Atherosclerosis in Patients with End-Stage Renal Failure Prior to Initiation of Hemodialysis

Abstract

Background. In dialysis patients cardiovascular mortality is 10 to 20 times higher than in general population. It remains uncertain whether atherosclerosis of dialysis patients is effectively accelerated because many of dialysis patients have more or less marked vascular lesions already at the start of dialysis treatment. Subjects and methods. Using B-mode ultrasonography (ATL HDI 3000), we compared intima-media thickness (IMT) and plaque occurrence (indicators of atherosclerosis) in the common carotid arteries (CC), in the area of bifurcation (CB) and in the proximal part of internal carotid arteries (CI) in 28 hemodialysis patients (14 men and 14 women; mean age 49.4 years; mean duration of HD treatment 66.6 months) with that in 28 age-sex matched patients prior to initiation of hemodialysis. We also investigated possible differences in atherosclerotic risk factors in both groups. Results. The IMT values of CC (0.71 vs. 0.70 mm; p = 0.937), CB (0.81 vs. 0.77 mm; p = 0,423) and CI (0.72 vs. 0.71 mm; p = 0.935) were not significantly different in dialysis patients and patients starting dialysis treatment. We also found no difference in plaque occurrence (61% vs. 54%; p = 0.787) and in atherosclerotic risk factors (hypertension, smoking, lipids) between both groups. Conclusions. In our study we found no difference in atherosclerotic lesions in carotid arteries between dialysis patients and patients with end-stage renal failure starting dialysis treatment. Patients with chronic renal failure are at high risk for cardiovascular diseases so we should intervene earlier and more actively long before dialysis treatment in order to reduce the atherosclerotic risk factors.

• Atherosclerosis
• Cardiovascular disease
• Chronic renal failure
• Dialysis
• Risk factors
• Ultrasound

Introduction

Increased mortality from cardiovascular disease (CVD) has been consistently reported in patients on maintenance hemodialysis since the initial study of Lindner et al.[[1]] CVD is the main cause of morbidity and mortality in patients on renal replacement treatment, accounting for about 50% of the deaths.[[2]] The risk of cardiac events in patients on renal replacement treatment is estimated to be between 3.5 and 50 times higher than in the general population and the prevalence of coronary artery disease (CAD) is approximately 40% in the dialysis patients.[[2]], [[3]], [[4]], [[5]], [[6]] Cardiovascular mortality has been estimated to be approximately 9% per year in dialysis patients.[[5]], [[6]] The prevalence of CVD in renal transplant recipients is also higher than in general population and is now the major cause of death also in renal transplant patients.[[5]], [[7]], [[8]], [[9]] In most previous studies in the hemodialysis patients atherosclerosis has not been associated with duration of dialysis treatment and this suggests that atherosclerosis may be accelerated by uremic state per se rather than hemodialysis.[[10]], [[11]], [[12]], [[13]] Atherosclerosis in patients with chronic renal failure before dialysis treatment has received scant attention to date and it is very likely that the burden of CVD is very large.[[5]]

Atherosclerotic lesions are moderately or severely advanced by the time they produce clinical signs and symptoms, so early detection and prevention of atherosclerosis are desirable.[[14]] It is assumed that the atherosclerotic changes in the carotid artery mirror general atherosclerosis. Ultrasound measurements of the intima-media thickness (IMT) and plaque occurrence in the carotid artery have been used as indicator of coronary atherosclerosis, also in dialysis patients.[[11]], [[12]], [[13]], [[14]], [[15]]

The aim of our study was to establish IMT and plaque occurrence in the carotid artery in patients with chronic renal failure prior to initiation of dialysis and in patients treated with maintenance hemodialysis. The possible atherosclerotic risk factors (hypertension, smoking, total cholesterol, HDL- and LDL-cholesterol, triglycerides and lipoprotein(a)) in both groups were determined.

Subjects and Methods

Twenty-eight patients (14 men and 14 women; mean age 49.4 years, SD ± 14.98; range from 18 to 71 years) with chronic renal failure just prior to initiation of dialysis were included in our study. They were matched with 28 hemodialysis patients by age and sex (mean duration of dialysis treatment 66.6 months; SD ± 52.35; range from 12 to 217 months). Diabetic patients were excluded from the study.

Ultrasonographic scanning of the carotid artery was done with high-resolution echo color Doppler ultrasonography with multifrequency 5–10 MHz linear probe, ATL HDI 3000 machine (Advanced Technology Laboratories, High Definition Imaging; Bothel, Washington, USA). All subjects lay supine with their necks slightly hyperextended and rotated away from the imaging transducer. Several images were captured in real time on the cineloop frame grabber and three most clearly visible ones were used for measurements. Images were displayed with a constant fourfold magnification. Both carotid artery systems were scanned. We investigated IMT and plaque occurrence in the common carotid arteries, in the area of bifurcation, and in the proximal part of internal carotid arteries. As in other studies, IMT was defined as the distance between the leading edge of the lumen-intimal interface and the leading edge of the media adventitia interface of the far wall.[[11]], [[12]], [[13]], [[16]], [[17]], [[19]] IMT was measured in plaque free section. Three digitized still images from the same section of the artery were measured and mean value calculated. Mean value was also calculated from the left and right carotid artery.

Systolic and diastolic blood pressure were routinely measured before and after each dialysis. Blood pressure was determined with a standard mercury sphygmomanometer. Results are reported as the average of one-month measurements. The presence of hypertension was defined, as in study of Kawagishi et al.,[[11]] by the administration of antihypertensive agents, systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg.

Information on smoking habits was obtained by questionnaire. Hemodialysis patients were divided in two subgroups: smokers (present or former) and non-smokers.

Serum cholesterol (total, LDL and HDL cholesterol), triglyceride and lipoprotein (a) were measured by routine laboratory methods.

Data are expressed as mean ± SD. Differences in IMT between patients with chronic renal failure just prior to initiation of dialysis and hemodialysis patients were compared with Student's t test, differences in plaque occurrence were compared with chi-square test. Differences in atherosclerotic risk factors between patients with chronic renal failure just prior to initiation of dialysis and hemodialysis patients were compared with t test and Mann Whitney test for non-parametric data. Statistical analysis was done on the SPSS 8.0 software.

Results

The IMT values of carotid arteries in patients with end-stage renal failure prior to initiation of hemodialysis and in hemodialysis patients are shown in Table 1 and were not significantly different in both groups.

Table 1. Intima-media thickness in patients with end-stage renal failure prior to initiation of hemodialysis and in hemodialysis patients

	Intima-media thickness (mm) (mean, SD, range)
	Patients prior to initiation of hemodialysis	Hemodialysis patients	p<
Common carotid arteries	0.70 ± 0.17 (0.45–1.15)	0.71 ± 0.16 (0.40–1.00)	NS
Area of bifurcation	0.77 ± 0.18 (0.55–1.20)	0.81 ± 0.25 (0.40–1.40)	NS
Internal carotid arteries	0.71 ± 0.17 (0.50–1.15)	0.72 ± 0,16 (0.40–1.05)	NS

NS-not significant.

Plaques were found in 17 of 28 (61%) hemodialysis patients and in 15 of 28 (54%) patients prior to initiation of hemodialysis. More hemodialysis patients had plaques but the difference was not statistically significant (P = 0.787). We also found no difference in atherosclerotic risk factors between both groups (Table 2).

Table 2. Atherosclerotic risk factors in patients with end-stage renal failure prior to initiation of hemodialysis and in hemodialysis patients

	Patients prior to initiation of hemodialysis	Hemodialysis patients	p<
Hypertensiona (Nb, %)	21 (75)/7 (25)	20 (71)/8 (29)	NS
Smokingb (Nb, %)	14 (50)/14 (50)	10 (36)/18 (64)	NS
Total cholesterol (mmol/L)	5.06 ± 1.38	4.94 ± 1.15	NS
HDL cholesterol (mmol/L)	1.18 ± 0.45	1.27 ± 0.45	NS
LDL cholesterol (mmol/L)	3.12 ± 1.27	2.90 ± 1.14	NS
Triglycerides (mmol/L)	2.13 ± 1.54	1.80 ± 0.96	NS
Lipoprotein(a) (g/L)	0.32 ± 0.27	0.29 ± 0.37	NS

NS-not significant.

^aPresence/absence.

^bSmokers/non-smokers.

Discussion

In our study we compared the IMT of carotid arteries in patients with end-stage renal failure prior to initiation of hemodialysis and in hemodialysis patients using high-resolution echo color Doppler ultrasonography. This method is reliable, reproducible, and non-invasive for detecting and monitoring the progression of pre-clinical atherosclerosis.[[12]], [[18]], [[19]] Ultrasound measurements of the IMT in carotid arteries were used as indicator of coronary atherosclerosis, also in studies with dialysis patients.[[11]], [[12]], [[13]], [[17]], [[20]], [[21]] In our study we found neither difference in the IMT and nor in plaque occurrence between patients prior to initiation of hemodialysis and in hemodialysis patients. The high prevalence of cardiovascular mortality and morbidity in chronic dialysis patients was confirmed in numerous studies.[[3]], [[4]], [[5]], [[6]], [[11]], [[12]], [[13]] Less is known about CVD before starting dialysis treatment and many dialysis patients have more or less marked vascular lesions already at the start of dialysis treatment.[[22]] Jungers et al.[[23]] in their retrospective study found that incidence and age at onset of first myocardial infarction was similar in predialysis and dialysis patients. The prevalence of CAD was 38% among new dialysis patients in the study of Stack and Bloembergen (data from the United States Renal Data System) and similar prevalence of CAD among incident and prevalent patients was found.[[24]] The prevalence of ischemic heart disease on starting dialysis, as reported by the national registries, was 36% in Australia and New Zealand and 28% in Canada.[[25]] In all these reports only clinical correlates of CAD were used. There is little information about asymptomatic atherosclerosis in patients with end-stage renal failure prior to initiation of hemodialysis. Atherosclerotic lesions are moderately or severely advanced by the time they produce clinical signs and symptoms.[[14]] Joki et al. demonstrated that development of CAD precedes the start of dialysis, coronary angiography was performed on 24 patients within 1 month after starting dialysis.[[26]] Coronary angiography was performed regardless of the absence or presence of angina, significant coronary stenosis (at least 75% narrowing) was found in 62.5% of patients.[[26]] Hojs et al. found that patients with chronic renal failure before starting hemodialysis showed advanced asymptomatic atherosclerosis in carotid arteries (higher IMT values and plaque occurrence) compared with control subjects without renal failure.[[27]] In our present study we found no difference in asymptomatic atherosclerosis between patients with end-stage renal failure prior to initiation of hemodialysis and hemodialysis patients.This is also in accordance with studies where atherosclerosis was not associated with duration of dialysis treatment.[[10]], [[11]], [[12]], [[13]] Our results together with previous studies strongly suggest that uremic state, rather than dialysis, is the main determinant of accelerated atherosclerosis.

In the general population, there was reduction in the mortality and morbidity rates for CAD through the implementation of effective risk factor reduction programs.[[28]] Among risk factors cigarette smoking is a well known predictor of atherosclerosis in general population,[[29]] and Kawagashi et al.[[11]] and London et al.[[20]] found association between IMT and smoking in hemodialysis patients, but neither Burdick et al.[[17]] nor Hojs[[13]] could confirm such an association. Although arterial hypertension is a well recognized risk factor for atherosclerosis in general population, previous studies were unable to establish a role of blood pressure as a determinant of IMT in dialysis patients.[[11]], [[13]], [[17]], [[20]], [[26]] Majority of previous studies failed to find a significant correlation between carotid atherosclerosis and potential risk factors such as hypercholesterolemia, elevated LDL levels, hypertriglyceridemia and elevated lipoprotein (a) in dialysis patients.[[11]], [[13]], [[26]], [[30]], [[31]] In general population risk factors for atherosclerosis may be more often present as single, separate items. Dialysis patients exhibit a number of coexisting risk factors which are additive, so it is more difficult to establish the importance of a single risk factor in pathogenesis of atherosclerosis in these patients. The same can be established for patients starting dialysis according to our present study where we found no difference in atherosclerotic risk factors between patients with end-stage renal failure prior to initiation of hemodialysis and hemodialysis patients. It is also known that the burden of CAD has not changed substantially among incident end-stage renal disease patients in the past 10 years.[[24]] So we should intervene earlier and more actively before starting dialysis treatment in order to reduce the atherosclerotic risk factors and to reduce the mortality and morbidity rates for CAD in patients with chronic renal insufficiency and end-stage renal disease.

In summary, we found no difference in IMT and plaque occurrence (atherosclerotic lesions) in carotid arteries between patients with end-stage renal failure prior to initiation of hemodialysis and hemodialysis patients using high-resolution ultrasonography. We also found no difference in atherosclerotic risk factors between both groups of patients. Because of the usually long duration of the predialysis period and because of the potential atherogenic role of factors (hypertension, dyslipidemia,), which develop early in the course of chronic renal failure, there is clearly a need for preventive measures aimed towards a limiting atherogenesis in uremic patients long before initiation of renal replacement therapy.