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Print version ISSN 0101-2800
J. Bras. Nefrol. vol.34 no.1 São Paulo Jan./Mar. 2012
Andrea Lordsleem; Ana Paula Santana Gueiros; José Edevanilson de Barros Gueiros; Brivaldo Markman Filho; Edgar Guimarães Victor
Universidade Federal de Pernambuco UFPE
INTRODUCTION: Patients with chronic kidney disease (CKD) experiment a synergistic effect of the traditional and the emerging uremia-related risk factors for atherosclerosis.
OBJECTIVE: Draw the epidemiologic profile of a group of CKD patients who underwent cardiac evaluation.
METHODS: Symptomatic patients, patients with ischemia on myocardial scintigraphy and/or systolic dysfunction on echocardiography, patients older than 50 years and diabetes mellitus (DM) as a cause of CKD, and those with two or more risk factors underwent coronary angiography. Asymptomatic, non-diabetic patients and patients with no risk factors were investigated with echocardiography. Those with a single risk factor were investigated with echocardiography and scintigraphy.
RESULTS: 46 patients (58.7% men) were enrolled. Their mean age was 50.7 ± 11.7 years. 91.3% were on dialysis, for 61.96 ± 55.1 months. Hypertension was the cause of CKD in 56.5%. Of the 28 patients (60.9%) who underwent angiography, 53.6% had coronary artery disease (CAD). The patients were divided into three groups: those with CAD (A), those without CAD (B) and those who didn't undergo coronary angiography (C). A significant difference occurred only between groups B and C, as regards an abnormal ABI (p = 0.026), with no ABI abnormality in group C, and as regards the mean age, which was higher in group B (p = 0.045). In group A, 53.3% of the patients were in the preoperative stage of parathyroidectomy.
CONCLUSION: This study confirmed the high rate of cardiovascular disorders, including CAD, in patients with CKD, especially those on dialysis.
Keywords: Coronary disease. Renal insufficiency, chronic. Inflammation. Atherosclerosis.
Chronic kidney disease (CKD) patients are at high risk of cardiovascular diseases (CVD), which account for 40-50% of the deaths in this population.1-4
The high cardiovascular risk could be explained, in part, by a synergy between traditional risk factors and the newly emerging uremia-related risk factors, resulting in accelerated atherosclerosis and early death. Furthermore, the diagnosis of CKD, made when CVD is already advanced (epidemiologic causality), and the malnutrition, inflammation and atherosclerosis (MIA) syndrome present in these patients, would lead to accelerated atherosclerosis.5,6
The emerging factors, mineral and bone metabolism disturbances, hyperhomocysteinemia, oxidative stress and inflammation, which are mostly cause or consequence of endothelial dysfunction, grow in importance as the renal impairment progresses.2,7,8 All risk factors interact and increase the cardiovascular mortality of CKD patients.8-12
Mineral and bone metabolism disturbances, characterized by abnormal serum levels of calcium, phosphorus and parathyroid-hormone (PTH), are associated with extraosseous (arterial, valvular and myocardial) calcifications, and play an important role in the pathogenesis of myocardial hypertrophy and fibrosis. Vascular calcification is strongly associated with cardiovascular events and death.2
In CKD, a paradoxical association between some risk factors and mortality has been observed. Curiously, systemic arterial hypertension and overweight apparently protect these patients, determining a reverse epidemiology. Serum cholesterol levels positively correlate with serum albumin levels, and negatively correlate with serum C-reactive protein (CRP) and interleukin-6 levels, in a reflection of the MIA syndrome.6
We assessed the clinical, demographic and laboratory characteristics of a group of stages 4 and 5 CKD patients, who underwent cardiac evaluation, including coronary angiography, in an attempt to know the epídemiologic profile of this population at cardiovascular risk.
This case-series study was undertaken at the Cardiology Division of the Hospital das Clínicas (HC) of the Federal University of Pernambuco, Brazil, during the October 2008 October 2009 period. The study was approved by the institutional Research Ethics Committee, and all participants signed their informed consent.
46 stages 4 and 5 CKD patients, over the age of 18 years, free from acute or chronic infectious diseases and with no severe liver disease, were included in the study. The patients were referred from the Nephrology Division of the same institution, with the following indications: pre-transplantation assessment, pre-parathyroidectomy (PTx) assessment, or cardiovascular signs/symptoms.
The following clinical and demographic parameters were assessed: age, sex, cause of CKD and time on dialysis. The patients were questioned about their symptoms, classic risk factors for coronary artery disease (CAD) (hypertension, diabetes mellitus, dyslipidemia and smoking), and use of cardioprotective medications. All the patients were scored according to Framingham's criteria, and underwent general and cardiac physical examinations. Weight was measured in kilograms and height and abdominal circumference in centimeters. Two consecutive blood pressure readings were obtained, one from an upper limb without an arteriovenous fistula and another from the ipsilateral lower limb, for calculation of the ankle-brachial index (ABI). The latter is the ratio between the systolic blood pressures obtained in the lower limb and in the upper limb, with values below 0.9 being abnormal.
The following serum determinations were performed at the Central laboratory of the same institution: albumin (bromocresol green method, Abott, reference: 3.5-5.2 g/dL); high-sensitivity CRP (Aptec nephelometry, Bisys, reference: 0-1 mg/dL); total cholesterol (colorimetric enzymatic method); high-density lipoprotein (HDL, enzymatic method); low-density lipoprotein (LDL, enzymatic method); triglycerides (enzymatic method); fasting glucose (enzymatic method, reference: 70-99 mg/dL); calcium (o-cresolphthalein method, reference: 8.5-10.1 mg/dL); phosphorus (modified phosphomolybdate method, reference: 2.5-4.9 mg/dL); intact PTH (chemoluminescence, reference: 15-68.3 pg/mL); hematocrit (automated method, Beckman Coulter, reference: 47% ± 5 for men and 42% ± 5 for women.
A chest radiograph was obtained on an interdialytic day, for all patients, and it was considered abnormal when at least one of the following was found: increased cardiothoracic ratio, increased vascular markings, aortic calcification and increased diameter of the aortic root. Additionally, a 12-lead resting electrocardiogram was obtained, with an abnormal result consisting of at least one of the following: a rhythm other than sinus-driven, conduction disturbances, chamber overload and alterations of ventricular repolarization.
For CAD assessment, the patients were stratified in risk groups, according to Gowdak et al.12 The very high-risk group consisted of patients with symptoms suggestive of CAD or anginal equivalent. The high-risk group was composed of diabetics aged over 50 years and of patients with two or more classic CAD risk factors. Patients from the very high and high-risk groups underwent coronary angiography. The medium-risk group, consisting of asymptomatic non-diabetics, with a single classic CAD risk factor, was investigated with resting echocardiography and with resting and stress myocardial scintigraphy. The low-risk group, consisting of asymptomatic non-diabetics without CAD risk factors, was investigated with resting echocardiography.
Other criteria for coronary angiography indication were evidence of ischemia on resting/stress myocardial scintigraphy and the presence of systolic dysfunction (left ventricular ejection fraction under 45%) on resting echocardiography.
Obstructive coronary disease was defined by the presence of stenotic lesions of 50% or more of the arterial lumen, in at least one coronary artery and/or its main branches.
According to the coronary angiography-defined CAD status, the patients were divided into two groups: Group A, composed of those with CAD and Group B, composed of those without CAD. Another group (C), was composed of the medium and low-risk patients. A comparative analysis between the groups was performed.
Left ventricular hypertrophy (LVH) was diagnosed when the echocardiography-defined left ventricular mass index was > 134 g/m2 (men) and > 110 g/m2 (women).13
To assess the MIA syndrome, we used serum albumin as a nutritional parameter, serum CRP as an inflammation marker, and the ABI as an indicator of atherosclerosis. The MIA syndrome was diagnosed when all the following were present: serum albumin level < 3.5 g/dL, CRP level > 1 mg/dL and ABI < 0.9.
PTH levels were presented as median and first and third quartiles. The other variables were presented as means and standard deviations. Kolmogorov-Smirnov's test was applied for normality supposition. For comparative analysis of the quantitative variables, we used Student's t test for independent samples, with the chi-squared and Fisher's exact tests being used for analysis of the qualitative variables. For between-groups comparison of the PTH levels, we used Mann-Whitney's non-parametric test. The significance level was set at 5%. The Excel 2000 and SPSS v 8.0 software were used.
Of the 46 patients (mean age 50.7 years) assessed, 58.7% were men and 42 (91.3%) were on dialysis, with a mean dialysis time of 61.96 ± 55.1 months. 4 (8.7%) patients were referred from the CKD conservative treatment outpatient service, and were characterized as having a very high risk. The main causes of CKD were hypertension (56.5%) and diabetes mellitus (17.4%). As for the traditional risk factors, 91.3% of the patients had hypertension, 23.9% diabetes and 23.9% dyslipidemia. 13.0% actively smoked and 41.3% were former smokers.
As shown in Table 1, there was a low rate of cardioprotective medication use, with aspirin as the most frequently used drug, by around 40% of those at very high and high risk. Table 2 shows the Framingham's score for Groups A and B.
As for symptoms, 67.4% of the patients were asymptomatic, with dyspnea being the most frequent symptom (32.6%), and chest pain occurring in only 17.4%. 40% of Group A patients were asymptomatic.
Of all the patients, 30.4% were seen during their PTx preoperative assessment.
Obstructive CAD was diagnosed in 15 patients (32%) of the total sample. Of the 28 patients (61.9%) with coronary angiography indication, CAD was diagnosed in 53.6% (Group A). Tables 1 and 3 show the comparative analyses between Groups A and B. As can be seen, in spite of the lack of a significant difference between the PTH medians, the third quartile of the PTH of Group A was twice that of Group B. In addition, 53.3% of Group A patients were in the PTx perioperative period, compared with 15.4% of Group B (p = 0.055).
Medium and low-risk patients (n = 18, Group C) were non-invasively assessed. The comparative analysis between Groups B and C is shown in Table 4. The patients of these groups differed as for age, abdominal circumference and chest radiograph abnormalities, which were all more frequent in Group B.
Mean Echocardiography-defined left ventricular ejection fraction (LVEF) was 63 ± 9% (n = 44) and diastolic function (n = 43) was normal in only 34.9% of the patients. LVH was frequent, being detected in 71.4% (Group A), 50% (Group B) and 47% (Group C).
As for the MIA syndrome, no patient had the three parameters at the same time. The most frequently altered parameter in Group A was inflammation (Table 5).
The unacceptably high mortality rate of CKD patients remains even after stratification of the known cardiovascular risk factors, such as age, sex, smoking, sedentariness, hypertension and diabetes mellitus.1,2 Therefore, factors which are inherent in the uremic state are added to the classic factors to promote accelerated atherosclerosis and early mortality.
Cardiac assessment of CKD patients, chiefly those on dialysis, is a permanent challenge to cardiologists, as myocardial scintigraphy frequently yields false-positive results (because of the high rate of LVH), and because complications (increased blood pressure) frequently occur during pharmacological-stress echocardiography.12
Besides, chest pain is a poor indicator of CAD in this population.14 Because of the high rates of microvascular dysfunction and LVH in CKD patients, angina without relevant CAD is reported to occur in 30-44% of these patients, in contrast with only 17% of the general population.14 On the other hand, the absence of angina does not rule out CAD, a finding that has been attributed to diabetic neuropathy and uremia.15
We observed a low rate of chest pain (17.4%), and even in the group with CAD, a large number of patients was totally asymptomatic, confirming what was reported elsewhere.14,15 Furthermore, because dyspnea, the main symptom reported by our patients, is frequent in patients on dialysis, due to volume overload, its presence does not always alert the nephrologist to the possibility of CAD. These peculiarities, among others, make the cardiovascular assessment of CKD patients a particularly difficult task.
In spite of the high rate of electrocardiographic abnormalities found, which is in agreement with the literature data,16 there was no significant difference between Groups A and B. This decreases the importance of electrocardiography for the cardiac assessment of CKD patients.
It is noteworthy that liaison between nephrologist and cardiologist is still insufficient in Brazil. This is due, in part, to cardiologists' lack of knowledge about this particular population and the difficulty to find a cardiologist to whom the patient can be referred. In fact, most large cardiac studies exclude CKD patients, further contributing to the paucity of knowledge and strategies targeting this population.
We demonstrated that the cardiac evaluation of our patients was delayed, that is, it was performed in those with PTx indication and mean dialysis time of five years. Besides, the low rate of cardioprotective drug use found indicates the need of greater liaison between cardiologist and nephrologist. Other authors have also shown a low rate of cardioprotective drug use in CKD patients.17 This fact is associated with high early and late mortality, and inferior therapeutic response to pharmacological and non-pharmacological interventions alike.1,2
CKD patients have both classic and uremia-related risk factors. The rate of classic risk factors, such as hypertension and smoking, was high, in accordance with what was reported by Gowdak et al.,9 demostrating that the epidemiologic profile of CKD favors atherosclerosis. However, the mean 10-year Framingham's risk of our patients with CAD was low (5.3% for women and 6.3% for men), which does not reflect the high cardiovascular risk seen in CKD, and characterizes this population as an exception, besides confirming the importance of other pro-atherosclerotic factors that are not quantified by this classic score.
The prevalence of CAD in our sample was 32.6%, a high rate, chiefly because it was mainly early CAD. In fact, our patients' mean age was 50 years. This prevalence increased to 53.6%, when those who underwent coronary arteriography were analyzed, which demonstrates the high CAD risk in the group selected for coronary angiography.
Because of the higher pre-test likelihood of CAD with non-invasive stratification of the CKD population, coronary angiography is indicated in high and very high-risk groups, as well as in symptomatic patients, those over the age of 50 years, diabetics, and/or those with structural alterations, such as a reduced LVEF, even when asymptomatic.16
The high LVH rate we found confirmed the data reported by Kundhal et al.,18 who observed LVH in 74% of the dialysis population. There are several factors implicated in the development of LVH in the CKD population, such as arterial thickening (due to alterations of the calcium, phosphorus, PTH and vitamin D metabolism) and systolic hypertension (due to a chronic state of hypervolemia and anemia-related increased after-load).
Mineral and bone metabolism impairment was evident in this study, as shown by our patients' serum PTH levels. In fact, a PTH serum level over 300 pg/mL indicates considerable hyperparathyroidism. Furthermore, 53.3% of Group A patients were in the PTx perioperative stage, indicating more severe secondary hyperparathyroidism in these individuals.
Our study should alert nephrologists and cardiologists to the fact that CKD patients on the PTx waiting list are at risk of CAD. Hence, should patients being considered for PTx undergo coronary angiography? Because of our small sample size we could not answer this question. It would also be interesting to assess the impact of the PTx waiting time, as this is determinant of all the deleterious effects of the PTH on the heart.
PTH directly affects muscle cells in vessels and the heart, altering the energy metabolism and leading to calcium accumulation. Hyperparathyroidism has been suggested to play a role in the pathogenesis of myocardial fibrosis and hypertrophy, vascular calcification, endothelium-mediated vasodilation dysfunction and alterations in the diastolic function of CKD patients.19 The complexity of the alterations surrounding the bone metabolism and vascular calcification, both in hyperparathyroidism and adynamic bone disease, in which PTH is reduced, has made it difficult to correctly associate PTH with CAD.18 Decreased and increased PTH levels are likely to be associated with CVD.
As for the MIA syndrome, which is known to be associated with atherosclerosis, it was not diagnosed in any of our patients. Stenvinkel et al.20 reported malnutrition in 44%, inflammation in 32% and carotid plaques in 72% of their patients, although an association of the three parameters occurred in only 30% of the cases. Inflammation was the parameter most frequently found in our CAD patients. Because of the results reported by Silva Júnior.,3 who demonstrated that inflammation is the main determinant of the MIA syndrome, we cannot totally exclude the association of this syndrome with the CAD of our patients.
An abnormal ABI indicates peripheral atherosclerosis in the general population, being associated with a higher risk of CAD and carotid disease.21 Gabriel et al.21 observed ABI values over 1.3 to be associated with diffuse atherosclerotic disease, with calcification of the middle layer and vascular rigidity. This phenomenon would be more frequent in high-risk groups, such as diabetics, elders and those with CKD. The low rate of abnormal ABI we found could be explained by the high rate of hyperparathyroidism, once this metabolic disorder is associated with vascular calcification and increased arterial rigidity, which would then increase the ABI. We might thus have used a parameter that influenced the low diagnostic rate of atherosclerosis in our population.
We used serum albumin to diagnose the nutritional status of our patients. Although this is not sensitive enough for the diagnosis of malnutrition, albumin measurement was the available exam during the study period. Hypoalbuminemia may be due to a combination of inflammation and low protein-energy intake, contributing to reduced fat stores and muscle mass and being associated with the high mortality seen in patients on hemodialysis.22,23 The combination of a normal serum albumin level and an increased body mass index (BMI) suggested a good nutritional status.
When the patients who did not undergo coronary arteriography (Group C) were assessed, we observed a younger population, with smaller abdominal circumference, lower rate of chest radiograph alterations and more favorable atherosclerosis parameters (ABI), that is, patients with less severity criteria. Obviously, CAD cannot be safely ruled out in these patients, but this is less likely because of their better clinical profile in comparison with Group B patients, that is, those who underwent coronary arteriography and did not have CAD.
We confirmed the high rate of cardiovascular alterations, including CAD in our CKD patients, chiefly those on dialysis.
Although the MIA syndrome was not diagnosed in any patient, we were able to demonstrate the importance of other uremia-related factors, such as mineral and bone metabolism disturbances, in the development of CAD.
Furthermore, we demonstrated that in spite of the high cardiovascular mortality in the CKD population, these patients are still under-assessed and under-treated with cardioprotective drugs, which is against common sense.
Finally, this study consolidates the notion that the CKD patient has particular characteristics that make him an exception as long as the cardiovascular risk is concerned.
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Correspondence to: Submitted on: 02/03/2011. This study was undertaken at the UFPE.
Avenida Professor Moraes Rego, 1.235
Bairro Cidade Universitária
Recife PE Brasil
Zip code 50670-901
Approved on: 11/16/2011.
The authors report no conflict of interest.
Submitted on: 02/03/2011.
This study was undertaken at the UFPE.