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

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

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

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

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%

CI)

Baseline Quartiles of Albuminuria (mg/mmol)

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

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

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

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.

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

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

181614121086420

1 2 3 4

*4.2

11.4 **10.8

16.6

Vasodilatory response (%)

Flow-mediated dilation: FMDNitroglycerine-dependent dilation: NDD

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

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

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)

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.

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

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.

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.

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

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