Specialists in Hyperlocal Digital Marketing Dick O’Hare CEO [email protected].
Dick de Zeeuw Department of Clinical Pharmacology University Medical Center Groningen The...
-
Upload
randell-hodges -
Category
Documents
-
view
212 -
download
0
Transcript of 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?
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
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?
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; Albuminuria Reduction (<0% versus >30%) at Month 6 determines the renal outcomeRENAAL; Albuminuria Reduction (<0% versus
>30%) at Month 6 determines the renal outcome
De Zeeuw et al; Kidney Int 2004
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
De Zeeuw et al; Kidney Int 2004
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
De Zeeuw et al; Kidney Int 2004
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)
Eijkelkamp et al; JASN 2007
Questions
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; High residual albuminuria levels
De Zeeuw et al; Kidney Int 2004
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
Eijkelkamp et al; JASN 2007
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