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Age and Ageing Advance Access originally published online on November 14, 2007
Age and Ageing 2008 37(1):77-82; doi:10.1093/ageing/afm148
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Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

The association between urinary albumin excretion and ankle-brachial index in elderly Taiwanese patients with type 2 diabetes mellitus

Chin-Hsiao Tseng1,2,3,4,5,, Choon-Khim Chong6, Ching-Ping Tseng7 and Tong-Yuan Tai1,2

1 Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
2 Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
3 Department of Medical Research and Development, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan
4 School of Public Health, Taipei Medical University, Taipei, Taiwan
5 Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Taipei, Taiwan
6 Department of Rehabilitation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
7 School of Medical Technology, Chang Gung University, Taoyuan, Taiwan

Address correspondence to: Chin-Hsiao Tseng. Tel and Fax: (02)2388-3578. Email: ccktsh{at}ms6.hinet.net


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Key points
 References
 
Objective: this study examined the association between urinary albumin/creatinine ratio (ACR) and ankle-brachial index (ABI), or peripheral arterial disease (PAD), in elderly patients with type 2 diabetes mellitus (T2DM).

Methods: a total of 290 (108 men, 182 women) T2DM, aged ≥65 (71.6 ± 4.9) years were recruited. PAD was diagnosed by ABI<0.9, and ACR was divided into normoalbuminuria (<30.0 µg/mg), microalbuminuria (30.0 – 299.9 µg/mg), and macroalbuminuria (≥ 300.0 µg/mg).

Results: patients with PAD (n = 45) had higher ln(ACR) than patients without: 4.48 ± 1.48 versus 3.73 ± 1.39 (P<0.01). For normoalbuminuria (n = 112), microalbuminuria (n = 152), and macroalbuminuria (n = 26), respective PAD prevalence was 8.0, 17.1 and 38.5% (P<0.001). The proportion of normoalbuminuria, microalbuminuria and macroalbuminuria in patients with PAD was 20.0, 57.8 and 22.2%, respectively; and 42.0, 51.4 and 6.5%, respectively, in patients without (P<0.001). Ln(ACR) was inversely correlated with ABI in all patients ({gamma} = –0.198, P<0.01) and in separate sexes ({gamma} = –0.211 for men and {gamma} = –0.181 for women). The multivariate-adjusted odds ratios for PAD for every 1 unit increment of ln(ACR) was 1.66 (1.17–2.34); and for microalbuminuria versus normoalbuminuria and macroalbuminuria versus normoalbuminuria were 2.54 (1.05–6.17) and 5.86 (1.76–19.52), respectively.

Conclusions: urinary ACR is not only associated with PAD, it is also significantly correlated with ABI in an inverse pattern in elderly Taiwanese with T2DM.

Keywords: ankle-brachial index, microalbuminuria, peripheral arterial disease, urinary albumin/creatinine ratio, Taiwan, elderly


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Key points
 References
 
The incidence of diabetes mellitus has been increasing in Taiwan [1]. In a national survey of more than 6,500 residents in 2002, the age-standardised (to the World Health Organization year 2000 population) prevalence is 6.6% (unpublished data). The prevalence increased with age and was approximately 20% in those aged ≥65 years (unpublished data).

Peripheral arterial disease (PAD) is twenty times more prevalent in patients with diabetes [2] and more than half the diabetic patients who underwent an amputation had PAD in Taiwan [3]. In a previous Taiwanese study, the prevalence of PAD in patients with type 2 diabetes mellitus (T2DM) was 10% [4]. PAD was especially rare in diabetic patients aged <65 years in our population, and the respective prevalence for the age groups of <55, 55–64, 65–74 and ≥75 years was 2.5, 4.4, 12.9 and 25.3%, respectively (P<0.001) [4].

Diabetic foot problems including ulcers, gangrene and lower extremity amputations is also age-dependent [5]. The prevalence of lower extremity amputations in diabetic patients increased significantly from 0.6 and 0.8 to 1.2% in men aged <55, 55–64 and ≥65 years, respectively; and from 0.4 and 0.5 to 1.0% in women of the same age groups [6]. Elderly patients (≥65 years) with T2DM after lower extremity amputations in Taiwan also suffer from a 1.9-fold higher risk of mortality than those of a younger age [7]. Therefore, elderly T2DM patients represent a unique group of individuals who are at the highest risk of PAD, which may eventually lead to lower extremity amputation and mortality. Clinically, identification of PAD in the elderly diabetic patients is important because they are more prone to develop symptoms of claudication [8, 9] and have higher risk of frailty, falls and foot problems [5, 10, 11].

Microalbuminuria is highly prevalent and is an indicator for overt nephropathy and early cardiovascular disease [12–16]. Again, the prevalence of microalbuminuria, or clinical proteinuria, increased with age [17, 18]. In one study in Kinmen, Taiwan, the prevalence of proteinuria (defined by a urinary protein/creatinine ratio ≥0.2) in elderly diabetic patients aged ≥65 years is 36.5% in comparison to 26.6 and 17.9% in those aged 55–64 and 40–54 years, respectively [18].

Whether increased urinary albumin excretion rate (UAER) is a risk factor for PAD has not been extensively studied. A population-based study in Australia [19] and a study evaluating the baseline data from the register of the Helsinki Diabetes Association in Finland [20] suggested that UAER was associated with PAD. However, whether UAER is correlated with ankle-brachial index (ABI) remains to be answered. Clinical studies on the relationship between albuminuria and PAD are important in view of the availability of urine testing facilities and the relationship between PAD and frailty, falls and foot problems in the older people. Therefore, this study evaluated the correlation between UAER and ABI, and whether increased UAER or microalbuminuria/macroalbuminuria was associated with PAD in elderly Taiwanese with T2DM.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Key points
 References
 
Study subjects
A total of 290 patients with T2DM (108 men and 182 women), aged ≥65 years, were recruited consecutively from a diabetes clinic at the National Taiwan University Hospital. The patients did not show a history of diabetic ketoacidosis at the onset of diabetes, and they were treated with either oral anti-diabetic drugs or insulin at the time of recruitment. For those under insulin treatment, none received such treatment within one year of diagnosis. Type 1 diabetes mellitus (T1DM) is rare and considered a severe disease in Taiwan. A patient with such a disease may be issued a severe morbidity card after certified diagnosis. Patients with such a card are granted free medical treatment, and almost all type 1 diabetic patients have such a card. Patients holding a severe morbidity card were not recruited into the study for the assurance of not including patients with T1DM. Patients with moderate or severe congestive heart failure (New York Heart Association classification of heart failure symptoms, class III or IV), acute illness, fever or urinary tract infection were excluded because of their potential influence on urinary albumin excretion.

Diagnosis of PAD
Diagnosis of PAD was based on an ABI<0.9 in either lower extremity [4, 21]. In brief, Doppler ultrasonography (Medacord PVL, MedaSonic Inc., Mountain View, CA) was used to measure the systolic blood pressure in the bilateral brachial, posterior tibial, and dorsal pedal arteries. For this assessment, the patient was placed in a supine position, and the systolic blood pressure was determined after a 20-min rest. An 8-MHz Doppler probe was used, and the occluding cuffs (55 x 12.5 cm) were applied just above the malleoli for the measurement of ankle pressures. The device automatically calculated the right and left ABIs by dividing the higher pressure on the dorsal pedal or posterior tibial artery on right and left sides, respectively, by the higher brachial pressure on either side. The smaller ABI from either the right or the left side was used for classification of PAD and for data analyses. To prevent possible misclassification of PAD in patients with medial arterial calcification (a common arterial pathology found in diabetic patients [22]), patients with an ABI ≥1.3 were not included.

Measurement of urine and blood biospecimens
In order to reduce the potential influence of within-person day-to-day variability, we not only excluded patients with underlying morbidity (as described above) that might have caused an increase or fluctuation in UAER, but also tried to standardise the methods during urine collection. The subjects were instructed not to participate in any vigorous physical activity 1 day before examination. Urine specimens and blood samples were collected in the early morning after fasting for at least 12 h. First-void and mid-stream urine was collected, followed by venous blood sampling. Urinary albumin concentration was measured by means of particle-enhanced turbidimetric immunoassay (Biolatex, Logrono, Spain). Urinary creatinine concentration was measured after 10x dilution on an automatic biochemistry analyser (Cobas Mira S, Roche Diagnostica, Basel, Switzerland) with reagents obtained from Randox Laboratories Ltd. (Antrium, UK). Urinary albumin/creatinine ratio (ACR) was calculated by dividing the urinary albumin concentration in µg by the urinary creatinine concentration in mg. ACR <30.0 µg/mg was defined as normoalbuminuria, 30.0–299.9 µg/mg as microalbuminuria, and ≥300.0 µg/mg as macroalbuminuria [13].

Venous blood samples were collected in the morning after the subjects fasted overnight for more than 12 h. Fasting plasma glucose and serum total cholesterol and triglyceride were measured by an automatic biochemistry analyser (Cobas Mira S, Roche Diagnostica, Basel, Switzerland) with reagents obtained from Randox Laboratories Ltd. (Antrium, UK).

Other risk factors
The patients' age, sex, body mass index, diabetic duration, history of hypertension, insulin therapy, and smoking habit were recorded. Measurements of blood pressure and anthropometric parameters were described elsewhere [23–25]. In brief, blood pressure was measured in the right arm using a mercury sphygmomanometer after 20 min of rest with the patient in a sitting position; and body height and body weight were measured with the patient wearing light clothes and without socks and shoes. Body mass index was calculated as body weight in kilograms divided by the square of the body height in meters.

Statistical analyses
Data were expressed as mean ± SD or percentage, and a P<0.05 was considered statistically significant, and 0.05<P<0.1 as borderline significant. Because the distribution of ACR was highly skewed, the natural logarithm of ACR [ln(ACR)] was used for statistical analyses. Baseline characteristics between patients with and without PAD were compared by Student's t-test or chi-square test. The prevalence of PAD in patients with normoalbuminuria, microalbuminuria and macroalbuminuria were also calculated and compared by chi-square test. Scatter plot of ABI versus ln(ACR) was drawn and Pearson correlation coefficients between ln(ACR) and continuous covariates and ABI were calculated in separate sexes and in all patients together.

Logistic regression models were then used to estimate odds ratios and their 95% CI for PAD as a dependent variable and ln(ACR) or ACR subgroups (i.e. normoalbuminuria, microalbuminuria and macroalbuminuria) as independent variables. The models were created both before and after adjustment for confounders. The potential confounders selected into the adjusted models included age and sex, and those variables showing differences between PAD and non-PAD groups in the Student's t-test or chi-square test or showing correlation coefficients with ln(ACR) with P-values <0.10.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Key points
 References
 
The mean (SD) age of the subjects was 71.6 (4.9) years. Among the subjects, 45 (15.5%) were diagnosed as having PAD, while 112 (38.6%) were classified as normoalbuminuria, 152 (52.4%) as microalbuminuria and 26 (9.0%) as macroalbuminuria.

Table 1 compares the baseline characteristics of the subjects with and without PAD. Patients with PAD were characterised by older age, lower body mass index, longer diabetic duration, more insulin users, higher systolic blood pressure, higher ln(ACR) and higher prevalence of microalbuminuria/macroalbuminuria.


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  		Table 1. Comparison of baseline characteristics between patients with and without peripheral arterial disease

 
Figure 1 shows the scatter plot of ABI versus ln(ACR). Table 2 shows the Pearson correlation coefficients between ln(ACR) and the continuous covariates and ABI. Age, diabetic duration, systolic blood pressure, total cholesterol, triglyceride and ABI were correlated significantly with ln(ACR) in all subjects. For men, age, fasting plasma glucose, triglyceride and ABI were correlated with ln(ACR) with P-values <0.1; and for women, diabetic duration, systolic blood pressure, total cholesterol, triglyceride and ABI were correlated with P<0.1.


Figure 1
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  		Figure 1. Scatter plot of ankle-brachial index versus natural logarithm of urinary albumin/creatinine ratio (µg/mg).

 


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  		Table 2. Pearson correlation coefficients between the natural logarithm of urinary albumin/creatinine ratio and continuous covariates and ankle-brachial index by sex

 
In patients with normoalbuminuria, microalbuminuria and macroalbuminuria, the prevalences of PAD were 8.0, 17.1 and 38.5%, respectively, with unadjusted odds ratios (95% CI) of 1.00, 2.36 (1.06–5.26) and 7.08 (2.50–20.11). The respective odds ratios after adjustment for potential confounders (i.e. age, sex, body mass index, diabetic duration, insulin therapy, systolic blood pressure, fasting plasma glucose, total cholesterol and triglyceride) were 1.00, 2.54 (1.05–6.17) and 5.86 (1.76–19.52). Ln(ACR) as a continuous variable was also significantly associated with PAD with an unadjusted OR of 1.53 (1.21–1.95) and an adjusted OR of 1.66 (1.17–2.34).


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Key points
 References
 
This was probably the first study evaluating the association between UAER and ABI or PAD in the elderly Asian population. Microalbuminuria and macroalbuminuria were both significantly associated with PAD, independent of the other major confounders. In addition, ln(ACR) as a continuous variable was also correlated significantly with ABI in an inverse pattern (Figure 1, Table 2), and associated with PAD in the logistic regression. The association between PAD and microalbuminuria/macroalbuminuria suggested the need for an intensive search for the presence of the other complication when one of them exists.

The significant association between ln(ACR) and PAD, and between microalbuminuria and PAD were not attenuated with adjustment of potential confounders in the logistic analyses. We could not exclude the possibility that some factor(s), other than those adjusted, may explain the link. The association between UAER and PAD may not necessarily be causal, and may simply be a result of the effect of common antecedents. The presence of PAD might imply significant atherosclerosis involving not only vasculatures of the heart, the brain, and the lower limbs, but also the vasculatures of the kidneys, which could cause intra-glomerular hypertension, glomerular injury, and leakage of albumin.

Prospective studies evaluating UAER and PAD are still rare. In a study carried out in patients with T2DM randomly selected from the register of the Helsinki Diabetes Association, UAER was associated with PAD at baseline, but not predictive for new PAD during a mean follow-up of 11 years [20]. It is not known whether UAER is not a true risk factor, or the small sample sizes in the follow-up cohort (n = 89) and the new PAD (n = 21) could be responsible for the lack of predictive power of UAER in that study. In another population-based study in Australia, UAER was also associated with PAD in T2DM patients in cross-sectional analyses [19]. Although both studies examined the association between UAER and PAD, none reported the association or correlation between UAER and ABI as continuous variables. Despite the fact that our findings of a positive association between UAER and PAD were quite similar to the other studies [19, 20], the present study further demonstrated that UAER was significantly correlated with ABI in an inverse pattern (Figure 1, Table 2). The correlation remained significant after adjusting for the effect of age and sex (data not shown).

There are some potential implications. First, the association between UAER and ABI or PAD may or may not be causal, and some unexplored common antecedents could have existed which determined the development of both UAER and PAD in a dose-responsive pattern. Second, if such common antecedents did exist, the impact of these antecedents could be stronger on UAER than on PAD in our population, taking into account the much higher prevalence of microalbuminuria/macroalbuminuria than the prevalence of PAD observed in this study. However, it is not known whether more sensitive techniques used to detect PAD, such as measuring ABI, arterial waveforms or near-infrared spectroscopy both at rest and during exercise, could yield similar effects on albuminuria and PAD. Third, in clinical practice of geriatricians, seeing elderly diabetic patients with frailty, falls and foot problems should remind them to check for the presence of PAD and the coexistence of diabetic nephropathy. On the other hand, in elderly patients with microalbuminuria or macroalbuminuria, the geriatricians should carefully look for the coexistence of PAD and preventive measures such as diabetic foot care should be reinforced.

Because the prevalence of PAD is low in our population [4] and the clinical course of PAD is insidious with a relatively low incident rate (24% after 11 years of follow-up [20]), future studies to investigate whether UAER is predictive for PAD with prospective study design in our population should recruit a much larger sample size, and better with patients at a high risk of PAD, such as the elderly T2DM.

There are some limitations. First, since this was a cross-sectional and hospital-based study, cause–effect relationship could not be clarified, and referral bias could not be completely excluded. Second, extrapolation of the results to patients of younger ages might not be valid. Third, within-person day-to-day variability could not be completely excluded albeit some careful approaches have been taken during the processes of subject recruitment, urine collection and statistical analyses. Fourth, the diagnosis of micro- and macroalbuminuria did not completely conform to the requirement of multiple urine collections over 3 to 6 months as stipulated by the American Diabetes Association [13]. Fifth, the association between UAER and other diabetic microvascular complications (i.e. retinopathy and neuropathy) and macrovascular complications (i.e. coronary artery disease and cerebrovascular disease) was not evaluated in this study. Sixth, because patients with ABI ≥1.3 were excluded, we might have missed some patients with medial arterial calcification. It is not known whether this group of patients would also have increased UAER. Therefore, future studies are needed to address these limitations.

In summary, increased UAER is significantly correlated with ABI. Prevalence of PAD doubles from normoalbuminuria to microalbuminuria and doubles again from microalbuminuria to macroalbuminuria. The association between UAER and ABI or PAD is independent of traditional risk factors and the link between the kidney disease and atherosclerotic disease in elderly Taiwanese patients with T2DM is worth further investigation. Geriatricians should carefully look for the coexistence of PAD and albuminuria in their clinical practice.


   Conflicts of interest
 
No conflict to disclose.


   Key points
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Key points
References
 

  • Increased urinary albumin excretion rate is significantly correlated with ABI in an inverse pattern in elderly patients with T2DM.
  • Prevalence of PAD doubles from normoalbuminuria to microalbuminuria and doubles again from microalbuminuria to macroalbuminuria.
  • Geriatricians should carefully look for the coexistence of PAD and albuminuria in their clinical practice.


   Acknowledgements
 
This study was partly supported by grants from the Department of Health (DOH89-TD-1035), the National Taiwan University Hospital Yun-Lin Branch (NTUHYL96.G001) and the National Science Council (NSC-86-2314-B-002-326, NSC-87-2314-B-002-245, NSC88-2621-B-002-030, NSC89-2320-B002-125, NSC-90-2320-B-002-197, NSC-92-2320-B-002-156, NSC-93-2320-B-002-071, NSC-94-2314-B-002-142 and NSC-95-2314-B-002-311), Taiwan.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Key points
 References
 

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Received 10 October 2006; accepted in revised form 12 September 2007.


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