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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