High Prevalence of Occult Coronary Artery Stenosis in Patients with Chronic Kidney Disease at the Initiation of Renal Replacement Therapy: An Angiographic Examination : Journal of the American Society of Nephrology

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Chronic Kidney Disease

High Prevalence of Occult Coronary Artery Stenosis in Patients with Chronic Kidney Disease at the Initiation of Renal Replacement Therapy

An Angiographic Examination

Ohtake, Takayasu*; Kobayashi, Shuzo*; Moriya, Hidekazu*; Negishi, Kousuke*; Okamoto, Kouji*; Maesato, Kyoko*; Saito, Shigeru

Author Information
Journal of the American Society of Nephrology 16(4):p 1141-1148, April 2005. | DOI: 10.1681/ASN.2004090765
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Abstract

In patients who have chronic kidney disease (CKD) and undergo renal replacement therapy (RRT), cardiovascular disease has a great impact on morbidity and mortality. Cardiac death accounts for almost 40% of total deaths among patients who receive RRT; and approximately 20% of these deaths are due to acute myocardial infarction (AMI) (1,2). After AMI occurs in dialysis patients, the 1-yr survival rate falls dramatically to 40.7% in the United States (1) and 36.5% in Japan (3).

Dialysis therapy or uremic factors may contribute to the atherosclerosis in dialysis patients. Since Lindner et al. (4) reported that acceleration of atherosclerosis occurs after the initiation of hemodialysis (HD), dialysis therapy itself has been considered to be the major cause of the accelerated progression of atherosclerosis in these patients. However, besides the high prevalence of the traditional and important coronary risk factors such as hypertension and/or diabetes among patients with ESRD, those patients are known to have additional atherosclerotic risk factors related to uremia such as hyperfibrinogenemia, hyperhomocysteinemia, and lipoprotein (a) abnormalities. Therefore, stage 5 CKD patients may already be a high-risk group for coronary artery stenosis (CAS) at the predialysis uremic stage. In fact, AMI tends to occur within a short time after the initiation of dialysis rather than after a prolonged dialysis period (29% within 1 yr and 52% within 2 yr after the start of dialysis) (1). In addition, even minor renal dysfunction was recently shown to be an independent cardiovascular risk factor (5,6). Therefore, to improve the prognosis of patients who receive RRT, it is important to assess accurately the cardiac risk of all CKD patients, whether they have ischemic symptoms or not, at the time of initiating RRT.

Generally, less invasive methods such as stress electrocardiography or stress cardiac scintigraphy have been used for the evaluation of CAS in patients without any chest symptoms. Because of a reduced exercise capacity as a result of anemia, peripheral vascular disease, or peripheral neuropathy, dipyridamole is usually used to produce cardiac stress in dialysis patients instead of exercise. However, Marwick et al. (7) reported that dipyridamole single photon emission computed tomography thallium imaging was not effective in ESRD patients (50% false-positive rate and 83% false-negative rate). It is also clear that stress electrocardiography has limitations related to a high prevalence of electrolyte disorders and/or left ventricular hypertrophy in ESRD patients. Blunted or absent tachycardia as a result of autonomic disturbance may also complicate the interpretation of whether there is a hidden cardiac ischemia in ESRD patients. In this study, we investigated the prevalence of significant CAS by coronary angiography (CAG) in asymptomatic stage 5 CKD patients at the initiation of RRT and the relationship with various risk factors, including intima-media thickness (IMT) or ankle-brachial pressure index (ABI) to determine associations, if any, with other atherosclerotic vascular disorders.

Materials and Methods

Patients

As shown in Figure 1, the potential subjects comprised all 69 patients who were referred to our hospital for maintenance HD or continuous ambulatory peritoneal dialysis (CAPD) over 2 yr between January 2002 and December 2003. Patients with a history of angina and/or AMI were excluded, removing 21 (30.4%) of the 69 patients who had already been proved by CAG to have significant CAS and/or coronary occlusion. Eleven of these 21 patients had undergone percutaneous coronary intervention (PCI), and three patients had undergone coronary artery bypass graft before the initiation of RRT. The other exclusion criteria were patients older than 80 yr, patients with malignancy, patients with severe liver disease, and patients who were being treated with steroids. Among the remaining 48 patients without a history of coronary artery disease (CAD), five were excluded because of an age over 80 yr and two patients were excluded because of long-term steroid therapy. As a result, 41 asymptomatic CKD patients who started RRT without previous CAD were tentatively enrolled. Thirty of these 41 patients gave written informed consent to undergo CAG, whereas 11 patients did not agree. Performance of CAG in asymptomatic CKD patients was given prior approval by the institutional ethics committee of our hospital.

CAG and Stress Cardiac Scintigraphy

In all patients, CAG was performed via the femoral approach using Judkins technique. CAS was defined as significant when coronary artery narrowing exceeded 50% of the luminal diameter. Coronary narrowing of >50% on angiography is thought to be associated with 75% or more cross-sectional luminal narrowing on direct anatomic study (8). The severity of CAS was evaluated using quantitative computer-assisted angiography (on-line quantitative coronary analysis system on Philips H5000; Philips Co., Ltd., Tokyo, Japan) by two independent cardiologists without previous knowledge of any information about the patients. When severe CAS with luminal narrowing >90% was found, dipyridamole stress cardiac scintigraphy was also performed to evaluate whether ischemia was detectable by scintigraphy. For the patients with severe coronary stenosis, PCI was performed with balloon angioplasty and stenting. To decrease the risk of exposure to contrast medium, we performed a 3-h HD session immediately after CAG in all patients (both HD and CAPD patients). A high-performance triacetate dialyzer with a surface area of 2.1 m2 (FB210-U; Nipro Co. Ltd., Osaka, Japan) was used: Qb was set at 200 ml/min and Qd was set at 500 ml/min using Kindary AF 3 dialysate solution (Fuso Co. Ltd., Osaka, Japan). More than 80% of the infused contrast medium was removed by this single dialysis session (data not shown). In all patients, CAG was performed within 3 wk after the initiation of RRT.

Echocardiography

All patients were examined by echocardiography to determine the ejection fraction (EF) and left ventricular mass index (LVMI) within 1 wk before CAG, at a time when the electrolyte and volume disorders as a result of ESRD had been almost completely corrected by RRT. LVMI was calculated according to the Penn convention (LVMI g/m2: LVMI = 1.04×[(LVDd + IVSth + PWth)3 − (LVDd)3] − 13.6 g/m2, where LVDd is left ventricular end-diastolic diameter, IVSth is interventricular septal thickness, and PWth is left ventricular posterior wall thickness).

Measurement of IMT

According to our previous report (9), both carotid arteries were examined by high-resolution B-mode ultrasound (Aloka Co. Ltd., Tokyo, Japan) using a 7.5-MHz linear array transducer. This method could measure the arterial wall thickness in 0.1-mm increments. The carotid arteries were examined bilaterally at the following three sites: The common carotid artery (1 cm proximal to the carotid bulb), the carotid bifurcation (1 cm proximal to the division of flow), and the internal carotid artery (1 cm distal to the division of flow). The IMT was defined as the distance between the leading edge of the lumen-intima echo of the near wall and the leading edge of the media-adventitia echo. Measurement of IMT was done blindly by two carefully trained sonographers. In a separate series of IMT measurements performed in other patients, the interobserver coefficient of variation was 8%. For enhancing the reproducibility of measurements, standardized interrogation angles were used. The maximum thickness of the carotid wall was recorded.

Measurement of ABI

Recently, a new device for simple measurement of ABI (form ABI; Colin, Co. Ltd. Komaki, Japan) has been developed (10). The instrument simultaneously records the BP in the four extremities. ABI is calculated as the ratio of ankle to brachial systolic BP and is used for the assessment of the existence of atherosclerotic stenotic vascular lesions of lower extremities. A diagnosis of peripheral artery occlusive disease (PAOD) was made by the presence of intermittent claudication and/or ischemic skin ulceration with an ABI value <0.9.

Laboratory Parameters

Fasting blood samples were collected to examine serum total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprotein (a), plasma fibrinogen, total homocysteine (tHcy), and serum IgG and IgA antibodies for Chlamydia pneumoniae at the initiation of RRT. Hyperlipidemia was defined as a fasting serum total cholesterol level of >220 mg/dl or an LDL cholesterol level >130 mg/dl or triglycerides >150 mg/dl. The C. pneumoniae antibody titer was examined by ELISA, and subjects were classified as seropositive when IgG and IgA titers were above the cut-off index of 1.1.

Statistical Analyses

All data are presented as the mean ± SD. Comparison of group mean values was done with the two-tailed unpaired t test. Categorical variables were compared using the χ2 test and Fisher test. Stepwise logistic regression analysis was performed on the basis of a forward-backward procedure to define the variables related to CAS. The F value for entry or removal of candidate variables from the discriminant function was set at 4.0. Dummy variables were used for gender (male = 1, female = 0), hypertension (yes = 1, no = 0), diabetes (yes = 1, no = 0), hyperlipidemia (yes = 1, no = 0), smoking (yes = 1, no = 0), arteriosclerosis obliterans (ASO) (yes = 1, no = 0), C. pneumoniae seropositivity (yes = 1, no = 0), and CAS (yes = 1, no = 0). StatView 5.0 software for Windows (SAS Institute, Cary, NC) was used for data analysis on a personal computer and P < 0.05 was considered significant.

Results

Patients

The clinical characteristics of the patients are presented in Table 1. Among 30 CKD patients who underwent CAG, the mean age was 63.0 ± 11.0 yr, ranging from 27 to 78 yr. All patients except one had hypertension, and 40.0% (12 patients) of them had diabetes. The underlying renal disease included chronic glomerulonephritis in 17 (56.7%) patients, diabetic nephropathy in 12 (40.0%) patients, and polycystic kidney disease in one (3.3%) patient. Twenty-one patients were started on HD, and nine patients received CAPD. The selection of dialysis modality (HD or CAPD) was done by considering the social circumstances and the ability of the patient. In this study population, the mean plasma levels of tHcy (26.6 nmol/ml; range, 12.6 to 79.9) and fibrinogen (442.4 mg/dl; range, 279.8 to 755.0) were significantly elevated above their normal reference ranges. The mean serum levels of serum total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein (a) all were within their normal reference ranges. Although patients who did not perform CAG had younger age (55.2 ± 14.9 versus 63.0 ± 11.0 yr), lower prevalence of diabetes (18.2 versus 40.0%) and hyperlipidemia (9.1 versus 26.6%), and lower levels of LDL cholesterol (92.8 ± 17.4 versus 108.0 ± 36.0 mg/dl) and C. pneumoniae antibody titer (IgG, 1.6 ± 0.7 versus 2.1 ± 0.9; IgA, 1.0 ± 0.52 versus 1.3 ± 0.8) compared with those who underwent CAG; all these parameters were not statistically significantly different. Mean levels of plasma homocysteine (31.1 ± 13.3 versus 26.6 ± 13.9 nmol/ml), fibrinogen (487.7 ± 111.0 versus 442.4 ± 120.2 mg/dl), and serum lipoprotein (a) (39.8 ± 29.1 versus 29.7 ± 21.7 mg/dl) were higher in groups without CAG than in groups with CAG. However, these variables also did not show a statistically significant difference between the two groups.

CAG Findings in 16 Patients with Significant CAS

Among 30 asymptomatic CKD patients who underwent CAG, 16 (53.3%) patients had significant CAS. Of these 16 patients, 10 (62.5%) had single-vessel disease, four (25%) had two-vessel disease, and two (12.5%) had triple-vessel disease (Table 2). Among the 16 patients with significant CAS, five had severe CAS with luminal narrowing of >90%. When stress cardiac scintigraphy was done in these five patients with severe CAS, it was positive in two patients and negative in three patients (sensitivity, 40%). Two patients with single-vessel disease (each had 90% luminal narrowing of the left anterior descending coronary artery #7), and one patient with triple-vessel disease showed no coronary ischemia on dipyridamole thallium scintigraphy. In the five patients with severe CAS (two patients with single-vessel, one patient with two-vessel, and two patients with triple-vessel disease), PCI was performed considering the future risk for MI. PCI was selected instead of coronary artery bypass graft for two patients with diabetes and triple-vessel disease considering their performance status. PCI was successful in four of five patients. In one CKD patient with diabetes and triple-vessel disease (100% stenosis of #2, 75% of #7, and 90% of #11), the stenosis at #2 was dilated by balloon angioplasty and a coronary stent was placed successfully. However, flow through the lesion at #11 did not recover after balloon dilation, so rotational atherectomy (11) was performed for this lesion. There were no adverse events as a result of CAG and/or PCI.

Association between Significant CAS and Other Variables

The association between traditional coronary risk factors and significant CAS was evaluated (Table 3). Among several risk factors, diabetes (P = 0.01) and hyperlipidemia (P = 0.04) were significantly correlated with the presence of CAS. Other factors, including age, hypertension, and smoking, were not correlated with the presence of CAS.

Several atherosclerosis-related factors, including LVMI (P = 0.04), total cholesterol (P = 0.02), LDL cholesterol (P < 0.01), IMT (P = 0.04), fibrinogen (P = 0.01), and ABI (P < 0.01), showed a significant difference between the groups with and without CAS. LVMI, total cholesterol, LDL cholesterol, IMT, and fibrinogen were positively correlated with the presence of CAS, whereas ABI was inversely correlated (Table 3). The EF (%) of CAS-positive patients was lower than that of CAS-negative patients, although the difference was not statistically significant. An EF of <50% was seen in five patients. Except for one with an EF of 42% who did not have significant CAS, the remaining four patients had significant CAS. Lipoprotein (a) was higher in CAS-positive patients than in those without CAS (34.5 ± 23.7 versus 25.0 ± 18.7), although the difference was not statistically significant. Plasma tHcy level and serum antibody titer against C. pneumoniae did not show any significant association with CAS.

Association between Significant CAS and Stratified ABI and IMT

Stratified data demonstrated the close relationship between ABI and significant CAS (Table 4). Three CKD patients had clinically apparent PAOD. They each had intermittent claudication with ABI <0.9. These three patients with PAOD and two patients with ABI value <0.9 without intermittent claudication had significant CAS. When the cut-off value of ABI was set at 0.9, significant correlation was found between significant CAS and ABI (P = 0.04). The stratified IMT had a tendency to predict significant CAS, although it was not statistically significant (P = 0.07). Seventy-five percent of the patients with IMT exceeded 1.0 mm (nine of 12) had significant CAS.

Results of Stepwise Logistic Regression Analysis

Factors that were independently associated with CAS were examined by stepwise logistic regression analysis (Table 5). The first model included variables that were shown to be significant by univariate analysis, and diabetes and fibrinogen were chosen as independent risk factors for CAS. In model 2, in which all of the other factors that we examined were added, diabetes remained as a significant and independent factor associated with an increased prevalence of CAS.

Discussion

We showed that 16 (53.3%) of 30 asymptomatic CKD patients had significant CAS on CAG. When the 21 CKD patients who had a history of angina and/or MI and had CAS proved by CAG before RRT are added, the prevalence of CAS reaches at least 53.6% among all of our CKD patients at the initiation of RRT (37 of 69 eligible patients). Accordingly, CKD patients should be regarded as a high-risk group for CAD even at the start of RRT.

In 1984, Rostand et al. (12) studied the prevalence of significant CAS among 44 CKD patients who were undergoing RRT (dialysis duration, 36.9 ± 5.1 mo). They reported that one (10%) of 10 dialysis patients without ischemic cardiac symptoms had significant CAS and that the prevalence of occult CAS among dialysis patients was not so different from that in the general population (5 to 10%) (13). In contrast to their report, almost 50% of asymptomatic CKD patients had significant CAS at the start of RRT in our study. This discrepancy in the prevalence of occult CAS between the study of Rostand et al. and this report may be due to differences of age and the prevalence of diabetes among the patients. The mean age of our patients who underwent CAG was 63.0 ± 11.0 yr, whereas it was 50.1 ± 1.9 yr in Rostand’s study. We had 12 (40.0%) diabetic CKD patients, whereas Rostand had only one (2.3%) patient with diabetes. The percentage of CKD patients with diabetes among those who started RRT in Japan (2) has now risen to 38.1%. As time has passed, the underlying causes of CKD have changed. Therefore, we believe that the prevalence of CAS has also increased.

There have been other reports about occult CAS in dialysis patients. Braun et al. (14) reported that 75% of diabetic dialysis patients with angiographically proven significant CAS had no symptoms. Koch et al. (15) reported that only nine (26.3%) of 38 HD patients with CAS (>50% stenosis) had symptoms, and a CAG study performed by Pidgeon et al. (16) on dialysis patients before renal transplantation showed that only 43% had symptoms. In contrast to these reports on occult CAS in CKD patients who were already on long-standing RRT, there have been few reports concerning the prevalence of CAS in patients with CKD just before the initiation of RRT. Joki et al. (17) reported that 53.8% of asymptomatic patients (7 of 13) had significant CAS detected by CAG at the initiation of RRT. The sensitivity and specificity of chest symptoms as a predictor of CAS in their study was 72.7 and 46.2%, respectively. Our study population had a greater number of asymptomatic patients than Joki’s and further supports their findings that development of CAS precedes the start of RRT and that almost half of asymptomatic CKD patients have significant CAS. Although Joki et al. did not indicate the significant differences of clinical and biochemical factors between groups with and without CAS, our study clearly demonstrated that diabetes, hyperlipidemia, total cholesterol, LDL cholesterol, LVMI, ABI, IMT, and fibrinogen were significantly correlated with the presence of CAS in asymptomatic CKD patients at the initiation of RRT. Whether patients had ischemic cardiac symptoms or not showed little impact on the presence of CAS at the initiation of RRT.

Discrepancy between significant CAG findings and the lack of chest symptoms may be due to uremic and/or diabetic autonomic neuropathy (18). Marchant et al. (19) reported that patients with diabetes and silent exertional ischemia had evidence of significant autonomic impairment compared with symptomatic patients. This difference was not seen in nondiabetic patients and suggested that subclinical neuropathy was an important cause of silent ischemia in patients with diabetes. Furthermore, Shakespeare et al. (20) reported an existence of the differences in autonomic nerve function in patients with silent and symptomatic myocardial ischemia. Patients with pure silent ischemia had evidence of sympathetic autonomic dysfunction.

Although we studied only a limited number of patients, poor sensitivity of dipyridamole thallium scintigraphy for the detection of significant CAS among CKD patients was demonstrated, as was found by Marwick et al. (7). The common causes of a false-negative thallium study include single-vessel disease, balanced multivessel disease with global ischemia, and collaterals that prevent the detection of differential flow changes. Electron-beam computerized tomography (EBCT) may be another noninvasive screening test for CAS. In the general population, a strong correlation between coronary artery calcification score measured by EBCT and vessel stenosis measured by CAG has been documented (21). Calcification score correlated with total plaque burden and is predictive of future ischemic events in the general population (22,23). In the dialysis population, however, there was no significant correlation between degree of vessel stenosis and calcification score (24). We did not examine EBCT in our patients, but EBCT might not be used as a single screening test for atherosclerotic coronary disease in the dialysis population. Therefore, although a less invasive method would be desirable to detect significant CAS, CAG seems to be the only test that precisely identifies significant CAS in CKD patients at the initiation of RRT.

Factors that are correlated with cardiovascular disease in predialysis CKD patients or dialysis patients include older age (12,25), male gender (12,26), smoking (26,27), diabetes (26), a high systolic or diastolic BP (2529), hypercholesterolemia (12,29), low HDL cholesterol (27), increased lipoprotein (a) (28), increased fibrinogen (27,29), decreased alkaline phosphatase (12), abnormal left ventricular wall motion (12), and the presence of symptomatic ischemic heart disease before the start of RRT (12). Among these factors, those that were reported as independent risk factors for CAG-proven significant CAS are smoking and diabetes in predialysis CKD patients and dialysis patients by Hase et al. (26); smoking, high systolic BP, low HDL cholesterol, and increased fibrinogen in predialysis CKD patients by Jungers et al. (27); and low molecular weight Apo (a) phenotype in dialysis patients by Kronenberg et al. (29). Independent risk factors for significant CAS in CKD patients at the initiation of RRT were diabetes and fibrinogen in our study.

Although low ABI has close associations with significant CAS and cardiovascular events in the general population (30,31), there have been few attempts to identify the link between CAS and ABI among patients with ESRD. Ono et al. (32) reported that low ABI predicted all-cause and cardiovascular mortality in hemodialysis patients. However, not only myocardial infarction but also other events such as heart failure, aortic valve stenosis, ischemic gangrene of the foot, cerebral infarction/hemorrhage, and pulmonary embolism were included as fatal cardiovascular events. A direct relationship between CAS and ABI in dialysis patients was not demonstrated in their report. In our study, we could demonstrate the direct and close relationship between ABI and significant CAS in stage 5 CKD patients. CKD patients with significant CAS had significant lower ABI values than those without CAS. Stratified ABI showed that ABI value <0.9 was closely associated with significant CAS in stage 5 CKD patients (Table 4). Three of our patients had PAOD, and all of these patients had significant CAS. If a larger study would be done, then PAOD with ABI value <0.9 might independently predict the significant CAS in CKD patients.

Although an increased plasma tHcy level and serum lipoprotein (a) level are known to be risk factors for an increase of cardiovascular events in the general population (3336), these parameters were not associated with CAS in our CKD patients. As for fibrinogen, Jungers et al. (27) reported it as a significant independent risk factor for cardiovascular events only in predialysis CKD patients. Fibrinogen is usually elevated in CKD patients compared with the general population (27). The reason for the increase of fibrinogen is thought to be due to stimulation by inflammatory cytokines such as IL-1 and TNF, probably induced by uremia-associated immune dysregulation (37). Our study also demonstrated that fibrinogen was an independent risk factor for CAS in CKD patients. Because our study is a cross-sectional design, it may be hard to say the direct cause–effect relationship between high fibrinogen and CAS. However, high fibrinogen at the initiation of RRT was closely associated with significant CAS. In view of the pathogenesis of atherosclerosis, it is interesting to note that not only the vascular wall damage but also a blood component such as fibrinogen may be significantly related to the progression of CAS in CKD patients. It has been reported that C. pneumoniae infection may be involved in the pathogenesis of atherosclerosis (38). However, our study did not show any positive association of the C. pneumoniae antibody titer with CAS in CKD patients at the initiation of RRT.

Because hard plaque that is often seen in dialysis patients may be difficult to rupture, it is important to elucidate the future risk of AMI in asymptomatic CKD patients with significant CAS. We found that CAS is common among CKD patients at the initiation of RRT and performed PCI in patients with severe CAS. However, whether making a diagnosis of CAS and performing PCI in these patients actually help these patients from future cardiovascular events needs further study. We are now investigating follow-up CAG and subsequent cardiovascular events in these asymptomatic CKD patients with significant CAS. Answers as to whether CAS would progress after the start of RRT, how high is the future risk of AMI, and whether the early intervention to CKD patients with silent CAS would actually help these patients would be provided in the future.

In summary, this study provided direct evidence that nearly 50% of asymptomatic patients with stage 5 CKD have significant CAS at the initiation of RRT. It may be desirable for stage 5 CKD patients to be examined by CAG regardless of whether they have ischemic symptoms.

F1-42
Figure 1:
Design of the study. CKD, chronic kidney disease; RRT, renal replacement therapy; CAD, coronary artery disease; CAG, coronary angiography.
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Table 1:
Basic characteristics of 41 asymptomatic CKD patients at the initiation of RRTa
T2-42
Table 2:
Prevalence of CAS by CAG among 30 asymptomatic CKD patientsa
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Table 3:
Association between significant CAS and several factors in asymptomatic CKD patientsa
T4-42
Table 4:
Association between significant CAS and stratified ABI and IMT
T5-42
Table 5:
Stepwise logistic regression analysis of factors that affect significant CAS in asymptomatic CKD patients at the initiation of RRT

Acknowledgments

This research was supported by a grant from the Japan Kidney Foundation (JFK03-2).

We thank the staff of the Cardiology Department and Catheterization Laboratories at our hospital for the performance of CAG and PCI in the CKD patients at the initiation of RRT.

Published online ahead of print. Publication date available at www.jasn.org.

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