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NDT Advance Access originally published online on May 30, 2006
Nephrology Dialysis Transplantation 2006 21(9):2464-2471; doi:10.1093/ndt/gfl291
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

The impact of traditional and non-traditional risk factors on coronary calcification in pre-dialysis patients

Cristianne Tomiyama1, Andrea Higa1, Maria A. Dalboni1, Miguel Cendoroglo1, Sergio A. Draibe1, Lilian Cuppari1, Aluizio B. Carvalho1, Emilio M. Neto2 and Maria Eugenia F. Canziani1

1 Department of Internal Medicine/Nephrology Division, Federal University of São Paulo and 2 Brazil Diagnostic Center, São Paulo, Brazil

Correspondence and offprint requests to: Maria Eugênia F. Canziani, R. Pedro de Toledo 282, São Paulo, SP, Brazil, CEP 04039-000. Email: dialisefor{at}uol.com.br



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Coronary heart disease (CHD) is the leading cause of death among end-stage renal disease patients. There is evidence that coronary calcification is a marker of atherosclerotic vascular disease and is predictive of cardiovascular events, especially in patients on renal replacement therapy. It has recently been suggested that CHD begins in the pre-dialysis period. However, data regarding coronary calcification in this population is scarce. This study was aimed at evaluating such coronary calcification and identifying related factors.

Methods. A total of 96 chronic kidney disease out-patients who were not on dialysis were included. Patients presenting neoplastic, infectious or inflammatory diseases were excluded. Demographic characteristics, clinical profiles, laboratory test results and multislice computed tomography scans were evaluated.

Results. The median age was 55 years (range 20–69 years), 67% were men and the median creatinine clearance was 37 ml/min/1.73 m2. Coronary calcification, defined as a coronary artery calcification score (CACS) >0 Agatston units (AU), was seen in 61 patients (median 89.1 AU, range 0.37–2299.3 AU). On average, these patients were older, more often had diabetes, higher body mass indices and higher Framingham risk indices, as well as presenting higher proteinuria, intact parathyroid hormone (iPTH), blood glucose and triglyceride levels compared with those without calcification. Multiple logistic regression analysis, adjusted for age and diabetes, identified iPTH and triglyceride levels as independent determinants of calcification. Severe calcification (CACS >400 AU) was seen in 22 patients, who were also older and more frequently had a history of cardiovascular disease (CVD), as well as having higher levels of phosphorus, blood glucose and soluble Fas (sFas). Multiple logistic regression analysis, adjusted for age and diabetes, identified phosphorus and sFas levels as independent determinants of severe coronary calcification.

Conclusion. Coronary calcification is highly prevalent in pre-dialysis patients and correlates with traditional and non-traditional risk factors for CVD.

Keywords: chronic kidney disease; coronary arteriosclerosis; multislice computed tomography; vascular calcification



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
More than half of all the deaths among dialysis patients are due to cardiovascular disease (CVD). The CVD mortality rate among such patients is as much as 20–30 times higher than that seen in the general population [1]. Since overt CVD and its risk factors are common findings at the initiation of dialysis [2], it seems reasonable to expect that the incidence of CVD in pre-dialysis patients would be high. In fact, data from several recent population-based epidemiological studies demonstrated a correlation between reduced renal function and risk for all-cause mortality and CVD mortality, even after being adjusted for traditional CVD risk factors [3,4]. In a study involving patients with stage 4 chronic kidney disease (CKD), as defined in the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, 45.7% died before receiving dialysis [5]. The authors of that study also found that CVD events increased in parallel with decreases in the estimated glomerular filtration rate [3].

Coronary artery calcification, a marker of atherosclerosis, is a common finding in CKD patients, especially in those undergoing dialysis [6,7]. The extent of calcification is directly correlated with the extent and severity of the atherosclerotic lesions observed by angiography [8]. Although the mechanisms responsible for coronary calcification remain unclear, traditional and non-traditional cardiovascular risk factors both appear to be involved in this process. The aims of this study were to examine the prevalence of coronary artery calcification in pre-dialysis patients and to identify factors that are potentially related to its occurrence.



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Subjects
This cross-sectional study involved 96 patients monitored at the out-patient nephrology clinic of the Federal University of São Paulo Hospital for at least 3 months. The inclusion criteria were age from 18 to 70 years and creatinine clearance from 15 to 90 ml/min/1.73 m2. Patients with neoplastic, infectious or inflammatory diseases were excluded.

All of the selected patients were submitted to clinical and physical evaluation. Of the 96 patients studied, 32% were receiving lipid-lowering drugs, 27% were taking acetylsalicylic acid and only 8% were not using any antihypertensive drugs. None of the patients were receiving calcium-containing phosphate-binders (calcium or carbonate acetate) or vitamin D and three patients were regularly using human recombinant erythropoietin and oral iron therapy. Weight and height were measured in order to calculate the body mass index (BMI). Diabetic patients were considered those in regular use of insulin or oral hypoglycaemic drugs. The risk of developing CVD was assessed for each patient according to Framingham risk index [9,10]. The information regarding previous CVD was obtained by a questionnaire in the inclusion visit as well as assessed by the clinical charts. It was characterized by the presence of myocardial infarction, angina pectoris, coronary artery revascularization, cerebral vascular stroke or positive diagnostic procedure result (stress test, coronary angiography or radionuclide imaging). Cardiac insufficiency was defined as an ejection fraction <55%, and left ventricular hypertrophy (LVH) was defined as left ventricular mass index >110 g/m2 in women and >134 g/m2 in men. Laboratory tests and multislice computed tomography (MSCT) were performed within 30 days after patient selection.

All patients gave written informed consent. The study protocol was reviewed and approved by the local Ethics Committee.

Laboratory tests
Blood samples were drawn in the fasting state for determination of serum levels of creatinine, urea, ionized calcium, phosphorus, alkaline phosphatase (reference values: <270 U/l for males; <240 U/l for females), intact parathyroid hormone (iPTH; reference range 10–65 pg/ml), osteoprotegerin (reference range 18.35–42.55 pg/ml), albumin (reference range, 3.4–4.8 g/dl), C-reactive protein (CRP; reference values: >1.1 mg/l = indicative risk of CVD; >5.5 mg/l = indicative risk of inflammation) and soluble Fas (sFas; detection limit: 8 pg/ml), as well as for blood counts, blood gas analysis and determination of lipid profiles. Levels of iPTH were assessed through chemiluminescence immunoassay (Immulite; DPC-Biermann, Bad Nauheim, Germany). Osteoprotegerin levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit (Immundiagnostik, Benheim, Germany). A Hitachi 912 chemistry analyser (Roche Diagnostics, Indianapolis, IN, USA) was used to measure albumin through colorimetric assay. An immunometric assay (Immulite; DPC-Biermann) was used to assess CRP with a functional sensibility <0.2 mg/l. Serum levels of sFas were determined using a commercial ELISA kit (BD Pharmingen, San Diego, CA, USA).

We collected 24 h urine samples to determine proteinuria and to assess creatinine levels. The resulting data were used in the calculation of creatinine clearance, which was corrected for body surface area. The study population was grouped according to the stages of CKD, in keeping with K/DOQI guidelines [11]. Proteinuria was defined as urinary protein excretion >150 mg/24 h. Hyperparathyroidism, hyperphosphataemia and hypercalcaemia were defined according to K/DOQI guidelines regarding bone metabolism in the different stages of CKD [12].

Coronary tomography
Coronary artery calcification was evaluated using MSCT (SOMATOM® Volume Zoom; Siemens, Erlangen, Germany) to determine the coronary artery calcification score (CACS). The heart was scanned for 20–30 s, with a 3 mm gap between slices. The overall area scanned was from the level of the carina to the diaphragm, and the timing of image acquisition was coordinated with the diastolic phase of the cardiac cycle at 60% of the R wave to R wave interval RR interval as determined through electrocardiographic monitoring. This equipment is capable of detecting lesions of a density of at least 130 Hounsfield units (HU) and a minimum area of 0.5 mm2. Total CACS was calculated based on formulas using measurements of total volume and area of calcified lesions, as well as mean and maximum density. The CACS was calculated individually for the left main coronary artery, descending branch of the left coronary artery, circumflex branch of the left coronary artery and right coronary artery. The scores were then summed to calculate the total CACS. The final score is expressed as modified Agatston units (AU) [13]. Coronary calcification was defined as a CACS >0 AU and severe calcification as a CACS >400 AU.

Statistical analysis
All values are expressed as median and range or as frequency and proportion. The patients were divided into groups according to the presence or absence of calcification and severe calcification. The Mann–Whitney test or Student's t-test, when appropriate, was used for comparisons between groups. The distribution of categorical variables among the groups was assessed by chi-square analysis or by Fisher's exact test, when appropriate. The comparison of median CACS in the different stages of CKD was performed using the Kruskal–Wallis test. Multiple logistic regression analysis was applied to identify determinants of calcification and of severe calcification. All variables presenting a significance of at least 0.10 in the univariate analysis were included in the multiple logistic regression model for coronary calcification, which was adjusted for age and diabetes. For each variable, the odds ratio (OR) and the 95% confidence interval (95% CI) were calculated. Values of P < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS for Windows (SPSS Inc., Chicago, IL, USA).



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Demographics and clinical characteristics of the 96 patients studied are displayed in Table 1. The patients were young males, predominantly Caucasian, who were under treatment by a nephrologist for a median of 20 months. Hypertension and diabetes were the main causes of CKD, and a high prevalence of cardiovascular risk factors was observed in the study population.


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  		Table 1. Demographics and clinical characteristics (n = 96)

 
Laboratory test results are presented in Table 2. The median creatinine clearance was 37 ml/min/1.73 m2 (range 15–82 ml/min/1.73 m2). There were 13 patients who were classified as having stage 2 CKD, 51 who were classified as having stage 3 CKD and 32 who were classified as having stage 4 CKD. Proteinuria was found in 54% of the patients. Although median haemoglobin values were within the normal range, anaemia (haemoglobin <11 g/dl) was observed in 13% of the patients, all of whom had stage 3 or stage 4 CKD.


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  		Table 2. Laboratorial parameters (n = 96)

 
Bone mineral metabolism was altered by CKD, as evidenced by the fact that 68% of the patients presented elevated levels of iPTH. Hyperphosphataemia and hypercalcaemia were found in 8 and 3%, respectively. Elevated levels of alkaline phosphatase were seen in 10% of the patients. Serum osteoprotegerin was found to be >42.5 pg/ml in 47% of the patients.

Total cholesterol levels were >200 mg/dl in 51% of the patients, LDL cholesterol was >100 mg/dl in 65%, triglycerides were >150 mg/dl in 47% and HDL cholesterol was <40 mg/dl in 20%. In 83% of the patients, at least one lipid profile abnormality was found.

Levels of CRP were >1.1 mg/l in 81% of the patients and >5.5 mg/l in 34%.

The MSCT scans revealed calcification in 64% of the patients. The median CACS among those patients was 89.1 AU (range 0.37–2299.3 AU). It is important to note that 23% of the patients presented severe calcification (CACS >400 AU). Stratified by CKD stage, calcification was detected in 9 (69%) of the 13 patients with stage 2 CKD (median CACS, 74 AU; range 0.4–560.9 AU); in 31 (61%) of the 51 patients with stage 3 CKD (median CACS, 31.7 AU; range 0.37–1301.8 AU) and in 21 (66%) of the 32 patients with stage 4 CKD (median CACS, 403.9 AU; range 1.5–2299.3 AU). Severe calcification was detected in 2 (15%) of the stage 2 CKD patients, in 9 (18%) of the stage 3 CKD patients and in 11 (34%) of the stage 4 CKD patients. There were no significant differences in the prevalence of CACS as well as of severe CACS among the stages of CKD.

The significant differences between patients with and without calcification are shown in Table 3. The patients with calcification were older, had higher BMIs and more often had diabetes, as well as presenting higher levels of proteinuria, ionized calcium, iPTH (Figure 1), blood glucose and triglycerides. In addition, Framingham risk indices were higher among these patients.


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  		Table 3. Comparison between patients with (CACS >0) and without (CACS = 0) calcification

 

Figure 1
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  		Fig. 1. iPTH levels in patients with and without calcification.

 
In the multiple logistic regression model to analyse the independent predictors of the presence of CACS, the following variables were included: duration of CKD (months), hypertension (%), BMI (kg/m2), proteinuria (g/24 h), ionized calcium (mmol/l), iPTH (pg/dl), alkaline phosphatase (U/l), blood glucose (mg/dl), triglycerides (mg/dl) and Framingham risk index. After being adjusted for age and diabetes, the multiple logistic regression analysis identified the independent determinants of coronary calcification as iPTH (P = 0.001; OR = 1.014; 95% CI 1.006–1.023) and triglycerides (P = 0.026; OR = 1.010; 95% CI 1.001–1.019).

A total of 22 patients presented severe calcification (CACS >400 AU). The comparison between these patients and those without severe calcification (CACS ≤400 AU) is detailed in Table 4. The patients with severe calcification were older and more often had a history of CVD or cardiac insufficiency and had a shorter duration of CKD. These patients also presented higher levels of phosphorus, blood glucose and sFas (Figure 2). Median CRP levels did not differ among the groups, although CRP levels >1.1 mg/l were more common in patients with severe calcification than in those without (96 vs 77%; P = 0.029).


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  		Table 4. Comparison between patients with CACS ≤400 and CACS >400

 

Figure 2
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  		Fig. 2. sFas levels in patients with and without severe calcification.

 
In the multiple logistic regression model to analyse the independent predictors of the presence of severe CACS, the following variables were included: duration of CKD (months), previous CVD (%), cardiac insufficiency (%), phosphorus (mg/dl), alkaline phosphatase (U/l), triglycerides (mg/dl), sFas (mg/dl) and CRP (mg/l). The independent determinants of severe calcification, after adjustment for age and diabetes, were phosphorus (P = 0.007; OR = 5.783; 95% CI 1.601–20.885) and sFas (P = 0.009; OR = 1.098; 95% CI 1.024–1.178). It is of note that, even after adjustment for kidney function, phosphorus and sFas remained as independent determinants of severe calcification.



   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Incident dialysis patients have a high prevalence of LVH, congestive heart failure and ischaemic heart disease, suggesting that the excess risk for CVD is present in the early stages of CKD [3,4]. In the general population, the CACS provides a quantitative estimate of total atherosclerotic plaque burden, correlates with degree of obstructive coronary artery disease and predicts CV outcomes [14–17]. Recent research demonstrated that, in dialysis patients, coronary calcification is frequent and severe, and that it correlates significantly with CVD [6,7,18]. A recent study conducted by Block et al. [19] showed that new haemodialysis patients with an evidence of at least mild coronary calcification presented significant increases in CACS within 6 months of starting dialysis, indicating that the calcification process probably begins prior to the initiation of dialysis treatment.

The prevalence of coronary calcification found in the present study was high (64%), a finding that is in contrast to those of some other studies in which lower prevalences (27–40%) were demonstrated [20,21]. This discrepancy could be accredited to differences in the sample selection and patient classification processes. For example, the study carried out by Russo et al. [20] did not include diabetic patients or patients with a history of CVD. Similarly, in the study conducted by Kramer et al. [21], the study sample was younger, patients in all stages of CKD (including stage 1) were selected, and calcification was defined as a CACS >11 AU. Our results are more comparable with those of other studies involving dialysis patients [18,22].

In the present study, patients presenting calcification were older and more often suffered comorbidities such as hypertension (97%), abnormal lipid profile (87%), being overweight/obese (56%) and diabetes (51%). All of these conditions are believed to be components of the metabolic syndrome, which is associated with higher cardiovascular morbidity and mortality, from coronary artery disease in particular, in the general population. In a subsample of the subjects participating in the third National Health and Nutrition Examination Survey, the metabolic syndrome was found to be a strong and independent risk factor for CKD, and there was a graded relationship between the number of metabolic syndrome components and the risk for CKD [23]. Therefore, the higher prevalence of CVD in renal patients could be attributed to the fact that the two diseases have the same risk factors for development and progression.

However, it remains unknown why CVD mortality is higher among CKD patients than among patients with normal renal function who otherwise present the same characteristics. Some studies have suggested that coronary disease is more aggressive in dialysis patients, in whom atherosclerotic lesions are more frequent and severe, and in whom such lesions progress more rapidly than in CVD patients without renal failure [6]. It has been recently proposed that non-traditional risk factors related to uraemia status per se play a role. Special attention has been given to inflammation and bone mineral metabolism disorders. These alterations have been well described in the dialysis population, although little is known regarding the early stages of CKD.

Ross et al. [24] stated that atherosclerosis is an inflammatory disease. Ridker et al. [25] showed that inflammation, assessed by CRP levels, among apparently healthy men is predictive of a first myocardial infarction and ischaemic stroke. It has been suggested that CRP is one of the key mediators of vessel wall calcification in haemodialysis patients [26]. In the present study, 96% of the patients with severe calcification presented CRP levels >1.1 mg/l. Such levels have been associated with cardiovascular risk in the general population.

In the present study, a relationship was observed between sFas and coronary calcification. The results of a previous study conducted by our group suggest that sFas is a marker of inflammation [27]. In renal patients, sFas has also been correlated with coronary artery disease [28]. The Fas antigen and Fas ligand constitute an important regulating system responsible for the activation of apoptosis in various cell types. There is mounting evidence that the development of atherosclerosis is associated with dysregulation of apoptosis in the vessel wall [29,30]. Some authors have reported increased Fas expression at the site of atherosclerotic plaque in humans [30,31]. Perianayagam et al. [32] suggested that high levels of sFas are a compensatory response designed to minimize cellular apoptosis in dialysis patients. In the present study, sFas was correlated with inflammatory markers and was found to be an independent determinant of coronary calcification and of its severity. However, the relationship between these two processes remains undetermined.

Recent data suggest that abnormalities in calcium and phosphorus metabolism influence the development and progression of median wall calcification in CKD patients [7,18,33,34]. In fact, in the present study, higher levels of phosphorus were correlated with the presence of severe calcification. It is of note that the majority of the patients had normal levels of phosphorus and none of the patients in the present study were receiving phosphate-binders, as most of them presented phosphorus concentration in the normal range. In addition, Kestenbaum et al. [35] evaluated a cohort of pre-dialysis patients and observed that serum phosphate levels >3.5 mg/dl were associated with a significantly increased risk for death and that higher levels of phosphorus were independently associated with the risk of myocardial infarction and with mortality risk in this population. Therefore, it could be important to review the phosphorus target levels in the earlier stages of CKD.

It has been suggested that excess phosphate also influences mortality and cardiovascular risk by decreasing 1,25-dihydroxyvitamin D or by increasing circulating iPTH [35]. We also found iPTH to be an independent determinant of coronary calcification. Clinical studies of chronic dialysis patients have shown that excess iPTH correlates with LVH [36], as well as with cardiovascular and all-cause mortality risk [37]. In a study involving non-renal primary hyperparathyroidism patients, Stefenelli et al. [38] detected calcification in the aortic valves of 63% of the patients studied and in the mitral valves of 49%, compared with 12.5 and 15%, respectively, among the gender- and age-matched controls. However, the role that iPTH plays in the process of calcification in CKD patients remains unclear. It seems reasonable to suppose that the calcification process is the result of a complex interaction of iPTH, calcium and phosphorus, as demonstrated by Stevens et al. [39].

There is currently new evidence that vascular calcification is a regulated process, influenced by a tissue-specific cellular mechanism and by selected components present in plasma. Such components include osteopontin, osteoprotegerin, bone morphogenic proteins, matrix Gla protein gene and fetuin-A [40,41]. In fact, in a previous study carried out by our group, we found a correlation between osteoprotegerin levels and coronary calcification in dialysis patients [22], although we were unable to demonstrate this correlation in pre-dialysis patients.

Another intriguing finding was that patients with severe calcification had pre-existing depressed cardiac function. A CACS >400 AU could indicate severe and extensive atherosclerosis. Patients scoring within this range are very likely to have obstructive coronary artery disease and consequently to be at higher risk of developing ischaemic myocardiopathy [42].

Although our study was limited by its cross-sectional design, the results indicate that the prevalence of coronary calcification is high in pre-dialysis patients, and that non-traditional, as well as traditional, risk factors are probably involved in the development and progression of CVD in pre-dialysis patients. Further studies are needed in order to elucidate the mechanisms involved and to identify the causes of the appearance and rapid progression of coronary calcification in pre-dialysis patients.



   Acknowledgments
 
The authors thank Baxter Hospitalar Ltda. of Sao Paulo for supplying the physical space in which to examine their patients.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 6. 2.06
Accepted in revised form: 28. 4.06


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