Microalbuminuria –pathogenesis and clinical implications

Eberhard Ritz

Heidelberg (Germany)

Jan Steen

1626-1679

Pisskijker

Microalbuminuria

• 30 – 300 mg / day albumin excretion

or• 20 – 200 µg / min or µg/ml respectively (1 day = 1440 min = 1500 ml urine ~ 1 ml/min)

- high day-to-day variability (VC 30%) diagnosis of MA : 2/3 urine samples positive exclude : renal causes (microhematuria,bacteriuria)

comorbidity (uncontrolled hyperglycemia,hypertension, cardiac failure)

Brinkman, Kidn.Intern.(2004) 92: (S92) S69

Comparison albumin measurement using HPLC vsnephelometry in the ranges normo-,micro- and macroalbuminuria

normo

micro

macro

Are albumin excretion rates in the

upper normal range innocuous ?

Progressive increase of renal and CV riskwith albuminuria within the normal range

in type 2 diabetes

relative risk progression to

microalbuminuria CV endpoint

0-10 1 110-20 2.34 1.920-30 12.4 9.8

albuminuria(mg/day)

Rachmani, Diab.Res. (2000) 49:187

In non-diabetics more frequent development of microalbuminuria if at baseline urinary albumin

high-normal

urinary albumin 15-30 vs 0-15 mg/24h 23,7

(11,7-47,9)

age (per 1 year) 1,03 ( 1,0-1,06)

smoking vs nonsmoking 3,9

(1,1-6,5)

hypertension (± treatment) 2,4

(1,0-5,7)

odds ratio (95%CI)

Stuveling,J.Am.Soc.Nephrol.(2003) 14:679a

Increasing cardiovascular risk above median of urinary albumin –

HOPE - study

Gerstein, JAMA (2001) 268:421

<0.25

>0.25

to <

0.41

>0.41

to <

0.59

>0.59

to <

0.82

>0.82

to <

1.16

>1.16

to <

1.67

>1.67

to <

2.53

>2.53

to <

4.32

>4.43

to <

9.43

>9.43

0.0

0.5

1.0

1.5

2.0

2.5

Dezile des Albumin-Kreatinin-Quotienten im Urin

ad

jus

ted

ha

zard

ra

tio

Wachtell, Ann Intern Med (2003) 139: 244

Increased cardiovascular risk above the median of urine albumin excretion

LIFE - study

Deciles of albumin-creatinine ratio

no threshold,no plateau

Nord Tröndelag Health Study2,089 apparently healthy individuals

4.4 years follow-up

crude mortalitypercentile albumin/creatinine rel.risk ratio µg/mg) (multivariate adjusted)

95th 22.0 8.6 90th 14.5 5.1 80th 9.7 4.5 60th 6.7 2.3

Romundstad, Am.J.Kid.Dis. (2003) 42:466

Is the renal risk identical in microalbuminuria of

diabetic and nondiabetic individuals ?

Gross, Kidn Intern (2002) 62:51

Glycation renders albumin more nephrotoxic

NaCl 1.23 ± 0.5 0.40 ± 0.05

albumin 2.74 ± 0.4 2.87 ± 0.7

glycated 3.70 ± 0.4 3.30 ± 0.6albumin

protein droplets peritubular fibrosis

Scores

Gross et al, submitted

How frequent is microalbuminuria ?

Which factors predispose to

microalbuminuria ?

normal 0-10mg/lnormal 0-10mg/l

macroproteinuriamacroproteinuria>200 mg/l>200 mg/l

microalbuminuriamicroalbuminuria 20-200 mg/l20-200 mg/l

high-normalhigh-normal albuminuriaalbuminuria 10-20 mg/l10-20 mg/l

n=40,856n=40,856

Hillege, J.Intern.Med. (2001) 249:519

(0.7%)(7.2%)

(16.6%)

Albumin excretion rates in 40,619 citizensof Groningen

plasma glucose (mmol/l)

3 4 5 6 7 8

UAE (mg/24h)

6

7

8

9

10

11

12

13

Male

Female

Verhave, JASN (2003) 14:1330

Risk of microalbuminuria - fasting glycemia

Nondiabetic subjects –insulin resistance associated with

microalbuminuria

• 982 nondiabetic subjects• insulin sensitivity with frequently sampled iv

glucose tolerance test (HOMA)• subjects with microalbuminuria :

lower insulin sensitivity ( 1.70 ± 0.11 vs 2.25 ±0.07 )

and higher IRI ( 17.4 ± 1.1 vs 15.7 ± 0.5 mU/L )

Mykkanen,Diabetes(1998) 47:793

• 712 type 2 diabetic patients• 61 years, diabetes duration 11 years, HbA1c 8.6%

HOMA index # significant correlation to albuminuria in male, but not in

female patients (pinteraction0.04)

# male pat. with HOMA index above median (insulin

resistance) odds ratio for microalbuminuria 2.2

DeCosmo, Diabetes Care (2005) 28:910

Male type 2 diabetics –insulin resistance associated with

microalbuminuria

Albuminuria predicts new onset diabetes (Prevend study, 4.2 year follow-up)

>30030 - 30015 – 290 - 14

Ne

w o

nse

t D

iab

ete

s (%

)14

12

10

8

6

4

2

0

Albuminuria (mg/day)

Brantsma ; Diaberes Care (2005) 28: 2525

2.2

4.3

7.9

11.8

Early onset of insulin resistance in renal disease (renal insulin resistance syndrome)

Becker, J.Am.Soc.Nephrol(2005) 16:1091

control >90 45-90 <45

GFR (ml/min/1.73m2)

Adiponectin predicts cardiovascular events in patients with renal failure

Becker, J.Am.Soc.Nephrol(2005) e-pub

Risk of microalbuminuria - metabolic syndrome

Chen, Ann.Int.Med. (2004) 140:167

prevalenceCKD (%)

prevalencemicroalbuminuria (%)

metabolic syndrome risk factors

metabolic syndrome risk factors

metabolic syndromerisk factors :waist > 102 cm/menfasting glucose>110 mg/dlHDL-C <40mg/dl/mentriglycerides >140 mg/dlblood pressure >130/85mmHg

Microalbuminuria correlated to indices of metabolic syndrome

In nondiabetic patients albumin

excretion rate related to :• 24 h blood pressure• Left ventricular mass• body weight• fasting insulin• reduced insulin sensitivity (HOMA)• higher creatinine clearance

Del’Omo, Am.J.Kid.Dis. (2002) 40:1

662 diabetics from 310 families,

422 of whom siblings concordant for diabetes

diabetes 10.8 years

H2 (adjusted) = 0,46 ± 0,12 (p< 0,0001)

Langefeld, Am.J.Kid.Dis.(2004) 43:796

Risk of microalbuminuria - hereditary factors

Offspring of type 2 diabetic parents with nephropathy –

higher albuminuria

Strojek, Kidn.Intern.(1997) 51:1602

albumin (mg/24h)offspring of type 2 diabetic parents

- with nephropathy (n=26)- without nephropathy (n=30)

controls(n=30)

increasewith treadmill

7.8

4.8

4.4

x 16

x 6.3

x 4.8

What are the consequences of

microalbuminuria ?

Does microalbuminuria matter for CV

endpoints and survival ?

Albuminuria predicts development of moderate chronic kidney disease

(Prevend study)

>30030 - 30015 – 290 - 14

Sta

ge

3 C

KD

(%

)70

60

50

40

30

20

10

0

Albuminuria (mg/day)

913

22

58

Verhave, Kidney Int (2004) Suppl.92, S18

Albuminuria predicts CV death in the general population

(Prevend study, 3 year follow up)

>30030 - 30015 – 290 - 14

CV

dea

th (

% p

er

10

00

pj)

35

30

25

20

15

10

5

0

Albuminuria (mg/day)

3.54.5

11.2

29.1

Hillege; Circulation (2002);106 : 1777

Same correlation albuminuria and cardiovascular mortality in type 2 diabetes

Valmadrid, Arch.Int.Med.(2000) 160:1093

Borch-Johnsen,Arter.Thromb.Vasc.Biol.(1999)19:1992

Microalbuminuria and ischemic heart disease

without microalbuminnuria

with microalbuminuria

Microalbuminuria – coronary heart disease and death

Copenhagen City Heart study

Klausen,Circulation(2004) 110:32

Albuminuria - predictor of cardiovascular risk(Hoorn study)

smoking 2.8

diabetes type 2 3.7

history CV events 3.6

microalbuminuria 3.3

significant risk even when corrected for GFR

adjusted rel. risk

Stehouwer and Jager

Change of albuminuria translates intochange of cardiovascular endpoints (CEP)

Ibsen,Hypertension(2005) 45:198

high baseline/high year 1

high baseline/low year 1

low baseline/high year 1

low baseline/low year 1

Does treatment of microalbuminuria

matter ?

Pravastatin vs Placebo PREVEND IT study–

effect on cardiovascular endpoints

Asselbergs, Circulation (2004) 110:2809

Asselbergs, Circulation (2004) 110:2809

Fosinopril vs Placebo PREVEND IT study

reduction of CV cardiovascular events

Treat the kidney to cure your heart !

de Zeeuw, 2004

Progression from microalbuminuria to proteinuria –effect of ACE inhibitor and ARB treatment

Hollenberg, Arch.Int,Med.(2004) 164:125

Hollenberg, Arch.Int,Med.(2004) 164:125

Regression from microalbuminuria to normoalbuminuria –

effect of ACE inhibitor and ARB treatment

Reduction of microalbuminuria in type 2 diabetic patients

albuminuria 117±31.1 40.4±12.3

(mg/24h)

systolic BP 140±3.7 137±3.3

(mmHg)

Pistrosch, Diabetes (2005) 54: 2206

Placebo Rosiglitazone

ARB and prevention of onset of microalbuminuria in diabetic patients –

LIFE study

• 1195 patient type 2 diabetes• de novo microalbuminuria• Losartan 7 %

Atenolol 13 %

p< 0.01

Lindholm, Lancet (2002) 359:1004

Why does microalbuminuria cause

cardio-vascular complications ?

Urinary albumin excretion (UAE) in diabetics correlates with retina thickness and transcapillary

albumin escape rate (TER)

Knudsen, Diabetes Care (2002) 25:2328

retinal thickness

transcapillary escaoe

What did he say?

• microalbuminuria frequent• indicator (causal factor for?) renal and

cardiovascular risk• routine determination in high risk

patients recommended by ESH and ASH

• treatment with RAS blockade reduces CV events

• RAS blockade and glitazones reduce existing albuminuria