Dick de Zeeuw

1
Albuminuria a tool for measuring non-blood
pressure related renal protection. Data from the
RENAAL trial

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

2
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 gt 300 mg/g
• Dosing 50 mg losartan or 100 mg if blood
  pressure gt140/90
• Measurements
• Albuminuria morning void ACR 24 hour Albumin
  and ACR in subgroup (n710)
• Proteinuria 24 hour proteinuria, in subgroup
  (n710)
• Change in albuminuria
• Individual ACR change comparing baseline to 6
  months
• End-points
• Combined endpoint Doubling serum creatinine,
  ESRD, Death
• Single of each

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RENAAL AII-antagonist more renal protective than
placebo in type 2 diabetes similar blood
pressure, different albuminuria
Placebo
Risk Reduction 16
50
p0.024
40
Losartan
30
with event
20
40
10
20
P
0
0
Albuminuria (Change,)
0
12
24
36
48
-20
35 Overall Reduction
plt0.001
-40
L
-60
0
12
24
36
48Mo
Brenner et al New Engl J Med 2001
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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?

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RENAAL Baseline proteinuria as a determinant for
renal events in type 2 diabetic nephropathy
Primary composite Endpoint
ESRD
15
10
Hazard ratio
Hazard ratio
5
0
0
³
³
³
³
³
³
³
³
lt.5
2.0
2.95
4.4
5.25
³
lt.5
2.0
2.95
4.4
5.25
Baseline Albuminuria (g/g)
Baseline Albuminuria (g/g)
De Zeeuw et al Kidney Int 2004
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RENAAL Model for independent renal risk factors
during (optimal) blood pressure treatment in type
2 diabetic nephropathy (n1300)
p-Value
95 Conf Interval
Hazard Ratio
6.2
Urine albumincreatinine (log, mg/g)
lt0.0001
4.4 - 8.7
lt0.0001
1.7 2.5
2.1
Serum creatinine (mg/dL)
lt0.0001
0.61 - 0.80
0.70
Serum albumin (per 0.5 g/dL)
0.0001
0.84 - 0.95
0.89
Hemoglobin (g/dL)
RENAAL RISK SCORE (1.96 log urinary
albumincreatinine ratio) (0.78 serum albumin
g/dl) (1.28 serum creatinine mg/dl)
(0.11 hemoglobin g/dl).
Keane et al, Kidney Int 2003 and Keane et al,
Clin J Am Soc Nephrol 2006
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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?

8
RENAAL Albuminuria Reduction (lt0 versus gt30)
at Month 6 determines the renal outcome
Renal Endpoint
ESRD
De Zeeuw et al Kidney Int 2004
9
RENAAL Initial anti-albuminuric response
predicts renal outcome
De Zeeuw et al Kidney Int 2004
10
RENAAL Antialbuminuric effect of losartan
expIains the renal protective effect
Outcome Outcome Outcome adjusted for albuminuria Outcome adjusted for albuminuria
RR (97CI) P value RR (97CI) P value
Primary Composite 16.1 (2.5-27.8) 0.022 1.7 (-14.5- 15.5) 0.829
ESRD 28.6 (11.5-42.4) 0.002 14.1 (-6.6-30.8) 0.168
De Zeeuw et al Kidney Int 2004
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RENAAL Response variability discordant for blood
pressure and albuminuria
Losartan N715 Losartan N715 Increased blood pressure (systolic) Increased blood pressure (systolic) Decreased blood pressure (systolic) Decreased blood pressure (systolic)
Losartan N715 Losartan N715 gt 15 mmHg 15 to 0 mmHg 0 to -15 mmHg gt -15 mmHg
Increased albuminuria gt30 4.6 4.3 5.7 3.2
Increased albuminuria 0 to 30 2.0 3.8 4.1 3.4
Decreased Albuminuria -30 to 0 3.2 5.0 9.0 5.3
Decreased Albuminuria gt-30 5.6 8.5 15.9 16.6

15 16 31
22 47 69
37 63
Eijkelkamp et al JASN 2007
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RENAAL Differential effect of antihypertensive
treatment on albuminuria and BP has differential
effect on ESRD
Eijkelkamp et al JASN 2007
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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?

14
RENAAL High residual albuminuria levels
300
300
272
264
252
247
250
250
230
196
189
200
200
169
165
160
158
155
150
150
123
106
99
100
100
79
47
43
35
50
37
50
0
0
lt.5
.5-1.5
1.5-3.5
3.5-5.0
gt5.0
lt.5
.5-1.5
1.5-3.5
3.5-5.0
gt5.0
Losartan 0 mo (n751)
Placebo 0 mo (n762)
Losartan 6 mo (n751)
Placebo 6 mo (n762)
De Zeeuw et al Kidney Int 2004
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RENAAL Residual high albuminuria and not
residual high blood pressure determines risk for
ESRD
Eijkelkamp et al JASN 2007
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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