Microalbuminuria – pathogenesis and clinical implications.
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Transcript of Microalbuminuria – pathogenesis and clinical implications.
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