The PREVEND Study Screening for microalbuminuria Towards targeted

The PREVEND Study: Screening for micro-albuminuria Towards targeted “primary” prevention to improve renal and cardiovascular care ? The PREVEND Study Group University Medical Center Groningen PREVEND

PREVEND The design of the PREVEND Study

PREVEND The PREVEND Study Acronym for: Prevention of REnal and Vascular ENd-stage Disease Study Since 1997 Groningen, The Netherlands www. PREVEND. org

PREVEND Study Selection procedure PREVEND 1997 85. 421 All inhabitants of the city of Groningen, aged 28 - 75 years, invited for study 40. 856 Positive response - spot morning urine sample, sent in a vial by post to a central laboratory, short questionnaire Inclusion criteria: - All with urinary albumin concentration >10 mg/L - Random sample with UAC <10 mg/L Exclusion criteria: - Diabetes mellitus - Pregnancy 8. 592 Screening in an outpatient clinic (once per 3 years) Albuminuria, renal function, BP, morbidity, mortality etc

Micro-albuminuria: Definition and classification Morning urine Albumin (mg/l) Normal < 20 24 h urine Alb/creat ratio (mg/mmol) M < 2. 5 F < 3. 5 Albumin (mg/24 h) Overnight urine (timed) Albumin ( g/min) < 30 < 20 Micro-albuminuria 20 – 200 M F > 2. 5 -25 > 3. 5 -35 30 – 300 20 – 200 Macro-albuminuria > 200 M F > 25 > 300 > 200

PREVEND The PREVEND Study Aknowledgements Other sponsors: Dutch Heart Foundation Bristol Myers Squibb de Cock Fund Dade Behring Ausam Roche Dutch Government (NWO) US National Institutes of Health (NIH) University Medical Center Groningen (UMCG)

PREVEND Introductory slides

The history of renal care De Jong PE, Brenner B: Kidney Int 2004; 66: 2109 -2118 EARLY RENAL DAMAGE ESTABLISHED RENAL DISEASE END-STAGE RENAL FAILURE 1960 -1980 TERTIARY PREVENTION Prevention of complications of ESRF in dialysis

The history of renal care De Jong PE, Brenner B: Kidney Int 2004; 66: 2109 -2118 EARLY RENAL DAMAGE ESTABLISHED RENAL DISEASE END-STAGE RENAL FAILURE 1980 -2000 1960 -1980 SECONDARY TERTIARY PREVENTION Prevention of progression to ESRF Prevention of complications of ESRF in dialysis

The history of renal care De Jong PE, Brenner B: Kidney Int 2004; 66: 2109 -2118 EARLY RENAL DAMAGE ESTABLISHED RENAL DISEASE END-STAGE RENAL FAILURE 1980 -2000 1960 -1980 “PRIMARY” SECONDARY TERTIARY PREVENTION Prevention of renal function loss in a very early phase Prevention of progression to ESRF Prevention of complications of ESRF in dialysis > 2000

Number of subjects in dialysis increases 2, 500, 000 1, 490, 000 426, 000 1990 Lysaght et al; J Am Soc Nephrol 2002 2000 2010

Incidence of dialysis in The Netherlands - Classical causes for ESRD decrease !!! - Crude incidence per year All age groups Diabetes type 1 Interstitial nephritis Glomerulonephritis Gansevoort et al; Kidney Int 2004

Incidence of dialysis in The Netherlands - Atherosclerosis related causes increase - Crude incidence per year All age groups Gansevoort et al; Kidney Int 2004 Renal Vascular Disease Unknown (probably atherosclerosis related) DM type 2

Renoprotection Especially effective when started early Renal function (%) Ear ly tr eatm ent Late trea tme nt 10 0 0 1 2 3 4 5 6 7 Follow-up (years) Necessity for dialysis 8 9 10

Albuminuria (mg/24 hr) Renal function (m. L/min) Natural course of untreated diabetic nephropathy 150 Hyperfiltration 125 Normal renal function 100 75 50 Overt nephropathy 25 0 10. 000 3. 000 Macro-albuminuria 1. 000 300 100 Micro-albuminuria 30 Normo-albuminuria 10 0 Mogensen et al; Diabetes 1990 4 8 12 16 20 24 28 Duration of diabetes (years)

PREVEND Slides from the publications of 2000

Renal function in relation to albuminuria in the non-diabetic general population creatinine clearance (ml/min) PREVEND 120 n= 8, 592 100 80 0 -7. 5 -15 15 -22. 5 Pinto-Sietsma et al; JASN 2000; 11: 1882 -1888 22. 5 -30 30 -175 175 -300 >300 UAE mg/d

Renal function (m. L/min) Albuminuria (mg/24 hr) PREVEND The natural course of renal function in the non-diabetic general population 150 Hyperfiltration 125 Normal renal function 100 75 50 Overt nephropathy 25 0 10. 000 3. 000 Macro-albuminuria 1. 000 300 Micro-albuminuria 100 30 Normo-albuminuria 10 Increasing age (years)

PREVEND Slides from the publications of 2001

PREVEND Prevalence of albuminuria in the general population Macro-albuminuria >200 mg/l Micro-albuminuria High-normal 20 -200 mg/l 7. 2% 0. 7% albuminuria 10 -20 mg/l 16. 6% n=40, 856 Hillege et al; J Int Med 2001; 249: 519 -526 Normal 0 -10 mg/l 75%

PREVEND Microalbuminuria in relation to underlying mechanism in the general population Diabetes 6. 2% Hypertension 18. 9% n=2, 918 Hillege et al; J Int Med 2001; 249: 519 -526 “Healthy” 75%

PREVEND Slides from the publications of 2002

PREVEND Albuminuria as predictor of CV mortality in the general population Risk of CV mortality (HR) 5 N=40. 856 4 3 2 10 1000 Albumin concentration (mg/L) Hillege et al; Circulation 2002; 106: 1777 -1782

PREVEND Albuminuria predicts cardiovascular death in the general population CV death (% per 1000 pj) 35 29. 1 30 25 20 15 11. 2 10 5 3. 5 4. 5 0 0 - 14 15 – 29 30 - 300 Albuminuria (mg/day) Hillege et al; Circulation 2002; 106: 1777 -1782 >300

PREVEND Slides from the publications of 2004

Blood pressure and proteinuria lowering effect of antihypertensives: a meta-analysis Proteinuria (% change) - 10 -5 - 20 - 10 - 30 - 15 - 40 - 20 - 50 ACEi Others CCB BB Rest N=34 N=593 N=40 N=632 N=23 N=394 N=8 N=129 N=109 Gansevoort et al; Nephrol Dial Transplant 1995 - 25 Mean Arterial Pressure (% change) 0 0

PREVEND IT Study Baseline characteristics Placebo (n=429) Fosinopril (n=425) 51. 5 ± 11. 4 51. 0 ± 12. 1 Male gender Smoking, past current 63. 9 % 31. 2 % 34. 4 % 66. 1 % 34. 4 % 36. 0 % Obesity (BMI > 30 kg/m 2) 18. 6 % 14. 6 % Cholesterol, mg/dl (mmol/l) 220 ± 39 (5. 7 ± 1. 0) 224 ± 39 (5. 8 ± 1. 0) SBP, mm. Hg 130 ± 17. 9 129 ± 17. 1 DBP, mm. Hg 76 ± 9. 7 Prior CV event 2. 3 % 4. 0 % Cardiovascular drugs 5. 8 % 3. 8 % Albuminuria, mg/24 h * 21. 7 (15. 2 - 39. 6) 23. 7 (16. 9 - 44. 5) Age, years Asselbergs et al; Circulation 2004 * Expressed as median (interquartile range)

PREVEND IT Effects of ACEi in the “healthy” with albuminuria Change from baseline with Fosinopril 0 Change in albuminuria (%) - 10 - 20 - 30 - 29. 5 * - 31. 43 * * p < 0. 001 3 Months Asselbergs et al; Circulation 2004 4 Years

PREVEND IT Treatment that lowers albuminuria reduces CV risk in the “healthy” with albuminuria 7. 5 Placebo 5 2. 5 0 ACEi (fosinopril) 0 Combined CV endpoint (%) 10 10 20 30 40 Months Asselbergs et al; Circulation 2004 Risk Reduction 40% NNT 29

Incidence of Stage 3 CKD (%) PREVEND Albuminuria predicts CKD in the non-diabetic general population 70 58 60 50 40 30 22 20 10 9 13 0 0 - 14 15 – 29 30 - 300 >300 Albuminuria (mg/day) Verhave et al; Kidney Int 2004; 66(suppl 92): 1 -4 Stage 3 CKD = creatinine clearance < 60 m. L/min

PREVEND Slides from the publications of 2005

PREVEND Albuminuria predicts new onset diabetes in the general population New onset Diabetes (%) 14 11. 8 12 10 7. 9 8 6 4. 3 4 2 2. 2 0 0 - 14 15 – 29 30 - 300 Albuminuria (mg/day) Brantsma et al; Diabetes Care 2005 >300