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The caseof microalbuminuria
prevention:the ROADMAP study
Department forClinical Pharmacology
and HypertensionCharité – University Medicine
Berlin, Germany
Reinhold Kreutz, FAHA
Charité, AG R. KreutzKannel WB et al. Am Heart J 1984;108:1347-52
Ag
e-ad
just
ed a
nn
ual
inci
den
ce
per
100
0
Women Men
Proteinuria present
10
20
30
15
25
35
5
0
40
Women Men
Proteinuria absent
Cardiovascular Mortality
Overall Mortality
5209 men and women, 16 years follow up
Mortality and Proteinuria: Framingham-Study
Charité, AG R. Kreutz
Survival without CV death
A: U-Prot <150 mg/L B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L
1
0.9
0.8
0.7
0.6
0.5
00 10 20 30 40 50 60 70 80 90 stroke coronary
events
p<0.001 for stepwise trend
(%)
months
AB
Cp<0.001
0
10
20
30
40
Miettinen H et al. Stroke. 1996;27:2033-2039.
Proteinuria: cardiovascular events in T2D mellitus
Incidence (%)
-1056 ptsin Finland-7 yearfollow up
Charité, AG R. KreutzHallan S et al. Arch Intern Med. 2007;167:2490-2496.
Second Nord-Trøndelag Health Study (HUNT II) - Norway
- 9709 individuals
- community based
- 8.3 years follow-up- 71% participation rate
recommended cut off for micro-albuminuria
Albumin to creatinine ratio in spot urine and cardiovascular mortality in the normal population
RR: median ofACR =1 (albumin to creatinine ratio)
Albuminuria isa continuous
parameter
Charité, AG R. Kreutz
Determination of urinary albumin excretion (UAE)in cardiorenal medicine
UAE or MAUUAE or MAU
Charité, AG R. Kreutz
Spot Night 24 hour
mg/24 h
mg/min
mg/mmol Cr
mg/g Cr
Urine sample
Un
its
UAE: samples and units of measurement
*Witte EC et al. J Am Soc Nephrol. 2009;20:436-443 – first morning urine suggested.
Charité, AG R. Kreutz
Spot Night 24 hour
mg/24 h 30-299
mg/min 20-199
mg/mmol Cr 3-29
mg/g Cr 30-299*
Urine sample
Un
its
UAE: samples and units of measurement
*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
Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study
Albuminuria (mg/mol)
Number of patientsBaseline Year 2 Year 4
≤0.5 1961 3385 24580.5-1 1591 1587 18141-3 2219 1827 1946>3 2435 1708 1760
24
22
20
18
16
14
12
10
8
6
4
2
0
0 6 12 24 30 36 42 48 54 60 6618
En
dp
oin
t ra
tio
(%
)
≤ 0.5 mg/mmol
0.5-1 mg/mmol
1-3 mg/mmol
> 3 mg/mmol
Month
• 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
9193 hypertensivesBP: 200-160/115-95 mmHgand LVH ECG positive
randomized:losartan vs. atenolol
endpoint:death, MI, stroke
Ibsen H et al. Hypertension2005;45:198-202
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
Increasedpermeability
Macromolecules/ plasma proteins
What is the link between a renal phenotype, i.e. albuminuria and cardiovascular disease?
Charité, AG R. Kreutz
Increasedpermeability
Macromolecules/ plasma proteins
Steno hypothesis:Albuminuria reflects widespread vascular damage
Deckert T et al. Diabetologia. 1989;32:219 –226.
• oxidative stress• inflammation• metabolic syndrome
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
32.0
16.0
8.0
4.0
2.0
1.0
0.5
0.25
3 30 300
MABaseline UACR (mg/g)
P for trend < 0.0001
Ha
zard
ra
tio
(9
5%
CI)
Albuminuria predicts renal events in diabetes
• ACR predicted renal events in
patients with type 2 diabetes in the
ADVANCE study
• 10,640 patients followed for
4.3 years
• 10-fold increase in
baseline ACR
– 3.3-fold increase in risk
of renal event
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 orientationNinomiya T, et al. J Am Soc Nephrol. 2009;20:1813–21.
death as a result of kidney disease,requirement for dialysis or transplantation or doubling of serum creatinine to >200 mol/L
Charité, AG R. Kreutz
Causes of chronic kidney diseaseUrsache 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
Risk factors
Target organ damageAsymptomatic
CKDmicroalbuminuria
Atherosclerosis Target organ damage
Symptomatic
ESRD
Diabetes Hypertension
Cardiorenal continuum describes the interrelated progression of CVD and renal disease
MI, HF,stroke
Death
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
CrCl=creatinine clearance (ml/min)
Randomization to double-blind treatment
4-weekpre-
randomization
Follow-upuntil 326 MA
cases
End of study
MA detected MA detected
MI, stroke, orCrCl <30
Observation only
Observation only
Open-labelolmesartan 40 mg/day
MI, stroke, orCrCl <30
Olmesartan 40 mg/day (n=2200)
Placebo(n=2200)
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
Risk factors
Target organ damageAsymptomatic
CKDmicroalbuminuria
Atherosclerosis Target organ damage
Symptomatic
ESRD
DeathDiabetes Hypertension
Measure urinary albumin excretion and prevent diabetic kidney disease
MI, HF,stroke
Thank you !