Association between serum aluminum levels and cardiothoracic ratio in patients on chronic hemodialysis
Association between serum aluminum levels and cardiothoracic ratio in patients on chronic hemodialysis
Tzu-Lin Wang 0 1
Yu-Wei Fang 1
Jyh-Gang Leu 1
Ming-Hsien Tsai 1 2
0 Division of Cardiology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital , Taipei, Taiwan , R.O.C. , 2 Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital , Taipei, Taiwan , R.O.C. , 3 Fu-Jen Catholic University School of Medicine , Taipei, Taiwan , R.O.C.
1 Editor: Yoshihiro Fukumoto, Kurume University School of Medicine , JAPAN
2 Division of Biostatistics, Institutes of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University , Taipei , Taiwan, R.O.C
The cardiothoracic ratio (CTR) and serum aluminum levels are both associated with mortality in hemodialysis patients. However, limited data regarding the association between serum aluminum levels and the CTR have been published to date. Therefore, we aimed to elucidate this association in patients on chronic hemodialysis (CHD). We investigated the association between the serum aluminum level and the CTR in CHD in a retrospective crosssectional study of 547 Taiwanese patients on CHD. The mean age of patients was 62.5 ±13.2 years, with a mean hemodialysis time of 7.1±5.2 years. Among the patients, 36.9% were diabetic and 47.9% were male. After natural logarithmic transformation (ln(aluminum)), the serum aluminum level exhibited an independent and linear relationship with the CTR (β: 1.40, 95% confidence interval (CI), 0.6±2.2). A high serum aluminum level ( 6 ng/dL) was significantly associated with a CTR >0.5 in the crude analysis (odds ratio (OR): 2.15, 95% CI, 1.52±3.04) and remained significant after multivariable adjustment (OR: 2.45, 95% CI, 1.63±3.67). Moreover, the ln(aluminum) value was significantly associated with a CTR >0.5 (OR: 1.71, 95%CI, 1.28±2.29) in multivariable analysis, indicating a dose effect of aluminum on cardiomegaly. In conclusion, the serum aluminum level was independently associated with cardiac remodeling (elevated CTR) in patients on CHD.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
The cardiothoracic ratio (CTR) is estimated by measuring the proportion of the heart size to
the thoracic diameter on chest radiographs and it has been shown weakly and negatively
associated with cardiac systolic dysfunction [
]. Moreover, a CTR >50% is considered
cardiomegaly, and an increased CTR will lead to a poor clinical prognosis in the elderly , patients
with heart failure [4±6], hypertension [
] and chronic dialysis [8±14]. Ventricular remodeling
refers to changes in the size, shape, structure, and function of the heart [
]. Therefore, the
CTR could be representative of the ventricular remodeling status and is a simple method to assess the heart conditions of patients on chronic dialysis.
An elevated aluminum level contributes to the development of dialysis dementia, adynamic
bone disease, and anemia in patients on chronic hemodialysis (CHD) [16±18]. Currently,
overt aluminum toxicity is uncommon in patients on CHD [
] because the aluminum in
the water used for dialysis is removed by reverse osmosis and deionization. However, serum
aluminum remains an important issue for patients on CHD due to inefficient removal of
aluminum by dialysis and more frequent exposure to aluminum-containing medications [
Some studies have reported that elevated serum aluminum levels are associated with mortality in patients on CHD [23, 24]. Moreover, aluminum might have a damaging effect on cardiac remodeling, as evidenced by studies showing a significant association between heart damage and aluminum levels [25, 26].
However, no study has examined the association between the CTR and serum aluminum level in dialysis patients. Therefore, we conducted the present study to investigate their association in patients on CHD.
Materials and methods
Study design and patients
We conducted a retrospective cross-sectional study in a single medical center of Shin-Kong
Wu Ho-Su Memorial Hospital. The inclusion criteria were that patients had undergone regu
lar hemodialysis for at least three months before being enrolled in the study and must have
been clinically stable for three months preceding the study, without hospitalization for any
reason. Moreover, patients without serum aluminum level and CTR data were excluded.
Thereafter, a total of 547 patients receiving regular hemodialysis in the dialysis unit of the Shin Kong
Wu Ho-Su Memorial Hospital were included in the study from December 2009 to December
2012. Just first dataset of every patient was put into analysis. This study was performed in
accordance with the principles of the Declaration of Helsinki and was approved by the Ethics
Committee of the Shin-Kong Wu Ho-Su Memorial Hospital. Moreover, Informed consent was waived by the Ethics Committee of the Shin-Kong Wu Ho-Su Memorial Hospital because our study was based on a medical chart review. Patient information was anonymized and deidentified prior to analysis.
Medical and laboratory data
We obtained the data from patients' medical records, including demographic data and
comorbidity and dialysis-related biochemistry results. The information included age, gender,
smoking history (never versus ever), blood pressure, which was recorded as the mean value of two
measurements before the last dialysis session of a week, history of diabetes mellitus (DM),
cardiovascular disease (CVD) diagnosed according to a documented history of coronary artery or
cerebrovascular disease, body mass index, HD vintage, CTR, serum aluminum and albumin
levels, total cholesterol, triglyceride, iron profile, hemoglobin levels, intact parathyroid
hormone (iPTH), ionized calcium, phosphate levels, and urea kinetics (Kt/V). Blood samples were
collected for laboratory testing after at least 8 h of fasting and before the dialysis session.
Biochemical measurements were performed with standard commercial assays and automated
testing instruments (Beckman, Lane Cove, NSW, Australia). iPTH was measured using the Roche
Elecsys assay (Roche Diagnostics, Basel, Switzerland). Additionally, aluminum was measured
by graphite furnace atomic absorption spectrometry using a GBC 906AA (Braeside VIC,
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Cardiothoracic ratio measurement
Posterior-anterior chest radiographs were obtained to regularly measure the CTR at the end of
the year for patients on CHD after a mid-week HD session at our medical center. We used
computer software (UniWeb Viewer, EBM Technologies Inc., Taiwan) to ensure the accuracy
of measurements. The CTR was calculated by dividing the maximal horizontal width of the
heart by the horizontal diameter of inner borders of the rib cage. Therefore, a CTR >0.5 was
defined as cardiomegaly, with higher CTR levels indicating a greater severity of cardiomegaly.
Data are expressed as the mean ± standard deviation (SD) or median with interquartile range
(25th±75th percentile, IQR) as appropriate for continuous variables and as proportions for
categorical data. A natural log transformation (ln) was used to approximate a normal distribution
if the variable did not have a normal distribution. The Pearson correlation coefficient was
adopted to examine the correlations between variables. Linear regression analyses were
performed using the CTR as the dependent variable to investigate its association with the
ln(aluminum) value. Moreover, a generalized linear model was used to determine the risk of a CTR
>0.5 using the link function of logit. Subgroup analysis was also performed and was stratified
by the factors of gender (male and female), age ( 60 and >60 years), previous CVD (yes and
no), DM (yes and no), and hemoglobin level ( 9 and >9 g/dL) separately. A two-tailed
Pvalue of <0.05 was considered statistically significant. All statistical analyses were performed
using SAS for Windows version 9.4 (SAS Institute Inc., Cary, NC, USA).
The mean age of the 547 patients on CHD was 62.5±13.2 years, with a mean HD time of 7.1
±5.2 years. Among them, 36.9% were diabetic and 47.9% were male. Two hundred fifty-four
(46.4%) patients had a CTR >0.5, and 55 (10%) patients had a CTR >0.6. The mean CTR was
50.4±7.1% (IQR, 46±56%). Moreover, two hundred twenty-eight (41.6%) patients had an
aluminum level 6 ng/mL and 22 (4%) patients had the level more than 20 ng/mL. The other
clinical characteristics of the participants are shown in Table 1. The median serum aluminum
level was 5.3 (IQR, 3.5±8.6) ng/mL with a distribution skewed toward the right (Fig 1).
Moreover, the significant linear association between ln(aluminum) values and the CTR is shown in
Fig 2. The CTR distribution was stratified based on a serum aluminum level of 6 ng/mL, and
the group with an aluminum level 6 ng/mL had a greater mean CTR (Fig 3).
Determinants of the CTR in patients on CHD
Association between serum aluminum levels and the CTR
In further stepwise modeling and analysis (Table 3), a higher serum aluminum level ( 6 ng/
mL) was significantly associated with a CTR >0.5 (odds ratio [OR], 2.15; 95% confidence
interval [CI], 1.52±3.04) in the crude analysis. After further adjustment to demographic
variables and comorbidity and dialysis-related parameters, significance was maintained with an
OR of 2.45 (95% CI 1.63±3.67). Moreover, the ln(aluminum) value was also significantly
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Abbreviations: SD, standard deviation; CVD, cardiovascular disease; BP, blood pressure; Kt/V, urea
kinetics; iPTH, intact parathyroid hormone; SAL, serum aluminum level; IRQ, interquartile range; CTR,
associated with a CTR >0.5 (OR, 1.67; 95% CI, 1.30±2.14) in the crude analysis. After further
adjustment for confounding variables, significance was maintained with an OR of 1.71 (95%
We investigated the association between the bivariate aluminum level (with a cutoff value of 6
ng/mL) and a CTR >0.5 in analyses stratified by covariates including a history of DM,
previous CVD, hemoglobin, age, and gender. Fig 4 shows that a higher aluminum level ( 6 ng/dL)
was significantly associated with a CTR >0.5 in the group without CVD and the group with a
hemoglobin value >9 g/dL after multivariable adjustment for demographic characteristics and
laboratory data regarding HD. The serum aluminum level seems to have no discrepant effect
in groups with different genders, ages or DM histories.
In this cross-sectional study of 547 patients on CHD, both higher serum aluminum ( 6 ng/ mL) and ln(aluminum) levels were independently correlated with a CTR >0.5. Moreover, a linear association was also noted between ln(aluminum) and continuous CTR values. These
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Fig 1. Distribution of serum aluminum levels in patients on chronic hemodialysis.
relationships were independent of traditional anemia risk factors. This finding emphasizes
that aluminum may have a toxic effect on cardiac remodeling in patients on CHD and may
serve as an initiator of cardiomegaly. Physicians should maintain serum aluminum levels as
low as possible in dialysis patients.
The echocardiography is the optimal method for determination of cardiomegaly and espe
cially left ventricular function because CTR can be increased due to epicardial fat pad,
expiration, and fluid overload [
]. However, an autopsy study has reported a satisfactory
association between CTR and heart size . Moreover, some studies have disclosed that CTR
had significant association with CV mortality [
9, 12, 14
] or CV events [
] in patients on
CHD. Thereafter, an elevated CTR may indicate heart problem in certain extent and then it
allows us to use CTR as the surrogate of ventricular remodeling in patients on CHD because
CTR is a simple and inexpensive method.
We proposed a hypothesis regarding our finding that the serum aluminum level is indepen
dently and significantly associated with cardiomegaly (CTR >0.5) in patients on CHD. A
previous in vitro study indicated that aluminum inhibits the regeneration of reduced glutathione,
thereby leading to oxidative damage [
]. Oxidative stress induced by aluminum will cause a
disturbance of the intracellular redox system and will consequently contribute to
cardiomyopathy and atherosclerosis [
], which could partially explain the poor clinical outcomes in
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Fig 2. Regression plot of cardiothoracic ratios (%) with serum aluminum levels after natural log transformation (ln(aluminum)). Lines indicate
bestfit regression lines derived from the least mean square method.
patients on CHD. However, the actual mechanism still requires further exploration. Moreover,
in our subgroup analysis, a higher serum aluminum level was not significantly associated with
cardiomegaly in groups with hemoglobin levels 9 g/dL or CVD history. This may have
occurred because anemia and CVD are both strong risk factors for the development of
cardiomegaly in patients on CHD [
] and may negate the impact of the hazardous effect of
aluminum on the heart.
The National Kidney Foundation±Kidney Disease Outcomes Quality Initiative (KDOQI)
] recommends that physicians should take actions to decrease the serum
aluminum level in patients on CHD when it exceeds 20 ng/mL. However, according to our study,
we suggest that an early alert is needed, even when the aluminum level is only slightly above
the normal range (0±6 ng/mL) due to its hazardous effect on cardiac remodeling. Clinically,
dialysis patients have a higher chance of being exposed to aluminum-containing products,
including aluminum-containing phosphate binders and antacids, iron and calcium-containing
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Fig 3. Distribution of the cardiothoracic ratio (%) in groups of patients on chronic hemodialysis with serum aluminum levels
(a) <6 ng/mL and (b) 6 ng/mL.
Abbreviation: aOR, adjusted odds ratio; CVD, cardiovascular disease; BP, blood pressure; Kt/V, urea kinetics; iPTH, intact parathyroid hormone
medications, calcitriol, vitamin B complex, erythropoietin, and insulin [21, 35±37].
Aluminum-containing phosphate binders are one of the most common sources of aluminum [
and the KDOQI has suggested discontinuing their use. However, aluminum-containing
phosphate binders are still being used in some countries due to financial reasons or uncontrolled
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Fig 4. Subgroup analysis of the association between a cardiothoracic ratio >0.5 and (a) the serum aluminum level with a cut-off value of 6 ng/dL;
and (b) the serum aluminum level after natural log transformation (ln(aluminum)). The full model comprised adjusted variables, including age, gender,
hemodialysis vintage, diabetes mellitus, cardiovascular disease, smoking history, systolic blood pressure, diastolic blood pressure, body mass index,
albumin, hemoglobin, transferrin saturation, ionized calcium, and phosphate levels.
]. Therefore, more intensive screening of the serum aluminum level is
needed for such patients, and an early response is necessary if the serum aluminum level is
beyond the normal range.
Our study had some limitations that should be considered when elaborating the results.
First, due to the cross-sectional design, the causal relationship between serum aluminum levels
and CTRs cannot be inferred. However, according to previous studies [
] and based on
the pathological view, we suggest that an elevated serum aluminum level occurs before
cardiomegaly. Second, this was a single-center study, and the results might not be applicable to all
CHD populations. Generalization of the results should be clarified in further studies. However,
the strong association between the serum aluminum level and CTR >0.5 in our study may
extenuate this limitation. Third, some patients might not follow the guideline to take the
picture of chest X-ray, which would introduce an overestimate of CTR due to fluid overload.
However, this occurred at a random pattern and then the inferred result would not be altered
because this bias contributed equally to the groups. Finally, we did not assess the internal
variability of the CTR measurement. However, the use of computer-assisted CTR measurements
may diminish this bias because this method has been shown to be a simple and reliable method
to assess the heart [
A significant and independent association was observed between higher serum aluminum levels (higher than the normal range) and cardiomegaly (CTR >0.5) in patients on CHD. Therefore, exposure to aluminum-containing medication should be avoided as much as possible to impede the elevation of serum aluminum levels in patients on CHD.
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S1 Dataset. The collected data in the study.
We thank our patients for contributing the dataset to this study.
Conceptualization: Yu-Wei Fang.
Data curation: Tzu-Lin Wang, Ming-Hsien Tsai.
Formal analysis: Ming-Hsien Tsai.
Investigation: Ming-Hsien Tsai.
Methodology: Jyh-Gang Leu, Ming-Hsien Tsai.
Supervision: Ming-Hsien Tsai.
Validation: Tzu-Lin Wang, Yu-Wei Fang, Ming-Hsien Tsai.
Writing ± original draft: Tzu-Lin Wang.
Writing ± review & editing: Yu-Wei Fang, Jyh-Gang Leu, Ming-Hsien Tsai.
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