The case of microalbuminuria prevention: the ROADMAP study Department for Clinical Pharmacology and...

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 !