Evaluation of Carotid Intima-Media Thickness in Maintenance Hemodialysis Patients in Dakar (West Africa)

Introduction

Atherosclerosis is the leading cause of cardiovascular disease (CVD) worldwide [1]. In its early stages, atherosclerosis is often asymptomatic and characterised by a progressive increase in arte- rial intima-media thickness [2]. In its advanced stages, complica- tions such as coronary artery disease, stroke and peripheral artery disease (PAD) can occur due to the formation of atherosclerotic plaques and occlusive lesions within the arterial wall [3,4]. In patients with end-stage renal disease (ESRD), accelerated athero- sclerosis is caused by both traditional cardiovascular risk factors (CVRFs) and non-traditional risk factors (oxydative stress, inflam- mation, uremic toxin, mineral bone metabolism disorders…) [3- 5]. Mineral and bone disorders, (e.g. hyperphosphatemia, second- ary hyperparathyroidism) play an important role among these [6]. In particular, hyperphosphatemia, is independently associated with an increased risk of cardiovascular disease and subclinical athero- sclerosis in patients with chronic kidney disease (CKD), potential- ly through mechanisms involving de novo cholesterol synthesis in vascular cells and macrophages [6,7]. Carotid intima-media thickness (CIMT) measurement is a cost-effective, non-invasive tool that can be used to diagnose subclinical atherosclerosis [2]. In sub-Saharan Africa, few studies have been conducted on carotid atherosclerosis in hemodialysis patients. This study aimed to as- sess CIMT and its correlations with cardiovascular risk factors in patients undergoing maintenance hemodialysis.

Patients and Methods

This cross-sectional study was conducted from 1 July to 31 December 2012 in the Nephrology Department at the Aristide Le Dantec University Hospital (CHU-ALD) in Dakar, Senegal.

Study Population and Clinical Data

All patients with end-stage renal disease (ESRD), undergoing haemodialysis for at least six months were included in the study. Clinical data were collected using a questionnaire and physical examination. Blood pressure (BP) was measured before and after dialysis, after a 10–15-minute rest period. The average of the BP measurements taken during the month prior to data collection was used for analysis. Hypertension was defined as the use of antihy- pertensive medication and/or a systolic blood pressure (SBP) of 140 mmHg and/or a diastolic blood pressure (DBP) of 90 mmHg [8]. Pulse pressure (PP) was calculated as the difference between the systolic and diastolic blood pressures. PP ≥60 mmHg was con- sidered high. BMI was calculated by dividing “dry weight” (kg) by height squared (m2).

Biological Parameters

Fasting blood tests -hemoglobin, albumin, calcium, phosphate, in- tact parathyroid hormone (iPTH), total cholesterol, HDL cholester- ol, LDL cholesterol, triglycerides, C-reactive protein (CRP)- were performed. The following abnormalities were identified: high CRP (CRP ≥ 6mg/l); hypoalbuminemia (albumin <35g/l); hypocalce- mia (calcium <88mg/l); hyperphosphatemia (phosphate ≥49mg/l); high total cholesterol (cholesterol ≥2.4g/l); low HDL cholesterol (HDL cholesterol <0.4g/l); high LDL cholesterol (LDL cholesterol ≥1.6g/l) and hypertriglyceridaemia (triglycerides ≥2g/l). Second- ary hyperparathyroidism was defined as an iPTH level greater than 585 pg/ml (> 9 x the upper normal limit) [9].

CIMT Measurement

Patients were examined in the supine position with their heads slightly extended and rotated in the opposite direction to the side under examination. This was performed by a single operator using a Hitachi® Doppler ultrasound device equipped with a 7.5 MHz linear transducer. A two-dimensional longitudinal section of the common carotid artery was performed 1 to 2 cm below the carotid bifurcation. CIMT was measured in plaque-free areas on the far wall of the right and left common carotid arteries, defined as as the distance between the leading edge of the first echogenic line (lumen-intima interface) and the second echogenic line (media-ad- ventitia interface) [10]. Three measurements were taken on each side. The average of the six CIMT measurements was calculated and used in this study. Carotid plaque was defined as focal lesion protruding into the arterial lumen, at least 0.5mm or 50% greater than the adjacent wall, or a CIMT greater than 1.5 mm [10].

Statistical Analysis

Statistical analyses were performed using R software version 3.5.3. The data were tested for normal distribution using quantile-quan- tile (QQ) plots and the Shapiro-Wilk test. Continuous variables were expressed as mean ± standard deviation if they were normal- ly distributed or as median (interquartile range) if they were not. Categorical variables were expressed as number (%). Continuous variables were compared using the Mann-Whitney U test or Stu- dent’s t test as appropriate. The relationship between continuous variables were examined using the Pearson’s test for normally distributed variables, and the Spearman's test for non-normal dis- tribution. A p-value <0.05 was considered statistically significant.

Results

A total of 57 patients were included in the study. The mean age was 48.36 ± 14.93 years (range 18–81 years). Of these, 24 were male (42.1%). The most common medical antecedents were hyperten- sion and smoking, present in 91.2% and 19.3% of patients, respec- tively. Half of the patients (50.9%) had hypertensive nephropathy. Thirteen patients (22.8%) had a history of peripheral arterial dis- ease (PAD), and 20 patients (35.1%) had carotid atherosclerotic plaques (Table 1).

                                                    Table 1: Baseline Characteristics of Study Population (N=57)

The mean CIMT was 0.835 ±0.21 mm (range: 0.12 to 1.39 mm), with no significant difference observed between men (0.86 ± 0.25 mm) and women (0.83±0.23 mm). CIMT was significantly higher in patients who were aged ≥50 years (p=0.005), in former smokers (p=0.034) or those who had a history of PAD (p=0.02). It was also higher in patients with predialysis SBP ≥140 mmHg (p=0.039) and predialysis PP ≥60 mmHg (p=0.029) (Table 2). No statistically significant differences in CIMT were found in patients with a history of hypertension, diabetes, or for the following parameters: post-dialysis SBP, post-dialysis PP, CRP, hyperphosphatemia, dyslipidemia, or the presence of carotid plaques (Table 2).

                         Table 2: Median (Interquartile Range) of CIMT According to the Variable Studied

A positive correlation was found between CIMT and age (r=0.38; p=0.004), pre-dialysis SBP (r=0.32; p=0.015), pre-dialysis and PP (r=0.33; p=0.013), post-dialysis SBP (r=0.26; p=0.047) and post-dialysis PP (r=0.26; p=0.049). In contrast, no significant correlation was observed with serum phosphate levels ((r= -0.03; p=0.83) (Table 3).

                                      Table 3: Correlations of CIMT with Clinical and Paraclinical Parameters

Discussion

Carotid atherosclerosis is a surrogate marker of systemic athero- sclerotic disease. CIMT is an independent predictor of cardiovas-cular mortality.The mean CIMT of the patients in this study was0.835 ÃÂ?± 0.21 mm, which is comparable to the values reported by Vieira et al. [11] in Brazil, but lower than those reported in older populations [5,12,13]. This variability between studies reflects the influence of factors such as age, gender, ethnicity and geography on CIMT [14]. Traditional cardiovascular risk factors (CVRFs) such as age, male gender, hypertension, diabetes, smoking, and dyslip- idemia are key contributors to the development of atherosclerosis [1,3,15]. Age and male gender are major non-modifiable risk fac- tors for atherosclerosis [16]. CIMT increases with ageing, regard- less of the presence of CVRFs or pre-existing CVD [16,17]. How- ever, this increase in CIM with age is significantly greater in the presence of CVRFs or pre-existing CVD [17]. Consistent with pre- vious studies, age was positively correlated with CIMT [12,18-21]. Regardless of age, men have a higher average CIMT than women [16]. In CKD, vascular remodelling involves both atherosclerosis and arteriosclerosis and these two processes contribute to the high morbidity and mortality observed in patients with CKD [22].

Atherosclerosis compromises arterial "conduit" function and be- gins with an increase in IMT; this is followed by the development of atherosclerotic plaques, which can lead to ischemic events (acute coronary syndromes, stroke, PAD) when the plaques become oc- clusive [22,23]. Increased IMT is an independent predictor of car- diovascular mortality and reflects systemic vascular disease, which is consistent with our finding of its association with peripheral ar- tery disease (PAD) (p=0.02) [2]. Arteriosclerosis is characterized by a stiffening of the arterial tree, altering their viscoelastic proper- ties This results in an elevated pulse pressure (PP) due to increased systolic blood pressure (SBP) and decreased diastolic blood pres- sure (DBP) [24]. An elevated PP is associated with higher rates of cardiovascular events and mortality [23,24].

Hypertension plays an important role in the pathogenesis of ath- erosclerosis [21,22]. As reported by some authors, we found a cor- relation between CIMT and SBP and PP, but not DBP [12,18-20]. A history of smoking was also significantly associated with increased CIMT (p=0.034). Diabetes is associated with carotid atherosclero- sis, from the early stage of increased carotid intima-media thick- ness to the advanced stage [3,21].

Although dyslipidemia is implicated in atherosclerosis, supported by evidence that statins slow CIMT progression, we found no sig- nificant correlation between standard quatitative lipids parameters (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and CIMT [25]. Qualitative lipid abnormalities have been described in CKD that could contribute to a higher atherogenic profile, in- cluding an accumulation of very-low-density lipoprotein (VLDL), the oxidation, glycation and carbamylation of LDL and HDL, and elevated lipoprotein(a) [4].

In addition to traditional cardiovascular risk factors, patients with CKD are exposed to specific risk factors, including disorders of mineral and bone metabolism [4,6]. Hyperphosphatemia, which is common in patients with CKD is associated with increased cardio- vascular morbidity and mortality [6]. This is because it promotes atherosclerosis through endothelial dysfunction, vascular calcifica- tion, and altered lipid metabolism in vascular smooth muscle cells [6,7]. Many studies have established a link between hyperphospha- temia and increased CIMT [12,18,20]. But in our study, no signifi- cant association was found with hyperphosphatemia as reported by other authors [5,26]. This could be explained by the smaller sample size, younger population or potential ethnic variations. In the Unit- ed States, for example, African-American haemodialysis patients have more severe hyperparathyroidism, but paradoxically have fewer vascular calcifications and lower cardiovascular and overall mortality than non-Hispanic white patients [27].

Inflammation contributes to the development of atherosclerosis [3,21]. Consistent with the findings of Kuang et al. and Sharma et al., we found no association between CIMT and C-reactive protein (CRP) [12,18]. However, some risk factors such as male gender, diabetes mellitus, and hypercholesterolemia appear to influence this association [28].

Our study had certain limitations: it cross-sectional design which did not allow us to establish a causal relationship, the small sample size that may underpower associations and the single-point biolog- ical measurements. Despite these limitations, our study provides valuable preliminary data. Larger cohort studies are needed to iden- tify CIMT risk factors in in West African hemodialysis patients.

Conclusion

CIMT measurement is a non-invasive method of detecting subclin- ical atherosclerosis. Hemodialysis patients are at high cardiovas- cular risk due to the high prevalence of traditional CVRFs and risk factors specific to uremia. This study found an association between CIMT and age, smoking, systolic blood pressure (SBP), pulse pres- sure (PP) and peripheral arterial disease (PAD).

Conflicts of interest: None

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