Implications of MDRD for Validity of Proteinuria as a Surrogate Endpoint.
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Transcript of Implications of MDRD for Validity of Proteinuria as a Surrogate Endpoint.
Implications of MDRD for Validity of Proteinuria as a Surrogate Endpoint
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.
Individual Level Association
Impact of Reduction of Proteinuria in MDRD Study -- Results
MDRD Study slope SE p-value
A -0.92 0.31 .003
B -1.32 0.46 .005
Interpretation: A 1 g/d initial decline in urine proteinexcretion was associated with a reduction in the meanslope 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; 123:754
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%
Baseline GFR <= 24.5 <= 24.5
Baseline GFR 24.5-55.5 24.5-55.5Baseline GFR > 55.5 > 55.5
Cu
mu
lati
ve In
cid
ence
0
10
20
30
40
50
60
70
80
90
100
Follow-Up Time (Months)
0 12 24 36 48 60 72 84 96 108 120
Baseline UP ≤ 1 g/day Baseline UP > 1 g/day
Individual-Level Association of Baseline UP with Incidence of ESRDStratified by Baseline GFR (N = 1617 MDRD Enrollees)
Diet Interventions
Study AStudy B
Effect of Diet Interventions on % Changein Proteinuria from Baseline to 12 Months
Per
cen
t C
han
ge
-86
-63
0
172
639
LowProtein
UsualProtein
KetoAcid
Low Protein
Box-plots extend from25th to 75th percentiles
Study B: No significant different in GFR slope or time to ESRD or Death between Very Low and Low Protein diet groups.
Implications of BP Intervention
Effect of BP Goal on Percent Changein Proteinuria from Baseline to 12 Months
Per
cent
Cha
nge
-86
-63
0
172
639
0.3 - 1 1 - 3 > 3Usual Low Usual Low Usual Low Usual Low
< 0.3
BP Group
Baseline 24 Hr UP (g/day) Box-plots extend from25th to 75th percentiles
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
0.3 - 1 1 - 3 > 3Usual Low Usual Low Usual Low Usual Low
< 0.3
BP Group
Baseline 24 Hr UP (g/day) Box-plots extend from25th to 75th percentiles
Effect of BP Goal on Absolute Changein Proteinuria from Baseline to 12 Months
Effect of Low BP Goal in Study AC
han
ge
in G
FR
(m
l/m
in/1
.73m
2)
Low BP
Usual BP
P=.01p = 0.01
p = 0.30
MDRD: Impact of Blood Pressure Goal on Rate of Progression as a function of Proteinuria
Klahr S, N Engl J Med 1994; 330:877
MDRD Long-Term Cumulative Incidence of ESRD
554/840 (66%) of Randomized Patients Reached ESRD
____Usual Goal
Low Goal
Unadjusted P-value: 0.006Adjusted HR: 0.6895% CI: (0.57-0.82), p < 0.001
0.35 0.50 0.71 1.00 1.41
> 3g
1-3 g
0.3-1 g
<0.3 g
AllN=840
N=410
N=159
N=175
N=96
Hazard Ratio
Bas
elin
e U
P (
g/d
ay)
Hazard Ratios for Low BP Goal by Level of Baseline UP (g/day)
ESRD Alone
ESRD/Death
MDRD Trial Effects Assessment Summary
Compar-ison
Δ UP3-Yr
SlopeChronic 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 Δ UP and effects on slope & clinical endpoints.
THANK YOU
Extra Slides
MDRD: Long Term Outcomes - 2Sarnak et al, Ann Int Med 2005; 142:342
MDRD: Cumulative Variance of GFR Slopes Explained by
CovariatesStudy A Study B
Randomization 0.3 1.8Proteinuria 14.3 15.0PCKD 32.3 28.9Transferrin 33.2 31.8African-American 33.0 33.0Baseline MAP 33.6 33.7Baseline HDL 34.5 33.9
Hunsicker LG et al. Kidney Int 1997; 51:1908 - 1010
624/840 (74%) of Randomized Patients Reached ESRD or Death
Low BP Usual BP
Unadjusted P-value: 0.0502Adjusted HR: 0.7795% CI: (0.65-0.91), p = 0.002
MDRD Long-Term Cumulative Incidence of ESRD/Death
MDRD: Cumulative Variance of GFR Slopes Explained by
CovariatesStudy A Study B
Randomization 0.3 1.8Proteinuria 14.3 15.0PCKD 32.3 28.9Transferrin 33.2 31.8African-American 33.0 33.0Baseline MAP 33.6 33.7Baseline HDL 34.5 33.9
Hunsicker LG et al. Kidney Int 1997; 51:1908 - 1010
UP > 3g/day
UP 1-3g/day
UP 0.3 - 1 g/day
UP < 0.3 g/day
Per
cen
t C
han
ge
Effect of Low Protein Diet on Change in Proteinuria