Implications of MDRD for Validity of Proteinuria as a Surrogate Endpoint

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Implications of MDRD for Validity of Proteinuria
as a Surrogate Endpoint
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MDRD Follow-up

• Randomized Trial Phase
• 2 to 4 years of planned follow-up,
• Mean actual follow-up, with censoring due to ESRD
  and death was 2.2 years
• Primary outcome was iothalamate GFR slope, with
  iGFR measured every 4 months
• Long-Term Follow-up ESRD and Death ascertained
  through Dec 31, 2000.

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Individual Level Association
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Impact of Reduction of Proteinuria in MDRD Study
-- Results
Interpretation A 1 g/d initial decline in urine
protein excretion was associated with a reduction
in the mean slope in the period after 4 months of
0.92 ml/min/yr in Study A and of 1.32 ml/min/y
in Study B
Peterson JC et al, Ann Int Med 1995 123754
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Association of GFR Slope with Initial GFR in
MDRD and AASK
Study Mean Initial GFR (ml/min/1.73m2) Mean Initial UP (g/day) of Variance in GFR Slope Explained
MDRD Study A 38.6 0.93 g/d 14.0
MDRD Study B 18.5 1.44 g/d 13.2
AASK Study 45.7 0.53 g/d 17.5
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Individual-Level Association of Baseline UP with
Incidence of ESRD Stratified by Baseline GFR (N
1617 MDRD Enrollees)
Baseline UP gt 1 g/day
Baseline UP 1 g/day
Baseline GFR lt 24.5
lt 24.5
Baseline GFR 24.5-55.5
24.5-55.5
100
Baseline GFR gt 55.5
gt 55.5
90
80
70
Cumulative Incidence
60
50
40
30
20
10
0
0
12
24
36
48
60
72
84
96
108
120
Follow-Up Time (Months)
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Diet Interventions
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Effect of Diet Interventions on Change
in Proteinuria from Baseline to 12 Months
639
Study A
Study B
172
Percent Change
0
-63
-86
Low Protein
Usual Protein
Keto Acid
Low Protein
Box-plots extend from 25th to 75th percentiles
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Study B No significant different in GFR slope or
time to ESRD or Death between Very Low and Low
Protein diet groups.
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Implications of BP Intervention
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Effect of BP Goal on Percent Change
in Proteinuria from Baseline to 12 Months
639
172
Percent Change
0
-63
-86
BP Group
Usual
Low
Usual
Low
Usual Low
Usual
Low
lt 0.3
1 - 3
gt 3
0.3 - 1
Baseline 24 Hr UP (g/day)
Box-plots extend from 25th to 75th percentiles
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Effect of BP Goal on Absolute Change
in Proteinuria from Baseline to 12 Months
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
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Effect of Low BP Goal in Study A
Usual BP
Change in GFR (ml/min/1.73m2)
Low BP
P.01
p 0.01
p 0.30
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MDRD Impact of Blood Pressure Goal on Rate of
Progression as a function of Proteinuria
Klahr S, N Engl J Med 1994 330877
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MDRD Long-Term Cumulative Incidence of ESRD
____
Usual Goal Low Goal
Unadjusted P-value 0.006 Adjusted HR 0.68 95
CI (0.57-0.82), p lt 0.001
554/840 (66) of Randomized Patients Reached ESRD
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Hazard Ratios for Low BP Goal by Level of
Baseline UP (g/day)
All
N840
lt0.3 g
N410
Baseline UP (g/day)
0.3-1 g
N159
1-3 g
N175
gt 3g
N96
0.35
0.50
0.71
1.00
1.41
Hazard Ratio

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MDRD Trial Effects Assessment Summary
Compar-ison ? UP 3-Yr Slope Chronic Slope Long-term ESRD or Death
Low vs. Usual Protein Low Protein (small) NULL Low Protein Equivocal
Very Low vs. Low Protein NULL NULL NULL NULL
Low vs. Usual BP Low BP (big) NULL Low BP Low BP
Low vs. Usual BP Effect Modification by Baseline
UP General consistency between effect on
absolute ? UP and effects on slope clinical
endpoints.
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THANK YOU
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Extra Slides
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MDRD Long Term Outcomes - 2Sarnak et al, Ann
Int Med 2005 142342
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MDRD Cumulative Variance of GFR Slopes
Explained by Covariates
Hunsicker LG et al. Kidney Int 1997 511908 -
1010
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MDRD Long-Term Cumulative Incidence of ESRD/Death
Low BP Usual BP
Unadjusted P-value 0.0502 Adjusted HR 0.77 95
CI (0.65-0.91), p 0.002
624/840 (74) of Randomized Patients Reached ESRD
or Death
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MDRD Cumulative Variance of GFR Slopes
Explained by Covariates
Hunsicker LG et al. Kidney Int 1997 511908 -
1010
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Effect of Low Protein Diet on Change in
Proteinuria
Percent Change