Nephrol Dial Transplant (2006) 21: Editorial Comments
28. Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7
induces mesenchymal-to-epithelial transition in adult renal
fibroblasts and facilitates regeneration of injured kidney. J Biol
Chem 2005; 280: 8034–8100
Nephrol Dial Transplant (2006) 21: 573–576
doi:10.1093/ndt/gfk014
Advance Access publication 29 December 2005
Measurement of microalbuminuria – what the nephrologist
should know
Josep Redon
Hypertension Clinic, Department of Internal Medicine, Hospital Clı́nico, University of Valencia, Valencia, Spain
Keywords: microalbuminuria; urinary albumin excretion;
hypertension; diabetes; cardiovascular risk
Introduction
During the last few years, a subtle increase in urinary
albumin excretion (UAE) not detectable by routine
methods, so called microalbuminuria, has been identi-
fied as a prognostic marker for renal and/or cardio-
vascular risk in diabetic and non-diabetic subjects [1].
Consequently, assessment of microalbuminuria is now
recommended as a risk stratification strategy not only
in diabetic subjects, but also in the management of
hypertensive patients [2–5]. In order to make the best
clinical use of UAE, the physician who measures UAE
should know several facts:
a. what kind of albumin molecules are present in the
urine, and which methods are most suitable for
assessing each of them;
b. what method of urine sampling is recommended and
how should one interpret the UAE values;
c. how can one reduce the variability of the UAE
estimate and
Correspondence and offprint requests to: Josep Redon, Hypertension
Clinic, Internal Medicine, Hospı̀tal Clinico, Avda Blasco Ibañez,
17 46010 Valencia, Spain. Email: josep.redon@uv.es
ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org
573
29. Wang S, Chen Q, Simon TC et al. Bone morphogenic protein-7
(BMP-7), a novel therapy for diabetic nephropathy. Kidney Int
2003; 63: 2037–2049
Received for publication: 9.11.05
Accepted in revised form: 28.11.05
Downloaded from http://ndt.oxfordjournals.org by on April 17, 2010
d. how should one evaluate the results and manage the
patient based on the results of UAE determination.
Albumin is an electronegative serum protein with
a molecular mass of 66 349 Da. After glomerular
filtration, part of the albumin is reabsorbed by tubular
epithelial cells. Proteases split the albumin molecule
into fragments, some of which back-leak into the
tubular fluid [6]. In addition, albumin can reach the
urine from an inflammatory lesion at any site from
the renal pelvis to the urethra. In the absence of
inflammation in the urinary tract, intact albumin of
glomerular origin is the major source of albumin in
the urine and only a small amount of small albumin
fragments are present.
Methods to measure urinary albumin
Albumin can be detected by several methods based
on precipitation (boiling, sulphosalicylic acid), dye-
binding (biuret, tetrabromphenol, albumin blue 580) or
immunologic detection (radioimmunoassay, nephelo-
metry, test-strip) (Table 1). While the immunoreactive
methods estimate only complete albumin molecules
recognized by antibodies, peptide fragments of albumin
can be assessed by dye tests and specific spectro-
photometry [7,8]. The immunologic methods are most
frequently used for clinical purposes, not only because
they are easy to use at relatively low cost, but also
because they are able to detect small amounts of
albumin in the range defined as microalbuminuria,
i.e. <200 mg/l.
574 Nephrol Dial Transplant (2006) 21: Editorial Comments

Table 1. Methods to assess albumin in urine Table 2. UAE threshold to define risk for nephropathy and for
cardiovascular risk according urine samples and units
Precipitation
Boiling, sulphosaticylic acid Units Urine sample
Dye-binding
Biuret, tetrabromphenol, albumin blue 580 Spot Night 24 h
Antibody-binding
Test strips, nephelometry, radioimmunoassay
mg/24 h 30 (15)
Molecular size/shape
mg/min 20 (5)
HPLC, spectrophotometry
mg/mmol Cr 3 (2)
mg/g Cr 30 (20)

Recently it has been emphasized that the amount

of complete molecules of albumin in the urine that is 1000
not recognized by the immunologic methods is not
negligible. These molecules are detected, however, by

Night UAE (mg/min)

high performance liquid chromatography (HPLC) [7].
Although its clinical significance is not fully under- 100
stood, the proportion of non-immunoreactive over
the immunoreactive albumin depends on the total

Downloaded from http://ndt.oxfordjournals.org by on April 17, 2010

amount of albumin in the urine: the lower the amount,
the higher the proportion of non-immunoreactive 10
albumin [9]. Whether or not the albumin which is
not immunnoreactive represents an early stage in the
natural history and indicates a high risk of progression
to the stage of microalbuminuria must be assessed in
1
future prospective studies [10]. Whatever the case, 1 10 100 1000
even when non-immunoreactive albumin can uncover
subjects at risk of increasing UAE over time, consid- Day UAE (mg/min)
ering cost and accessibility of the HPLC technique, Fig. 1. Circadian variation of UAE in subjects with essential
its widespread application in large populations will hypertension. UAE is lower in resting conditions at night than
be difficult unless more readily available methods during daytime activity.
are developed.
variability is affected by a large number of factors
Methods to report UAE which must be kept in mind when interpreting the
results. Fever, vigorous exercise, heart failure, haema-
turia and urinary tract infection produce a transitory
The concentration of urinary albumin depends on
increase in UAE which is more or less persistent
the amount of albumin excreted and on the urine
depending on the cause, the intensity and the duration
concentration. A precise assessment is only possible if
of the respective condition [11].
these two factors are considered. Methods based on
Urinary albumin excretion follows a circadian
timed urine collection or on simultaneous assessment
pattern. In normal volunteers, UAE decreases at night-
of urine creatinine concentration have been used to
time in recumbent position to approximately 70% of
avoid these confounders of the urinary albumin
the values during the period of activity [12] (Figure 1).
concentration. Collecting and measuring albumin in
A similar circadian variability is also observed in
urine samples during 24 h (mg/24 h) or timed-overnight
hypertensive subjects, although their UAE is signifi-
(mg/min) is frequently used in specialized settings.
cantly higher than in healthy normotensive individuals.
In contrast, for primary care and epidemiological
In patients with type 1 diabetes, however, the differ-
studies, a correction is performed by simultaneously
ences in UAE between periods of activity and sleep are
assessing creatinine excretion (mg/g Cr or mg/mmol Cr)
quite large when compared to non-diabetic subjects
in spot samples, collected from the first voided urine or
(Figure 2). This may reflect a greater damage to and
at the time of the clinic visit. The correspondence
permeability of the glomerular basal membrane in
between different UAE values at the level of
diabetic subjects, coupled with higher variability
the classical threshold to define microalbuminuria,
in glomerular filtration as a consequence of transitory
i.e. >30 mg/24 h, and at the lowest UAE that points
hyperglycaemic periods.
to an increased cardiovascular risk, i.e. 5 mg/min at
Besides transitory factors and circadian variability,
night, is shown in Table 2.
the reproducibility of UAE is limited and several
studies have reported coefficients varying from of 10
Variability of UAE to 25% [12]. This variability depends not only on the
collection time of the urine sample, but also on the
The variability of UAE is one of the most important type of disease and the absolute amount of urinary
limitations of assessment for clinical purposes. This albumin excreted. From the above, it is clear that
Nephrol Dial Transplant (2006) 21: Editorial Comments
1000
First day 24 h (mg/min)
100
10
1 observed in subjects who are prone to develop diabetic
1 10 100 1000
Second day 24 h (mg/min)
Fig. 2. Relationship between UAE assessed on two different days
1 week apart in patients with type 1 diabetes (open circles) and
essential hypertension (closed circles).
the reproducibility is lower in collections obtained
during awake periods than for samples obtained
during night time or for the first voided urine.
Likewise, the reproducibility is poorer in type 1 diabetic
as compared to hypertensive patients, even when
the UAE is in the same range. Finally, the reproduc-
ibility is better in the low range than in the high
range of UAE. UAE is largely skewed towards high
values.
From a practical point of view, assessing taking all
these factors into consideration, we suggest UAE by
determination of albumin in at least two urine samples
obtained in the same fashion within a period of
several days. The best samples are those collected
from night time or first morning urine. Although it is
advisable to test the urine shortly after its collection, if
necessary, urine can be kept at 4 C and without
exposure to light for a week before the measurement
is made [13].
Evaluation of UAE
Conventionally, UAE values have been categorized
according to the presence or the absence of micro-
albuminuria. The presence of microalbuminuria points
to a high cardiovascular and/or renal risk which
requires intensification of treatment:
further reduction of blood pressure by more intensi-
fied antihypertensive treatment,
improvement of glucose control and
blockade of the renin–angiotensin system according to
current guidelines.
Microalbuminuria has classically been defined as
UAE from 30–300 mg/24 h or equivalent amounts when
timed overnight or spot urine samples are used
(see Table 2). The definition is based on the results
of studies in diabetic patients which established
575
microalbuminuria as a marker of the risk to develop
nephropathy [14]. Several pieces of evidence indicate
that one misses valuable information when one uses
this categorization of UAE. Treating UAE values as
a continuous variable provides advantages when used
at baseline to assess the risk and during the follow-up
to assess the effect of treatment.
Although the natural history of microalbuminuria
is not well defined, subjects with UAE below the
outlined threshold, but with values in the highest range
of ‘normality’, are at risk of advancing toward the stage
of microalbuminuria. In type 1 diabetes, a progressive
increment of UAE in a relatively short period of time is
nephropathy, while subjects not prone maintain low
stable UAE for years [15–17]. No data are available
for hypertensive patients or for the general population,
but it is logical to assume that a progressive increase
of albuminuria will occur over time in these individuals
Downloaded from http://ndt.oxfordjournals.org by on April 17, 2010
as well [18,19]. The rate of change in this case is slower,
however, than that observed in patients with type 1
diabetes. If the subject develops type 2 diabetes, the rate
of progression is accelerated [20]. In one study of our
group, hypertensive subjects with an initial UAE level
in the high normal range, from 15–29 mg/24 h, had
an increased risk of progressing towards microalbu-
minuria despite antihypertensive treatment [18].
Consequently, the importance of UAE values in the
highest range of normality is not negligible with respect
to the risk of progression of UAE when assessed at
baseline.
Even more important is the prognostic value
of subtle increments in UAE. In studies on the poten-
tial prognostic value of microalbuminuria for car-
diovascular events, the threshold value indicating
an increased risk was well below the UAE values
defining microalbuminuria regardless of the population
included [21]. The progressive increase of risk at values
below the threshold of microalbuminuria was also
confirmed by Klausen who noted that the risk of
cardiovascular events was increased in hypertensive
patients across a wide range of UAE values [22].
In hypertensive patients with a timed overnight
UAE above 5 mg/min, total mortality and coronary
events were increased independent of blood pressure
values and other potential confounders. The risk of
coronary heart disease and death increased significantly
by 70 and 50%, respectively, in patients with UAE
values between 5 and 10 mg/min, and even by 100%
for both outcomes in patients with UAE values higher
than 10 mg/min. These findings illustrate that even
such relatively low values of UAE have prognostic
value [22].
Furthermore, reduction of UAE is a well-established
treatment target in diabetic subjects. It protects not
only against progression towards renal damage, but
also reduces the risk of cardiovascular disease in this
high risk group.
In non-diabetic subjects the potential of micro-
albuminuria as an intermediate endpoint during anti-
hypertensive treatment is still unclear, but recent
576
information shows that the in-treatment levels of
urinary albumin are closely related to the risk of a
subsequent cardiovascular event [19]: the greater the
reduction of UAE, the lower the cardiovascular risk.
Monitoring UAE can therefore be clinically useful to
assess the success of interventions.
Conclusions
The assessment of subtle increases in UAE is a powerful
way to identify individuals at high cardiovascular risk
in need of multiple cardiovascular risk factor interven-
tion. Changes in UAE seem to run in parallel to
changes in cardiovascular risk. Prompt intervention to
avoid a progressive increase of UAE may provide better
protection. Assessment of albuminuria during treat-
ment is an easy way to monitor the success of the
therapy. Values of UAE lower than considered in the
past are associated with increased cardiovascular risk
and a higher risk of progression towards higher values
of UAE. These considerations illustrate the necessity to
avoid categorization of UAE according to whether the
threshold of microalbuminuria is transgressed or not.
We therefore encourage to treat UAE as a continuous
variable and to base evaluation on the absolute values
of UAE [21].
Conflict of interest statement. This is to confirm that no conflict of
interest exist concerning to the above manuscript entitled
‘Measurement of microalbuminuria – what the nephrologist
should know’.
References
1. de Zeeuw D, Hillege HL, de Jong PE. The kidney, a
cardiovascular risk marker, and a new target for therapy.
Kidney Int Suppl 2005; 98: S25–S29
2. Cooper ME. Pathogenesis, prevention and treatment of
diabetic nephropathy. Lancet 1998; 352: 213–219
3. Bakris G. Inclusion of albuminuria in hypertension and
heart guidelines. Kidney Int Suppl 2004; 66 [Suppl 92]:
S124–S125
4. Chobanian AV, Bakris GL, Black HR et al. National Heart,
Lung, and Blood Institute Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High
Blood Pressure; National High Blood Pressure Education
Program Coordinating Committee. The Seventh Report of
the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the JNC
7 report. JAMA 2003; 289: 2560–2572
5. Guidelines Committee. 2003 European Society of
Hypertension – European Society of Cardiology guidelines
Nephrol Dial Transplant (2006) 21: Editorial Comments
for the management of arterial hypertension. J Hypertens 2003;
21: 1011–1053
6. Russo LM, Bakris GL, Comper WD. Renal handling of
albumin: a critical review of basic concepts and perspective.
Am J Kidney Dis 2002; 39: 899–919
7. Comper WD, Jerums G, Osicka TM. Differences in urinary
albumin detected by four immunoassays and high-performance
liquid chromatography. Clin Biochem 2004; 37: 105–111
8. Pegoraro A, Singh A, Bakir AA, Arruda JA, Dunea G.
Simplified screening for microalbuminuria. Ann Intern Med
1997; 127: 817–819
9. Comper WD, Osicka TM, Jerums G. High prevalence of
immuno-unreactive intact albumin in urine of diabetic patients.
Am J Kidney Dis 2003; 41: 336–342
10. Brinkman JW, Bakker SJL, Gansevoort RT et al. Which
method for quantifying urinary albumin excretion gives what
outcome? A comparison of immunonephelometry with high-
performance liquid chromatography. Kidney Int 66 [Suppl 92]:
69–75
11. Bigazzi R, Bianchi S. Microalbuminuria as a marker of
cardiovascular and renal disease in essential hypertension.
Nephrol Dial Transplant 1995; 10 [Suppl 6]: 10–14
Downloaded from http://ndt.oxfordjournals.org by on April 17, 2010
12. Redon J, Miralles A, Lurbe A, Pascual JM, Lozano JV.
Urinary albumin excretion at night in essential hipertensión.
Med Clin (Barc) 1995; 104: 608–611 (in Spanish)
13. Gonzalez Castro ML, Sagredo Perez J, Cebrecos Tamayo R,
Enriquez Duenas O, de Baranda RA, Cordero Guevara J. The
stability of the microalbuminuria numbers in relation to their
reading time and mode of preservation. Aten Primaria 1999 31;
23: 533–536 (in Spanish)
14. Redon J, Williams B. Microalbuminuria in essential
hypertension. Redefining the threshold. J Hypertens 2002; 20:
353–355
15. Andersen AE, Christiansen JS, Andersen JK, Kreiner S,
Deckert T. Diabetic nephropathy in Type 1 (insulin-dependent)
diabetes: an epidemiological study. Diabetologia 1983; 25:
496–501
16. Batlle D. Clinical and cellular markers of diabetic nephropathy.
Kidney Int 2003; 63: 2319–2330
17. Lurbe A, Redon J, Pascual JM, Tacons J, Alvarez V,
Batlle D. Altered blood pressure during sleep in normotensive
subjects with type I diabetes. Hypertension 1993; 21: 227–235
18. Pascual JM, Rodilla E, Gonzalez C, Perez-Hoyos S, Redon J.
Long-term impact of systolic blood pressure and glycemia on
the development of microalbuminuria in essential hypertension.
Hypertension 2005; 45: 1125–1130
19. Ibsen H, Olsen MH, Wachtell K et al. Reduction in
albuminuria translates to reduction in cardiovascular events
in hypertensive patients: a LIFE study. Hypertension 2005; 45:
198–202
20. William J, Hogan D, Batlle D. Prediciting the development of
diabetic nephropathy and its progression. Adv Chronic Kidney
Dis. 2005; 12: 202–211
21. Redon J. Urinary albumin excretion: lowering the threshold of
risk in hypertension. Hypertension 2005; 46: 19–20
22. Klausen KP, Scharling H, Jensen G, Jensen JS. New definition
of microalbuminuria in hypertensive subjects: association
with incident coronary heart disease and death. Hypertension
2005; 46: 33–37
Received for publication: 18.10.05
Accepted in revised form: 29.11.05