Microalbuminuria As A Risk Factor Type diabetes

The prevalence of microalbuminuria is 16 to 22% (27, 62) and the incidence over 7.3 years were recently demonstrated to be 12.6% [63]. Normally no other signs of micro- or macroangiopathy are present at the first diagnosis of microalbuminuria. Later on with higher levels of microalbuminuria retinopathy will become much more frequent, and in fact microalbuminuria is a strong risk marker of severe retinopathy [20,22,23]. The blood-pressure is usually below 160/95 mmHg, but the mean blood-pressure is increasing by 3 mmHg per year [20,22,65]. The kidney function in terms of S-creatinine and glomerular filtration rate (GFR) are normal. The loss of kidney function is observed only in patients with the highest levels of UAER in the microalbuminuric range in whom a decline rate of GFR of 3 to 4 ml/(min*year) has been described [20,22,62]. The risk of clinical diabetic nephropathy is the highest among patients with an UAER in the range of 100 to 300 mg/24h (70 to 200 |g/min) [64,65]. The classical definition of clinical diabetic nephropathy at levels of UAER above 300 mg/24h therefore seems to be historical and dictated by the low sensitivity of the older methods for determining protein in urine.

Type 1 diabetic patients with classical proteinuria >0.5g/l are carrying almost the entire burden of the overmortality of diabetic patients [19]. This overmortality is only to a small extent caused by end stage renal failure. By far most of the patients are dying from cardiovascular diseases [19]. It is therefore widely accepted that microalbuminuria in the Type 1 diabetic patient is a valuable diagnostic parameter being highly predictive of excess mortality and cardiovascular morbidity [7-10]. The predictive value of microalbuminuria for cardiovascular diseases seems to be independent of conventional atherosclerotic risk factors, diabetic nephropathy, and diabetes duration and control [7].

It is important to identify all Type 1 diabetic patients with microalbuminuria because the progression of their disease can be delayed. Antihypertensive treatment reduces the fall rate of GFR by 50 % from 10 to less than 5 ml/(min*year) as observed in patients with clinical nephropathy [66-69]. The effect may be even more impressive when treatment is started at the first signs of an increasing blood-pressure but before development of overt hypertension [56, 70]. The effect of antihypertensive treatment is further emphasized by the important observation of an increased patient survival following the implementation in the late seventies of early antihypertensive treatment [71].

Optimizing the glycaemic control has also shown to be effective in arresting the progression of diabetic renal disease in its early stages i.e. delaying development and in some cases also the progression of microalbuminuria [57, 64, 72-75].

Non-insulin-dependent diabetes mellitus (Type 2 diabetes)

The prevalence of microalbuminuria is also high in Type 2 diabetic patients : 30 to 40 % [24,25,76]. Microalbuminuria is often present at diagnosis of the diabetic state. It is primarily associated to cardiovascular disease and Type 2 diabetic patients with microalbuminuria are at an increased risk of cardiovascular death compared with patients with a normal UAER [11-18,25].

End stage renal failure only occurs in 3 to 8 % of Type 2 diabetic patients despite the high prevalence of microalbuminuria. On the other hand microalbuminuria is a predictor of increasing levels of very low density lipoprotein cholesterol and a decrease of high density lipoprotein cholesterol [77]. Microalbuminuria therefore seems to be a risk factor of generalized disease to an even higher extent than in Type 1 diabetic patients and in fact microalbuminuria appears to be an independent risk factor as is the case in Type 1 diabetic patients [53, 78].

Also in Type 2 diabetic patients the causal link between microalbuminuria and generalized vascular disease is unknown. It is likely that a link should be found in alterations in the composition of the basal membranes of the capillaries and of the extracellular matrices as also hypothesized in Type 1 diabetic patients. In any case presence of the well-known risk factors is not sufficient to explain the entire overmortality of patients with Type 2 diabetes: hypertension, dyslipidaemia, atherogenic changes in the haemostatic system (increased von Willebrand factor and plasma fibrinogen) [24,25]. In a 10-year follow-up of 328 Type 2 diabetic patients it has recently been shown that increased UAER, endothelial dysfunction, and chronic inflammation are interrelated processes that develop in parallel, progress with time and are strongly and independently associated with risk of death [78].

Treating normotensive Type 2 diabetic patients with microalbuminuria with ACE inhibitors delays the progression to diabetic nephropathy [79, 80]. In 2001 it was convincingly demonstrated that treatment with Angiotensin 2 receptor antagonists also delays the progression from microalbuminuria to clinical nephropathy [54]. Furthermore in early 2003 the Steno 2 study clearly demonstrated the effect of multifactorial intervention and cardiovascular diseases in patients with Type 2 diabetes and microalbuminuria [55].

Non-diabetics

Microalbuminuria is also present in the non-diabetic population. This has been described in a number of studies [35-52]. Whenever mentioned, the reference range of the UAER seems to be rather low in relation to the classical definition of microalbuminuria. In table 3 is shown the reference range of UAER in 10 different studies. Except for one study with a higher level, the median or mean value of UAER is given from 2.6 to 8 |g/min and the upper 95% percentile in more than 50% of the studies as 15 |g/min or below [36, 37, 41, 43, 44, 46, 48, 81-84]. Microalbuminuria in its classical definition therefore seems to represent a relatively high UAER among non-diabetics. In an English 4-year follow-up study microalbuminuria, however, increased the mortality rate 24 times [36]. In a Danish study UAER was measured in 216 non-diabetic subjects, 60 to 74 years of age [37]. The median UAER was 7.52 |g/min (25 and 75 percentiles were 4.77 and 14.85 |g/min). The subjects were reexamined 7 years later. Among the 107 subjects with an initial UAER above the median value 23 had died in contrast to 8 out of 107 below the median UAER (p<0.008). In both studies the predictive effect of microalbuminuria was independent of the conventional atherosclerotic risk factors [36,37], which are usually increased among non-diabetic subjects with microalbuminuria (table 2).

Two larger scaled population based studies have also confirmed that a UAER above a certain level is predictive of developing ischaemic heart disease and increased mortality [47]. In a Finnish study of Kuusisto et al, 1.069 elderly inhabitants were followed for 3-4 years. Those who at baseline had an A/C ratio above the upper quintile (>3.2 mg albumin/mmol creatinine) had a higher morbidity and mortality from ischaemic heart disease (odds ratio 2.2) [49]. In our own study of 2.181 participants of the 1st Monica Population Study, Glostrup, Copenhagen County, an A/C ratio above the upper decile (>0.65 mg albumin/mmol creatinine) was significantly associated with an increased relative risk of 2.3 for development of ischaemic heart disease [47]. Also in the two latter studies, the predictive effect of microalbuminuria was independent of the conventional atherosclerotic risk factors.

Finally, a sub-analysis of the Heart Outcomes Prevention Evaluation Study (HOPE) indicated that any degree of albuminuria is a risk factor for cardiovascular events in individuals with or without diabetes; the risk increased at levels of UAER well below the microalbuminuric cut off [53].

It is likely that the link between microalbuminuria and cardiovascular disease may be explained by other pathophysiologic mechanisms, e.g. an universally increased transvascular albumin leakage [85,86] as well as other signs of endothelial dysfunction [87,88].

Prospective population studies including our own are in progress aiming to further clarify the role of UAER as a predictor of premature death of cardiovascular disease in apparently healthy subjects.

Table 2. Associations between microalbuminuria and atherosclerotic risk factors

Author

Haffner

Winocour Woo

Metcalf

Gould

Dimmitt Beatty

Mykkänen Jensen

Publication

1990

1992

1992

1992 &

1993

1993

1993

1994

1997

year

1993

Microal

Un,b>30

Ualb>20

UJ

U,b

UAER

Un,b>

UAER

Ualb/Ucreate

UAER

buminuria

mg/l

mg/l

UC t> continu-

20-200

medial

20-200

>2

>90%

90%

ous

|lg/min

|i,g/min

-ile

-ile

variable

Sample size 316

447

1.333

5.349

959

474

264

1.068

2.613

Male sex

T

T

T

Age

T

4

T

Blood

T

T

T

T

T

T

T

pressure

S-insulin

T

T

T

P-lipids

T

T

T

T

T

Body mass

T

T

index

Smoking

T

T

Height

4

B-glucose

T

T

T, microalbuminuria is assoiated with increased levels of the risk factor; 4-, microalbuminuria is assoiated with increased levels of the risk factor.

Ualb, urinary albumin concentretion; Ucreat, urinary creatinine concentretion; UAER, urinary albumin excretion rate.

T, microalbuminuria is assoiated with increased levels of the risk factor; 4-, microalbuminuria is assoiated with increased levels of the risk factor.

Ualb, urinary albumin concentretion; Ucreat, urinary creatinine concentretion; UAER, urinary albumin excretion rate.

Table 3. Reference values of urinary excretion in non-diabetic individuals.

Study

(Author, country, publication year)

Urine collection

Sample size Age (Numbers) (Years)

Sex (M/F)

Urinary albumin excretion

Marre et al, France (1987)

Timed overnight

60

40±13

28/32

4.2±4.1 |/mina a

Marre et al, France (1987)

Timed daytime

60

40±13

28/32

6.6 ±7.7 | /mina a

Marre et al, France (1987)

Timed 24-hours

60

40±13

28/32

8.0±8.1 | /amin a

Watts et al, UK (1988)

Morning spot

127

33±12

59/68

3.9(0.9-16.2)a mg/l f

Watts et al, UK (1988)

Timed overnight

127

33±12

59/68

3.2(1.2-8.6) |g/amin f

Watts et al, UK (1988)

Timed daytime

127

33±12

59/68

4.5(1.0-9.1) |g/amin f

Yudkin et al, UK (1988)

Timed daytime

184

60±12

68/116

2.8(0.09-154.6) a |g/min c

Gosling & Beevers, UK (1989)

Timed 24-hours

199

40±11

99/100

3.7(0.1-22.9) |ga/min c

Damsgaard et al, Denmark (1990)

Timed daytime

223

68(64-71) 89/134

7.5(4.8-14.9) |g/bmin b

Metcalf et al, New Zealand (1992)

Morning spot

5.670

49(40-78) 4.106/1.564

5.2(5.1-5.4) mg/lc g

Dimmitt et al, Australia (1993)

Morning spot

474

ch

Mykkanen et al, Finland (1994)

Morning spot

826

69.0± 0.1

312/514

23.7±2.5mg/ld d

Gould et al, UK (1994)

Timed overnight

812

40-75

359/453

2.6(0.1-148.8)e | g/min c

Gould et al, UK (1994)

Timed daytime

913

40-75

411/502

4.1(0.1-165.6) | g/min c

Jensen et al, Denmark (1997)

Timed overnight

2.613

30-70

I

aMean±SD bMedian (1-3. Interquartile range) cmedian (range) dmean± SE erange fmean (95% C.I.) ggeometric mean (95% C.I.) hmedian imedian(10-90 interpercentile range)

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