diabetes research and clinical practice 108 (2015) 258–264

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Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es

Serum cystatin C levels are associated with asymptomatic peripheral arterial disease in type 2 diabetes mellitus patients without overt nephropathy Ji Hye Huh a, EunHee Choi b, Jung Soo Lim a, Mi Young Lee a, Choon Hee Chung a, Jang Yel Shin a,* a b

Department of Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju-Si, Republic of Korea Institute of Lifestyle Medicine, Yonsei University, Wonju College of Medicine, Wonju-Si, Republic of Korea

article info

abstract

Article history:

Aims: We investigated the association between serum cystatin C and asymptomatic pe-

Received 21 July 2014

ripheral artery disease (PAD) in type 2 diabetes mellitus patients with normal renal function

Received in revised form

or mild renal impairment and we compared cystatin C with albuminuria and estimated

6 October 2014

glomerular filtration rate (eGFR) for prediction of PAD.

Accepted 6 February 2015

Methods: We enrolled 272 patients with type 2 diabetes. Patients were excluded if they had

Available online 16 February 2015

an eGFR < 60 mL/min per 1.73 m2, 24-h urine albumin (24 h-uAlb)  300 mg/day, serum

Keywords:

as having an ankle brachial index (ABI)  0.9.

Cystatin C

Results: Patients with PAD were more likely to have a lower eGFR and higher values of 24 h-

creatinine (Cr) > 1.3 mg/dL, or previous history of cardiovascular disease. PAD was defined

Renal impairment

uAlb, cystatin C, and serum Cr than subjects without PAD. Cystatin C was independently

Peripheral arterial disease

associated with age, current smoking, HDL, eGFR, and PAD. Odds ratios (ORs) for PAD after

Type 2 diabetes

adjustment for age, gender, smoking, and hypertension were 1.71 (95% CI, 1.02–2.85), 1.51 (95% CI, 0.93–2.44), and 0.78 (95% CI, 0.41–1.49) for a one standard deviation increase in cystatin C, 24 h-uAlb, and eGFR, respectively. Conclusions: Cystatin C was independently associated with PAD in type 2 diabetes mellitus patients without overt nephropathy. # 2015 Elsevier Ireland Ltd. All rights reserved.

1.

Introduction

Peripheral arterial disease (PAD) is suggested to be associated with an increased risk of cardiovascular disease (CVD) events and mortality [1,2]. The prevalence and risk of PAD is higher in * Corresponding author. Tel.: +82 33 741 0501; fax: +82 33 731 5884. E-mail address: [email protected] (J.Y. Shin). http://dx.doi.org/10.1016/j.diabres.2015.02.006 0168-8227/# 2015 Elsevier Ireland Ltd. All rights reserved.

individuals with diabetes than in those without diabetes [3–5]. PAD is one of the major risk factors for diabetic foot ulcers and lower extremity amputation. Additionally, the prevalence of PAD in patients with chronic kidney disease (CKD) is higher than in those without CKD [6,7]. Diabetes is the most common cause of CKD in patients receiving renal replacement therapy

diabetes research and clinical practice 108 (2015) 258–264

in developed countries, and approximately 40 percent of all patients with type 2 diabetes mellitus are likely to suffer from diabetic nephropathy. CKD and albuminuria are known to be independent risk factors for CVD and mortality in diabetic patients [8–13]. Therefore, early identification of individuals with elevated risk for PAD, as well as renal impairment, is essential for prevention of serious complications of diabetes. Several observational studies have demonstrated that CKD markers, such as albuminuria and a reduced estimated glomerular filtration rate (eGFR), are associated with an elevated risk of PAD in the general population [14–16]. Hsieh et al. demonstrated that markers for renal function, including elevated serum creatinine (Cr), reduced eGFR, and albuminuria, were strongly associated with PAD in Chinese patients with type 2 diabetes mellitus [17]. A recent study observed that PAD in patients with diabetes was more strongly associated with albuminuric CKD than non-albuminuric CKD [18]. However, the relationship between markers for renal impairment and PAD is not clear in individuals with type 2 diabetes, especially in those who have normal renal function or mild renal impairment. Generally, measurement of urinary albumin excretion has been used as a standard screening tool for detecting renal complication in patients with diabetes. However, more than half of all patients with renal impairment are observed to be normoalbuminuric [19]. Hence, there is a need for new surrogate markers for early detection of declining renal function that can be used in place of albuminuria. Cystatin C, the most potent endogenous inhibitor of cathepsins synthesized in nucleated cells, is suggested to be a more reliable surrogate marker than serum Cr and Cr-based eGFR for early detection of renal impairment in patients with diabetes [20,21]. In several prospective studies, elevated circulating cystatin C has been shown to be associated with increased risk of CVD morbidity and mortality [22–25]. In addition, two recent prospective studies found that cystatin C at baseline is a predictor for increased CVD mortality independent of renal impairment and other traditional risk factors [26,27]. Some observational studies have demonstrated that serum cystatin C and cystatin C-based eGFR are associated with PAD in the general population [28–30]. However, there are few studies that have investigated the association between cystatin C and PAD in patients with diabetes. Ix et al. found that cystatin C-based CKD, rather than Cr-based CKD, was independently associated with a lower ankle brachial index (ABI < 0.9) in subjects with diabetes [15]. Another cross-sectional study showed a close association between serum cystatin C and lower limb ischemia in Chinese type 2 diabetic patients [31]. However, since these studies enrolled subjects with a broad range of renal function from normal to severe CKD, there is the possibility that the association between cystatin C and PAD may have been affected by confounding related to the presence of CKD. On the basis of these findings, we hypothesized that cystatin C may be associated with PAD in individuals without overt nephropathy because cystatin C is a reliable marker for early detection of declining renal function. In this study, we investigated whether serum cystatin C is associated with asymptomatic PAD in type 2 diabetes mellitus patients with normal renal function or mild renal impairment. In addition, we compared serum cystatin C with other

259

surrogate markers for renal function, such as albuminuria and Cr-based eGFR, for prediction of the presence of PAD.

2.

Materials and methods

2.1.

Patient population

We consecutively recruited a total of 309 patients with type 2 diabetes who visited the diabetes clinic at Wonju Severance Kidok-Hospital between January 2008 and December 2008. Patients were excluded if they had an eGFR < 60 mL/min per 1.73 m2, 24-h urinary albumin excretion rate 300 mg/24 h, or serum Cr > 1.3 mg/dL. We also excluded subjects who had a previous history of CVD. Among the 309 recruited patients, 37 were excluded because they did not meet the inclusion criteria. The Institutional Review Board approved the study protocol prior to initiation of the study. Written informed consent was obtained from all subjects.

2.2. Measurements of clinical and biochemical metabolic parameters A complete medical history, including smoking habits and medication history, was obtained from medical records and patient interviews. We measured blood pressure and anthropometric characteristics including weight, height, and waist circumference. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2). Hypertension was defined as participants with measured blood pressures greater than 140/ 90 mmHg or those taking anti-hypertensive medication. An ophthalmologist assessed patients for the presence of diabetic retinopathy. Diabetic nephropathy was diagnosed if the 24-h urinary albumin excretion rate was greater than 30 mg/24 h. All blood samples were obtained after an overnight fast. Fasting plasma glucose, glycated hemoglobin (HbA1c), high sensitivity C-reactive protein (hsCRP) level, and lipid profiles were measured. Plasma glucose was measured using the glucose oxidase method and HbA1c was measured by high-performance liquid chromatography (HPLC) using Variant II Turbo (Bio-Rad Laboratories, Hercules, CA). HsCRP was measured by high-sensitivity latex-enhanced immunonephelometric assay method with a chemical analyzer (Hitachi 7600). Plasma triglyceride (TG), total cholesterol, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol were assayed by routine Hitachi 7600 autoanalyzer (Hitachi Instruments Service, Tokyo, Japan). Serum insulin concentration was determined using a chemiluminescent immunoassay (CLIA; Siemens, Los Angeles, CA, USA). Insulin resistance was calculated using the homeostasis model assessment-insulin resistance (HOMA-IR) equation [HOMA-IR = fasting insulin (mU/ mL)  fasting plasma glucose (mg/dL)/405].

2.3.

Assessment of renal function

Serum Cr concentrations (mg/dL) were measured using the traceable kinetic Jaffe method on a Roche/Hitachi 747 analyzer. GFR was estimated using the CKD-epidemiology collaboration (CKD-EPI) equation: eGFR (mL/min per 1.73 m2) = 141  min(Scr/k, 1)a  max(Scr/k, 1)1.209  0.993age (years)  1.018

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diabetes research and clinical practice 108 (2015) 258–264

(if female)  1.159 (if black) [32]. Serum cystatin C concentrations (mg/L) were assessed using the N-Latex Cystatin C kit on a Behring Nephelometer II (Siemens, Marburg, Germany). Twenty-four-hour urine collection was performed to measure the urinary albumin excretion rate (mg/24 h). Urinary albumin was evaluated by turbidimetric assay using a Hitachi Automatic Analyzer 7600 (Hitachi, Tokyo, Japan).

2.4.

Measurement of the ABI and assessment of PAD

A trained technician measured the ABI according to a standard protocol using VP-10001 (Colin Co., Komaki, Japan). The examination was performed with the participant in the supine position. After 5 min of rest, four standard cuffs were placed on both arms and ankles, and the systolic pressures of the bilateral brachial, posterior tibial, and dorsalis pedis arteries were measured simultaneously. The ABI values of both legs were calculated by dividing the maximum systolic pressure in the right and left ankle by the higher of the two brachial systolic pressures. For diagnosis of PAD, the lower ABI value was used. PAD was defined as an ABI  0.9.

2.5.

Statistical analysis

Data are presented as means  standard deviation (SD), medians (inter-quartile range (IQR)), or numbers (percentages) for categorical variables. To analyze differences between groups with and without PAD, continuous variables were compared using an independent-sample t-test. The x2 test was used to compare categorical variables between groups. The statistical power of major variables such as cystatin C, 24-h urine albuminand eGFR was 99.9%, 99.2% and 99.9%, respectively. Data were logarithmically transformed before analysis if they were not normally distributed. The correlations of cystatin C and ABI with various metabolic parameters were analyzed using Pearson correlation. Multivariate regression analyses were preformed to assess independent associations of cystatin C and ABI with associated variables. Multiple logistic regression analyses after adjustment for age, gender, current smoking, and hypertension were conducted to assess odds ratios (ORs) for predicting the presence of PAD per a 1-SD increase in cystatin C, 24-h urine albumin, and eGFR, respectively. Analyses were performed using SPSS statistical software (ver. 15.0; SPSS Inc, Chicago, IL, USA). Receiver Operating Characteristic (ROC) curve analysis was conducted to determine the accuracy of markers for renal impairment, such as cystatin C, 24-h urine albumin, and eGFR, for predicting the presence of PAD. The area under the ROC curves (AUC) was calculated using binary logistic regression. These analyses were performed using SAS, version 9.2 (SAS Institute, Cary, NC, USA). A P value

Serum cystatin C levels are associated with asymptomatic peripheral arterial disease in type 2 diabetes mellitus patients without overt nephropathy.

We investigated the association between serum cystatin C and asymptomatic peripheral artery disease (PAD) in type 2 diabetes mellitus patients with no...
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