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