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The case
of microalbuminuria
prevention:
the ROADMAP study
Reinhold Kreutz, FAHA
Department for
Clinical Pharmacology
and Hypertension
Charité – University Medicine
Berlin, Germany
Mortality and Proteinuria: Framingham-Study
Age-adjusted annual incidence
per 1000
5209 men and women, 16 years follow up
40
Proteinuria present
35
Proteinuria absent
30
25
Overall
Mortality
Cardiovascular Mortality
20
15
10
5
0
Women
Men
Women
Men
Kannel WB et al. Am Heart J 1984;108:1347-52
Charité, AG R. Kreutz
Proteinuria:
cardiovascular events in T2D mellitus
Survival without CV death
(%) 40
1
0.9
A
B
0.8
0.7
0.6
0.5
p<0.001
C
30
Incidence (%)
p<0.001 for
stepwise trend
20
10
0
-1056 pts 0 0 10 20 30 40 50 60 70 80 90
stroke
coronary
in Finland
events
months
-7 year
A: U-Prot <150 mg/L
B: U-Prot 150–300 mg/L
C: U-Prot >300 mg/L
follow up
Miettinen H et al. Stroke. 1996;27:2033-2039.
Charité, AG R. Kreutz
Albumin to creatinine ratio in spot urine and
cardiovascular mortality in the normal population
Second Nord-Trøndelag Health Study (HUNT II) - Norway
- 9709 individuals
- community based
- 8.3 years
follow-up
- 71% participation
rate
recommended
cut off for microalbuminuria
Albuminuria is
a continuous
parameter
RR: median of
ACR =1
(albumin to creatinine ratio)
Hallan S et al. Arch Intern Med. 2007;167:2490-2496.
Charité, AG R. Kreutz
Determination of urinary albumin excretion (UAE)
in cardiorenal medicine
UAE or MAU
Charité, AG R. Kreutz
UAE: samples and units of measurement
Urine sample
Spot
Night
24 hour
Units
mg/24 h
mg/min
mg/mmol Cr
mg/g Cr
*Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.
Charité, AG R. Kreutz
UAE: samples and units of measurement
Urine sample
Spot
Night
Units
mg/24 h
30-299
mg/min
mg/mmol Cr
mg/g Cr
24 hour
20-199
3-29
30-299*
*Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.
Charité, AG R. Kreutz
Reduction in Albuminuria Translates to Reduction in CV
Events in Hypertension
9193 hypertensives
BP: 200-160/115-95 mmHg
and
LVH ECG positive
randomized:
losartan vs. atenolol
endpoint:
death, MI, stroke
Endpoint ratio (%)
Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study
24
≤ 0.5 mg/mmol
22
20
18
16
0.5-1 mg/mmol
1-3 mg/mmol
> 3 mg/mmol
14
12
10
8
6
4
2
• Number of at-risk patients in the strata
indicates patients shifted from higher level of
UACR at baseline to lower level at years 2
and 4
• Risk for composite endpoint was lower with
reduced albuminuria
Ibsen H et al. Hypertension2005;45:198-202
0
0
6
12
18
24
30
36
42
48
54
60
66
Month
Albuminuria
(mg/mol)
≤0.5
0.5-1
1-3
>3
Number of patients
Baseline
Year 2
Year 4
1961
3385
2458
1591
1587
1814
2219
1827
1946
2435
1708
1760
Charité, AG R. Kreutz
Availability, prognostic value and cost of some
markers of organ damage
ESC / ESH Hypertension guidelines 2007
Mancia G et al. J Hypertens 2007 2007;25:1105-1187
Charité, AG R. Kreutz
What is the link between a renal phenotype,
i.e. albuminuria and cardiovascular disease?
Increased
permeability
Macromolecules/
plasma proteins
Charité, AG R. Kreutz
Steno hypothesis:
Albuminuria reflects widespread vascular damage
Deckert T et al. Diabetologia. 1989;32:219 –226.
Increased
permeability
• oxidative stress
• inflammation
• metabolic syndrome
Macromolecules/
plasma proteins
de Zeeuw D et al. Kidney Int Suppl 2005 ;98:S25-S29, Ritz E et al. Diabetologia 2010;53:49-57
Charité, AG R. Kreutz
Albuminuria predicts renal events in diabetes
• ACR predicted renal events in
patients with type 2 diabetes in the
P for trend < 0.0001
32.0
• 10,640 patients followed for
16.0
4.3 years
• 10-fold increase in
baseline ACR
Hazard ratio (95% CI)
ADVANCE study
– 3.3-fold increase in risk
8.0
4.0
2.0
1.0
0.5
0.25
3
of renal event
30
300
MA
Baseline UACR (mg/g)
death as a result of kidney disease,
requirement for dialysis or transplantation
or doubling of serum creatinine to >200 mmol/L
ADVANCE = Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation Albuminuria is
considered a continuous event and these ranges serve only as an orientation
Ninomiya T, et al. J Am Soc Nephrol. 2009;20:1813–21.
Charité, AG R. Kreutz
Causes of chronic kidney disease
Ursache
Prozent
Diabetes mellitus
44.9
Typ 1
3.9
Typ 2
41.0
Hypertension
27.2
Glomerulonephritis (GN)
8.2
Chronic interstitial nephritis or obstruction
3.6
Genetic causes (e.g. PKD)
3.1
Secondary GN or vasculitis
2.1
Malignancies
2.1
Others, e.g. HIV
4.6
Unclear or unknown
5.2
Abboud H & Henrich WL New Engl J Med 2010;362:56-65
Charité, AG R. Kreutz
The cardiorenal continuum
Cardiorenal continuum describes the interrelated
progression of CVD and renal disease
Target organ damage
Asymptomatic
CKD
microalbuminuria
Atherosclerosis
Risk factors
Target organ
damage
Symptomatic
MI, HF,
stroke ESRD
Death
Diabetes
Hypertension
Charité, AG R. Kreutz
Randomised Olmesartan and Diabetes
Microalbuminuria Prevention study (ROADMAP)
• First study to examine whether an ARB can prevent or delay the onset of
Microalbuminuria in patients with T2DM
• 4,400 patients with T2DM and normoalbuminuria and with at least 1
cardiovascular risk factor randomized to olmesartan 40 mg /d or placebo
Haller H, et al. J Hypertens. 2006;24:403–8.
Charité, AG R. Kreutz
ROADMAP: study design
Randomization to double-blind treatment
4-week
prerandomization
Olmesartan
40 mg/day
(n=2200)
Placebo
(n=2200)
MA detected
MA detected
Open-label
MI, stroke, or olmesartan
40 mg/day
CrCl <30
Observation
only
MI, stroke, or
CrCl <30
Follow-up
until 326 MA
cases
Observation
only
End of study
CrCl=creatinine clearance (ml/min)
Haller H, et al. J Hypertens. 2006;24:403–8.
Charité, AG R. Kreutz
ROADMAP: preliminary results
• Patients were followed for a mean of 3.2 years
• Approximately 80% achieved the diabetes
blood pressure goal of
 130/80 mm Hg
• Time to first occurrence of microalbuminuria was
significantly different after one year
– 178 patients in the olmesartan group vs. 210 in the placebo group
(p<0.05)
Haller H et al. Late-breaking clinical trial. Presented at: Renal Week 2009; Oct. 27-Nov. 1; San Diego.
Charité, AG R. Kreutz
The cardiorenal continuum
Measure urinary albumin excretion
and prevent diabetic kidney disease
Target organ damage
Asymptomatic
CKD
microalbuminuria
Atherosclerosis
Risk factors
Target organ
damage
Symptomatic
MI, HF,
stroke ESRD
Death
Diabetes
Hypertension
Charité, AG R. Kreutz
Thank you !