Perit Dial Int
29(Supplement_2):
96-101
2009
© 2009 International Society for Peritoneal Dialysis
Part 3: Clinical Experiences |
CAROTID INTIMAL THICKNESS AND FLOW-MEDIATED DILATATION IN DIABETIC AND NONDIABETIC CONTINUOUS AMBULATORY PERITONEAL DIALYSIS PATIENTS
Narayan Prasad,
Sudeep Kumar1,
Anurag Singh,
Archana Sinha,
Kamal Chawla1,
Amit Gupta,
R.K. Sharma,
Nakul Sinha1 and
Aditya Kapoor1
Departments of Nephrology and of Cardiology,1
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Correspondence to: N. Prasad, Department of Nephrology, Sanjay Gandhi
Postgraduate Institute of Medical Sciences, Lucknow, UP 226014 India.
narayan{at}sgpgi.ac.in
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ABSTRACT
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Objectives: We compared carotid intima media thickness
(CIMT) and flow-mediated dilatation (FMD) between cases [end-stage renal
disease patients (diabetic and nondiabetic) on peritoneal dialysis (PD)] and
controls (diabetic and hypertensive patients with normal renal function) with
the objective of identifying risk factors predicting atherosclerosis.
Methods: This cross-sectional study involved 124
subjects (62 cases, 62 controls). In both the case and control populations, we
used B-mode ultrasonography to study CIMT and endothelium-dependent FMD,
according to American College of Cardiology guidelines on brachial artery
measurement. Pearson correlation was used to evaluate the correlation between
CIMT and other variables.
Results: Compared with controls, cases had
significantly higher systolic blood pressure, total cholesterol, low-density
lipoprotein cholesterol, triglycerides, serum uric acid, inorganic phosphate,
C-reactive protein, and parathyroid hormone, and significantly lower
hemoglobin, calcium, and high-density lipoprotein. Compared with controls,
cases showed significantly greater CIMT (0.60 ± 0.08 mm vs 0.54
± 0.03 mm, p < 0.001) and significantly lower FMD (0.15
± 0.08 cm vs 0.21 ± 0.04 cm, p = 0.02). Among cases,
patients with diabetes had significantly greater CIMT (0.62 ± 0.08 mm
vs 0.58 ± 0.07 mm, p = 0.05) than did patients without
diabetes; FMD was similar in diabetic and nondiabetic patients on continuous
ambulatory PD (0.16 ± 0.03 cm vs 0.18 ± 0.03 cm, p =
0.20).
Conclusions: Compared with controls, cases had
significantly higher CIMT and lower FMD. Cases with diabetes had significantly
higher CIMT than did cases without diabetes, but FMD was similar in diabetic
and nondiabetic cases. Serum inorganic phosphate is an independent risk factor
for atherosclerosis and was significantly correlated with CIMT. The
noninvasive CIMT and FMD tests can be used to monitor atherosclerosis and
endothelial dysfunction.
KEY WORDS: Carotid intima media thickness; flow-mediated dilatation.
Cardiovascular disease and stroke are the leading cause of death in
patients with end-stage renal disease (ESRD) who require dialysis. These
patients have a risk of death 10–20 times that of an age- and
sex-matched general population
(1–3).
In a general population, advanced age, hypertension, cigarette smoking, and
hyperlipidemia are important risk factors for advanced atherosclerosis
(4). Advanced atherosclerosis
is characteristic of nonuremic patients with diabetes mellitus
(5,6).
Chronic kidney disease has recently been suggested to be an independent
nontraditional risk factor for cardiovascular disease
(7,8),
but it remains unclear whether the risk factors associated with
atherosclerosis and cardiovascular mortality are similar for uremic and
nonuremic, diabetic and nondiabetic ESRD patients. Carotid intima media
thickness (CIMT) and flow-mediated dilatation (FMD) are surrogate markers for,
and a noninvasive means of measuring, atherosclerosis
(9,10).
The hemodynamic and metabolic risk factors for atherosclerosis vary in renal
transplantation, hemodialysis, and continuous ambulatory peritoneal dialysis
(CAPD) patients. The risk factors associated with CIMT and FMD in PD patients
have, per se, never been studied in detail. We therefore undertook
the present study to compare differences in CIMT and FMD, the surrogate
markers of atherosclerosis, between ESRD patients on CAPD and age- and
sex-matched patients with diabetes and hypertension but with normal renal
function. We also determined the factors predicting atherosclerosis in the
patients.
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PATIENTS AND METHODS
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This cross-sectional case–control study included 124 subjects (62
cases, 62 controls) who visited the nephrology and cardiology outpatient
clinics of our institute from July 2006 to July 2007. The ESRD cases (38 with
and 24 without diabetes) were on PD, and the age- and sex-matched controls had
diabetes and hypertension but normal renal function. "Normal renal
function" was defined as a serum creatinine level of 1.4 mg/dL and a
glomerular filtration rate of 60 mL/min/1.73 m2 or better, as
calculated by the Cockcroft–Gault formula. A detailed clinical history
and physical examination was obtained for each patient before acceptance into
the study. Demographics including age, sex, systolic blood pressure (SBP),
diastolic blood pressure (SBP), and smoking status were obtained for cases and
controls alike.
BIOCHEMICAL ASSAYS
Serum creatinine, blood urea nitrogen (BUN), serum albumin, C-reactive
protein (CRP), calcium, phosphorus, alkaline phosphatase, total serum
cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol,
and triglycerides, were measured in all cases and controls. Glycosylated
hemoglobin was estimated in patients with diabetes. Serum intact parathyroid
hormone (PTH) was also determined in all PD patients.
MEASUREMENT OF CIMT
We measured CIMT as previously described
(11). Briefly, the carotid
segments used for measurement of CIMT were the distal straight 1 cm of the
common carotid arteries, the carotid bifurcations, and the proximal 1 cm of
the internal carotid arteries. The average of measurements taken during 3
cardiac cycles at end-diastole and the average of right and left CIMT were
taken as the mean CIMT. Plaque was defined as a distinct area protruding into
the vessel lumen, with a thickness greater than that found in surrounding
areas (12). Each measurement
was repeated 4 times.
MEASUREMENT OF BRACHIAL FMD
We measured FMD of the brachial artery according to the American College of
Cardiology guidelines (13).
The brachial artery was scanned 5–15 cm above the antecubital fossa.
Resting diameter was measured, and then a blood pressure cuff was inflated
around the arm to at least 50 mm Hg above SBP for 4.5 minutes. A longitudinal
scan was recorded continuously from 30 seconds before to 2 minutes after cuff
release. A measurement of maximum diameter was taken 45–60 seconds after
cuff release. After 15 minutes, a further measurement of diameter was taken at
rest and 3 minutes after sublingual spray with 400 µg glyceryl trinitrate.
All measurements were taken at end-diastole, coinciding with the R-wave on an
electrocardiograph monitor. Distance was measured from the anterior to the
posterior M lines (media–adventitia interface), and every measurement
was taken as the average of 3 consecutive cardiac cycles.
We used the following formula to determine FMD:
To assess reproducibility of the technique, we looked at the reliability of
the same observer reading scans on 3 separate occasions.
The known traditional and nontraditional risk factors associated with
atherosclerosis measured by CIMT and FMD were determined. The differences for
all these cardiovascular mortality risk factors—cardiovascular variables
measured on echocardiography, lipid profiles, the inflammation marker CRP, and
dialysis adequacy—were determined between the ESRD patients and the age-
and sex-matched controls. Differences for all these risk factors were also
determined between patients with and without diabetes.
STATISTICAL ANALYSIS
All data are expressed as mean ± standard deviation. The Student
t-test was used to compare means between groups, and the chi-square
test was used to compare proportions between groups. A p value less
than 0.05 was considered statistically significant. The Pearson correlation
was used to analyze the correlations between CIMT and other risk factor
variables.
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RESULTS
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Table 1 shows the details of
the demographic, clinical, and biochemical parameters of the case and control
groups. The ESRD patients on CAPD (cases) had significantly higher SBP levels
than did the controls (p = 0.04), but there was no significant
difference of DBP between the two groups. In ESRD patients as compared with
controls, BUN, serum creatinine, phosphate, total cholesterol, triglycerides,
and LDL cholesterol levels were significantly higher (p < 0.001).
As compared with controls, patients also showed significantly lower levels of
HDL cholesterol, hemoglobin, and calcium. Serum albumin was significantly
lower in cases than in controls (3.73 ± 0.67 g/dL vs 4.15 ± 0.30
g/dL, p = 0.001). Mean parathyroid hormone was significantly higher
in patients than in controls (224.86 pg/mL vs 27.8 pg/mL, p = 0.001).
Levels of CRP were also significantly higher in cases than in controls (2.64
± 2.33 mg/L vs 0.20 ± 0.13 mg/L, p = 0.001).
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TABLE 1 Comparison of Clinical and Biochemical Characteristics Between Cases and
Controls and Between Patients With and Without Diabetes
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Of the 62 CAPD patients studied, 38 had diabetes, and 24 did not. In
diabetic as compared with nondiabetic patients, SBP was significantly higher
(165 ± 15 mm Hg vs 153 ± 17 mm Hg, p = 0.03); however,
DBP was similar in patients with and without diabetes. Compared with
nondiabetic patients, patients with diabetes had significantly lower PTH
levels (53.49 pg/mL vs 301.02 pg/mL, p = 0.02). Similarly, diabetic
patients had significantly higher levels of CRP (3.70 ± 2.49 mg/L vs
1.22 ± 1.19 mg/L, p = 0.002).
Table 2 shows the results of
comparing CIMT and FMD in cases and controls and in diabetic and nondiabetic
cases. The CIMT of cases was significantly greater than that of controls (0.60
± 0.08 mm vs 0.54 ± 0.03 mm, p < 0.001). The greater
CIMT in ESRD patients on CAPD suggests that uremia is an independent risk
factor for atherosclerosis. On the other hand, FMD was significantly lower in
cases than in controls (0.15 ± 0.08 cm vs 0.21 ± 0.04 cm,
p = 0.02). In diabetic CAPD patients, CIMT was significantly greater
than in nondiabetic patients (0.62 ± 0.08 mm vs 0.58 ± 0.07 mm,
p = 0.05). However, in diabetic and nondiabetic cases, FMD was
statistically similar (0.16± 0.03 cm vs 0.18 ± 0.03 cm,
p = 0.20).
Table 3 shows correlations
between CIMT and other variables. We observed a significant positive
correlation between CIMT and serum inorganic phosphate, but the correlation
with serum calcium was negative and weak. We observed no correlation of CIMT
with CaxP, alkaline phosphatase, or intact PTH. We observed a
significant negative correlation between CIMT and HDL cholesterol and a weakly
significant positive correlation between CIMT and LDL cholesterol. However, no
correlation was evident between CIMT and total cholesterol, triglycerides, or
very-low-density lipoprotein cholesterol.
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TABLE 3 Pearson Correlation Between Carotid Intima Media Thickness (CIMT) and Other
Variables Affecting Atherosclerosis in End-Stage Renal Disease Patients on
Continuous Ambulatory Peritoneal Dialysis
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DISCUSSION
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In past studies, CIMT (which can be measured noninvasively using B-mode
ultrasonography) has been reported be an early marker of atherosclerosis and a
predictor of vascular events
(9,10).
In the present study, we observed that, in ESRD patients on CAPD as compared
with nonuremic patients, atherosclerosis was significantly advanced as
assessed by CIMT and FMD. Also, in diabetic as compared with nondiabetic CAPD
patients, CIMT was significantly higher. But despite a significantly higher
CIMT in diabetic patients, FMD in those patients— a marker of early
endothelial dysfunction in arteries— was similar to that found in
nondiabetic CAPD patients. A higher CIMT but a similar FMD in diabetic as
compared with nondiabetic ESRD patients suggests that uremia is an independent
risk factor for functional impairment from atherosclerosis, in terms of
dilatation of vessels in response to stress and nitroglycerine. Previous
studies also reported higher CIMT in dialysis and pre-dialysis uremic patients
(14,15)
In a study by Verbeke et al.
(16), patients with ESRD and
control subjects had similar brachial artery blood flow, but shear stress was
lower in patients with ESRD; control subjects showed a lower shear rate and
lower whole-blood viscosity. In patients with ESRD, larger arterial diameter
was associated with low shear stress and increased elastic modulus of the
arterial wall. Anemia-associated low whole-blood viscosity aggravates low
shear rate, further contributing to shear stress reduction. These
abnormalities are associated with a decreased vasodilatation response to
mechanical endothelium stimulation. In patients as compared with control
subjects, brachial artery compliance and FMD both increased in response to
increased stress induced by hand-warming. In the present study, we observed a
similar result of lower FMD and brachial artery compliance. We also found that
hemoglobin is significantly correlated with CIMT and predicts CIMT.
The other important observation in the present study was the presence of
other predictors of CIMT in ESRD patients on CAPD. Age, diabetes, and SBP were
other risk factors and predictors of atherosclerosis in these patients.
Ishimura et al. (17)
reported similar observations in hemodialysis patients. Advanced
atherosclerosis measured by CIMT is characteristic in ESRD patients with
diabetes mellitus on hemodialysis
(17). Recently,
atherosclerosis was reported to be advanced in patients with chronic renal
failure, and chronic kidney disease has been emphasized as a significant
predictor of cardiovascular disease in many studies
(7,8).
Other studies also showed that, as compared with control subjects, patients
with uremia—not only those on hemodialysis, but also pre-dialysis uremic
patients— had CIMT values reflecting advanced atherosclerosis
(14,15).
Dyslipidemia is another established risk factor for atherosclerosis in
uremic and nonuremic patients. We showed that LDL cholesterol is positively
correlated with CIMT (r = 0.18, p = 0.04) and that HDL
cholesterol is negatively correlated with atherosclerosis (r
=–0.33, p = 0.001) in these CAPD patients. However, CIMT was
not correlated with total cholesterol, possibly because CAPD patients have low
total cholesterol as a result of malnutrition. Serum albumin was significantly
lower in ESRD patients than in controls with normal renal function.
Serum inorganic phosphate was observed to be significantly correlated with
CIMT (r = 0.38, p = 0.001) and is a significant predictor of
CIMT. In accord with our observations, Ishimura et al.
(17) also reported that
inorganic phosphate is an independent risk factor for CIMT in hemodialysis
patients, and that CIMT is not correlated with CaxP, alkaline
phosphatase, or intact PTH. The negative correlation of serum calcium with
CIMT (r =–0.21, p = 0.02) again indirectly suggests
that hyperphosphatemia is more responsible for the increased CIMT in these
patients. In dialysis patients, hyperphosphatemia has been emphasized as a
significant risk factor for the development of secondary hyperparathyroidism
and uremic bone disease
(18,19).
Hyperphosphatemia has been reported to be significant risk factor for vascular
calcification, and sevelamer hydrochloride therapy to reduce phosphate levels
has been reported to attenuate vascular calcification
(20). As in our study,
Ishimura et al. also showed that intact PTH is not correlated with
CIMT (17). Recently, inorganic
phosphate was reported to induce, in vitro, a phenotypic change of
vascular smooth muscle cells into osteoblast-like cells, secreting
calcium-binding proteins such as osteocalcin and osteopontin
(21). Inorganic phosphate also
induced core binding factor a1, a key transcription factor in osteoblastic
differentiation, in vascular smooth cells in vitro
(21,22).
These in vitro studies, together with the study by Ishimura et
al. in hemodialysis patients, suggest that hyperphosphatemia may induce
osteoblastic phenotypic changes in vascular smooth cells and proliferation of
vascular cells, possibly leading to increased arterial wall thickness in
affected patients. Our study indirectly supports the Ishimura group's in
vitro studies.
The significant correlation of CRP with CIMT in our study again supports
the hypothesis of inflammation and atherosclerosis in ESRD patients on
dialysis (23). However, Lorenz
et al. recently showed that highly sensitive CRP is not associated
with CIMT progression
(24).
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CONCLUSIONS
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We conclude that ESRD patients on CAPD have significantly greater CIMT and
lesser FMD than do diabetic and hypertensive control subjects with normal
renal function. Among ESRD patients on CAPD, those with diabetes have
significantly greater CIMT than do those without diabetes. However, FMD, an
early marker of endothelial dysfunction and atherosclerosis, was similar in
diabetic and nondiabetic ESRD patients on CAPD. That finding suggests that
ESRD itself is a strong predictor of poor FMD, a result that is not affected
by the presence or absence of diabetes, a major risk factor for increased
atherosclerosis. Age, diabetes, higher SBP, higher LDL and lower HDL
cholesterol, and higher CRP are the risk factors and predictors of
atherosclerosis in these patients. Serum inorganic phosphate is an independent
risk factor for atherosclerosis and is significantly correlated with CIMT in
ESRD patients on CAPD. In patients with ESRD, CIMT and FMD can be used as
noninvasive tools to monitor atherosclerosis and endothelial dysfunction
respectively.
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ABSTRACT
PATIENTS AND METHODS
