Screening for albuminuria and microalbuminuria: epidemiological and prognostic interest

1. Screening for albuminuria and microalbuminuria:epidemiological and prognostic interest Martin Wissing MD. PhD Department of Nephrology CUB Hopital Erasme wissing@ulb.ac.be

2. 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.

3. 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)

4. 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

5. 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

6. 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.

7. 1 g/g increase: Increase 17% (12 to 23) of CV endpoint Increase 26% (18 to 34) of HF endpoint Albuminuria as predictor of cardiovascular outcome.De Zeeuw D. et al. Circulation 2004; 110: 921

8. 50% reduction of albuminuria: Risk reduction 18% (9 to 25%) for CV end point Risk reduction 27% (14 to 38%) for HF end point Albuminuria reduction as predictor of cardiovascular outcome.De Zeeuw D. et al. Circulation 2004; 110: 921

9. 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.

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

11. 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%)

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

13. 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.

14. 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 subjects 823/5545 (14.8%) of non-diabetic subjects

15. <1.9 1.9-5.0 5.1-14.3 >14.3 (mg/g creatinine) Impact of ACRs below the microalbuminuria threshhold on cardiovascular outcomes.Gerstein H. et al. JAMA 286:421; 2001

16. Development of renal disease in people at high cardiovascular risk: Results of the HOPE randomized studyMann 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.

17. 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 diabetics 17% of non diabetics

18. Risk of clinical proteinuria by degree of albuminuriaMann J.F. et al. JASN 14:641; 2003 ACRs: 0.21 mg/mmol = 1.9 mg/g 0.57 mg/mmol = 5.0 mg/g 1.57 mg/mmol = 13.9 mg/g

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

20. Albuminuria and cardiovascular risk in patients with left ventricular hypertrophy: The LIFE studyWachtell 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.

21. 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

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

23. 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.

24. H/H L/H H/L L/L End point rates subdivided according to UACR above or below the median value at baseline and at year 1Ibsen H. et al. Hypertension 45:198; 2005

25. 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 The effect of irbesartan on the development of diabetic nephropathy in type 2 diabetesParving H. et al. N Engl J Med 345:870; 2001 Endpoint: development of clinical albuminuria with at least a 30% increase from baseline values.

26. P=0.006 vs placebo P=0.004 irbesartan vs placebo Parving HH. N Engl J Med 345:870,2001

27. 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.

28. Regression of microalbuminuria in type 1 diabetesPerkins B. et al. N Engl J Med 348:2285;2003 6-year cumulative incidence of regression of proteinuria: 58% (52 to 64%)

29. Regression of microalbuminuria in type 1 diabetesPerkins B. et al. N Engl J Med 348:2285;2003 5% 23% 41% 31% Salutary factors: HbA1C<8% SBP<115 mmHg Cho<198 mg/dl & TGL < 145 mg/dl Adjustment for other variables

30. Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetesAraki 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.

31. The ORs of factors associated with the regression and remission of microalbuminuria with the pooled logistic regression modelAraki S. Diabetes 54:2983; 2005 Adjusted OR (95% CI)* Regression Remission Nonmodifiable factors Incidence cohort (vs. prevalence) 2.0 (1.03–3.9) 2.0 (1.1–3.9) Modifiable factors Use 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 6.95A1C < 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.

32. Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetesAraki S. Diabetes 54:2983; 2005 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.). N=216

33. Is screening of microalbuminuria warranted in the general population without arterial hypertension and diabetes ?

34. Validity of diagnostic tests • 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

35. Validity of diagnostic tests Common disease: Sensitivity: 90/100=90% Specificity 90/100=90% PPV: 90/100=90% NPV: 90/100=90% Rare disease: Sensitivity: 90/100=90% Specificity 9000/10000=90% PPV: 90/1090=8.3% NPV: 9000/9010=99%

36. 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.

37. 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

38. 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.

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

40. 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

41. Validity of microalbuminuria as a screening test to detect subjects at high risk of CV disease eventsÄrnlöv 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

42. Screening for proteinuria in US adultsA cost-effectiveness analysisBoulware 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).