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Katherine R. Tuttle, MD, FASN, FACPKatherine R. Tuttle, MD, FASN, FACPMedical and Scientific DirectorMedical and Scientific Director
Providence Medical Research CenterProvidence Medical Research Center
Clinical Professor of MedicineClinical Professor of MedicineDivision of NephrologyDivision of Nephrology
University of Washington School of MedicineUniversity of Washington School of Medicine
Spokane and Seattle, WashingtonSpokane and Seattle, WashingtonUSAUSA
View from the NKF-KDOQI Diabetes and View from the NKF-KDOQI Diabetes and Chronic Kidney Disease Work GroupChronic Kidney Disease Work Group
Albuminuria as a Surrogate Outcome in Diabetic Kidney Disease:
Pitfalls and OpportunitiesPitfalls and Opportunities
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Historical Perspective on Microalbuminuria as a Historical Perspective on Microalbuminuria as a Predictor of Clinical Outcomes in DiabetesPredictor of Clinical Outcomes in Diabetes
Early marker of diabetic kidney disease (DKD) in type 1 diabetes
Predictor of cardiovascular disease (CVD) mortality in type 2 diabetes Death rate increased 100-150% Most deaths were due to CVD causes
Mogensen CE. N Engl J Med 1984;310:356-60
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High GFR
Natural History of Diabetic Kidney DiseaseNatural History of Diabetic Kidney Disease
Macroalbuminuria
Onset of Hyperglycemia DIABETES
Cellular Injury
Rising Blood Pressure
Rising Blood Creatinine
Cardiovascular Death
Microalbuminuria
Diabetes 2 5 10 20 30
Years
End-Stage Kidney Disease
Normal GFR Low GFR
Glomerulosclerosis and Tubulointerstitial Fibrosis
Hypertension
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Annual Rates of Kidney Disease Progression and Annual Rates of Kidney Disease Progression and Death in Type 2 Diabetes (UKPDS)Death in Type 2 Diabetes (UKPDS)
DEATH
No Kidney Disease
Macroalbuminuria
Microalbuminuria
Elevated blood creatinine level or kidney replacement
therapy
0.1%(0.0% to 0.1%
0.1%(0.1% to 0.2%)
0.3%(0.1% to 0.4%)
2.0%(1.9% to 2.2%)
2.8%(2.5% to 3.2%)
2.3%(1.5% to 3.0%)
1.4%(1.3% to 1.5%)
3.0%(2.6% to 3.4%)
4.6%(3.6% to 5.7%)
19.2%(14.0% to 24.4%)
Adler AI et al. Kidney Int 2003;61:225-232
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Risks of CVD Death, MI, and Stroke by Risks of CVD Death, MI, and Stroke by Quartiles of Albuminuria in Diabetes (LIFE)Quartiles of Albuminuria in Diabetes (LIFE)
Ibsen H et al. Diabetes Care 2006;29:595-600
*Adjusted for: LVH, Framingham risk, treatment
Unadjusted hazard ratio*Adjusted hazard ratio
4
3
2
1
0<1 1-3 3-12 >12
Haz
ard
Rat
io (
95%
C
I)
Baseline Quartiles of Albuminuria (mg/mmol)
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Structural Correlate: Albuminuria and Severity Structural Correlate: Albuminuria and Severity of Angiographic Coronary Artery Diseaseof Angiographic Coronary Artery Disease
1013
2531
Absent Mild Moderate
Severe
**
UrinaryAlbumin toCreatinine
Ratio(mg/g)
0
10
20
30
40
50
Tuttle KR et al. Am J Kidney Dis 1999;34:918-925
Angiographic Severity Score
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Relationship of Albuminuria and Angiographic Relationship of Albuminuria and Angiographic Coronary Artery Disease by Diabetes StatusCoronary Artery Disease by Diabetes Status
22
9
49
23
Present Absent Present Absent
†
UrinaryAlbumin toCreatinine
Ratio(mg/g)
‡
0
10
20
30
40
50
60
70
Type 2 Diabetic PatientsNon-Diabetic Patients
Tuttle KR et al. Am J Kidney Dis 1999;34:918-925
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Degree of Overt Proteinuria Predicts Stroke and Degree of Overt Proteinuria Predicts Stroke and CVD Event Rates in Type 2 DiabetesCVD Event Rates in Type 2 Diabetes
A: U-Prot < 150 mg/L B: U-Prot 150–300 mg/L C: U-Prot > 300 mg/L
Incidence (%)
Months
Miettinen H et al. Stroke 1996;27:2033-2039
Stroke Coronary events
p <0.001
0
10
20
30
401
0.9
0.8
0.7
0.6
0.5
00 10 20 30 40 50 60 70 80 90
Survival Free of CVD
Mortality
A
B
COverall between-group p<0.001
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Pitfalls of Albuminuria as a Surrogate Outcome: Pitfalls of Albuminuria as a Surrogate Outcome: Measurement, Analysis, InterpretationMeasurement, Analysis, Interpretation
Intra-patient variability in albuminuria measurement is often large.
Urinary albumin excretion can fluctuate considerably from day-to-day, a particular problem at the low-end range.
Analytic approaches for albuminuria are not standardized. Relationships between albuminuria and glomerular structure
are inconsistent. Increased levels of urinary albumin are not always present in
DKD. Connection of albuminuria to systemic vascular disease is
indirect.
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How Does the Kidney Reflect Status of the Circulation-at-Large?How Does the Kidney Reflect Status of the Circulation-at-Large? Glomerular StructureGlomerular Structure
MesangialCell
Endothelial Cell
Capillary Loop
AfferentArteriole
Juxtaglomerular Apparatus
EfferentArteriole
Podocyte
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Albuminuria Response to ACE Inhibition Predicts Endothelial Albuminuria Response to ACE Inhibition Predicts Endothelial and Non-Endothelial-Dependent Vascular Reactivity in Diabetesand Non-Endothelial-Dependent Vascular Reactivity in Diabetes
Jawa A. et al. J Clin Endo Metab 2006;91:31-35
With vs. without Microalbuminuria
(MA)*p<0.001
**p=0.011
FMD
With MA Without MA With MA Without MA
NDD
1816141210
86420
1 2 3 4
*4.2
11.4 **10.8
16.6
Vasodilatory response (%)
Flow-mediated dilation: FMDNitroglycerine-dependent dilation: NDD
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Pitfalls of Albuminuria as a Surrogate Outcome: Pitfalls of Albuminuria as a Surrogate Outcome: Clinical UtilityClinical Utility
Transition between albuminuria categories (normo-, micro-, macro-) is not a clinical endpoint.
Data relating albuminuria to chronic kidney disease (CKD) endpoints are limited to observational analyses primarily from studies of renin angiotensin system (RAS) inhibition in patients with type 2 diabetes and macroalbuminuria.
“Masking” phenomenon? Applicability to other populations (type 1 diabetes, earlier and later CKD stages,
normal- or low-level albuminuria) or treatments (novel therapies)?
Albuminuria per se has not been a treatment target in phase 3 trials.
Blood pressure with RAS inhibition Glycemic control
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Death, CKD, and CVD Events by Microalbuminuria Death, CKD, and CVD Events by Microalbuminuria Status in Type 2 Diabetes (multi-factorial approach)Status in Type 2 Diabetes (multi-factorial approach)
Araki S et al. Diabetes 2007;56:1727-1730
0 2 4 6 8 10
Time (years)
40
30
20
10
0Cu
mu
lati
ve in
cid
ence
(%
)
>50 % reduction
Non-reduction
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Ibsen H et al. Diabetes Care 2006;29:595-600
CVD Death, MI, and Stroke by Time-Varying CVD Death, MI, and Stroke by Time-Varying Albuminuria in Type 2 Diabetes (LIFE)Albuminuria in Type 2 Diabetes (LIFE)
*Baseline, years 2and 4
0.36
0.24
0.12
0.0010 20 30 40 50 60 70
Month
Pro
por
tion
al E
nd
poi
nt
Rat
e *<1 mg/mmol (n=274, 408, 311)1-3 mg/mmol (n=255, 239, 250)
3-12 mg/mmol (n=267, 230, 213)
>12 mg/mmol (n=267, 174, 175)
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Pitfalls of Albuminuria as a Surrogate Outcome: Pitfalls of Albuminuria as a Surrogate Outcome: Missing other Prospects?Missing other Prospects?
Failure to reduce albuminuria/proteinuria does not necessarily preclude therapeutic benefit. Primary reliance on this marker could lead to missed
prospects for other effective therapies that work through different pathways or mechanisms.
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Reduced Protein Diet Decreased ESRD andReduced Protein Diet Decreased ESRD andDeath in Type 1 Diabetic Kidney DiseaseDeath in Type 1 Diabetic Kidney Disease
Cu
mu
lati
ve I
nci
den
ce
of E
SR
D o
r D
eath
(%
)
Follow-up Time (Years)
Usual Protein Diet (1.02 g/kg/d)
Reduced Protein Diet (0.89 g/kg/d)
30
20
10
00 1 32 4
Hansen HP et al. Kidney Int 2002;62:220-228
• Stage 2 CKD (inferred)• 90% on ACEI, good BP control• No difference in albuminuria• Independent of risk factors, CVD
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Opportunities for Albuminuria as a Surrogate Opportunities for Albuminuria as a Surrogate Outcome: Confirm Treatment TargetOutcome: Confirm Treatment Target
Interventions that reduce albuminuria are promising as potential therapies for preventing or reducing complications of CKD and associated CVD.
Observational associations raise a strong hypothesis that albuminuria reduction produces clinical benefits.
An alternate explanation is that albuminuria reduction marks patients who are more responsive to treatment.
Clinical trials of therapies targeting albuminuria reduction with clinical endpoints as primary outcomes are necessary to confirm efficacy and safety.
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Opportunities for Albuminuria as a Surrogate Opportunities for Albuminuria as a Surrogate Outcome: Identify Novel TherapiesOutcome: Identify Novel Therapies
Novel therapies for DKD are urgently needed to reduce this devastating complication of the worldwide diabetes epidemic. PKC inhibitors, AGE inhibitors, anti-fibrotic agents
Albuminuria, as well as emerging biomarkers, should be useful for screening potentially effective therapies.
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Biomarker Discovery: Key Clinical PointsBiomarker Discovery: Key Clinical Points
Biological plausibility Adjudicated clinical endpoints
Doubling of blood creatinine, dialysis, kidney transplant, MI, stroke, death
Verification by test performance characteristics True positive rate, false positive rate ROC curve analysis
Generalizable to population of interest Validated in different clinical groups
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Process for Connecting Protein Biomarker Process for Connecting Protein Biomarker Discovery with Rigorous Clinical ValidationDiscovery with Rigorous Clinical Validation
Rifai N et al. Nature Biotechnol 2006;24:971-983