Proteinuria as a Surrogate Outcome in
Chronic Kidney Disease
Andrew S. Levey, MD
Thomas Hostetter, MD
Co-Chairs
May 1-2, 2008
Goals
– Acknowledgements
– Summarize the strength of evidence for
proteinuria as a surrogate outcome in CKD
– Conclusions
– Framing the issues
– Mechanics of the conference
• Agenda
• Format for presentations
Acknowledgements
A workshop co-sponsored by the National Kidney Foundation
and U.S. Food and Drug Administration
Planning Committee: Daniel Cattran MD, Aaron Friedman MD,
Federico Goodsaid PhD, Bertram Kasiske MD, Aliza
Thompson MD, Greg Miller PhD, John Sedor MD, Katherine
Tuttle, MD
NKF: Kerry Willis, Tom Manley, Heather McCown, Maggie
Goldstein
FDA: Norman Stockbridge MD PhD, Shirley Murphy MD,
ShaAvhree Buckman MD PhD, Cassandra Pusey, Doug
Throckmorton MD
Summarizing the Strength of Evidence
What we will be doing:
• Review of concepts
• Review of background information
• Review of primary data
What we will not be doing:
• Systematic review
• Meta-analysis
• Guidelines
• FDA Policy
Possible Conclusions from Conference
1.
2.
3.
4.
Strengths and limitations of criteria for surrogacy
Strengths and limitations of available data for
assessment of surrogacy
Application to specific clinical circumstances/
therapeutic agents
What more needs to be done: additional analyses of
existing data vs. additional studies
Importance of Proteinuria
Marker of kidney damage
Clue to the diagnosis of CKD
Risk factor for progression (causal in animal models)
Modifier for efficacy of ACE inhibitor therapy in nondiabetic kidney disease
• Hypothesized marker of vascular permeability
(“generalized endothelial dysfunction”)
• Risk factor for CVD at lower levels than defined as
CKD
• Hypothesized surrogate outcome for kidney disease
progression and CVD risk reduction
Biomarker
•
•
•
•
Definitions
• Biomaker: a characteristic that is objectively measured
and evaluated as an indicator of normal biologic
processes, pathogenic processes, or pharmacologic
responses to a therapeutic intervention. (Biomarkers Definitions
Working Group. Clin Pharmacol Ther 2001; 69: 89-95.)
• Clinical end point: a direct measure of how a patient
feels, functions or survives
• Intermediate Endpoint: a biomarker which is intermediate
in the causal pathway between an intervention and a
clinical endpoint
• Surrogate: a laboratory measurement or physical sign
that is used in therapeutic trials as a substitute for a
clinically meaningful end point … and is expected to
predict the effect of the therapy (Temple R. JAMA 1999; 282: 790795.)
Relationships Among Biomarkers,
Intermediate Endpoints
and Surrogate Endpoints
Biomarkers
Surrogate
Endpoints
Intermediate
Endpoints
Conceptual Model for CKD
Complications
Normal
Increased
risk
Damage
 GFR
Kidney
failure
Death
Operational Definition of CKD for
Epidemiologic Studies and
Public Health Programs
Complications
Normal
Increased
risk
Urine
alb/creat
>30
7.7 m
eGFR
<60
Damage
 GFR
eGFR
<15 or
dialysis
Kidney
failure
Death
Stevens LA, Greene T, Levey AS. Clin J Am Soc Nephrol 1: 874–884, 2006
Criteria for Surrogacy
Desai M, Stockbridge N, Temple R
The AAPS Journal 2006; 8 (1) Article 17
(http://www.aapsj.org)
• Biologic plausibility - sometimes intuitive, sometimes
supported by animal data or by favorable responses in
extreme cases.
• Epidemiologic data - increases (or decreases) in the
putative surrogate are correlated with unfavorable (or
favorable) clinical outcomes.
• Clinical trials - changes in the putative surrogate
resulting from at least 1 type of intervention, and
preferably many types, working by different mechanisms,
affect clinical outcomes in a predictable manner that is
fully accounted for by the effect on the surrogate
(Prentice).
Other issues
• Measurement
– Which proteins?
– How to collect the urine?
– Measurement methods?
– How to express the result?
– Cut-off (threshold) values?
• Context
– Which diseases and interventions?
– What amount (baseline and change)?
– How long?
Proteinuria and Other Markers of
Chronic Kidney Disease:
A Position Statement of the NKF and NIDDK
Eknoyan G, Hostetter T, Bakris GL, Hebert L,
Levey AS, Parving HH, Steffes MW, Toto R.
Am J Kidney Dis 42: 617-622, 2003
Albuminuria Measurement and Terminology
• For screening, albumin preferred in adults, total protein in children.
• Untimed samples, indexed to creatinine (random “spot” in adults,
first-morning preferred in children).
• Report as mg/g; reference range <30 mg/g
• Immunoassays for albumin have “sufficient precision.” There is a
need for standardization among laboratories.
• For monitoring at high levels, can substitute total protein, report as
mg/g; reference range <200 mg/g.
Proteinuria and Other Markers of
Chronic Kidney Disease:
A Position Statement of the NKF and NIDDK
Eknoyan G, Hostetter T, Bakris GL, Hebert L,
Levey AS, Parving HH, Steffes MW, Toto R.
Am J Kidney Dis 42: 617-622, 2003
Albuminuria as a Surrogate Marker for Clinical Trials
• Development of albuminuria in diabetes
• Remission of nephrotic syndrome
• Progression of CKD
Research recommendations
• Compile data from existing RCTs to assess relationship of change in
proteinuria with clinical endpoints:
– Baseline levels of albuminuria
– Relative or absolute changes during follow-up
– Specific kidney diseases
• New clinical trials, designed to assess
• New markers of kidney damage
Agenda
Session 1
General concepts
Session 2
Session 3
Early diabetic kidney disease
(microalbuminuria)
Nephrotic syndrome
Session 4
CKD progression (ACEI/ARB)
Session 5
CKD progression (others)
Analyses
Clinical
trials
Observational
studies
Baseline proteinuria vs. CKD progression
X
X
Early change in proteinuria (6-12 months)
vs. later CKD progression (after early
change)
X
X
Effect of treatment on CKD progression
(comparison of randomized groups) after
adjustment for baseline and early change in
proteinuria
X
NA
Possible Conclusions from Conference
1.
2.
3.
4.
Strengths and limitations of criteria for surrogacy
Strengths and limitations of available data for
assessment of surrogacy
Application to specific clinical circumstances/
therapeutic agents
What more needs to be done: additional analyses of
existing data vs. additional studies
Albuminuria
(“microalbuminuria”)
Rationale
Males
Females
0.25
0.85
0.2
0.8
0.15
0.1
0.05
Albumin Creatinine Ratio (mg/g)
NHANES III
4
0+
30
28
4
027
24
0-
25
4
22
4
021
18
0-
19
4
16
4
0-
13
15
0-
04
12
-1
4
90
-7
60
30
-4
4
0
<1
5
Proportion of Population
0.3
0.9
• Spot urine albumin to
creatinine ratio >30 mg/g
(some consider sexspecific cut-off values)
• 2-3 times greater than the
normal value
• Infrequent in general
population
• Earliest marker of kidney
damage due to diabetes,
glomerular diseases, and
hypertension
• Associated with adverse
outcomes
Simplified Classification of Chronic Kidney
Disease by Diagnosis
Disease
Diabetic kidney
disease
Nondiabetic
kidney
diseases
Major Types (Examples)
Type 1 and type 2 diabetes
Glomerular diseases
(autoimmune diseases, systemic infections, drugs,
neoplasia)
Vascular diseases
(large vessel disease, hypertension,
microangiopathy)
Tubulointerstitial diseases
(urinary tract infection, stones, obstruction, drug
toxicity)
Cystic diseases
(polycystic kidney disease)
Diseases in the Chronic rejection
transplant Drug toxicity (cyclosporine or tacrolimus)
Recurrent diseases (glomerular diseases)
Transplant glomerulopathy
Risk of Developing Clinical Proteinuria by
Baseline Microalbuminuria (MA) in HOPE
Mann et al, J Am Soc Nephrol 14: 641-647, 2003
OR (95% CI)
Unadjusted Adjusted1 Adjusted2
MA+
MA-
All
16.7%
0.8%
26.3
26.2
17.5
N=7674
(271/1619)
(46/6055)
(19.1-36.1)
(19.1-36.1)
(12.6-24.4)
DM
22.8%
1.5%
19.5
19.4
18.2
N=3223
(231/1013)
(33/2210)
(13.4-28.3)
(13.4-28.2)
(12.4-26.7)
No DM
6.60%
0.34%
20.8
20.9
16.7
N=4451
(40/606)
(13/3845)
(11.1-39.2)
(11.1-39.4)
(8.6-32.4)
MA defined as >2 mg/mmol (22.6 mg/g). 1Adjusted for randomized group (ramipril vs. placebo). 2In all, adjusted for
age, gender, smoking, hypertension, dyslipidemia, DM, abdominal obesity, and renal insufficiency. For DM, adjusted
for DM duration, use of oral hypoglycemic agents or insulin, and for glycated hemoglobin level.
NKF-K/DOQI Definition of CKD (2002)
KDIGO Modifications (2004)
Structural or functional abnormalities of the kidneys
for >3 months, as manifested by either:
1. Kidney damage, with or without decreased GFR,
as defined by
• pathologic abnormalities
• markers of kidney damage
– urinary abnormalities (albuminuria)
– blood abnormalities (renal tubular syndromes)
– imaging abnormalities
• kidney transplantation
2. GFR <60 ml/min/1.73 m2, with or without kidney
damage
Example Slide 1
(for observational studies and clinical trials)
Baseline
Participants (N)
Urine P-C ratio (mean, SD)
Six Months
Participants (N)
Early change (50% decline in Urine P-C ratio) (N)
Study End
Outcome (50% decline in eGFR, N)
Outcome (50% decline in eGFR after six months, N)
Example Slide 2
(for observational studies and clinical trials)
Regression of Outcome vs. Baseline
HR (CI)
Baseline urine P-C ratio
Regression of Outcome vs. Baseline and Early Change
HR (CI)
Baseline urine P-C ratio
50% decline in Urine P-C ratio
Note: If proteinuria is a surrogate marker of kidney disease progression,
HR for baseline proteinuria will be >1.0 and HR for early change will be <1.0
Example Slide 3
(for clinical trials)
Regression of Outcome vs. Treatment
HR (CI)
Treatment
Regression of Outcome vs. Treatment Adjusted for
Baseline
HR (CI)
Treatment
Baseline urine P-C ratio
Regression of Outcome vs. Treatment Adjusted for
Baseline and Early Change
HR (CI)
Treatment
Baseline urine P-C ratio
50% decline in urine P-C ratio
Note: If treatment is effective, HR for treatment will be <1.0. If proteinuria
is a surrogate marker for treatment effect, HR for treatment effect will
increase from <1.0 to closer to 1.0 in adjusted models.