1. 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

2. The design of the PREVEND Study

3. Prevention of REnal and Vascular ENd-stage Disease Study
PREVEND
The PREVEND Study
Acronym for:
Prevention of REnal and Vascular ENd-stage Disease Study
Since 1997
Groningen, The Netherlands
PREVEND is the acronym for the Prevention of Renal and Vascular End-stage Disease study, running since 1997 in Groningen, the Netherlands. Information on the study is to derive from our website

4. PREVEND Study Selection procedure
1997
All inhabitants of the city of Groningen,
aged years, invited for study
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
In 1997 PREVEND invited all 85,421 subjects aged years in the city of Groningen to deliver a morning urine sample and to answer a short questionnaire. Subjects using insulin and pregnant subjects were excluded. Of them, 40,856 subjects responded. Of this group overall 11,163 were invited (see slide 3) for more detailed studies. Altogether 8,592 subjects were seen. They form the actual PREVEND cohort. They are followed for CV and renal events, and are seen every 3-4 years for a follow up screening. For details see
Screening in an outpatient clinic (once per 3 years)
Albuminuria, renal function, BP, morbidity, mortality etc

5. Micro-albuminuria: Definition and classification
Morning urine
>
>
< 2.5
< 3.5
Alb/creat ratio (mg/mmol)
> 200
> 300
Macro-albuminuria
20 – 200
30 – 300 M F
Micro-albuminuria
< 20
< 30
Normal
Albumin (g/min)
Albumin
(mg/24h)
(mg/l)
Overnight urine (timed)
24h urine M F
> 25
> 35

6. 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)
The PREVEND study has been made possible by many grants. The Dutch Kidney Foundation took the initiative by giving generous support that made the start of the study possible. Afterwards many followed, both health care foundations and industries as well as governmental organizations. For details see

7. PREVEND
Introductory slides

8. The history of renal care
De Jong PE, Brenner B: Kidney Int 2004;66:
EARLY RENAL DAMAGE
ESTABLISHED RENAL DISEASE
END-STAGE RENAL FAILURE
TERTIARY
PREVENTION
Prevention of complications of ESRF in dialysis
In the early years of nephrology, most attention was directed to set up the dialysis and transplant programs. At that time preventive actions were only aimed to prevent the (cardiovascular) complications of end stage renal disease. Derived from de Jong PE and Brenner BM. Kidney Int 2004; 66:

9. The history of renal care
De Jong PE, Brenner B: Kidney Int 2004;66:
EARLY RENAL DAMAGE
ESTABLISHED RENAL DISEASE
END-STAGE RENAL FAILURE
SECONDARY
PREVENTION
Prevention of progression to ESRF
TERTIARY
PREVENTION
Prevention of complications of ESRF in dialysis
In the eighties attention shifted after the demonstration that in subjects with a given kidney disease after the loss of part of their functioning nephrons renal function gradually continuous to decline to the stage of ESRD. In those years it became also clear that that progressive process of glomerulosclerosis could (partly) be prevented with ACE inhibitors and low protein diets. Derived from de Jong PE and Brenner BM. Kidney Int 2004; 66:

10. The history of renal care
De Jong PE, Brenner B: Kidney Int 2004;66:
EARLY RENAL DAMAGE
ESTABLISHED RENAL DISEASE
END-STAGE RENAL FAILURE
> 2000
“PRIMARY”
PREVENTION
Prevention of renal function loss in a very early phase
SECONDARY
PREVENTION
Prevention of progression to ESRF
TERTIARY
PREVENTION
Prevention of complications of ESRF in dialysis
Nowadays, most patients that reach ESRD, have no glomerular or interstitial renal diseases as the underlying cause, but have renal failure due to type 2 diabetes, hypertension and generalized vascular disease (see also the previous two slides). It may also be that the cause is not to detect anymore, because only shrunken kidneys are present. If we are able to diagnose these patients in an early phase, e.g. before the stage 3-5 CKD, we reach the phase of “primary” prevention of CKD. Derived from de Jong PE and Brenner BM. Kidney Int 2004; 66:

11. Number of subjects in dialysis increases
2,500,000
1,490,000
426,000
The worldwide number of subjects on renal replacement therapies is increasing steadily. From in 1990, to in It is expected that in subjects will be on some form of renal replacement therapy. This poses an important healthcare problem. Screening programmes to identify subjects at risk for accelerated renal function decline, with subsequent preventive treatment, may offer a solution.
1990
2000
2010
Lysaght et al; J Am Soc Nephrol 2002

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

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

14. Especially effective when started early
Renoprotection
Especially effective when started early
Renal function (%)
Early treatment
Late treatment
Necessity for dialysis 10 1 2 3 4 5 6 7 8 9 10
Follow-up (years)

15. Natural course of untreated diabetic nephropathy
150
Hyperfiltration
125
Normal renal function
100
Renal function (mL/min) 75 50
Overt nephropathy 25
10.000
3.000
Macro-albuminuria
1.000
Albuminuria (mg/24hr)
300
100
Micro-albuminuria 30
Normo-albuminuria 10 4 8 12 16 20 24 28
Duration of diabetes (years)
Mogensen et al; Diabetes 1990

16. Slides from the publications of 2000
PREVEND
Slides from the publications of 2000

17. Renal function in relation to albuminuria in the non-diabetic general population
PREVEND
120
n= 8,592
creatinine clearance (ml/min)
100
All subjects of the PREVEND cohort delivered two 24 hr urine samples, in which urinary albumin excretion (UAE) and creatinine excretion was measured. Together with a blood sample, creatinine clearance (CrCl) was measured. The relation between UAE and CrCl was bimodal: as compared to the subjects with a low normal albumin excretion (<15 mg/day), those with a high-normal UAE (15-30 mg/d) and with microalbuminuria ( mg/d) had an elevated creatinine clearance. High normal and micro-albuminuria thus were associated with glomerular hyperfiltration. Macroalbuminuria (>300 mg/d) was associated with an impaired GFR. This pattern thus is to compare with the situation in diabetics. From Pinto-Sietsma SJ et al: Journ Am Soc Nephrol 2000; 11: 80
UAE mg/d
0-7.5
7.5-15
30-175
>300
Pinto-Sietsma et al; JASN 2000;11:

18. The natural course of renal function in the non-diabetic general population
PREVEND
150
Hyperfiltration
125
Normal renal function
100
Renal function (mL/min) 75 50
Overt nephropathy 25
10.000
3.000
Macro-albuminuria
1.000
Albuminuria (mg/24hr)
300
Micro-albuminuria
100 30
Normo-albuminuria 10
Increasing age (years)

19. Slides from the publications of 2001
PREVEND
Slides from the publications of 2001

20. Prevalence of albuminuria in the general population
PREVEND
Macro-albuminuria
>200 mg/l
0.7%
Micro-albuminuria
mg/l
7.2%
High-normal
albuminuria
10-20 mg/l
16.6%
The prevalence of microalbuminuria in an aselect sample (n=40,856) of the mostly Caucasian population of years in the city of Groningen is 7.2%. Micro-albuminuria was defined as a morning urinary albumin concentration of mg/l. Another 16.6% of the population had a borderline albuminuria, or high-normal albuminuria, defined as a urinary albumin concentration of mg/L, while 282 subjects had macroalbuminuria. From Hillege HL et al: J Int Med 2001;J Int Med 2001; 249:
Normal
0-10mg/l
75%
n=40,856
Hillege et al; J Int Med 2001;249:

21. Microalbuminuria in relation to underlying mechanism in the general population
PREVEND
Diabetes
6.2%
Hypertension
18.9%
Of the 2,918 subjects, that were found to be microalbuminuric (defined as a morning urinary albumin concentration of mg/L) only 6.2% was known to be diabetic and 18.9% was known to be hypertensive. Although we should realize that insulin using diabetics were not included, this emphasizes that many subjects having microalbuminuria were not known with disorders, traditionally associated with microalbuminuria. From Hillege HL et al: J Int Med 2001; 249:
“Healthy”
75%
n=2,918
Hillege et al; J Int Med 2001;249:

22. Slides from the publications of 2002
PREVEND
Slides from the publications of 2002

23. Albuminuria as predictor of CV mortality in the general population
PREVEND
Risk of CV mortality (HR)
Albumin concentration (mg/L) 1 2 3 4 5 10
100
1000
N=40.856
The hazard ratio for cardiovascular mortality in the group of 40,856 subjects shows a splay, without a specific cut-off value above which the risk is increased. For every doubling of UAC the risk for dying is increased 1.29fold. From Hillege HL et al. Circulation 2002;106:
Hillege et al; Circulation 2002;106:

24. Albuminuria predicts cardiovascular death in the general population
PREVEND 35 30 25 20 15 10 5
29.1
CV death (% per 1000 pj)
11.2
4.5
3.5
0 - 14
15 – 29
>300
Albuminuria (mg/day)
Hillege et al; Circulation 2002;106:

25. Slides from the publications of 2004
PREVEND
Slides from the publications of 2004

26. Proteinuria (% change) Mean Arterial Pressure (% change)
Blood pressure and proteinuria lowering effect of antihypertensives: a meta-analysis
- 10
- 5
- 20
- 10
Proteinuria (% change)
Mean Arterial Pressure (% change)
- 30
- 15
- 40
- 20
- 50
ACEi
N=34
N=593
Others
N=40
N=632
CCB
N=23
N=394 BB
N=8
N=129
Rest
N=9
N=109
- 25
Gansevoort et al; Nephrol Dial Transplant 1995

27. Baseline characteristics
PREVEND IT Study
Baseline characteristics
PREVEND IT
Placebo (n=429)
Fosinopril (n=425)
Age, years
51.5 ± 11.4
51.0 ± 12.1
Male gender
63.9 %
66.1 %
Smoking, past
current
31.2 %
34.4 %
36.0 %
Obesity (BMI > 30 kg/m2)
18.6 %
14.6 %
Cholesterol, mg/dl
(mmol/l)
220 ± 39
(5.7 ± 1.0)
224 ± 39
(5.8 ± 1.0)
SBP, mmHg
130 ± 17.9
129 ± 17.1
DBP, mmHg
76 ± 9.7
Prior CV event
2.3 %
4.0 %
Cardiovascular drugs
5.8 %
3.8 %
Albuminuria, mg/24h *
21.7 ( )
23.7 ( )
Asselbergs et al; Circulation 2004
* Expressed as median (interquartile range)

28. in the “healthy” with albuminuria
Effects of ACEi
in the “healthy” with albuminuria
PREVEND IT
Change from baseline
with Fosinopril
- 10
- 20
- 30
Change in
albuminuria
(%) * *
* p < 0.001
3 Months
4 Years
Asselbergs et al; Circulation 2004

29. Combined CV endpoint (%)
Treatment that lowers albuminuria reduces CV risk in the “healthy” with albuminuria
PREVEND IT 10
7.5
Risk
Reduction
40%
NNT 29
Placebo
Combined CV endpoint (%) 5
2.5
ACEi (fosinopril)
In the PREVEND IT study treatment with fosinopril resulted in a better event-free survival, although the difference was not statistically significant. From Asselbergs FW et al. Circulation 2004;110: 10 20 30 40
Months
Asselbergs et al; Circulation 2004

30. Albuminuria predicts CKD in the non-diabetic general population
PREVEND
Albuminuria predicts CKD
in the non-diabetic general population 70 60 50 40 30 20 10 58
Incidence of Stage 3 CKD (%) 22 13 9
The percentage of subjects with de novo development of renal function impairment (GFR<60 ml/min) after 4.2 years of follow up. Subjects with a higher UAE in the 97/98 screening had more frequently renal function impairment at the follow up screening in 2001/03. From Verhave JC et al. Kidney Int 2004;66(suppl 92):1-4
0 - 14
15 – 29
>300
Albuminuria (mg/day)
Stage 3 CKD = creatinine clearance < 60 mL/min
Verhave et al; Kidney Int 2004;66(suppl 92):1-4

31. Slides from the publications of 2005
PREVEND
Slides from the publications of 2005

32. Albuminuria predicts new onset diabetes in the general population
PREVEND 14 12 10 8 6 4 2
11.8
7.9
New onset Diabetes (%)
4.3
2.2
0 - 14
15 – 29
>300
Albuminuria (mg/day)
Brantsma et al; Diabetes Care 2005