Different effect of hypercholesterolemia on mortality in hemodialysis patients based on coronary artery disease or myocardial infarction
Lin et al. Lipids in Health and Disease
Different effect of hypercholesterolemia on mortality in hemodialysis patients based on coronary artery disease or myocardial infarction
Yi-Chun Lin 2 3
Yen-Chung Lin 0 1 5
Hsi-Hsien Chen 1 5
Tzen-Wen Chen 1
Chih-Cheng Hsu 4
Chiung-Chi Peng 0
Mai-Szu Wu 1 5
0 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei , Taiwan
1 Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital , Taipei , Taiwan
2 Faculty of Medicine, National Yang-Ming University , Taipei , Taiwan
3 Division of Endocrinology & Metabolism, Department of Medicine, Taipei Veterans General Hospital , Taipei , Taiwan
4 Institute of Population Health Sciences, National Health Research Institutes , Zhunan , Taiwan
5 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University , Taipei , Taiwan
Background: Studies on the association of total cholesterol (TC) levels and mortality in hemodialysis (HD) patients demonstrated conflicting results. The differenct effect of Hypercholesterolemia on HD patients based on the presence of myocardial infarction (MI) or coronary artery disease (CAD) is unknown. Methods: We analyzed data from the Taiwan Renal Registry Data System (TWRDS) between 2005 and 2012. Patients were divided into MI/CAD or non-MI/CAD group. The primary outcome was three-year mortality. The association between primary outcome and first year average TC and effect of change in cholesterol level between the first and third year of dialysis were explored. Results: Of 90,795 HD patients, 77,762 (85.6%) patients were assigned to non-MI/CAD group and 13,033 (14.4%) to the MI/CAD group. In the non-MI/CAD subjects, both TC > 250 mg/dL and < 150 mg/dL were associated with increased risk of mortality (adjusted hazard ratio [HR]; 95% confidence interval [CI]: 1.27; 1.17-1.37 and 1.14; 1.11-1.18) compared to the reference (TC: 150-200 mg/dL). In the MI/CAD patients, only TC < 150 mg/dL had increased risk (HR; 95% CI: 1. 15; 1.08-1.24). In addition, patients of the non-MI/CAD group with highest level of TC (>250 mg/dL) in both first and third year of dialysis had a 64% increased risk for mortality (HR: 1.64, 95% CI: 1.51-1.80). Conclusion: In this nationwide hemodialysis cohort, hypercholesterolemia was associated with increased mortality in HD patients without MI/CAD. Further investigation on primary prevention of CAD with statin is warranted.
Coronary artery disease; Total cholesterol; Hemodialysis; Mortality; Myocardial infarction
Chronic kidney disease (CKD) and end-stage renal
disease (ESRD) are emerging epidemiological issues in the
world and have a high mortality rate. Cardiovascular
disease (CVD) is the leading cause of mortality in this
population . In general, high cholesterol level is an
important precipitating factor affecting atherosclerotic
arterial wall changes and causing CVD, starting in young
age  and is associated with higher mortality rates in
many prospective studies . In patients with ESRD,
lipoprotein metabolism is also dysregulated. For
example, reduced high-density lipoprotein cholesterol
(HDL), increased plasma triglyceride (TG)
concentrations, defect in cholesterol transport, and the increase in
atherogenic small dense low-density lipoprotein
cholesterol (sdLDL) subclass are common in ESRD patients
. Despite lipoprotein dysregulation in HD patients,
high cholesterol level in dialysis patients is paradoxically
associated with higher survival rates, according to
several observational studies [5, 6].
The role of hypercholesterolemia varies between
different subgroups of dialysis patients. According to a
large population study from Japan renal data registry,
© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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although the onset of myocardial infarction is associated
with dyslipidemia, for those who had CVD, the death
after events is not positively associated with non-HDL
cholesterol level . Therefore, we aim to investigate
whether the association between serum total cholesterol
(TC) level and all-cause mortality would be altered in
HD patients by the presence of myocardial infarction or
coronary artery disease.
This study was approved by the ethics committee of
Taipei Medical University’s institutional review board
(Number: N201506012), and was conducted in
accordance with the principles of the Declaration of Helsinki.
The institutional review board of Taipei Medical University
approved the waiver of informed consent.
The Taiwan renal registry data system
The Taiwan Renal Registry Data system (TWRDS) was
built in 1987 initially for the accreditation of dialysis
therapy. All dialysis units in Taiwan are required to
provide the appropriate laboratory and clinical information
for inclusion in the TWRDS to obtain national health
insurance (NHI)-associated reimbursements. Every dialysis
unit submits a quarterly laboratory report. In 1997,
additional data were gathered, including those relating to
co-morbidities such as the history of myocardial
infarction (MI), coronary artery disease (CAD), the patients’
rehabilitation statuses, the dialysis adequacy indices,
biochemical and hematological parameters, the hepatitis
serological results, prescription of anti-hypertension
medications or not, anemia management, and mineral bone
indices . Because dialysis expenses are reimbursed to
each individual in full amount, the application for
maintenance of dialysis certification is processed after review of
the medical records by a senior physician and uploaded to
the system. Another senior nephrologist gives the
approval of reimbursement from NHI bureau. Presence of
MI or CAD was defined as per the medical record
documentation (history of percutaneous transluminal coronary
angioplasty, coronary artery bypass grafting, computed
tomography angiography, acute coronary syndrome…etc.)
of each individual. The Taiwan Renal Registry Data system
provide reliable information and data for the continual
survaliance and quality control of dialysis at the
nationwide level [9–12]. We analyzed the data in the TWRDS
database that was generated between 2005 and 2012.
Patient enrollment and study design
Patients registered with the TWRDS from 2005 to 2012
were included in the analysis (N = 102,599). After
excluding patients who had changed their dialysis modality
(N = 927), had concurrent malignant tumor (N = 7162),
are age younger than 20 or older than 90 years old
(N = 998), and without cholesterol data (N = 2717),
the final sample that went forward for analysis
comprised of 90,795 patients. Among them, 13,033
patients (14.4%) had MI or CAD (MI/CAD group), and
77,762 (85.6%) patients identified as without MI or
CAD (non-MI/CAD group) were included in analysis
(Fig. 1). The primary endpoint of this study was the
3-year all-cause mortality rate. An individual was
regarded dead if he or she was lost to follow-up in
the TWRDS based on the complete national coverage
provided by the NHI policy for all renal replacement
therapy expenditures. Patients were categorized into 4
groups by the first year average cholesterol level
(<150, 150–200, 200–250, > 250 mg/dL) according to
the definition of hypercholesteremia from The National
Cholesterol Education Program and the definition of
malnutrition in HD patients from the NKF KDOQI guidelines
. We also assessed the effect of change in cholesterol
level on mortality during the first three years of dialysis.
Nine groups were created on the basis of total cholesterol
(TC) (<150, 150–250, > 250 mg/dL) in the first and third
year of dialysis.
The biochemical data of hemodialysis patients in
TWRDS 2005–2012, including TC and fasting TG,
fasting glucose, albumin, hematocrit (Hct), white blood cell
(WBC) counts, calcium (Ca), phosphorus (P), alkaline
phosphatase (Alk-P) and intact parathyroid hormone
(i-PTH) were collected every 3 months. Fasting blood
samples were drawn before dialysis. About 80% of the
Once shifting dialysis
between HD/PD, N=927
Fig. 1 Flow chart of patient enrollment
Table 1 Baseline characteristics of 90,795 patients with
hemodialysis by presence of MI and CAD
45634 (50%) 38817 (50%) 6817 (52%)
47173 (52%) 38501 (50%) 8672 (67%)
39853 (44%) 30481 (39%) 9372 (72%)
12222 (13%) 7757 (10%)
49699 (55%) 40683 (52%) 9016 (69%)
Cardiomegaly (%) 12027 (13%) 7896 (10%)
Glucose (mg/dL) 148.5 ± 67.6 146.9 ± 67.5 157.5 ± 67.7
samples were sent to Union Clinical Laboratory.
Enzymatic methods on a Siemens (Munich, Germany)
autoanalyzer (ADVIA 1800) were used to determine
general chemistry including cholesterol (coefficient of
variation [CV] 1.1%). The average of four
measurements of cholesterol levels in the first year was used
as the baseline value to predict patient survival.
Cardiomegaly was defined by chest thoracic ratio more
than 0.5 on chest plain radiography.
The descriptive statistics were expressed as the means
(standard deviations [SD]), medians (ranges), or
frequencies (percentages) for continuous variables and
proportions for categorical variables. One-way ANOVA test or
Kruskal Wallis test was used for the analysis of
continuous variables as appropriate, and the differences between
nominal variables were compared by the chi-square test.
Log-rank test was used for Kaplan-Meier analysis. The
level of significance was set at 0.05, two-tailed for all
tests.. We performed Cox regression analysis to estimate
the hazard ratios (HR) of 3-year mortality in HD patients
for different cholesterol level. The case-mix adjusted
model included the following confounding factors: age,
gender, the presence of diabetes mellitus (DM),
hypertension (HTN), congestive heart failure (CHF), cardiomegaly,
cerebral vascular accident (CVA), and the use of
antihypertensive agents or not. The laboratory data of glucose,
Hct, Ca, P, HD treatment adequacy score (the single-pool
Kt/V), and malnutrition/inflammation markers, including
albumin level and WBC counts were also adjusted in Cox
regression analysis. All of the descriptive and multivariate
analyses were performed using the Statistical Package for
the Social Sciences software version 17.0 for Windows XP
(SPSS Inc., Chicago, IL, USA) and SAS version 9.1 (SAS
Institute, Cary, NC).
Baseline characteristics of the two groups categorized by
Table 1 summarizes the study population’s baseline
characteristics categorized by with or without MI or CAD. A
total of 77,762 (85.6%) HD patients without MI or CAD
were identified and 13033 of the whole cohort as with
MI or CAD. The mean (SD) age of the patients was 61.9
 years. Type 2 diabetes mellitus was present in 52%
of the whole cohort. Patients without MI or CAD had
younger age, significant less comorbidities including
DM, HTN, CHF, cardiomegaly and CVA (Table 1).
Survival analysis: Kaplan-Meier survival curve
Figure 2 showed an overall unadjusted Kaplan-Meier
survival curve. In patients without MI or CAD (Fig. 2a),
171.8 ± 37.3 171.4 ± 37.3 174.2 ± 37.1
164.6 ± 106.5 162.2 ± 104.9 178.6 ± 114.9 <0.0001
120.3 ± 96.9 121.0 ± 98.1 116.3 ± 89.6
199.1 ± 185.7 200.4 ± 186.9 191.5 ± 178.6 <0.0001
Abbreviations: HD hemodialysis, MI myocardial infarction, CAD coronary artery
disease, DM diabetes mellitus, HTN hypertension, CHF congestive heart failure,
CVA cerebral vascular accident, WBC white blood cells, TC total cholesterol, TG
triglyceride, Hct hematocrit, Ca calcium, P phosphorus, Alk-P alkaline
phosphatase, iPTH intact parathyroid hormone
the group with TC < 150 mg/dL had the worst survival rate,
followed by those groups with TC > 250, 150–200, and
200–250 mg/dL (Log rank, P < 0.001), respectively. In
patients with CAD (Fig. 2b), the group with TC < 150 mg/dL
had the worst survival rate, followed by the group with TC
150–200 mg/dL, whereas the group with TC > 200 mg/dL
had the best survival rate (Log rank, P < 0.001).
Cox regression model for cholesterol level and mortality
Table 2 showed the crude and adjusted HR of
mortality associated with total cholesterol in the Cox
regression model. Case mix and malnutrition/inflammation
markers, including WBC counts and albumin levels
were adjusted. In the population without MI or CAD,
compared to the group of TC between 150–200 mg/dL,
the adjusted HRs were statistically significant, which are
1.27 (95% confidence interval [CI]: 1.17–1.37) and 1.14
(95% CI: 1.11–1.18) in the groups of TC > 250 mg/dL and
< 150 mg/dL, respectively. In the patients with CAD,
significant increase in HR (1.15, 95% CI: 1.08–1.24) was
observed in the group of TC < 150 mg/dL compared to the
Fig. 2 Unadjusted survival curve by total cholesterol level in HD patients. a without MI or CAD. b with MI or CAD
reference group of TC 150–200 mg/dL. Figure 3 showed
the curve of crude and adjusted HR of TC levels in
nonMI/CAD and MI/CAD groups. An inverse association
between TC and HR of all-cause mortality was observed in
the MI/CAD group (Fig. 3b), while a U-curve was
observed in the non-MI/CAD group with a significantly
higher HR when TC was > 250 mg/dL or < 150 mg/dL
Mortality and cholesterol level between the first year and
the third year
Relative risk for mortality based on the change in
cholesterol level between the first and third year of dialysis is
shown in Table 3. In patients in non-MI/CAD group,
the level of TC >250 mg/dL between first and third year
of dialysis, showed a significant higher mortality risk
(HR: 1.64, 95% CI: 1.51–1.80) compared with normal
150–200 (38505) 173 (162–185)
150–200 (6607) 173 (162–186)
1.34 (1.26–1.43)* 1.15 (1.08–1.24)*
200–250 (14295) 215 (207–227)
0.88 (0.85–0.91)* 0.99 (0.96–1.03)
1.14 (1.07–1.22)* 1.27 (1.17–1.37)* >250 (394)
200–250 (2559) 215 (207–228)
Abbreviations: CI confidence interval, MI myocardial infarction, CAD coronary artery diease, TC total cholesterol, HR hazard ratio
*p < 0.01; **adjusted for age, gender, history of DM、HTN、cardiomegaly、CVA, levels of hematocrit, calcium, phosphorus, parathyroid hormone, alkaline
phosphatase, Kt/V, albumin and white blood cell counts
TC level (150–250 mg/dL). The lowest level of TC in
the first and third year of dialysis, irrespective of MI/
CAD in the patient, had the highest HR (non MI/CAD
group, HR: 1.76, 95% CI: 1.71–1.80; MI/CAD group,
HR: 1.55, 95% CI: 1.45–1.65;) compared to the levels in
In this nationwide, population based study, we
demonstrated that in patients under maintenance hemodialysis,
different patterns of association between TC and mortality
exist. In those without MI/CAD, an increased mortality
was observed when TC is higher than 250 mg/dL. In
addition, patients without MI/CAD who had TC levels >
250 mg/dL in the first and third years had a 64% increased
risk for mortality.
Although CV mortality was significantly higher in
patients under dialysis compared with the general
population , the correlation of TC values with the major
outcomes in the HD subgroups showed conflicting
Fig. 3 Hazard ratios of mortality by total cholesterol level in HD patients. a without MI or CAD. b with MI or CAD
B. With MI or CAD (N = 13033)
1.55 (1.45–1.65)* *
Table 3 Hazard ratio (95% CI) of all-cause mortality on HD patients
by changes in total cholesterol level (mg/dL) between 1st and 3rd
A. Without MI or CAD (N = 77762)
1.76 (1.71–1.80)* *
0.75 (0.70–0.80) **
150–250 1.11 (1.05–1.18) * * 1.00
150–250 1.20 (1.06–1.35) * * 1.00
results. There are no studies that compared the
differential influence of lipoproteins on HD patients with regard
to the presence of MI or CAD. Patients with previous
CAD were more likely to receive statins and other
antiplatelet medication such as aspirin, which have a
protective effect could be one of the confounding factors. A
study by Shoji et al. including 45,390 HD patients from
Japan renal registry reported that non-HDL was
associated with increased risk of CVD incidents, but the
mortality after new onset of CAD was not associated with
The positive correlation of cholesterol and mortality
when TC is above 250 mg/dL in the group of HD
without previous MI/CAD is similar to that in the general
population. Despite that only a few individuals with total
cholesterol > 250 mg/dL (N = 1975 and 394 in non-MI/
CAD and MI/CAD groups seperately) are on regular
HD, the mortality still correlated with the higher TC
levels in those without previous MI history. In the
general population, statin therapy for lipid-lowering is
fundamental and “the lower the better” is the strategy for
many physicians. According to the current KDIGO
guideline, lipid-lowering agents such as statins should be
used for all CKD patients with high CVD risk .
However, the lipid-lowering agents are under-prescribed for
CKD patients than non-CKD patients with dyslipidemia
in clinical practice . The results of large randomized
clinical trials (4D, AURORA, SHARP) on cardiovascular
benefits of LDL lowering therapy in HD patients have
been inconclusive [17–20]. The benefit of lowering serum
LDL cholesterol could be achieved only after 3 to 5 years
of statin therapy . Therefore, the initiation of statins is
no longer recommended in dialysis patients . In the
SHARP study which excluded patients with history of
coronary artery disease , it showed beneficial effect in
reducing major atherosclerotic events by reducing LDL
levels with daily simvastatin 20 mg plus ezetimibe 10 mg.
In our study, we found a U-curve relation between TC
and mortality in HD patients without MI or CAD from a
large population dataset which indicates that cholesterol
lowering therapy might be beneficial, but the goal and
candidate of treatment may not be the same as the
nondialysis patients with high CV risk.
Although a large body of evidence suggests the
positive correlation of TC with mortality in general
population , this correlation does not always exist in patients
with HD. Some authors proposed the reverse
epidemiology concept, where lower cholesterol is associated with
worsened CVD outcome by itself or maybe confounded
by malnutrition or inflammation when individual is on
maintenance dialysis therapy [5, 6]. Dialysis patients with
hypoalbuminemia interplayed with malnutrition that led
to proinflammatory condition and cytokine activation,
which is suggested to have higher prevalence in
cardiovascular diseases [23–25]. There are other possible
explanations of reverse epidemiology other than
malnutrition inflammation complex syndrome (MICS). Since
these dialysis patients underwent special selection for
renal replacement therapy and survived, they had
survival bias and had different characteristics when
compared to the general population. Hypercholesterolemia
was not associated with increased mortality in HD
patients with MI/CAD probably because the prevalence of
comorbidities was high. Moreover, HD patients with MI/
CAD tend to have shorter survival period, the harmful
insult from hyperlipidemia was considered in the long
term, which is not readily observed in this subgroup.
The association of low cholesterol with higher mortality
is also found in the group of chronic heart failure
patients as in those with chronic renal failure . The
possible explanation proposed is that lipoproteins may
potentially contribute to the reduction of endotoxin
bioactivity and consequently decrease cytokine production
[27–30]. It was also observed that cholesterol is a
protective factor in patients with chronic disabling disease
or old age .
The relationship of cholesterol and mortality in HD
patients was the same with general population in some
observational study. Liu et al. reported in a prospective study
of 823 patients that in the absence of
inflammation/malnutrition, a positive correlation exists between cholesterol
and all-cause mortality . However, in our study, the
markers of malnutrition and inflammation, albumin and
WBC counts, were found to be similar between MI/CAD
and non-MI/CAD group. After adjusted for these
parameters, TC level lower than 150 mg/dL still had an increased
risk for all-cause mortality in both MI/CAD and non-MI/
Patients in the lowest cholesterol group in the first
year and the third year had the highest HR in the
nonMI/CAD or MI/CAD group, although the effect was
more significant in the non-MI/CAD group. This is
similar to the observation in non-demanding people
older than 70 years from a study of the Honolulu Heart
Program, in which the same patients being in the lowest
group of cholesterol from two examination periods had
the worst CV outcome . However, patients without
previous MI/CAD who remained in the group of TC >
250 mg/dL in the first three years of dialysis showed a
64% increased risk in mortality in our study gave us a
hint that statin treatment maybe beneficial.
There were several limitations of this study. First,
there was no detailed data regarding anti-platelet,
antihypertension and most importantly, statin prescription
which may have effect on the mortality. The lower TC
level may have been due to the effect of medication.
However, it was noticed that even though the majority
of patients had TC level between 150 and 250 mg/dL, a
substantial proportion of the population had TC level <
150 mg/dL, with increased risk of mortality; this
suggests that the treatment goal should be TC <250 mg/dL
but not <150 mg/dL. Second, the actual cause of
mortality can’t be identified from the TWRDS dataset. The
cause of death of patients with higher or lower total
cholesterol level maybe different in patients under
maintenece dialysis and need further investigation. Third, the
lack of completeness of plasma lipoprotein profile in this
dataset was noted. However, we found there was no
association between plasma traiglyceride and all cause
mortality in this cohort (data not shown).
This nationwide population-based study showed
hypercholesterolemia was associated with increased mortality
in hemodialysis patients without MI/CAD. The effect of
hypercholesterolemia on mortality was not found in HD
patients with the presence of MI/CAD. Further studies
are warranted to confirm the benefit of early
intervention or monitoring of cholesterol level in HD patients
with different risk factors.
We would like to thank Mr. Kuang-wen Wang for analytical assistance and
Ms. Yi-Jiun Chen and Ms. Huey-May Lin for their secretarial assistance.
Conceived and designed the experiments: YL (Yi-Chung Lin); YL (Yen-Chung
Lin); MW. Performed the experiments: YL (Yi-Chun Lin). Analyzed the data: YL
(Yen-Chung Lin); CP. Contributed reagents/materials/analysis tools: YL (Yi-Chun
Lin); MW; HC; CH. Wrote the manuscript: YL (Yi-Chun Lin); YL (Yen-Chung Lin).
All authors read and approved the final manuscript.
Consent for publication
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