Welch Center Uniting Medicine & Public Health Prevalence of Albuminuria, and its Relationship to Decreased GFR and Outcomes Josef Coresh, MD, PhD Director,

Welch Center Uniting Medicine & Public Health

Prevalence of Albuminuria, and its Relationship to Decreased GFR and

Outcomes

Josef Coresh, MD, PhDDirector, Cardiovascular Epidemiology Program

Welch CenterDepartments of Epidemiology,

Medicine & BiostatisticsJohns Hopkins University

Disclosures: None

Proteinuria as a Surrogate Outcome in Chronic Kidney DiseaseA workshop co-sponsored by the National Kidney Foundation and U.S. Food

and Drug Administration

Outline

• CKD prevalence

– Albuminuria by stage & its persistence

• CVD risk in relation to:

– Albuminuria and eGFR

•Creatinine (eGFRMDRD)

•Cystatin C (eGFRCysC)

• Conclusions

Prevalence of CKD: NHANES Surveys Representing the US Adult Population

• Study Population: stratified random sample

– NHANES III (1988 to 1994): n=15,488*

– NHANES 1999-2000: n=4,101*

– NHANES 2001-2002: n=4,684

– NHANES 2003-2004: n=4,448• Serum creatinine: calibrated to be comparable to the

MDRD creatinine assay using frozen serum (Am J Kidney Dis. 2007;50:918-26)• GFR Estimate: MDRD Study 4-variable equation• Extrapolation to US population: NCHS published survey

weights adjusting for age, sex, race and non-response

*Coresh et al. JAMA. 2007; 298(17):2038-47

Distribution of Albumin to Creatinine Ratio: NHANES 1988-2004

0

5

10

15

20

25

30

35

40

45<5

10-1

4

20-2

4

30-3

4

40-4

4

50-5

4

60-6

4

70-7

4

80-8

4

90-9

4

100-

299

300+

Albumin to Creatinine Ratio, mg/g

Per

cent

age

1988-1994

1999-2004

0

0.5

1

1.5

30-3

4

40-4

4

50-5

4

60-6

4

70-7

4

80-8

4

90-9

4

100-

299

300+

Albumin to Creatinine Ratio, mg/g

Per

cen

tag

e

Albumin to Creatinine Ration, mg/g

micro”normal” macro

Prevalence of Diagnosed Diabetes and Hypertension by Albuminuria: NHANES 1988-2004

0%10%20%30%40%50%60%70%80%90%

100%

Normal High-Normal Micro- Macro-Albuminuria

Neither

Hypertension only

Diabetes only

Both

< 5 5-29 30-299 300+ACR mg/g

Proportion

Prevalence

Age, y

41% (9,920) 50% (13,000) 7.1% (2648) 1.2% (573)

42 48 56 60

CKD Prevalence Estimates Require GFR Estimation (eGFR)

• MDRD Study Equation (GFR ml/min/1.73m2)eGFR = 186 x (SCr)-1.154 x (age)-0.203

x (0.742 if female) x (1.210 if African American)eGFR = 175 x (Standardized SCr)-1.154 x (age)-0.203

x (0.742 if female) x (1.210 if African American)

• Cockcroft-Gault (CG ml/min)Ccr = (140-age) x weight x 0.85 (if female)/(SCr) BSA Adjusted = CG * 1.73 / BSA formula

• Equations in other populations – Children, Chinese, Japanese, Kidney Donors

N Engl J Med. 2006; 354(23):2473-83.

Clin Chem 2007; 53(4):766-72

Estimated GFR Distribution

The conservative trends analysis eliminated the difference in mean GFR between surveys. The vertical line demarcates an estimated GFR of 60 ml/min/1.73m2 which defines decreased GFR.

Estimated GFR, ml/min/1.73m2

Relationship of eGFR to Albuminuria & Hypertension: NHANES III

Am J Kidney Dis 2002;39:(2) S49

Albuminuriaonly

NormalHigh BP

onlyAlbuminuria & High BP

Chronic Kidney Disease (CKD) Definition

• Kidney damage for 3+ months as defined by structural of functional abnormalities of the kidney, with or without decreased GFR manifest by either:

– Pathological abnormalities, or

– Markers of kidney damage including abnormalities

in the composition of the blood or urine, or

abnormalities in imaging tests

• GFR < 60 ml/min/1.73m2 for 3+ months with or without kidney damage

Am J Kidney Dis 2002;39:(2) S1-S266Ann Intern Med 2003; 139(2):137-147

-5

0

5

10

Lo

g(A

CR

) –

Sec

on

d V

isit

-5 0 5 10

Log(ACR) – First Visit

Macro>300 mg/g

Micro30-299 mg/g

Macro>300 mg/g

Micro 30-299 mg/g

“Normal”

Persistence of Albuminuria – Spot Urine ACR in 2 visits a median of 17 days apart: NHANES III

Persistence of Albuminuria: NHANES III

Albuminuria at First Visit,mg/g

Albuminuria on a Repeat Visit (median 17 days later)

eGFR 90+ eGFR <90

Micro, 30-299* 50.9%

(n=57)

75.0%

(n=36)

Macro 300+ 100% 100%

* 53.9% and 72.7% for gender specific cutoffs for micro-albuminuria 17-250 mg/g for men and 25-355 mg/g for women

US Trends in the Prevalence of CKD by Age and Stage: NHANES 1988-2004

Coresh et al. JAMA. 2007;298:2038-2047

0%

10%

20%

30%

40%

50%

88-9

499

-04

88-9

499

-04

88-9

499

-04

88-9

499

-04

Age Group:

Pre

vale

nce

, % Stage 4

Stage 3

Stage 2Stage 1

CKD Stage

20-39 40-59 60-69 70+

Survey years:

Persistent albuminuria >30 mg/g

eGFRMDRD 15-29 eGFRMDRD 30-59

Prevalence of Elevated Cystatin C in US Women (>1.12 mg/L = 99th %ile for young healthy adults)

Women

0%

20%

40%

60%

80%

100%

Pro

po

rtio

n w

ith

cys

tati

n C

>1.

12 m

g/L

10 20 30 40 50 60 70 80 90

Age(years)

non-Hispanic whitenon-Hispanic blackMexican American

Kottgen et al. Am J Kidney Dis 2008;51:385-394

(n=7,596)

Different Outcomes of CKD

Outcome Importance for Different Outcomes

CKD Stage Type of Kidney Disease

(Diagnosis)**

Proteinuria

Concurrent complications*

+++ + +

Prognosis (next 10-years)

Risk of CVD or mortality +++ + ++ Risk of kidney failure +++ ++ + Rate of decline in GFR + +++ +++

*Hypertension, anemia, malnutrition, bone disease, neuropathy & decreased quality of life**For example, diabetic, glomerular, vascular, tubulointerstitial, & cystic

Albuminuria and Risk of Cardiovascular Death General Population: Risk Seen at Very Low Levels

PREVEND Study - Hillege HL et al, Circulation 2002;106:1777-82.

Micro-albuminuria

Urinary Albumin Concentration mg/day

1.0

2.0

3.0

4.0

5.0

Hazard Ratio 20 mg/day

(30 mg/g)200 mg/day(300 mg/g)

Glomerular Filtration Rate, Albuminuria, and Risk of Cardiovascular and All-Cause Mortality in the US Population(Astor et al. Am J Epidemiol 2008, April ePUB)

Cardiovascular Mortality

Models adjusted to incidence rates of a 60-year-old non-Hispanic White male.

All-Cause Mortality

Models adjusted to incidence rates of a 60-year-old non-Hispanic White male.

Cardiovascular mortality in NHANES III F/U Predicted incidence rates adjusted to the mortality rate

of a 60 year‑old, non-Hispanic white male

Astor et al. Am J Epidemiol 2008; April

All-Cause mortality in NHANES III F/U Predicted incidence rates adjusted to the mortality rate

of a 60 year‑old, non-Hispanic white male

Astor et al. Am J Epidemiol 2008; April

Association of Kidney Function and AlbuminuriaWith Cardiovascular Mortality in Older vs Younger Individuals: The HUNT II Study

Hallan et al. Arch Intern Med. 2007;167(22):2490-2496

eGFR ml/min/1.73m2ACR, mg/g

Ag

e &

Se

x A

dju

ste

d IR

R

ACR – average 3 spot urines• Optimal < median

• Men: < 5 • Women: < 7

• High normal• Men: 5 to 19• Women: 7 to 29

• Microalbuminuria • Men: 20 to 199 • Women: 30 to 299

30 505 20

Cardiovascular Mortality by eGFR and Albuminuria: HUNT II Study

Hallan et al. Arch Intern Med. 2007;167(22):2490-2496

Albuminuria, mg/g (average of 3 spot urines)

ACR• Optimal < median

• Men: < 5 • Women: < 7

• High normal• Men: 5 to 19• Women: 7 to 29

• Microalbuminuria • Men: 20 to 199 • Women: 30 to

299

*P.05. †P.01. ‡P.001.

0.5

11.

52

2.5

3

Ad

just

ed A

nn

ual

C

ard

iova

scu

lar

Mo

rtal

ity

(%)

30 40 50 60 70 80 90 100 110 120

Estimated GFR (mL/min/1.73m2)

Adjusted* Cardiovascular Mortality Risk in NHANES III Mortality Follow-Up Study

Astor et al. JASN 2007 abstract

High eGFRMDRD low muscle mass (BAD)

*Adjusted for 13 covariates

eGFRMDRD

eGFRCysC

Age > 65

Age ≤ 65

0

5

10

15

20

25

30

35

120 160 200 240Cholesterol, mg/dL

3-y

ea

r C

VD

Mo

rta

lity

Ra

te P

er

10

0

*Adjusted to the age of 60 years, female, Whites, HD and non-smokers.

Overall

Distorted Associations (Baseline Disease RF CVD)Adjusted* 3-year all-cause mortality in Dialysis Patients

Presence of Inflammation/Malnutrition

Absence of Inflammation/Malnutrition

Conclusions• Albuminuria is common in the population

– Spot ACR provides a reasonable measure– Cutoffs are somewhat arbitrary: sex dependent

cutoffs are more accurate but non-sex dependent cutoff are useful & less complicated

– Microalbuminuria varies within an individual – persistence is a useful indicator

– Much more common among diabetics; but a substantial proportion of the individuals with microalbuminuria have neither hypertension nor diabetes

• Albuminuria and eGFR are associated but confer independent risk (mortality, CVD mortality)

Thank you!

CKD-Epi

ARIC Staff CHOICE Study

CVD-Epi Stein Hallan