Abstract

Background.

Patients with chronic kidney disease (CKD) are associated with increased cardiovascular (CV) morbidity and mortality. Echocardiographic measures of heart structure and function have been reported to predict adverse CV outcomes in various pathologic conditions. The aim of this study is to assess whether echocardiographic parameters are independently associated with increased CV events in patients with CKD Stages 3–5.

Methods.

We consecutively enrolled 505 CKD patients from our outpatient department of internal medicine. CV events were defined as CV death, hospitalization for unstable angina, non-fatal myocardial infarction, sustained ventricular arrhythmia, hospitalization for congestive heart failure, transient ischemia attack and stroke. The relative CV events’ risk was analyzed by Cox regression methods.

Results.

In the multivariate analysis, old age, the presence of diabetes, coronary artery disease and atrial fibrillation; decreased serum albumin and hematocrit levels; left atrial diameter (LAD) >4.7 cm [hazard ratio (HR), 2.141; 95% confidence interval (CI), 1.155–3.971, P = 0.016]; increased left ventricular mass index (LVMI) (HR, 1.006; 95% CI, 1.002 to 1.010, P = 0.003) and left ventricular ejection fraction (LVEF) <55% (HR, 2.007; 95% CI, 1.007–3.743, P = 0.028) were independently associated with increased CV events.

Conclusions.

Our findings show that LAD >4.7 cm, increased LVMI and LVEF <55% are independently associated with adverse CV outcomes in CKD patients. Screening CKD patients by means of echocardiography may help identify a high-risk group of poor CV prognosis.

Introduction

Chronic kidney disease (CKD) is an increasing worldwide public health problem associated with increased morbidity and mortality. The cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with CKD [ 1 ]. This excess CV risk is in part attributed to an increase of traditional risk factors among people with CKD, including hypertension, diabetes and dyslipidemia, but may also relate to structural and functional abnormalities of the heart in CKD patients [ 2 , 3 ]. Early detection of abnormal geometry and dysfunction of the heart is important in disease attenuation and a prolonged survival.

The echocardiography is the most useful imaging study for a cardiac assessment. Echocardiographic measures of left ventricular function and structure as well as left atrial size have been reported to predict adverse CV outcomes in a variety of population [ 4–6 ]. Structural and functional heart abnormalities in chronic renal failure patients were frequently noted because of a pressure and volume overload [ 7 , 8 ]. An enlarged left atrium, left ventricular hypertrophy (LVH) and impaired left ventricular function were independently associated with high CV morbidity and mortality in patients with dialysis [ 6 , 9 , 10 ]. However, there are limited studies to evaluate the association between echocardiographic parameters and CV events in patients with moderate to advanced CKD. Accordingly, we conducted an observational cohort study to investigate whether echocardiographic parameters are independently associated with increased CV events in patients with CKD Stages 3–5.

Materials and methods

Study patients and design

The study was conducted in a regional hospital in southern Taiwan. We consecutively enrolled 518 pre-dialysis patients with Stages 3–5 of CKD according to the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative guidelines [ 11 ] from January 2007 to May 2010. We classified our patients with evidence of kidney damage lasting for >3 months into CKD Stages 3, 4 and 5, based on estimated glomerular filtration rate (eGFR) level (mL/min/1.73 m 2 ) of 30–59, 15–29 and <15, respectively. The study patients received regular follow-up at our Outpatient Department of Internal Medicine. They were selected to take part in this study if they agreed on an echocardiographic examination. Three patients refused echocardiography examinations due to personal reasons. Patients receiving renal replacement therapy were not included. Five patients with significant mitral regurgitation and five patients with inadequate image visualization were also excluded. A significant mitral regurgitation was defined as the regurgitant jet area >20% of the left atrial area [ 12 ]. Finally, a total of 505 patients were included. The protocol was approved by our institutional review board and all enrolled patients gave written informed consent.

Evaluation of cardiac structure and function

After patients agreed to participate in this study at the Outpatient Department of Internal Medicine, an echocardiographic examination was arranged within 2 weeks. It was performed by two experienced cardiologists certified by the Taiwan Society of Echocardiography with a VIVID 7 (General Electric Medical Systems, Horten, Norway), with the patient respiring quietly in the left decubitus position. The cardiologists were blind to the other data of patients. Study patients were followed after an echocardiographic examination. Two-dimensional and two-dimensionally guided M-mode images were recorded from the standardized views. Aortic root diameter, left atrial diameter (LAD), interventricular septal thickness in diastole (IVSTd), left ventricular posterior wall thickness in diastole (PWTd), left ventricular internal diameter in diastole (LVIDd) and left ventricular internal diameter in systole (LVIDs) were measured in the parasternal long axis view. The Doppler sample volume was placed at the tips of the mitral leaflets to get the left ventricular inflow waveforms from the apical 4-chamber view. All sample volumes were positioned with ultrasonic beam alignment to flow. The peak early transmitral filling wave velocity (E), peak late transmitral filling wave velocity (A) and the E/A ratio were also measured. Left ventricular ejection fraction (LVEF) was calculated as (left ventricular end-diastolic volume − left ventricular end-systolic volume)/left ventricular end-diastolic volume. The left ventricular mass was calculated using a Devereux-modified method, i.e. left ventricular mass = 1.04 × [(IVSTd + LVIDd + PWTd) 3 − LVIDd 3 ] − 13.6 g [ 13 ]. Left ventricular mass index (LVMI) was calculated by dividing left ventricular mass by body surface area. LVH was considered to be present when LVMI exceeded 134 g/m 2 and 110 g/m 2 for men and women, respectively [ 14 ]. Systolic dysfunction was defined as LVEF <55%.

Collection of demographic, medical and laboratory data

Demographic and medical data including age, gender, smoking history (ever versus never) and comorbid conditions were obtained from medical records or interviews with patients. Study subjects were defined as having diabetes mellitus (DM) if the fasting blood glucose level was >126 mg/dL or hypoglycemic agents were used to control blood glucose levels. Similarly, study patients were considered as having hypertension if the systolic blood pressure was ≥140 mmHg or the diastolic blood pressure ≥90 mmHg or if anti-hypertensive drugs were prescribed. The cerebrovascular disease was defined as a history of cerebrovascular accidents including cerebral bleeding and infarction. The coronary artery disease was defined as a history of typical angina with a positive stress test, an angiographically documented coronary artery disease, an old myocardial infarction or having undergone a coronary artery bypass surgery or angioplasty. The congestive heart failure was defined according to Framingham criteria. The body mass index was calculated as the ratio of weight in kilograms divided by the square of height in meters. Laboratory data were measured from fasting blood samples using an autoanalyzer (D-68298 Mannheim COBAS Integra 400; Roche Diagnostics GmbH). The Serum creatinine was measured by the compensated Jaffé (kinetic alkaline picrate) method in a Roche/Integra 400 Analyzer (Roche Diagnostics, Mannheim, Germany) using a calibrator traceable to isotope dilution mass spectrometry [ 15 ]. The value of eGFR was calculated using the 4-variable equation in the Modification of Diet in Renal Disease study [ 16 ]. Proteinuria was examined by dipsticks (Hema-Combistix; Bayer Diagnostics). A test result of 1+ or more was defined as positive. Blood and urine samples were obtained within 1 month of enrollment. In addition, information regarding patients intake of anti-hypertensive medications, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, calcium channel blockers and diuretics during the study period was obtained from medical records.

Definition of CV events and combined end points

CV events were defined as CV death, hospitalization for unstable angina, non-fatal myocardial infarction, sustained ventricular arrhythmia, hospitalization for congestive heart failure, transient ischemia attack and stroke. CV events were ascertained and adjudicated by cardiologists from the hospital course and medical record. The combined end points were defined as CV events and non-CV death. In patients reaching the combined end points, they were followed until the first episode of combined end points. The other patients were followed until February 2011.

Statistical analysis

A statistical analysis was performed using SPSS 12.0 for Windows (SPSS Inc., Chicago, IL). Data are expressed as percentages or mean ± SD or median (25th–75th percentile) for triglyceride. The differences between groups were checked by chi-square test for categorical variables or by independent t -test for continuous variables. Time to the CV events and covariates of risk factors were modeled using Cox proportional hazards model. Age, gender and significant variables in the univariate analysis were further analyzed by multivariate forward analysis. A significant difference was considered when the P value was <0.05.

Results

The differences between patients with and without CV events were shown in Table 1 . The mean age of all patients was 66.3 ± 12.2 years. Compared with patients without CV events, patients with CV events were significantly associated with older age, a higher prevalence of a history of DM, coronary artery disease, cerebrovascular disease, congestive heart failure and atrial fibrillation, more advanced CKD stage, higher systolic blood pressure, wider pulse pressure, lower albumin, lower hematocrit, lower baseline eGFR, higher phosphorous, higher intake percentages of diuretics; higher prevalence of proteinuria and shorter duration of follow-up period. In addition, patients with CV events had a larger LAD, a higher prevalence of LAD >4.7 cm, a larger LVIDd and LVIDs, a higher LVMI and prevalence of LVH, a lower LVEF and a higher prevalence of LVEF <55%.

Table 1.

Comparison of baseline characteristics between patients with and without CV events a

Characteristics  Patients with events ( n = 89)   Patients without events v ( n = 416)   All patients ( n = 505)  
Age (year) 71.1 ± 9.9 65.2 ± 12.4 <0.001 66.3 ± 12.2 
Male gender (%) 64.0 63.2 0.884 63.4 
Smoking history (%) 34.8 30.8 0.454 31.5 
DM (%) 71.9 53.1 0.001 56.4 
Hypertension (%) 86.5 81.0 0.220 82.0 
Coronary artery disease (%) 23.6 8.7 <0.001 11.3 
Cerebrovascular disease (%) 23.6 13.0 0.011 14.9 
Congestive heart failure (%) 27.0 9.4 <0.001 12.5 
Atrial fibrillation (%) 9.0 3.1 0.012 4.2 
Stage of CKD   0.002  
    Stage 3 (%) 24.7 43.0  39.8 
    Stage 4 (%) 32.6 30.3  30.7 
    Stage 5 (%) 42.7 26.7  29.5 
Systolic blood pressure (mmHg) 146.2 ± 23.7 140.4 ± 20.5 0.035 141.4 ± 21.2 
Diastolic blood pressure (mmHg) 77.2 ± 14.1 79.8 ± 12.6 0.090 79.3 ± 12.9 
Pulse pressure (mmHg) 69.1 ± 17.4 60.6 ± 17.3 <0.001 62.1 ± 17.6 
Body mass index (kg/m 2 )  25.1 ± 4.0 25.4 ± 3.9 0.496 25.3 ± 3.9 
Laboratory parameters     
    Albumin (g/dL) 3.80 ± 0.42 4.05 ± 0.38 <0.001 4.01 ± 0.40 
    Fasting glucose (mg/dL) 134.7 ± 65.6 124.2 ± 56.5 0.129 126.1 ± 58.4 
    Triglyceride (mg/dL) 136.0 (95.0–199.5) 138.5 (96.0-201.0) 0.998 138.0 (96.0–201.0) 
    Total cholesterol (mg/dL) 195.1 ± 44.2 194.0 ± 48.0 0.847 194.2 ± 47.3 
    Hematocrit (%) 32.1 ± 5.8 35.7 ± 6.6 <0.001 35.0 ± 6.6 
    Baseline eGFR (mL/min/1.73 m 2 )  21.6 ± 12.6 27.3 ± 14.4 <0.001 26.3 ± 14.3 
    Calcium (mg/dL) 9.3 ± 0.8 9.5 ± 0.9 0.056 9.5 ± 0.8 
    Phosphate (mg/dL) 4.3 ± 0.8 4.0 ± 1.1 0.034 4.1 ± 1.0 
    Calcium–phosphorus product (mg 2 /dL 2 )  39.8 ± 7.4 38.1 ± 8.9 0.087 38.4 ± 8.7 
    Uric acid (mg/dL) 8.5 ± 2.2 8.2 ± 2.3 0.182 8.2 ± 2.3 
Proteinuria (%) 76.1 63.6 0.024 65.5 
Anti-hypertensive medications     
    ACEI and/or ARB use (%) 72.1 73.3 0.821 71.5 
    β-Blocker use (%) 31.4 31.1 0.961 31.2 
    Calcium channel blocker use (%) 60.5 53.7 0.250 54.9 
    Diuretics use (%) 66.3 39.7 <0.001 44.3 
Echocardiographic data     
    Aortic root diameter (cm) 3.3 ± 0.4 3.3 ± 0.4 0.886 3.3 ± 0.4 
    LAD (cm) 4.0 ± 0.7 3.7 ± 0.6 <0.001 3.8 ± 0.6 
    LAD > 4.7cm (%) 15.7 4.3 <0.001 6.3 
    LVIDd (cm) 5.1 ± 0.8 4.9 ± 0.7 0.001 4.9 ± 0.7 
    LVIDs (cm) 3.3 ± 0.9 3.0 ± 0.7 0.002 3.0 ± 0.7 
    LVMI (g/m 2 )  173.2 ± 58.7 135.1 ± 45.6 <0.001 141.8 ± 50.2 
    LVH (%) 78.7 55.3 <0.001 59.4 
    LVEF (%) 64.7 ± 13.8 69.0 ± 10.1 0.007 68.2 ± 11.6 
    LVEF < 55% (%) 18.0 5.0 <0.001 6.5 
    E/A < 1 (%) 75.6 76.3 0.892 72.9 
Follow-up period (month) 13.1 ± 11.7 28.8 ± 11.0 <0.001 26.0 ± 12.6 
Characteristics  Patients with events ( n = 89)   Patients without events v ( n = 416)   All patients ( n = 505)  
Age (year) 71.1 ± 9.9 65.2 ± 12.4 <0.001 66.3 ± 12.2 
Male gender (%) 64.0 63.2 0.884 63.4 
Smoking history (%) 34.8 30.8 0.454 31.5 
DM (%) 71.9 53.1 0.001 56.4 
Hypertension (%) 86.5 81.0 0.220 82.0 
Coronary artery disease (%) 23.6 8.7 <0.001 11.3 
Cerebrovascular disease (%) 23.6 13.0 0.011 14.9 
Congestive heart failure (%) 27.0 9.4 <0.001 12.5 
Atrial fibrillation (%) 9.0 3.1 0.012 4.2 
Stage of CKD   0.002  
    Stage 3 (%) 24.7 43.0  39.8 
    Stage 4 (%) 32.6 30.3  30.7 
    Stage 5 (%) 42.7 26.7  29.5 
Systolic blood pressure (mmHg) 146.2 ± 23.7 140.4 ± 20.5 0.035 141.4 ± 21.2 
Diastolic blood pressure (mmHg) 77.2 ± 14.1 79.8 ± 12.6 0.090 79.3 ± 12.9 
Pulse pressure (mmHg) 69.1 ± 17.4 60.6 ± 17.3 <0.001 62.1 ± 17.6 
Body mass index (kg/m 2 )  25.1 ± 4.0 25.4 ± 3.9 0.496 25.3 ± 3.9 
Laboratory parameters     
    Albumin (g/dL) 3.80 ± 0.42 4.05 ± 0.38 <0.001 4.01 ± 0.40 
    Fasting glucose (mg/dL) 134.7 ± 65.6 124.2 ± 56.5 0.129 126.1 ± 58.4 
    Triglyceride (mg/dL) 136.0 (95.0–199.5) 138.5 (96.0-201.0) 0.998 138.0 (96.0–201.0) 
    Total cholesterol (mg/dL) 195.1 ± 44.2 194.0 ± 48.0 0.847 194.2 ± 47.3 
    Hematocrit (%) 32.1 ± 5.8 35.7 ± 6.6 <0.001 35.0 ± 6.6 
    Baseline eGFR (mL/min/1.73 m 2 )  21.6 ± 12.6 27.3 ± 14.4 <0.001 26.3 ± 14.3 
    Calcium (mg/dL) 9.3 ± 0.8 9.5 ± 0.9 0.056 9.5 ± 0.8 
    Phosphate (mg/dL) 4.3 ± 0.8 4.0 ± 1.1 0.034 4.1 ± 1.0 
    Calcium–phosphorus product (mg 2 /dL 2 )  39.8 ± 7.4 38.1 ± 8.9 0.087 38.4 ± 8.7 
    Uric acid (mg/dL) 8.5 ± 2.2 8.2 ± 2.3 0.182 8.2 ± 2.3 
Proteinuria (%) 76.1 63.6 0.024 65.5 
Anti-hypertensive medications     
    ACEI and/or ARB use (%) 72.1 73.3 0.821 71.5 
    β-Blocker use (%) 31.4 31.1 0.961 31.2 
    Calcium channel blocker use (%) 60.5 53.7 0.250 54.9 
    Diuretics use (%) 66.3 39.7 <0.001 44.3 
Echocardiographic data     
    Aortic root diameter (cm) 3.3 ± 0.4 3.3 ± 0.4 0.886 3.3 ± 0.4 
    LAD (cm) 4.0 ± 0.7 3.7 ± 0.6 <0.001 3.8 ± 0.6 
    LAD > 4.7cm (%) 15.7 4.3 <0.001 6.3 
    LVIDd (cm) 5.1 ± 0.8 4.9 ± 0.7 0.001 4.9 ± 0.7 
    LVIDs (cm) 3.3 ± 0.9 3.0 ± 0.7 0.002 3.0 ± 0.7 
    LVMI (g/m 2 )  173.2 ± 58.7 135.1 ± 45.6 <0.001 141.8 ± 50.2 
    LVH (%) 78.7 55.3 <0.001 59.4 
    LVEF (%) 64.7 ± 13.8 69.0 ± 10.1 0.007 68.2 ± 11.6 
    LVEF < 55% (%) 18.0 5.0 <0.001 6.5 
    E/A < 1 (%) 75.6 76.3 0.892 72.9 
Follow-up period (month) 13.1 ± 11.7 28.8 ± 11.0 <0.001 26.0 ± 12.6 
a

A, peak late transmitral filling wave velocity; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; E, peak early transmitral filling wave velocity.

Compared with patients without congestive heart failure, patients with congestive heart failure were significantly associated with higher intake percentages of aspirin (45.2 versus 22.5%, P < 0.001), β-blockers (48.4 versus 28.7%, P = 0.002) and diuretics (69.4 versus 40.7%, P < 0.001).

The follow-up period was 26.0 ± 12.6 months in all patients and 28.8 ± 11.0 months in patients without CV events (range 6–50 months). Eighty-nine CV events were documented during the follow-up period, including CV death ( n = 11), hospitalization for unstable angina and non-fatal myocardial infarction ( n = 17), sustained ventricular arrhythmia ( n = 9), hospitalization for congestive heart failure ( n = 30) and transient ischemia attack and stroke ( n = 22). A Cox proportional hazards regression analysis for CV events is shown in Table 2 . The univariate regression analysis showed old age, the presence of DM, coronary artery disease, cerebrovascular disease, congestive heart failure and atrial fibrillation, high systolic blood pressure, wide pulse pressure, low albumin, low hematocrit, decreased eGFR, low calcium, high phosphorous, the presence of proteinuria, diuretics use, LAD >4.7 cm, increased LVIDd, increased LVIDs, increased LVMI and LVEF <55% were significantly associated with an increase in CV events. After the multivariate forward analysis, old age, the presence of DM and coronary artery disease, decreased albumin, decreased hematocrit, LAD >4.7 cm [hazard ratio (HR), 2.141, 95% confidence interval (CI), 1.155–3.971, P = 0.016], increased LVMI (HR, 1.006; 95% CI, 1.002–1.010, P = 0.003) and LVEF <55% (HR, 2.007; 95% CI, 1.077–3.743, P = 0.028) were independently associated with increased CV events. Figure 1 illustrated the Kaplan–Meier curves for CV events-free survival in all patients subdivided according to (i) LAD >4.7 cm or <4.7 cm, (ii) the presence or absence of LVH and (iii) LVEF <55 or >55% (all log-rank P < 0.001).

Table 2.

Predictors of CV events using Cox proportional hazards model a

Parameter  Univariate
 
Multivariate (forward)
 
HR (95% CI) HR (95% CI) 
Age (per 1 year) 1.042 (1.022–1.063) <0.001 1.037 (1.015–1.060) 0.001 
Male versus female 1.053 (0.683–1.625) 0.815   
Smoking (ever versus never) 1.215 (0.785–1.880) 0.383   
DM 2.174 (1.368–3.455) 0.001 1.916 (1.140–3.222) 0.014 
Hypertension 1.395 (0.759–2.564) 0.283   
Coronary artery disease 2.754 (1.688–4.495) <0.001 2.777 (1.609–4.793) <0.001 
Cerebrovascular disease 2.054 (1.256–3.359) 0.004   
Congestive heart failure 3.354 (2.098–5.363) <0.001   
Atrial fibrillation 2.714 (1.311–5.619) 0.007 2.774 (1.054–7.301) 0.039 
Systolic blood pressure (per 1 mmHg) 1.013 (1.003–1.023) 0.009   
Diastolic blood pressure (per 1 mmHg) 0.986 (0.969–1.003) 0.110   
Pulse pressure (per 1 mmHg) 1.025 (1.014–1.037) <0.001   
Body mass index (per 1 kg/m 2 )  0.975 (0.924–1.029) 0.358   
Laboratory parameters     
    Albumin (per 1 g/dL) 0.270 (0.177–0.412) <0.001 0.369 (0.207–0.655) 0.001 
    Fasting glucose (per 1 mg/dL) 1.002 (0.999–1.005) 0.131   
    Triglyceride (per log 1 mg/dL) 0.876 (0.374–2.050) 0.760   
    Cholesterol (per 1 mg/dL) 1.000 (0.996–1.005) 0.925   
    Hematocrit (per 1%) 0.926 (0.898–0.956) <0.001 0.952 (0.912–0.993) 0.022 
    Baseline eGFR (per 1 mL/min/1.73 m 2 )  0.973 (0.957–0.988) 0.001   
    Calcium (per 1 mg/dL) 0.772 (0.616–0.968) 0.025   
    Phosphate (per 1 mg/dL) 1.205 (1.025–1.417) 0.024   
    Calcium–phosphorous product (per 1 mg 2 /dL 2 )  1.020 (0.998–1.042) 0.081   
    Uric acid (per 1 mg/dL) 1.075 (0.982–1.178) 0.118   
Proteinuria 1.711 (1.048–2.795) 0.032   
Anti-hypertensive medications     
    ACEI and/or ARB use 0.874 (0.545–1.401) 0.575   
    β-Blocker use 1.054 (0.667–1.664) 0.822   
    Calcium channel blocker use 1.262 (0.819–1.946) 0.292   
    Diuretics use 2.842 (1.816–4.447) <0.001   
Echocardiographic data     
    Aortic root diameter (per 1 cm) 0.993 (0.608–1.623) 0.978   
    LAD > 4.7cm 3.668 (2.069–6.505) <0.001 2.141 (1.155–3.971) 0.016 
    LVIDd (per 1 cm) 1.618 (1.241–2.109) <0.001   
    LVIDs (per 1 cm) 1.610 (1.290–2.009) <0.001   
    LVMI (per 1 g/m 2 )  1.010 (1.007–1.013) <0.001 1.006 (1.002–1.010) 0.003 
    LVEF < 55% 3.623 (2.104–6.239) <0.001 2.007 (1.077–3.743) 0.028 
    E/A < 1 0.905 (0.547–1.500) 0.700   
Parameter  Univariate
 
Multivariate (forward)
 
HR (95% CI) HR (95% CI) 
Age (per 1 year) 1.042 (1.022–1.063) <0.001 1.037 (1.015–1.060) 0.001 
Male versus female 1.053 (0.683–1.625) 0.815   
Smoking (ever versus never) 1.215 (0.785–1.880) 0.383   
DM 2.174 (1.368–3.455) 0.001 1.916 (1.140–3.222) 0.014 
Hypertension 1.395 (0.759–2.564) 0.283   
Coronary artery disease 2.754 (1.688–4.495) <0.001 2.777 (1.609–4.793) <0.001 
Cerebrovascular disease 2.054 (1.256–3.359) 0.004   
Congestive heart failure 3.354 (2.098–5.363) <0.001   
Atrial fibrillation 2.714 (1.311–5.619) 0.007 2.774 (1.054–7.301) 0.039 
Systolic blood pressure (per 1 mmHg) 1.013 (1.003–1.023) 0.009   
Diastolic blood pressure (per 1 mmHg) 0.986 (0.969–1.003) 0.110   
Pulse pressure (per 1 mmHg) 1.025 (1.014–1.037) <0.001   
Body mass index (per 1 kg/m 2 )  0.975 (0.924–1.029) 0.358   
Laboratory parameters     
    Albumin (per 1 g/dL) 0.270 (0.177–0.412) <0.001 0.369 (0.207–0.655) 0.001 
    Fasting glucose (per 1 mg/dL) 1.002 (0.999–1.005) 0.131   
    Triglyceride (per log 1 mg/dL) 0.876 (0.374–2.050) 0.760   
    Cholesterol (per 1 mg/dL) 1.000 (0.996–1.005) 0.925   
    Hematocrit (per 1%) 0.926 (0.898–0.956) <0.001 0.952 (0.912–0.993) 0.022 
    Baseline eGFR (per 1 mL/min/1.73 m 2 )  0.973 (0.957–0.988) 0.001   
    Calcium (per 1 mg/dL) 0.772 (0.616–0.968) 0.025   
    Phosphate (per 1 mg/dL) 1.205 (1.025–1.417) 0.024   
    Calcium–phosphorous product (per 1 mg 2 /dL 2 )  1.020 (0.998–1.042) 0.081   
    Uric acid (per 1 mg/dL) 1.075 (0.982–1.178) 0.118   
Proteinuria 1.711 (1.048–2.795) 0.032   
Anti-hypertensive medications     
    ACEI and/or ARB use 0.874 (0.545–1.401) 0.575   
    β-Blocker use 1.054 (0.667–1.664) 0.822   
    Calcium channel blocker use 1.262 (0.819–1.946) 0.292   
    Diuretics use 2.842 (1.816–4.447) <0.001   
Echocardiographic data     
    Aortic root diameter (per 1 cm) 0.993 (0.608–1.623) 0.978   
    LAD > 4.7cm 3.668 (2.069–6.505) <0.001 2.141 (1.155–3.971) 0.016 
    LVIDd (per 1 cm) 1.618 (1.241–2.109) <0.001   
    LVIDs (per 1 cm) 1.610 (1.290–2.009) <0.001   
    LVMI (per 1 g/m 2 )  1.010 (1.007–1.013) <0.001 1.006 (1.002–1.010) 0.003 
    LVEF < 55% 3.623 (2.104–6.239) <0.001 2.007 (1.077–3.743) 0.028 
    E/A < 1 0.905 (0.547–1.500) 0.700   
a

−2 Log likelihood = 823.6; chi-square = 118.8; P < 0.001. Values express as HR and 95% confidence interval (CI). A, peak late transmitral filling wave velocity; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; E, peak early transmitral filling wave velocity.

Fig. 1.

Kaplan–Meier analysis of CV events-free survival according to (A) LAD > 4.7 cm or < 4.7 cm, (B) the presence or absence of LVH and (C) LVEF < 55 or > 55% in patients with chronic kidney disease (all log-rank P < 0.001).

Fig. 1.

Kaplan–Meier analysis of CV events-free survival according to (A) LAD > 4.7 cm or < 4.7 cm, (B) the presence or absence of LVH and (C) LVEF < 55 or > 55% in patients with chronic kidney disease (all log-rank P < 0.001).

In order to elucidate the relationship between systolic blood pressure and CV outcomes, we compared the CV events among patients with systolic blood pressure <100 ( n = 14), ≥100 and <140 ( n = 227) and ≥140 mmHg ( n = 264) and found that the risk of CV events was higher in patients with systolic blood pressure <100 mmHg (HR, 3.577; 95% CI, 1.089–11.753, P = 0.036) and insignificantly higher in patients with systolic blood pressure ≥140 mmHg (HR, 1.566; 95% CI, 0.997–2.459, P = 0.052) than in those with systolic blood pressure ≥100 and <140 mmHg.

During the follow-up period, 106 patients started hemodialysis and 13 CV events occurred after hemodialysis. In contrast, 399 patients did not enter dialysis and 76 CV events occurred among these patients. The baseline eGFR was lower (11.6 ± 6.8 versus 30.2 ± 13.1, P < 0.001) but the percentage of CV events (12.3 versus 19.0%, P = 0.103) was not higher in patients entering hemodialysis than in those who did not enter dialysis.

Fifty-nine (11.7%) patients died; the deaths were attributed to fatal CV events ( n = 22), infectious disease ( n = 30), gastrointestinal bleeding ( n = 3) and other causes ( n = 4). We also performed the Cox proportional hazards regression analysis for combined end points. We found that similar results, i.e. old age, the presence of DM, coronary artery disease and atrial fibrillation, decreased albumin, decreased hematocrit, LAD >4.7 cm, increased LVMI and LVEF <55% were independently associated with increased combined end points.

Discussion

In the present study, we evaluated the association of echocardiographic parameters and CV outcomes in patients with CKD Stages 3–5. We found that LAD >4.7 cm, increased LVMI and LVEF <55% were independently associated with an increase in CV events. Other factors such as old age, the presence of DM, previous history of coronary artery disease, atrial fibrillation, decreased serum albumin and decreased hematocrit level were also correlated with CV events in the study.

Recently, an enlarged left atrium has been considered a marker of adverse CV outcomes such as stroke, congestive heart failure, atrial fibrillation and CV death in various pathologic conditions [ 17 , 18 ]. Both pressure and volume overload can contribute to left atrium enlargement. Left atrium size has also been shown to be a good predictor of left ventricular diastolic function [ 17 ]. Patients with a large left atrium size may have an impaired left ventricular diastolic function. Kim et al. [ 5 ] evaluated the impact of enlarged left atrium on all-cause and CV mortality in 216 patients with continuous ambulatory peritoneal dialysis (CAPD). They found that increased left atrium volume index (>32 mL/m 2 ) predicted all-cause and CV mortality. The traditional LAD >4.7 cm measured in the parasternal view was reported to be significantly correlated with left atrium volume index >32 mL/m 2 (P < 0.001) [ 19 ]. In our study, we demonstrated that LAD >4.7 cm was independently associated with increase CV events. This may imply that an impaired left ventricular diastolic function indicated by left atrium enlargement also predicts adverse CV outcomes in patients with CKD Stages 3–5.

LVH is reported to be a risk factor for poor CV prognosis [ 6 , 20–22 ]. Structural and functional abnormalities of heart in CKD patients were frequently noted because of pressure and volume overload [ 7 , 8 ]. Silaruks et al. [ 6 ] investigated the clinical outcome of LVH in 66 non-diabetic CAPD patients and found that severe LVH (left wall thickness > 1.4 cm) was significantly associated with high CV morbidity and mortality. The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial demonstrated that LVH is frequent and associated with poor CV outcomes in patients with CKD Stages 3–4 [ 4 ]. Our study involving patients with CKD Stages 3–5 also showed that an increased LVMI was independently associated with adverse CV outcomes.

A decrease of left ventricular systolic function was reported to predict poor CV outcomes in general population and in patients with heart failure [ 23 ]. Left ventricular systolic dysfunction was also an important risk factor of CV death in end-stage renal disease [ 9 ]. Patients with CKD have been reported to have high prevalence of left ventricular dysfunction [ 8 ]. Our study demonstrated that LVEF <55% was associated with increased CV events in patients with CKD Stages 3–5. Hence, left ventricular systolic dysfunction was a useful indicator of poor CV outcome in moderate to advanced CKD patients.

The present study also found that decreased serum albumin and hematocrit levels were significantly associated with poor CV prognosis. Malnutrition may worsen CKD patients’ outcome by aggravating existing inflammation and heart failure [ 24 ]. A low serum albumin level has been regarded as a malnutrition–inflammation–atherosclerosis state [ 25 ]. Shah and Dumler [ 26 ] studied the correlation between serum albumin level and CV morbidity in 376 CKD patients and found that hypoalbuminemia was an independent predictor for CV morbidity. Our study demonstrated that low serum albumin level was associated with increase in CV events, which was consistent with the previous findings. The anemia has also been identified as an important risk factor for LVH and poor CV prognosis [ 27 ]. Because anemia leads to a compensatory increase in cardiac output, this increase in the cardiac workload may enhance the left ventricular dilation and growth [ 28 ]. Our results consistently demonstrated that low serum hematocrit level was correlated with adverse CV outcomes.

Go et al. [ 1 ] reported there was an independent and graded association between the reduced eGFR and the risk of all-cause mortality, CV events and hospitalization in a large community-based population. In our study, although decreased eGFR was associated with increased CV events in univariate analysis, it did not achieve a significant level in the multivariate analysis. In Liu et al. [ 29 ] report, they compared left ventricular systolic strain of 37 patients with moderate to advanced CKD with that of 60 patients on chronic hemodialysis and found that hemodialysis patients had better left ventricular systolic function than CKD patients. They explained their findings by good volume control and uremic toxin removal, which might have favorable effects on left ventricular systolic function. Similarly, these favorable effects might also be present in our patients entering hemodialysis. In fact, during the period of follow-up, 106 patients started hemodialysis and 13 CV events occurred after hemodialysis. In contrast, 399 patients did not enter dialysis and 76 CV events occurred among these patients. Although the baseline eGFR was lower (11.6 ± 6.8 versus 30.2 ± 13.1, P < 0.001), the percentage of CV events (12.3 versus 19.0%, P = 0.103) was not higher in patients entering hemodialysis than in those who did not enter dialysis, which might partially explain there was no significant correlation between eGFR and CV events in our study.

In our study, the CV events included CV death in 11 patients (2.2%), hospitalization for unstable angina and non-fatal myocardial infarction in 17 patients (3.4%), sustained ventricular arrhythmia in 9 patients (1.8%), hospitalization for congestive heart failure in 30 patients (5.9%), transient ischemia attack and stroke in 22 patients (4.4%) during the follow-up period of 26.0 ± 12.6 months. Hase et al. [ 30 ] investigated the risk factors for CV events in 77 hemodialysis patients over 2 years and found that the event rate of an acute coronary syndrome (23.4%) was more than that of an acute ischemic heart failure (16.9%). The baseline prevalence of coronary artery disease in Hase’s study was 26.0% but only 13.3% in our study, which might explain the different ratio of CV events between these two studies. Gardin et al. [ 31 ] studied the correlation of echocardiography and 10-year incident CV events in patients >65 years of age without prevalent CV disease. The incident rates of congestive heart rate, acute coronary syndrome and stroke were 14.1, 9.6 and 10.4%, respectively. Besides, in Wang et al. [ 32 ] report, they evaluated CV events and mortality in 231 chronic peritoneal dialysis patients and found that the prevalence of first CV events was acute coronary syndrome (11.2%), cerebrovascular disease (12.1%), CV death (6.9%) and arrhythmia (5.6%) during the 4-year follow-up. The ratio of individual CV events in our study was similar to theirs [ 31 , 32 ].

An excessive reduction of blood pressure in some high-risk patients may confer a predisposition to an increased risk of death, the so-called J-curve effect [ 33 ]. In the present study we had the similar finding, i.e. the risk of CV events was higher in patients with systolic blood pressure <100 mmHg and insignificantly higher in patients with systolic blood pressure ≥140 mmHg than in those with systolic blood pressure ≥100 and <140 mmHg. The J-curve effect might partially explain systolic blood pressure was not a predictor of CV outcomes in this study. In addition, our patients with a congestive heart failure had taken higher percentages of aspirin, β-blockers and diuretics than those without congestive heart failure, which might partially explain congestive heart failure was not a useful predictor of CV outcomes in the present study.

There was a limitation to our study. Because our patients were followed with echocardiographic examination until February 2011, the follow-up period was not the same among them. However, we observed our study patients without CV events at least for 6 months.

In conclusion, our results demonstrated that LAD >4.7 cm, increased LVMI and LVEF <55% were independently associated with an increase in CV events. Hence, screening CKD patients by means of echocardiography may help identify a high-risk group of adverse CV outcomes.

The research presented in this article is supported by the grant from Kaohsiung Municipal Hsiao-Kang Hospital (Kmhk-100), Kaohsiung Medical University, Kaohsiung, and the statistical work by the department of Research Education and Training at Kaohsiung Municipal Hsiao-Kang Hospital.

Conflict of interest statement . We have no financial interest in the information contained in the manuscript. Here, I state that all authors have read and approved submission of the manuscript and the manuscript has not been published and is not being considered for publication elsewhere in whole or part in any language.

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