Diabetes is the leading cause of end-stage renal disease in the
US and Europe (1). Early detection of diabetic nephropathy
relies upon tests for urinary excretion of albumin. The detection
limits of conventional qualitative tests (chemical strips or "dipsticks")
for albuminuria are above that needed to detect early disease. For
this purpose, tests for "microalbuminuria" are used. Microalbuminuria
is defined (1) as excretion of 30 300 mg of albumin /24
h (or 20 200 ug/min or 30 300 ug/mg creatinine). [footnote:
Although the term microalbuminuria is recognized as a misnomer (the
albumin is not small), the term is well entrenched and not likely
to be replaced by alternatives (e.g., paucialbuminuria).]
The ADA recommends periodic qualitative ("dipstick")
testing for urine albumin in adults with diabetes (1). Positive
tests represent "clinical albuminuria" or "overt
nephropathy" in the ADA recommendations and correspond to protein
excretion > 300mg/24 hours ( > 200 ug/min or > 300 ug/mg
creatinine). In these patients, the ADA guidelines indicate that
quantitative measurement of urine protein excretion may be useful
for planning of treatment. Evidence for or against this conclusion
is not available. Negative "dipstick" tests for "clinical
proteinuria" (albumin excretion < 300 mg/day) should be
followed with a test for microalbuminuria. Testing for microalbuminuria
is recommended for children with type 1 diabetes after puberty and
after 5 years duration of diabetes.
In the ADA algorithm for urine protein testing (1), the
diagnosis of microalbuminuria requires the demonstration of increased
albumin excretion (as defined above) on 2 of 3 tests repeated at
intervals of 3 6 months, and exclusion of conditions that "invalidate"
the test. (See "Interferences" below.)
In 80 % of people with type 1 diabetes and microalbuminuria, urinary
albumin excretion increases at a rate of 10 20 % per year, with
development of clinical proteinuria (> 300 mg albumin/day) in
10 15 years (1). End-stage renal disease develops within
10 years in half of the type 1 individuals with overt nephropathy.
In type 2 diabetes, 20 40 % of patients with microalbuminuria
progress to overt nephropathy, but by 20 years after overt nephropathy
only ~ 20 % develop end-stage renal disease.
The roles of routine urinalysis and microalbumin measurements are
less clear in patients with a diagnosis of microalbuminuria. Some
have advocated urine protein testing to monitor treatment, which
may include increased glycemic control, control of hypertension,
protein restriction and therapy with angiotensin inhibitors (1).
Therapy (e.g., with angiotensin converting enzyme inhibitors) has
been shown to slow the rate of increase of urinary albumin excretion
rate or to prevent it in short-term studies, and progression is
associated with poorer glycemic control (for a recent study, see
Early detection of microalbuminuria allows early intervention
with a goal of delaying the onset of overt diabetic nephropathy.
Moreover, microalbuminuria is a marker of increased risk of cardiovascular
morbidity and mortality in both type 1 and type 2 diabetes. Thus,
it is a signal for efforts to reduce cardiovascular risk factors.
Microalbuminuria rarely occurs with short duration of Type 1
diabetes or before puberty. Thus testing is less urgent in these
situations. By contrast, the difficulty in precisely dating the
onset of Type 2 diabetes warrants initiation of annual testing
at the time of diagnosis of diabetes.
- Analytical Considerations
Recommendation: The analytical CV of methods to measure
urinary albumin should be < 15%.
The within-person variation of microalbumin excretion is large
in people without diabetes and even higher in patients with diabetes.
Howey et al (3) studied day-to-day variation, over 3-4 weeks,
of the 24-hour albumin excretion as well as both the concentration
of albumin and the albumin: creatinine ratio. The latter two were
measured in the 24-hour urine sample and also in (a) the first morning
void and (b) random untimed urine. In healthy volunteers, the lowest
within-person CVs were found for the concentration of albumin in
the first morning void (36 %) and for the albumin:creatinine ratio
in that sample (31 %). They recommended use of the urine albumin
concentration in the first morning void rather than 24-hour urinary
excretion of albumin which had a higher within-person CV.
Based on the widely-expressed view that analytical CV should be
less than half the biological CV, Howey (3) proposed an analytical
goal of 18 % CV. Alternatively, if the albumin: creatinine ratio
is to be used, one may calculate the need for somewhat lower imprecision
(to accommodate the lower biological CV for the ratio and the imprecision
contributed by the creatinine measurement). Assuming a CV of 5 %
for the measurement of creatinine, we calculate a goal of 14.7%
for the analytical CV for albumin when it is used to estimate the
albumin:creatinine ratio. A goal of 15% appears reasonable to accommodate
either use of the measurement of albumin.
In subjects with diabetes, the within-person variation (CV) was
61 % for albumin concentration in the first morning void and 39
% for the albumin:creatinine ratio. Thus the goals above appear
more than adequate for use in subjects with diabetes.
Recommendation: Acceptable samples to monitor urinary albumin
excretion are first morning void or 24-hour (timed) collections
for measurement of albumin concentration (or albumin excretion rate
in the 24-hour sample) and untimed samples for measurement of the
albumin:creatinine ratio, preferably on a first morning sample.
Collection of 24-hour samples appears to not be necessary as the
albumin:creatinine ratio appears to be an acceptable alternative.
The ratio has a low within-person, biological variation and correlates
well with timed excretion as well as with albumin concentration
in a first morning void of urine (3). A first-morning void
sample is to be preferred for the ratio as the ratio in a first
morning sample had a lower within-person variation than did the
ratio in a random sample of urine during the day (3).
Albumin is stable in untreated urine stored at 4 C for at least
4 weeks (4). Neither centrifugation nor filtration appears
necessary before storage at 20 C or 80 C (5). Whether
centrifuged, filtered or not treated, albumin concentration decreased
by 0.27 % per day at 20 C, but showed no decrease over 160 days
at 80 C (5).
Urinary albumin excretion rate reportedly has no marked diurnal
variation in diabetes, but does in essential hypertension (6).
- Measurement: Detection limit, imprecision
Commercially available quantitative methods for microalbuminuria
have documented detection limits of ~ 20 ug/L or less. Within-run
imprecision and day-to-day (total) imprecision are well within the
analytical goal of ~ 15 %, and often much less. A recent study showed
that most methods, but not all, agree well with each other and support
a reference interval of 2 20 ug albumin / mg creatinine (7).
Recommendation: Semiquantitative or qualitative for
microalbuminuria are acceptable for screening when used as intended,
that is, with laboratory confirmation of increased results.
Qualitative (or semiquantitative) tests for microalbuminuria are
available from several manufacturers. They are intended as screening
tests, that is, tests with high clinical sensitivity (low false
negative rates with albumin > 20 ug/L) and an acceptable false
positive rate. Positive results thus need to be confirmed by a quantitative
method. Further studies are needed before the "dipstick"
tests for microalbuminuria can be recommended as replacements for
the quantitative tests. The use of the qualitative tests at the
point of care is reasonable when it can avoid quantitative testing
in a sizeable proportion of the population in a patient care area.
- Nonanalytical sources of variation
Transient increases of urinary albumin excretion have been reported
with short-term hyperglycemia, exercise, urinary tract infections,
marked hypertension, heart failure and acute febrile illness (1).
The ADA recommends annual measurement in patients with negative
("dipstick") results for overt proteinuria. After the
documentation of a diagnosis of microalbuminuria (i.e., with results
as defined above on 2 of 3 tests performed within a period of 3
6 months), repeated testing is reasonable to determine whether
a chosen therapy is effective. It may also be useful in determining
the rate of progression of disease and thus support planning for
care of end-stage renal disease. Although the ADA recommendations
suggest that testing is not needed before puberty, a more recent
study makes a case for such testing (2). We believe that
there is insufficient evidence to conclude that such testing is
inappropriate in every case.
1. American Diabetes Association. Diabetic Nephropathy.
Diabetes Care 1999;22:S66-S69.
2. Holl RW, Grabert M, Thon A, Heinze E. Urinary excretion
of albumin in adolescents with type 1 diabetes: persistent versus
intermittent microalbuminuria and relationship to duration of
diabetes, sex, and metabolic control. Diabetes Care 1999;22:1555-60.
3. Howey JE, Browning MC, Fraser CG. Biologic variation
of urinary albumin: consequences for analysis, specimen collection,
interpretation of results, and screening programs. Am J Kidney
4. Gonzalez Castro ML, Sagredo PJ, Cebrecos TR, Enriquez
DO, de Baranda RA, Cordero GJ. [The stability of the microalbuminuria
numbers in relation to their reading time and mode of preservation].
Aten Primaria 1999;23:533-6.
5. MacNeil ML, Mueller PW, Caudill SP, Steinberg KK.
Considerations when measuring urinary albumin: precision, substances
that may interfere, and conditions for sample storage. Clin
6. Hishiki S, Tochikubo O, Miyajima E, Ishii M. Circadian
variation of urinary microalbumin excretion and ambulatory blood
pressure in patients with essential hypertension. J Hypertens
7. Roberts WL, Calcote CB, Cook CB, Gordon DL, Moore
ML, Moore S et al. Comparison of four commercial urinary albumin
(microalbumin) methods: implications for detecting diabetic
nephropathy using random urine specimens. Clin Chim Acta 1998;273:21-33.