- 31.43 *

* p < 0.001

ACEiACEiEffect on CV Effect on CV morbmorb/mort/mort






-65-65

-45-45

-25-25

00

2525

Irbesartan 150 mg

Irbesartan 300 mg

Placebo

00

55

1010

1515

2020

Control + Conv txAIIA Irbesartan 150 mg)

AIIA (Irbesartan 300 mg)

AIIA (irbesartan)AIIA (irbesartan)Effect on Effect on albuminuriaalbuminuria

AIIA (irbesartan)AIIA (irbesartan)Effect on Renal Effect on Renal MorbMorb

IRMA-2; Treatment associated with lowering of albuminuria reduces RENAL morbidity in hypertensive microalbuminuric type 2 diabetes.

Prevention of transition to overt proteinuria

Anderson S et al. Diabetes Care 2003Anderson S et al. Diabetes Care 2003Parving HParving H--H et al. N Engl J Med 2001H et al. N Engl J Med 2001

Dia

betic

Nep

hrop

athy

(%)

Cha

nge

in U

AE

(%)

Months

66 1212 1818 2424 24+124+10000 00 33 66 1212 1818 2222 2424

PREVEND-IT; Initial ACE-I (fosinopril) induced albuminuria reduction related to CV risk protection (n=800)

Follow-up (Months)0 10 20 30 40 50

Eve

nt fr

ee s

urvi

val

0.90

0.95

1.00

Albuminuria reduction < 25%

Albuminuria reduction > 25%

Data adapted from Asselbergs et al; Circulation 2004






Initial AII-A (losartan) induced reduction in albuminuria predicts long term CV/renal risk in normotensive type

diabetes (n=67)

130

135

140

145

Albuminuria reduction >30% (70 to 40 mg/d)Albuminuria increase >30% (80 to 220 mg/d)

end of study0 1 yr

Syst

olic

Blo

od P

ress

ure

(mm

HG

)

Zandbergen et al; Diabetes Care 2007

0 2 4 6

0

1

Follow up (yr)

Even

t fre

e su

rviv

al






Healthy populationHealthy populationdecreased GFRdecreased GFR

CKDCKDProteinuriaProteinuriaAnaemiaAnaemia

ESRDESRD

DeathDeath

Cardiovascular Cardiovascular dysfunctiondysfunction

de Zeeuw

Possible interaction between Renal dysfunction and Cardiac dysfunction in the general population

CHFCHF

MicroalbuminuriaMicroalbuminuria

CATS; RenalCATS; Renal Function (Function (eGFReGFR) determines CV outcome) determines CV outcomein firstin first myocardial infarction patientsmyocardial infarction patients

Days

1.0

0.9

0.8

0.7

0.6

0.05004003001000 200

HF-freesurvival >103 mL/min

81-103 mL/min

<81 mL/min

>103 mL/min vs < 81 mL/min, p=0.019

Hillege et al; Eur Heart J 2003

PREVEND; Effect of myocardial infarction onrenal function in general population

** Matched control cohort of subjects without ischaemic cardiac event, based on age, gender, serum creatinine, urinary albumin excretion, body mass index, mean arterial pressure, serum cholesterol, triglycerides, serum glucose, and smoking.

00

118282

Seru

m c

reat

inin

e (µ

mol

/l)

Years22 33 44

9494

8888

Cardiac event (n=66)

No cardiac event (n=6294)

9292

9090

8686

8484No cardiac event, matched controls* (n=66)

Eijkelkamp et al; Am J Cardiol 2007

KDOQI based Renal dysfunction classes

+ or -+ or -+ or -

++

Albuminuria

< 15 or RRT515 - 2930 - 5960 - 89

> 90

GFR (ml/min/1/73 m2)

4321

Stage

K/DOQI Clinical Practical GuidelinesAm J Kidney Dis 2003

0,01

0,1

1

10

100

1000

no CKD stage 1/2 stage 3 stage 4 stage 5

K/DOQI stage

Inci

denc

e ra

te p

er 1

000

pers

on y

ears

(lo

garit

hmic

sca

le)

ESRDCVD

De Jong et al. Clin J Am Soc Nephrol 2008

PREVEND; Incidence of cardiovascular events for stage of chronic kidney disease

KDOQI based Renal dysfunction classes

+ or -+ or -+ or -

++

Albuminuria

< 15 or RRT515 - 2930 - 5960 - 89

> 90

GFR (ml/min/1/73 m2)

4321

Stage

K/DOQI Clinical Practical GuidelinesAm J Kidney Dis 2003

Brantsma et al, NDT in pressBrantsma et al, NDT in press Survival curves are adjustedSurvival curves are adjusted forfor age and sexage and sex

0 2 4 6 8

0,90

0,92

0,94

0,96

0,98

1,00

No CKDNo CKD

Follow-up in years

Prop

ortio

nfr

ee o

f car

diov

ascu

lare

vent

Stage 3

PREVEND; eGFR or microalbuminuria and CV riskPREVEND; eGFR or microalbuminuria and CV riskMicroalbuminuria more important (Age/sex adjusted)Microalbuminuria more important (Age/sex adjusted)

Stage 3 and MA Stage 3 and MA ––

Stage 3 and MA +Stage 3 and MA +


0 2 4 6 8

0,90

0,92

0,94

0,96

0,98

1,00

No CKDNo CKD

Follow-up in years

Prop

ortio

nfr

ee o

f car

diov

ascu

lare

vent

Stage 3





0 2 4 6 8

0,90

0,92

0,94

0,96

0,98

1,00

No CKDNo CKD

Follow-up in years

Prop

ortio

nfr

ee o

f car

diov

ascu

lare

vent

Stage 3




Healthy populationHealthy populationMicroalbuminuriaMicroalbuminuria

CKDCKDProteinuriaProteinuriaAnaemiaAnaemia

ESRDESRD

DeathDeath

Cardiovascular Cardiovascular dysfunctiondysfunction

de Zeeuw

Possible interaction between Renal dysfunction and Cardiac dysfunction in the general population

CHFCHF

Vascular DysfunctionVascular Dysfunction

1

10

100

1000

0 20 40 60 80

MaleFemale

Age (yrs)Age (yrs)

Log

UAE

Log

UAE

(mg/

24h)

(mg/

24h)

Urinary albumin excretion and age (cross sectional) in general population children and adults

De Zeeuw et al, JASN, 2006De Zeeuw et al, JASN, 2006adapted from Verhave et al, JASN 2003 adapted from Verhave et al, JASN 2003

Children

Lehrnbecher et al. Pediatr Nephrol 1998 (children); Lehrnbecher et al. Pediatr Nephrol 1998 (children);

1

10

100

1000

0 20 40 60 80

MaleFemale

Age (yrs)Age (yrs)

Log

UAE

Log

UAE

(mg/

24h)

(mg/

24h)

Urinary albumin excretion and age (cross sectional) in general population children and adults

De Zeeuw et al, JASN, 2006De Zeeuw et al, JASN, 2006adapted from Verhave et al, JASN 2003 adapted from Verhave et al, JASN 2003

Children

Lehrnbecher et al. Pediatr Nephrol 1998 (children); Lehrnbecher et al. Pediatr Nephrol 1998 (children);

The albumin moleculeThe albumin moleculediovascular protection?diovascular protection?

The albumin moleculeThe albumin moleculeThe albumin molecule; which ever way you look at it, related to cardiovascular protection?

The albumin molecule; which ever way you look at it, related to cardiovascular protection?

The albumin moleculeThe albumin moleculediovascular protection?diovascular protection?

Summary

Summary

• Cardiac and renal dysfunction show interactions. Renal

dysfunction predicts cardiac dysfunction, and cardiac

dysfunction predicts renal dysfunction.

• The mechanism is still unknown, but a common inborn

vulnerability of the vasculature could make the kidney and

the heart seemingly interact.

Summary

Summary

• Hypothesis: Increased albumin levels are an early indicator of general vascular dysfunction. This may also affect the kidney resulting in a decreased GFR. Both the vascular dysfunction and the hormonal consequences of renal dysfunction can result in cardiac damage. Cardiac damage may result in further vascular dysfunction with renal implications.

TREATMENT IMPLICATION?

Treat the kidney to cure the heart.Treat the heart to cure the kidney?

Documents

Microalbuminuria; a cardiovascular or a renal risk factor ... · cardiac events in hypertension with LVH; (n=8206) 3.5 mg/mmol = 30 mg/day Microalbuminuria. Baseline Albumin concentration