Insulin Resistance and Cardiovascular Risks in Different Groups of Hemodialysis Patients: A Multicenter Study

Background To investigate the association between insulin resistance (IR) and cardiovascular disease (CVD) risks among hemodialysis patients. Methods We conducted a cross-sectional study between 2013 and 2017, on 384 hemodialysis patients from seven hospital-based-dialysis centers. HOMA-IR is classified according to median value. The CVD risks were defined by the K/DOQI Guidelines. Logistic regression analysis was used. Results Patients' age was 60.9 ± 11.8, 58.1% men, and 40.3% overweight/obese. The median of HOMA-IR was 5.4, 82.8% high systolic blood pressure, and 85.7% hyperhomocysteinemia. In multivariate analysis, IR was significantly associated with higher odds of low high-density lipoprotein cholesterol, high triglyceride, and impaired fasting glucose in groups of normal weight, overweight/obese, nondiabetes, diabetes, and overall sample. IR linked with elevated high-sensitive C-reactive protein in normal weight patients (odd ratio, OR=2.21, 95% confidence interval, 1.16-4.22, p < .05), with hypoalbuminemia in normal weight patients (OR=8.31, 95% CI, 2.35-29.37, p < .01), in nondiabetes patients (OR=6.59, 95% CI, 1.81-23.95, p < .01), and overall sample (OR=3.07, 1.51-6.23, p < .01). Conclusions The level of IR and prevalence of CVD risks were high in hemodialysis patients. IR was independently associated with CVD risks.


Introduction
The incidence and prevalence of treated end-stage renal disease (ESRD) have been steadily increased over the past decades across countries. In 2014, Taiwan has reported the highest number of treated ESRD with 455 new cases and the prevalence of 3219 patients per million general population (PMP). Taiwan has also experienced the highest number of maintenance hemodialysis in the world with 3093 patients PMP, 90% of them receiving in-center hemodialysis [1].

BioMed Research International
Cardiovascular disease (CVD) has been reported as the leading cause of death and disability all over the world. In 2013, CVD accounted for about 17 million deaths and 329 million disability adjusted life-years lost [2]. In ESRD patients, the cardiovascular cause of death is 10-20 times higher in the healthy population and accounted for more than half of all death [3].
Insulin resistance (IR) is with high prevalence in the ESRD patients [4]. IR its self is a risk for CVD and strongly associates with other CVD risks (dyslipidemia, hypertension, and inflammation) through several pathophysiologic mechanisms, which is well documented [5]. In ESRD patients undergoing hemodialysis, the cardiovascular risks worsen the arterial stiffness which contributes to the development of cardiovascular events and diseases [6]. IR is the anterior consequence of obesity [7]. In ESRD patients, IR then links to dyslipidemia, impaired fasting glucose, and cardiovascular risks and events [5,8,9]. In empirical researches, IR is closely associated with cardiovascular risks such as obesity, hypertension, and dyslipidemia [10], anemia [4], inflammation [11,12], and echocardiography parameters [12]. In turn, IR significantly predicts cardiovascular diseases and mortality in ESRD patients [13][14][15][16]. Therefore, assessment of IR is critically important work for nephrologist and nurses to follow up patients and have appropriate interventions.
The ESRD has created a heavy burden for the healthcare system all around the world over the past decade [1]. However, the number of clinicians has not adequately increased to meet the greater demand for renal treatment [17]. The early detection of the IR and its associated factors might contribute to prevent CVD risks and reduce the burden. On the other hand, improving IR might be an important therapeutic target and contribute to better health outcomes in hemodialysis patients [18,19]. This study was to assess the prevalence and explore the association between IR and CVD risk factors among ESRD patients undergoing hemodialysis.

Study Design.
A clinical cross-sectional study was conducted between September 2013 and April 2017 in seven dialysis centers in Taiwan

Hemodialysis
Patients and Data Sources. We included patients aged above 20 years, receiving thrice-weekly hemodialysis treatment for at least 3 months and adequate dialysis quality (equilibrated Kt/V ≥ 1.2 g/kg/day). The exclusion criteria were patients who were diagnosed with pregnancy, amputation, hyperthyroidism, hypothyroidism, and malignancy, received tube feeding, exhibited hepatic failure or cancer, were hospitalized within one month prior to the recruitment, or were scheduled for surgery. Volume overload or edema closely linked with other clinical instability [20]. Therefore, patients with evidence of edema were excluded in the current study and in previous studies [21][22][23].
The eligible patients in selected hospitals signed the informed consents before conducting chart reviews and laboratory evaluations. The patients' medical records were reviewed. The blood samples were collected by licensed nurses, at the start of the first dialysis session of the week, and then analyzed in the hospital laboratory by using commercially available test kits, which was described carefully in previous studies [24,25].

Insulin Resistance
Index. The blood samples collected by the registered nurse were centrifuged in each hospital laboratory. The serum was separated and kept in the icepack, then sent to the laboratory in Taipei Medical University Hospital for serum insulin analysis. Therefore, all samples were analyzed with the same commercial kit. The homeostatic model assessment of insulin resistance index (HOMA-IR) is used to assess IR. The index is calculated using the formula developed by Matthews et al. [26]: fasting plasma glucose (mg/dL) 405 . (1) Patients were separated into two groups based on the median value as the nonnormal distribution of HOMA-IR; this method was applied in previous studies [14,27].

Cardiovascular Risks.
The traditional and nontraditional CVD risks were described in the previous study [22] and the current study with the details below. In the present study, more factors were assessed and reported, such as physical activity, medical history (diabetes, hypertension, and cardiovascular disease), and other biochemical parameters (blood urea nitrogen, uric acid, creatinine, and fasting plasma insulin).

Statistical
Analysis. The descriptive analyses describe the patients' characteristics, insulin resistance (IR), cardiovascular disease risk factors via the mean, standard deviation, or median, interquartile range, frequency, and percentage. The independent-samples t-test, Chi-square test, and Mann-Whitney U test were used appropriately to test the distribution of patients' characteristics, CVD risks, and HOMA-IR in different groups of body mass index (BMI) and DM. In order to carefully examine the association between IR and traditional and nontraditional risk factors, the multivariate logistic regressions are used to estimate the odd ratios. Since obesity is the most common cause of IR [7], we analyzed the association in different groups of BMI (normal weight versus overweight/obese). The associations were also analyzed in a group of patients with diabetes and nondiabetes. The analyses were adjusted for age and gender, hemodialysis vintage, Charlson comorbidity index, and body mass index (for overall sample). These adjusted factors might be the confounders as they showed the relationship with IR [38][39][40][41][42]. All statistical analyses are performed by the SPSS for Windows v20.0 (IBM Corp., New York, USA). The significant level is set at p value < .05.

Results
Of the total sample, the average age of patients was 60.

Discussion
The level of IR is higher in overweight/obese and DM patients than in normal weight and non-DM patients in the current   study. Obesity is also reported as the most common cause of IR previously [7]. In regard to traditional CVD risks, IR is significantly associated with a higher prevalence of dyslipidemia such as low HDL-C, high TG in the current study. The finding was also found in both the general population [43] and hemodialysis patients [9]. In the previous study, IR was found to reduce HDL-C in hemodialysis patients [9]. On the other hand, IR was also associated with higher likelihood of having impaired fasting glucose in all groups of patients, independent of age, gender, hemodialysis vintage, Charlson comorbidity index, Physical activity, and body mass index. The IR was welldocumented as the immediate factor between obesity and impaired fasting glucose and cardiovascular diseases in the literature [5,8]. Therefore, early interventions at stages of obesity or IR are extremely important to prevent and mitigate the adverse consequences of CVD risks, such as dietary intake, physical activities, and medication [5].
Regarding the nontraditional risks, the prevalence of elevated hs-CRP was higher in overweight/obese patients than those with normal weight. A previous study has also reported that patients with central obesity had higher hs-CRP level than those without [44]. The level of hs-CRP was not significantly differed among HD patients with and without DM. This was also found in HD patients in Japan that hs-CRP was similar between HD patients with DM, HD patients with metabolic syndrome (MS), and those with neither DM nor MS [9]. In addition, the prevalence of malnutrition in the current study was with 12.0% hypoalbumin; it is much lower than in the previous study conducted in Turkey with 44.1% hypoalbumin [45].
In the current study, there is also no significant association between IR and hs-CRP in patients with DM or non-DM patients or overweight/obese, but it existed in normal weight patients. The association between IR and hs-CRP was found in the overall sample in Turkey [11,12] and in 598 overweight/obese patients in Spain [44]. On the other hand, the association between IR and hypoalbumin was found in hemodialysis patients with normal weight, and non-DM, and overall sample. This was also shown in a previous study [12]. It is important to take into account the evaluation of IR level, hs-CRP, and serum albumin, in order to prevent and intervene against CVD risks and diseases.
There were some contradictory findings between the current study and the previous one. Firstly, the IR associated with a lower likelihood of having high SBP in the current study which was in contrast with the previous finding [10]. Next, IR was related to a lower likelihood of hyperkalemia in normal weight, non-DM, and overall sample. This happened as the result of kalemia lowering treatment among hemodialysis patients. Finally, in normal weight, and non-DM sample, IR was associated with a lower likelihood of hyperphosphatemia in the current study. Hyperphosphatemia and high level of CaxPO 4 combination were found to link with higher allcause mortality in hemodialysis patients [46].
The study was of a cross-sectional nature; the causal relationship, therefore, cannot be generated. The interpretation of results should be cautious. The data related to supplement intake and medication was not explored. Therefore, the association between IR and some CVD risks was not well explained. Smoking is known as a major traditional cardiovascular risk factor. It is reported that 85.1% of patients were nonsmokers [47]. In the United State, based on data of USRDS, 6.2% of dialysis patients were smokers [48]. Therefore, we did not collect the data on smoking status in the current study. Future longitudinal, case-control, or intervention studies are encouraged to carefully examine the association.

Conclusions
The insulin resistance (IR) and CVD risks were common in hemodialysis patients. IR was associated with a higher prevalence of dyslipidemia (low HDL-C, high TG), impaired fasting glucose, elevated hs-CRP, and hypoalbuminemia. Addressing the assessment and treatment of IR and CVD risks in clinical practice could help with improving the hemodialysis outcomes.

Data Availability
Since the dataset contains sensitive and identifying information, any modification or deidentification on the dataset is restricted. The authors confirm that the data is available upon request. Requests may be sent to the corresponding author, Shwu-Huey Yang (sherry@tmu.edu.tw).

Disclosure
The funder had no role in the decision to collect data, data analysis, or reporting of the results. The abstract was presented at the Annual Dialysis Conference 2018, Mar 3-6, 2018, Orlando, Florida.