screening for albuminuria and microalbuminuria: epidemiological and prognostic interest

Screening for albuminuria and microalbuminuria:

epidemiological and prognostic interest

Martin Wissing MD. PhD

Department of Nephrology

CUB Hopital Erasme

[email protected]

• Renal glomerulus: structural basis of ultrafiltration

• Albuminuria as a a marker of renal damage.

• Albuminuria as a marker of endothelial injury and cardiovascular risk.

• Albuminuria as a tool to monitor the efficacy of therapeutic intervention in patients at high cardiovascular risk.

• Epidemiological aspects of monitoring albuminuria in the general population.

Renal glomerulus: structural basis of ultrafiltration

• Filtration barrier:– capillary endothelial cells (pores 50-100 nm)

– glomerular basement membrane

– Podocytes (slit membranes: <1.8 nm pass freely, >4 nm are completely blocked)

Definitions of albuminuria

• « Normal »: <20 mg/day (<15 µg/min)

• Microalbuminuria: 30 to 300 mg/day (20 to 200 µg/min)

• Overt proteinuria: > 300 mg/day (>200 µg/min)

• 24 h urine collection (timed collection) are impractical and error-prone

• Urinary albumin concentration does not take into account urine dilution or concentration

• Urinary Albumin-to-creatinine ration (UACR)

– Microalbuminuria: 30 mg/g (3.4 mg/mmol) to 300 mg/g

– Overt proteinuria: >300 mg/g

– Gender difference: men 2.5 to 25 mg/mmol; women 3.5 to 35 mg/mmol

Microalbuminuria as a marker of vascular injury

• Associated with increased CV morbidity and mortality• Independent risk factor for CV disease• Correlates with other markers of CV risk and endothelial injury

– Endothelial dysfunction– CRP levels– Increased vWF– Left ventricular hypertrophy, carotid intima media thickness (IMT)– Risk factors: hyperlipidemia, hypertension, smoking, age, diabetes.

• In diabetic patients– Associated with increased risk of CV disease and death– Associated with increased risk of diabetic nephropathy

• Hypothesis:– Continuous marker of endothelial injury and CV risk– Identificartion of high risk populations– Monitoring the efficacy of therapeutic intervention

Albuminuria, a therapeutic target for cardiovascular protection in Type 2 diabetic patients with nephropathy.

De Zeeuw D. et al. Circulation 2004; 110: 921

• RENAAL study:

– Type 2 diabetes with nephropathy

– P creat >1.5 mg/dl and <=3 mg/dl

– ACR >300 mg/g or 24h proteinuria >0.5 g.

– Randomized and double-blind comparison of losartan and placebo

– N=1513 Mean follow-up: 3.4 years

• Cardiovascular end-point: Myocardial infarct, stroke, heart failure, unstable angina, revascularization procedure, cardiovascular death.

Albuminuria as predictor of cardiovascular outcome.De Zeeuw D. et al. Circulation 2004; 110: 921

1 g/g increase:Increase 17% (12 to 23) of CV endpointIncrease 26% (18 to 34) of HF endpoint

Albuminuria reduction as predictor of cardiovascular outcome.De Zeeuw D. et al. Circulation 2004; 110: 921

50% reduction of albuminuria:Risk reduction 18% (9 to 25%) for CV end pointRisk reduction 27% (14 to 38%) for HF end point

Proteinuria as target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL.De Zeeuw D. et al. Kidney Int 65:2309; 2004

• RENAAL: Renal end point: doubling of serum creatinine, ESRD or death.

Reduction of albuminuria as a predictor of renal outcomeDe Zeeuw D. et al. Kidney Int 65:2309; 2004


Change in albuminuria at 6 months:Placebo: +4% (+8 to –1%)Losartan: -28% (-25 to –36%)

Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.

Heart Outcomes Prevention Evaluation (HOPE) studyGerstein H. et al. JAMA 286:421; 2001

• HOPE:– >= 55 years

– History of cardiovascular disease or diabetes with at least 1 CV risk factor.

– Exclusion if dipstick positive proteinuria or serum creatinine >= 2.3 mg/dl

– 3498 diabetic and 5545 nondiabetic subjects

– Double-blind randomization to ramipril 10 mg/d or placebo.

– Average follow-up 4.5 years.

• Primary end point:– Myocardial infarction, stroke, CV death

• Secondary end point:– Hospitalization for congestive heart failure.

Impact of microalbuminuria on cardiovascular outcomes.Gerstein H. et al. JAMA 286:421; 2001

Microalbuminuria defines as ACR >2 mg/mmol (>18 mg/g creatinine)

1140/3498 (32.6%) of diabetic subjects823/5545 (14.8%) of non-diabetic subjects

Impact of ACRs below the microalbuminuria threshhold on cardiovascular outcomes.

Gerstein H. et al. JAMA 286:421; 2001

<1.9 1.9-5.0 5.1-14.3 >14.3 (mg/g creatinine)

Development of renal disease in people at high cardiovascular risk: Results of the HOPE randomized study

Mann J.F. et al. JASN 14:641; 2003

• Risk to develop clinical proteinuria : ACR >36 mg/mmol (>320 mg/g creatinine) or >= 300 mg/d of albuminuria.

Risk factors for progression of proteinuriaMann J.F. et al. JASN 14:641; 2003

Progression of proteinuria:no µalbuminuria µalbuminuria µalbuminuria clinical proteinuria

34% of diabetics17% of non diabetics

Risk of clinical proteinuria by degree of albuminuriaMann J.F. et al. JASN 14:641; 2003

ACRs:0.21 mg/mmol = 1.9 mg/g0.57 mg/mmol = 5.0 mg/g1.57 mg/mmol = 13.9 mg/g

Role of baseline albuminuria in progression of proteinuriaMann J.F. et al. JASN 14:641; 2003

Albuminuria and cardiovascular risk in patients with left ventricular hypertrophy: The LIFE study

Wachtell K. et al. Ann Intern Med 139:901; 2003

• LIFE: Losartan Intervention For Endpoint reduction.– 55-88 years– stage II - III arterial hypertension– ECG-confirmed left ventricular hypertrophy– Double-blind randomization to losartan or atenolol– P creat >1.8 mg/dl excluded– N: 8206 patients with baseline UACR evaluation– Average follow-up: 4.8 years

• End points:– Primary combined end point: Myocardial infarction, stroke, CV death– Secondary end points:

• All cause mortality• Each component of the composite end point.

Wachtell, K. et. al. Ann Intern Med 2003;139:901-906

Deciles of Urine Albumin-Creatinine Ratio as Risk for Composite End Point, Cardiovascular and All-Cause Mortality, Stroke, and Myocardial Infarction in

7143 Nondiabetic Patients

Wachtell, K. et. al. Ann Intern Med 2003;139:901-906

Quintiles of Urine Albumin-Creatinine Ratio as Risk for Composite End Point, Cardiovascular and All-Cause Mortality, Stroke, and Myocardial Infarction in

1063 Diabetic Patients

Reduction in albuminuria translates in reduction in cardiovascular events in hypertensive patientsIbsen H. et al. Hypertension 45:198; 2005

UACR assessed at baseline and then yearly thereafter.Investigation of the relationship between the combined end point and albuminuria as a time-varying explanatory variable.

End point rates subdivided according to UACR above or below the median value at baseline and at year 1

Ibsen H. et al. Hypertension 45:198; 2005

H/H

L/H

H/L

L/L

The effect of irbesartan on the development of diabetic nephropathy in type 2 diabetes

Parving H. et al. N Engl J Med 345:870; 2001

30/201 (14.9%)

19/195 (9.7%)

10/194 (5.2%)

RR vs placebo:150 mg 0.61 (0.34 to 1.08)300 mg 0.30 (0.14 to 0.61)

N=590

Endpoint: development of clinical albuminuria with at least a 30% increase from baseline values.

Parving HH. N Engl J Med 345:870,2001

P=0.006 vs placebo

P=0.004 irbesartan vs placebo

Regression of microalbuminuria in type 1 diabetesPerkins B. et al. N Engl J Med 348:2285;2003

• Cohort of 1602 type 1 diabetics followed 1991-1992 at the Joslin Clinic in Boston.

• Follow-up of 4 two-year intervals.

• Microalbuminuria was present initially in 302 (prevalent cohort) or developed during follow-up (incident cohort N=109)

• ACR transformed in an estimation of the albumin excertion rate.µAlbuminuria: 30-299 µg/minute (43 to 430 mg/24 h).

• Aim of the study: Determine variables associated with regression of microalbuminuria.– 50% reduction of the average of three measurements of the AER from one

two-year observation period to the next.


6-year cumulative incidence of regression of proteinuria: 58% (52 to 64%)


Salutary factors:HbA1C<8%SBP<115 mmHgCho<198 mg/dl & TGL < 145 mg/dl

Adjustment for other variables

31%

41%

23%

5%

Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes

Araki S. Diabetes 54:2983; 2005

Follow-up period

Status Evaluation period First Second Third

Overt proteinuria 20 (9) 22 (13) 21 (19)

Microalbuminuria 216 (100) 147 (69) 92 (54) 66 (58)

Normoalbuminuria 48 (22) 55 (33) 26 (23)

Total 216 (100) 215 (100) 169 (100) 113 (100)

Data are n (%). Evaluation period was the first 2-year period during which microalbuminuria was present. Microalbuminuria was present initially in 179 patients (the prevalence cohort) and developed later in another 37 patients during the first or second follow-up period (the incidence cohort). In the incidence cohort, the initial evaluation period took place after 2 years in 24 subjects and after 4 years in 13 subjects.

Adjusted OR (95% CI)*

Regression RemissionNonmodifiable factors

Incidence cohort (vs. prevalence) 2.0 (1.03–3.9) 2.0 (1.1–3.9)

Modifiable factorsUse of ACE inhibitors or ARBs (vs. none) 2.3 (1.4–4.0) 1.9 (1.1–3.3

A1C (%)A1C < 6.95 2.2 (1.2–4.2) 3.0 (1.5–6.0

6.95A1C < 7.75 1.2 (0.6–2.3) 2.1 (1.01–4.2)

7.75 A1C 1.0 (ref.) 1.0 (ref.)

SBP (mmHg)SBP < 129 2.0 (1.04–3.9) 2.7 (1.4–5.2)

129 SBP < 143 1.6 (0.8–3.0) 1.8 (0.9–3.5)

143 SBP 1.0 (ref.) 1.0 (ref.)

* The multivariate model was adjusted for sex, mean urinary albumin excretion in the initial evaluation period, total cholesterol, estimated sodium intake, and estimated protein intake. Ref. = reference category.

The ORs of factors associated with the regression and remission of microalbuminuria with the pooled logistic regression model


Number of factors at salutary levels

0 1 2 3

Regression of microalbuminuria* 1.0 (ref.) 1.4 (0.8–2.5) 2.4 (1.2–4.6) 5.9 (1.3–25.8)

Remission of microalbuminuria* 1.0 (ref.) 1.2 (0.7–2.2) 2.0 (1.01–3.9) 6.2 (1.6–24.2)

Data are OR (95% CI).

Salutary factors: HbA1c <6.5%; BP <130/80; Chol<200 mg/dl & TGL <150 mg/dl

* The ORs were adjusted for sex, mean urinary albumin excretion in the initial evaluation period, the use of ACE inhibitors or ARBs, and the incidence cohort.

Absence of any of the three factors at a salutary level was considered the reference category (ref.).

Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes


N=216

Is screening of microalbuminuria warranted in the general

population without arterial hypertension and diabetes ?

Validity of diagnostic testsDisease No Disease

Test positive TP FP Total positive tests (T+)Test negative FN TN Total negative tests (T-)

Total disease Total without (Dis+) disease (Dis-)

•Sensitivity: Proportion of patients with disease correctly identified by the test. (TP/Dis+)•Specificity: Proportion of patients without disease correctly identified by the test. (TN/Dis-)•Positive predictive value: Proportion of patients with a positive test who have the disease. (TP/T+)•Negative predictive value: Proportion of patients with a negative test who do not have the disease. (TN/T-)

PPV and NPV but not sensitivity and specificity are influenced by disease prevalence. The proportion of FP increases and the PPV decreases with rare disease

Validity of diagnostic tests

Disease No DiseaseTest positive 90 10 100Test negative 10 90 100

100 100 200

Sensitivity: 90/100=90% Specificity 90/100=90%PPV: 90/100=90% NPV: 90/100=90%

Disease No DiseaseTest positive 90 1000 1090Test negative 10 9000 9010

100 10000 10100

Sensitivity: 90/100=90% Specificity 9000/10000=90%PPV: 90/1090=8.3% NPV: 9000/9010=99%

Common disease:

Rare disease:

Validity of diagnostic tests

• Very high NPV: A lot of normal subjects are tested to say that everything is ok.

• Low PPV: A high number of false positive tests– Additional studies to identify true positives– Medical treatment of FP– Preoccupation and anxiety in FP

• Screening of rare disease is justified when– test with very high sensitivity and specificity– disease with severe consequences in the majority of subjects– Availability of efficient therapeutic interventions.

Clinical studies assessing the association of low-grade albuminuria and cardiovascular disease events

in the general apparently healthy population

• Low-grade albuminuria and incidence of cardiovascular disease events in normotensive and non-diabetic individuals.– Ärnlöv J et al. Circulation 112:969; 2005

• Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population (Prevend study)– Hillege H. et al. Circulation 106:1777; 2002

• Microalbuminuria and all-cause mortality in 2089 apparently healthy individuals: a 4.4-year follow-up study. (HUNT study)– Romundstad S et al. Am J Kidney Dis 42:466, 2003

Low-grade albuminuria and incidence of cardiovascular disease events in normotensive and non-diabetic individuals.

(Framingham Heart Study)Ärnlöv J et al. Circulation 112:969; 2005

• Cohort of 3532 subjects (1995-1998)

• Exclusion of 1964 (CV disease, hypertension, diabetes, missing follow up data)

• Cohort of 1568 patients without arterial hypertension or diabetes.

• UACR in mg/g median: male 7.5 mg/g; female 3.9 mg/g.

• Correlation of µalbuminuria with CVD, hard CV endpoints (myocardial infaction, stroke, CV death, heart failure) during 8 year FU.



Relative risk above median vs. below median:Total CVD: 2.92 (1.57 to 5.44) P=0.0007Hard CVD: 4.26 (1.7 to 10.66) P=0.002

Validity of microalbuminuria as a screening test to detect subjects at high risk of CV disease events

Ärnlöv J et al. Circulation 112:969; 2005

• Optimal performance by ROC analysis for hard CVD and death:

• ACR 5 mg/g in men and 11 mg/g in women– Sensitivity: 0.74– Specificity: 0.64– Positive Predictive Value: 0.05– Negative Predictive Value: 0.99

Screening for proteinuria in US adultsA cost-effectiveness analysis

Boulware L. et al. JAMA 290:3101; 2003

• Cost-effectiveness ratio of screening vs non-screening unfavorable– Cost 282818 $ per quality of life year/person– Gain 0.0022 QALYs per person

• Screening is cost effective in high risk populations (hypertension, diabetes).

screening for albuminuria and microalbuminuria: epidemiological and prognostic interest

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