Dick de Zeeuw Department of Clinical Pharmacology University Medical Center Groningen The...

Dick de Zeeuw Department of Clinical Pharmacology

University Medical CenterGroningen

The Netherlands

Albuminuria; a tool for measuring

non-blood pressure related renal

protection.

Data from the RENAAL trial

RENAAL

Trial design: Rand control trial, double dummy intervention placebo vs losartan with conventional therapy background (without ACEi or ARB)

Population: 1513 type 2 diabetic nephropathy Serum creatinine: 1.3 to 3 mg/dl Albuminuria: > 300 mg/g

Dosing: 50 mg losartan or 100 mg if blood pressure >140/90 Measurements:

Albuminuria: morning void ACR; 24 hour Albumin and ACR in subgroup (n=710)

Proteinuria: 24 hour proteinuria, in subgroup (n=710) Change in albuminuria:

Individual ACR change comparing baseline to 6 months End-points:

Combined endpoint: Doubling serum creatinine, ESRD, Death Single of each

RENAAL; AII-antagonist more renal protective than placebo in type 2 diabetes; similar blood pressure,

different albuminuria

RENAAL; AII-antagonist more renal protective than placebo in type 2 diabetes; similar blood pressure,

different albuminuria

% w

ith e

vent

p=0.024

Risk Reduction: 16%Placebo

Losartan

0 12 24 36 480

10

20

30

40

50

Systolic

Diastolic

MAP

0 12 24 36 48 Mo60

80

100

120

140

160

Pulse PressureBlo

od P

ress

ure

(mm

Hg) P

L

Brenner et al; New Engl J Med 2001

Alb

umin

uria

(C

hang

e,%

)

p=<0.00135% Overall Reduction

40

0 12 24 36 48Mo-60

-40

-20

0

20P

L

QuestionsQuestions

Is Albuminuria a predictor of outcome? Is it independent from other risk markers? Is proteinuria different than albuminuria Is spot sampling different than 24 hour

Is Albuminuria lowering predictive of outcome? Is it independent from blood pressure lowering?

Is residual albuminuria predicting outcome?




RENAAL; Baseline proteinuria as a determinant for renal events in type 2 diabetic nephropathy

De Zeeuw et al; Kidney Int 2004

Primary composite Endpoint

0

10

15

5

Haz

ard

ratio

<.5 2.0 2.95 4.4 5.25

Baseline Albuminuria (g/g) Baseline Albuminuria (g/g)

0

<.5 2.0 2.95 4.4 5.25

ESRD

10

20

30

H

azar

d ra

tio

=0.00010.84 - 0.950.89Hemoglobin (g/dL)

<0.00010.61 - 0.800.70Serum albumin (per 0.5 g/dL)

<0.00011.7 – 2.52.1Serum creatinine (mg/dL)

<0.00014.4 - 8.76.2Urine albumin:creatinine (log, mg/g)

p-Value95% Conf Interval

Hazard Ratio*

RENAAL; Model for independent renal risk factors during (optimal) blood pressure treatment in type 2 diabetic nephropathy (n=1300)

Keane et al, Kidney Int 2003; and Keane et al, Clin J Am Soc Nephrol 2006

RENAAL RISK SCORE:(1.96 log [urinary albumin:creatinine ratio]) * (0.78 serum albumin [g/dl]) * (1.28 serum creatinine [mg/dl]) * (0.11 hemoglobin [g/dl]).

QuestionsQuestions







RENAAL; Albuminuria Reduction (<0% versus >30%) at Month 6 determines the renal outcomeRENAAL; Albuminuria Reduction (<0% versus

>30%) at Month 6 determines the renal outcome


Renal Endpoint ESRD

0 12 24 36 48

Month

0

10

20

30

40

50

60

% w

ith c

ompo

site

end

poin

t

>30%

<0%

0 12 24 36 48

Month

0

10

20

30

40

50

60

% w

ith E

SR

D

<0%

>30%

RENAAL; Initial anti-albuminuric response predicts renal outcome

RENAAL; Initial anti-albuminuric response predicts renal outcome

Albuminuria reduction (%)

-90 -25 0 25 50 72

Albuminuria reduction (%)

0.0

0.5

1.0

1.5

2.0

2.5

Haz

ard

ratio

-90 -25 0 25 50 72

Renal Endpoint ESRD

0.0

0.5

1.0

1.5

2.0

2.5


RENAAL; Antialbuminuric effect of losartan expIains the renal protective effect

OutcomeOutcome

adjusted for albuminuria

RR (97%CI) P value RR (97%CI) P value

Primary Composite

16.1(2.5-27.8)

0.0221.7

(-14.5- 15.5)0.829

ESRD 28.6(11.5-42.4)

0.00214.1

(-6.6-30.8)0.168


RENAAL; Response variability discordant for blood pressure and albuminuria

Losartan N=715

Increased blood pressure(systolic)

Decreased blood pressure(systolic)

> +15 mmHg +15 to 0 mmHg 0 to -15 mmHg > -15 mmHg

Increased albuminuria

>+30% 4.6% 4.3% 5.7% 3.2%

0 to +30% 2.0% 3.8% 4.1% 3.4%

DecreasedAlbuminuria

-30 to 0% 3.2% 5.0% 9.0% 5.3%

>-30% 5.6% 8.5% 15.9% 16.6%

Eijkelkamp et al; JASN 2007

15 16 31

22 47 69

37 63

RENAAL; Differential effect of antihypertensive treatment on albuminuria and BP has differential effect on ESRD

>+15

mm

Hg

0 to

+15

mm

Hg

-15

to 0

mm

Hg

>-15

mm

Hg

>+30%+30 to 0%

0 to -30%

>-30%

0,00

0,50

1,00

1,50

2,00

2,50

3,00

3,50

4,00

4,50

5,00

RR for ESRD

Delta Systolic BPDelta Albuminuria

(ACR)


Questions




RENAAL; High residual albuminuria levels


165

247264

230

169160

106

79

4735

0

50

100

150

200

250

300

<.5 .5-1.5 1.5-3.5 3.5-5.0 >5.0

Losartan 0 mo (n=751)

Losartan 6 mo (n=751)

158 155

272252

196189

99

123

3743

0

50

100

150

200

250

300

<.5 .5-1.5 1.5-3.5 3.5-5.0 >5.0

Placebo 0 mo (n=762)

Placebo 6 mo (n=762)

RENAAL: Residual high albuminuria and not residual high blood pressure determines risk for ESRD

>= 16

0 mm

Hg

140 t

o 16

0 mm

Hg

130 t

o 14

0 mm

Hg

< 130

mmHg

>3.5 g/g2 to 3.5 g/g

1 to 2 g/g

<1 g/g

0

0,2

0,4

0,6

0,8

1

1,2

1,4

RR for ESRD

Residual SBPResidual

Albuminuria


Summary

Is Albuminuria a predictor of outcome? YES Is it independent from other risk markers?

YES Is proteinuria different than albuminuria NO Is spot sampling different than 24 hour NO

Is Albuminuria lowering predictive of outcome? YES Is it independent from blood pressure lowering?

YES

Is residual albuminuria predicting outcome? YES

Dick de Zeeuw Department of Clinical Pharmacology University Medical Center Groningen The...

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