PHYSICAL ACTIVITY ALTERS URINARY ALBUMIN/ CREATININE
RATIO IN TYPE 1 DIABETIC PATIENT
|
Uludag
University School of Medicine, Department of Endocrinology, Bursa, Turkey
| Received |
|
09 November 2003 |
| Accepted |
|
11
December 2003 |
| Published |
|
01
March 2004 |
©
Journal of Sports Science and Medicine (2004) 3, 49 - 54
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| ABSTRACT |
|
While
the best way to identify microalbuminuria is to determine albumin
excretion rate (AER) in a 24 h urine sample. Published data have
shown that calculation of an albumin/creatinine ratio (ACR) in a
spot urine sample has reasonable rate of sensitivity and specificity.
We aimed to evaluate the effect of daily exercise on ACR and estimate
the best time for the examination of the ACR in a spot urine sample.
Sixteen eligible patients with Type 1 diabetes mellitus were asked
to perform varying degree of exercise periods. Urinary albumin and
creatinine excretion rates during each period were determined. ACR
and AER of timed urinary samples were compared with the 24 hour
urinary AER. We found significant correlations between timed and
24 hour urinary AER. According to diagnostic performance tests,
ACR and AER of timed urine samples were both found to be significantly
more sensitive during resting period when compared with mild or
moderate active periods. It is concluded that ACR and AER of a timed
urine sample are sensitive and specific methods for determining
microalbuminuria, while overnight resting samples give the impression
of being more diagnostic.
KEY
WORDS: Microalbuminuria, albumin/creatinine ratio, type 1 diabetes
mellitus, exercise, nephropathy.
|
| INTRODUCTION |
|
The
presence of microalbuminuria (30-299 mg·dL-1 or 20-199
µg·min-1) predicts deterioration of renal disease to
overt diabetic nephropathy in diabetic patients (Viberti et al.,
1982; Krolewski
et al., 1985)
and elevated risk of cardiovascular disease in diabetic and non-diabetic
individuals (Agewall et al., 1997;
Yudkin et al., 1988).
The early detection of microalbuminuria has been widely advocated
as means of diagnosing and treating early renal involvement in diabetes
(MCSG, 1993;
Bennett et al., 1995).
Measurement of albumin excretion rate (AER) in a 24 hour urine sample
is the most reliable way for the detection of microalbuminuria (Mogensen
et al., 1995;
Tobe et al., 2002).
Quantitative or qualitative assessment of AER in a spot urine sample
gives high rate of false negative and positive results due to water
intake. Published data have shown that the calculation of albumin/
creatinine ratio (ACR) in a spot urine sample exhibits a higher
sensitivity and specificity in the detection of microalbuminuria
(Gatling et al., 1985;
Eshoj et al., 1987;
Khawali et al., 2002).
This method has certain advantages, as it is easily available, non-expensive
and reproducible, but several conditions such as posture, exercise,
ketosis may lead to inappropriate increase of the urinary albumin
excretion (Abbott et al., 1994;
Gomes and Goncalves, 2001).
The value of ACR is controversially discussed in the literature.
Whereas some authors recommended ACR as the method of choice for
the detection of microalbuminuria (Shield et al., 1995;
Newman et al., 2000;
Tobe et al., 2002),
other published data demonstrated only a limited value of ACR as
a screening method of microalbuminuria (Marshall, 1991;
Derhasching et al., 2002).
The circadian rhythm of proteinuria, blood glucose control, dietary
protein content and physical activity are the main contributors
of the inaccuracy of ACR (Rowe et al., 1984;
Jefferson et al., 1985).
In this study we aimed to evaluate the effect of daily exercise
on ACR and estimate the best time and best intensity of the physical
activity for the examination of the ACR in a spot urine sample to
detect microalbuminuria in patients with Type 1 diabetes mellitus.
|
| METHODS |
Patient
selection
Patients with Type 1 diabetes mellitus without hypertension, macroalbuminuria
or renal insufficiency. Insulin treated diabetic patients with the
onset of diabetes before the age of 25, with duration of diabetes
more than 3 years and with no clinical evidence of cardiovascular,
peripheral vascular or renal disease were screened for AER. Patients
with the history of trauma, operation, ketoacidosis, hypoglycemia
leaded to unconsciousness in last 4 weeks or using medication except
insulin were not included into the study. Spot urine specimens were
tested for gross proteinuria by means of a reagent strip (Labstix,
Ames, Miles Inc., Elkhart, IN, USA) and patients with gross proteinuria
and abnormal urine sediments were excluded.
Patients were hospitalized to our medical center and they were instructed
to collect 24 hour urine specimens without any extra exercise other
than instructed. Patients were included into the study if their blood
pressure, AER and serum creatinine levels were less than 140/90 mmHg,
200 µg·min-1,
1.4 mg·dL-1, respectively. The study population consisted
of 9 patients with AER less than 20 µg·min-1
and 7 patients with AER more than 20 µg·min-1
but less than 200
µg·min-1.
Table 1 shows some of the clinical
and laboratory characteristics of the patients in which no statistical
difference was established between any characteristic. Patients gave
written informed consent to the study, which was approved by Ethics
Committee of Uludag University.
Urine sampling and analysis
Patients were asked to perform 4 periods with different physical activity
intensities. Exercise intensities were aimed to be in accordance with
daily activities which were validated with pedometer. In the first
period (Mild I), they stepped between 1000-5000 in 4 hours (08:00-12:00).
In the second period (Moderate) they were asked to walk more than
10 000 steps in 4 hours (13:00-17:00) and to be on upright position.
In the third period (Mild II) they were again asked to walk approximately
1000-5000 steps in 4 hours (18:00-22:00) and in the fourth period
(Resting ) they were requested to lay down as much as possible and
to have step count less than 500 (23:00-08:00). Timed urine samples
were collected separately by 1 hour further at the end each period.
Blood glucose levels were checked in every hour during the third period
and at 3 hour intervals during rest of the day to exclude hypoglycemia
and striking hyperglycemia.
Urinary albumin and creatinine excretion rates of urine samples were
determined. Timed urinary AER ( µg·min-1)
and ACR (µg·mg-1) of each period were calculated with the
contribution of albuminuria, creatininuria and urine volumes. Urinary
albumin level was measured using a competitive immunoassay (Immulite®,
DPC, Los Angeles, CA, USA) with interassay and intra-assay variations
of 4.4% and 6.7% respectively. Urinary creatinine concentration was
analyzed by the Jaffe reaction. Automated biochemical analysis was
used for the other determinations in plasma.
Statistical analysis
The albumin concentration measured in the timed urine samples were
compared with the albumin concentration quantified from 24-h urine
sample of the previous day. AER less than 20 µg·min-1
in the 24-h urine sample was considered as normoalbuminuria. Relationships
between 24-h urine samples and timed urine specimens were sought by
Pearson correlation. Cut-off values of ACR and AER in timed urine
samples were calculated by insertion of 95% confidence intervals to
the mean levels of patients with normoalbuminuria quantified from
24-h urine sample. Diagnostic performance was expressed in terms of
specificity, sensitivity, positive and negative predictive value.
Data are given as mean and standard deviation (SD). Statistical analyses
were performed with SPSS 10.0 / PC (SPSS Inc., Chicago, IL), and statistical
measures were calculated in the standard manner.
|
| RESULTS |
All
patients completed the exercising periods within the target step levels.
There were no major adverse events during this study. Any patient
did not have any symptoms resembling hypoglycemia. Patients blood
glucose levels were ranged between 72-282 mg·dL-1. Patients with blood
glucose levels higher than 200 mg·dL-1 were checked for ketonuria
which nobody presented.
Pearson's correlations between 24-h urinary AER and urinary ACR are
shown in Figure 1. Scatter plot
diagrams depict the significant relationship between 24-h urinary
AER and urinary ACR during all the periods. In according to calculate
the diagnostic performance of ACR, mean range with %95 confidence
interval was used as the cut point. The mean level of ACR in 9 patients
with normoalbuminuria was 17 µg·mg-1 with a 95% confidence
interval 9 µg·mg-1. Twenty six µg·mg-1 (17 µg·mg-1
+ 9 µg·mg-1) was accepted as the cut point for detecting
normoalbuminuria for using ACR in spot urine samples. According to
this cut off value of ACR, diagnostic performance was compared against
microalbuminuria results detected by 24-h urine samples (Table
2). Most predictive results were obtained during resting and mild
physical activity periods.
Similar calculations were done for urinary AER determined in timed
urine specimens during different periods (Figure
2). In patients without microalbuminuria cut point for urinary
AER in timed urinary specimens was found as 15 µg·min-1
(12 µg·min-1 + 3 µg·min-1) and diagnostic performance
of the AER for this cut-off value during different periods were calculated
(Table 3). Diagnostic performance
of urinary AER determined in timed urinary specimens showed very similar
percentages with ACR. When effect of intensity of exercise on AER
considered, resting and mild physical activity seem to be the most
accurate.
|
| DISCUSSION |
Early
detection of microalbuminuria through screening allows interventions
aimed at preventing diabetic nephropathy (Mogensen and Chritensen,
1984; Borch-Johnsen
et al., 1993).
Pathologic microalbuminuria was assumed when the albumin concentration
exceeded 20 µ·min-1 in a 24-h urine sample. Because collection
of 24-h urine is cumbersome for the patients, many authors claimed
that spot urine samples can give reliable results for detecting microalbuminuria.
The best method to diagnose microalbuminuria in a spot urine sample
is still a matter of discussion. Qualitative measurement of albuminuria
in a spot urine sample can give very high levels of false positive/negative
results depending on the volume of urine excreted that can be highly
variable depending mainly on the individual's fluid intake and physical
activity (Mckenna et al., 1991;
Carella et al., 1994;
Newman et al., 2000).
Proteinuria detected by using dipstick urinalysis despite correlates
well with radioimmunassay measurement also documented many false positive
values and necessitate repeated testing (Pegoraro et al., 1997).
Our results also showed low levels of sensitivity and specificity
when quantitative measurement of albuminuria in the urine samples
compared with 24-h urine microalbuminuria measurements (data not shown).
Timed urine collections, ACR in spot urine and early morning urine
are other alternative specimens for the measurement of albumin excretion.
Our results demonstrated a strong correlation between AER in the timed
urine specimens and 24-h urinary AER. We aimed to detect the best
cut-off value of timed urine sample for the limit of microalbuminuria.
In patients without microalbuminuria the cut-off value was calculated
as 15 µg·min-1 for timed urine specimens. So, it is assumed
that in a timed urine sample albumin excretion less than 15 µg·min-1
shows normoalbuminuria with 95% confidence. Sensitivity and specificity
rates of AER level < 15 µg·min-1 in a timed urine specimen
for detecting normoalbuminuria were found 71% and 82% respectively.
Our foremost aim was to identify the best time for collecting spot
urine sample in detecting microalbuminuria correctly. When diagnostic
performance tests were made for the timed urine samples by considering
15 µg·min-1 as the cut-off value, it was found that increased
physical activity leaded to low percentage of sensitivity and specificity.
For this cut-off value sensitivity and specificity values during the
resting period were 88% and 100% respectively, but in moderatively
active period these rates were 57% and 67% respectively. So it was
concluded that for the detection of urinary albumin excretion accurately
in a timed urine sample, inactivity is important.
In the resting period patients were instructed to be inactive as much
as they could. Sensitivity and specificity rates of the third period
with mild physical activity were very close to the resting period.
Since the third period activity (Mild II) was similar with the first
period (Mild I), it is obvious that physical activity is not the only
cause in the variation of urinary albumin excretion. Blood pressure,
sodium intake, protein intake, hyperglycemia could be factors for
low sensitivity and specificity of the daytime urine samples.
Timed collections are too cumbersome for the patients and comprise
potency for erroneousness during the collection of the timed urine
sample. In clinical practice it is very difficult to verify that a
timed collection of urine is complete, so urinary albumin measurement
in timed urine sample leads to considerable percentage of falsely
positive/negative results. Spot urine samples which can easily be
acquired in the ambulatory setting has many advantages. To evaluate
the diagnostic performance of the albumin excretion in a spot urine
sample, we calculated ACR for every period urine samples and compared
with the results of urinary albumin excretion results of the 24-h
urine samples.
Correlation between albumin/creatinine ratio and urinary albumin excretion
of 24-h urine sample was very significant. To find the best cut-off
value for results of albumin/creatinine ratio mean levels and 95%
confidence intervals were evaluated. In patients without microalbuminuria
calculated cut-off value was 26 µg·mg-1 and this level
was evaluated for the significance of diagnostic performance for different
periods. Sensitivity and specificity rates of ACR level < 26 µg·mg-1
for detecting normoalbuminuria were 80% and 79%, respectively. When
diagnostic performance tests were performed for each period, best
results were obtained during resting period with sensitivity rate
of 86% and specificity rate of 89%.
|
| CONCLUSIONS |
In
conclusion although spot urine samples give false positive and negative
results, timed urine samples can predict microalbuminuria with a very
high accurate percentage if samples collected without erroneously.
Our data did not provide any advantage of ACR compared with albuminuria
measured in timed urine sample. For timed urine samples albumin excretion
less than 15 µg·min-1 is highly predictive for normoalbuminuria. In
conditions of uncertainty about collection of timed urine sample,
albumin creatinine ratio can be used with great confidence. In this
condition, albumin creatinine ratio lower than 26 µg·mg-1 is well
predictive for normoalbuminuria. With increasing physical activity
during urine collection diagnostic performances of the cut-off values
go downhill. For detecting microalbuminuria best results are reached
with the early-morning urine samples.
|
| KEY
POINTS |
-
Timed urine samples can predict microalbuminuria but because of
the erroneous urine collections, microalbuminuria measurement
should be calculated with creatiniuria measurement.
- With
increasing physical activity during urine collection diagnostic
performances of the cut-off values go downhill.
- For
detecting microalbuminuria best results are reached with the early-morning
urine samples.
|
| AUTHORS
BIOGRAPHY |
Ercan TUNCEL
Employment: Assoc. Prof. Department of Endocrinology, Medical
Faculty, Uludag University
Degree: MD
Research interests: Diabetic complications, obesity,
dyslipidemia
Email: ercant@uludag.edu.tr
|
|
Erdinc
ERTURK
Employment: Assoc. Prof. Department
of Endocrinology, Medical Faculty, Uludag University
Degree: MD
Research interests: Secondary
diabetes, diabetic complications, adrenal disorders
Email: ererturk@uludag.edu.tr
|
|
Canan
ERSOY
Employment: Ass. Prof. Department of Endocrinology, Medical
Faculty, Uludag University
Degree: MD
Research interests: Diabetic complications, obesity,
dyslipidemia.
Email: cersoy@uludag.edu.tr
|
|
Sinem KIYICI
Employment: Physician, Department of Endocrinology, Medical
Faculty, Uludag University
Degree: MD
Research interests: Diabetic complications, obesity,
dyslipidemia
|
|
Cevdet
DURAN
Employment: Physician, Department of Endocrinology, Medical
Faculty, Uludag University
Degree: MD
Research interests: Diabetic complications, obesity,
dyslipidemia
|
|
Nesrin
KURU
Employment: Physician, Doruk Medical Center
Degree: MD
Research interests: Diabetes Mellitus
|
|
Sazi IMAMOGLU
Employment: Medical Director, Prof., Department of Endocrinology,
Medical Faculty, Uludag University
Degree: MD
Research interests: Diabetes treatment, diabetic complications.
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