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ABSTRACT
Dyslipidemia is a well-established traditional risk factor
for cardiovascular events in the general population, particularly those with preexisting cardiovascular disease
(CVD). In this population, reductions in total and low
density lipoprotein cholesterol (LDL-C) levels are effective
in reducing coronary artery events and mortality. Dyslipidemia is more common in patients with chronic kidney
disease (CKD) and is believed to contribute to the high
prevalence of CVD in these patients. To date, the treatment of dyslipidemia in patients with CKD followed the
guidelines recommended by the US National Cholesterol
Education Program Adult Treatment Panel III (ATP III)
for the treatment of lipid abnormalities. These guidelines
recommend that initiation of lipid-lowering therapy be
based on LDL-C level and the projected 10-year risk for
coronary artery disease (CAD). However, we now recognize that the relationship between serum cholesterol and
CVD is more complex in patients with CKD, particularly
those receiving maintenance hemodialysis. This has been
demonstrated by the failure of three large randomized
clinical trials to show a beneficial effect of lipid-lowering
therapy in reducing mortality in dialysis patients despite
significant reduction in LDL-C levels. These results have
caused uncertainty among nephrologists about how best
to manage dyslipidemia in their patients. In this review,
the role of dyslipidemia as a risk factor for atherosclerosis
in ESRD patients and the results of the 3 clinical trials
and other studies, including their limitations will be discussed, and a schema for treating dyslipidemia in dialysis
patients will be proposed.
The number of patients with end-stage renal disease (ESRD) who are receiving maintenance dialysis
in the United States is approaching 500,000 (1). Cardiovascular disease (CVD), the leading cause of
death among these patients, accounts for 45% of
deaths, a rate that is 1030 times higher than that in
the general population (25). This relative risk is even
greater in younger dialysis patients (6). Atherosclerosis is more common in dialysis patients than in the
general population (7) as is coronary artery disease
(CAD) which has been documented by angiographic
studies in >50% of patients at the initiation of renal
replacement therapy (8). More disturbing is the high
mortality rate in dialysis patients after a cardiovascular event. In-hospital mortality after acute myocardial infarction (MI) among patients on dialysis is
approximately 30%; at 1-year the mortality rate is
60% (9). Thus, risk factors for CAD must be identi-
Address correspondence to: Wajeh Y. Qunibi, MD, Professor of Medicine, University of Texas Health Sciences Center
at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX
78229-3900, Tel.: 210-358-2962, Fax: 210-358-4710, e-mail:
qunibi@uthscsa.edu.
Conflict of interest: The author has no conflict of interest
to declare.
Seminars in Dialysis2015
DOI: 10.1111/sdi.12375
2015 Wiley Periodicals, Inc.
1
Qunibi
HYPERLIPIDEMIA IN ESRD
TABLE 1. Comparison of the three major randomized controlled trials: 4D, AURORA and SHARP
4D
Author/year
# of patients
Age range (years)
CKD stage 5D
Drugs
Wanner et al./2005
1255-all diabetic
1880
All
Atorvastatin 20 mg daily vs. placebo
Follow-up period
(Median)
Main results
4 years
Risk of stroke
Other adverse events
AURORA
SHARP
Fellstr
om et al./2009
2773
5080
All
Rosuvastatin 20 mg
daily vs. placebo
3.8 years
Baigent et al./2011
9270
62 12
3023 on maintenance HD
Simvastatin plus ezetimibe
vs. placebo
4.9 years
No significant reduction in
major atherosclerotic events
in dialysis patients
No significant difference
between treatment groups
nonfatal stroke, and nonfatal MI. Secondary endpoints comprised all-cause mortality, cardiac events
and cerebrovascular events.
The trial succeeded in lowering the median LDLC level by 42% within 4 weeks in the atorvastatin
group vs. 1.3% by placebo. Despite that, and during a median follow-up period of 4 years, there was
only a nonsignificant 8% decrease in the primary
composite end-point in the atorvastatin treated
group (relative risk (RR), 0.92; 95% confidence
interval (CI) 0.771.10; p = 0.37). Atorvastatin significantly reduced the rate of all cardiac events combined by 18% (RR: 0.82; 95% CI: 0.680.99;
p = 0.03) but not total mortality (RR: 0.93; 95%
CI: 0.791.08; p = 0.33). There were no cases of
rhabdomyolysis or severe liver disease detected in
either group but, unexpectedly, there was 2-fold
increase in the relative risk of fatal stroke among
those receiving atorvastatin compared with placebo
(95% CI: 1.053.93; p = 0.04).
This study was limited by including only diabetic
patients and for excluding patients with LDLC > 190 mg per deciliter. In addition, 15% of the
placebo arm patients received nonstudy statins and
17% of the statin-treated group discontinued their
drug therapy. Moreover, the mean baseline serum
LDL-C was approximately 123 mg/dl and only
13% of patients had serum LDL-cholesterol levels
>160 mg/dl. Interestingly, a post hoc analysis of the
trial data that stratified patients into LDL-C levels
<103, 104122, 123144, and >145 mg/dl, showed
that atorvastatin significantly reduced the rate of
fatal and nonfatal cardiac events and death from
any cause if pretreatment LDL-cholesterol was
>145 mg/dl (31). Therefore, statins may still be considered for diabetic HD patients with high LDL-C
levels.
AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An
Assessment of Survival and Cardiovascular Events)
was published 4 years after the publication of the
4D trial (32). AURORA was an international, mul-
No significant increase in
myalgia, rhabdomyolysis,
transaminases, or hepatitis
Qunibi
(RR: 0.94; 95% CI: 0.821.07), major cardiovascular events or fatal and nonfatal stroke in dialysis
patients.
A second meta-analysis by Upadhyay and colleagues (35) in 18 RCTs showed that lipid-lowering
therapy decreased the risk for cardiac mortality, cardiovascular events (including revascularization), and
MI in patients with CKD. Significant benefit was also
seen for all-cause mortality but was limited by a high
degree of heterogeneity. Subgroup analysis revealed
that the benefit for all-cause mortality was limited to
studies in nondialysis patients with CKD.
A third meta-analysis by Barylski and colleagues
(36) of 11 RCTs with 21,295 CKD patients, including 6857 who were on dialysis, showed that use of
statins in subjects with nondialysis-dependent CKD
resulted in a marked reduction in death from all
causes, cardiac causes, cardiovascular events, and
stroke. However, the use of statins in dialysisdependent patients resulted in a nonsignificant effect
on death from all causes and stroke, but had significant effect in reducing death from cardiac causes
and cardiovascular events.
A more recent Cochrane meta-analysis (37) on
dialysis patients in 25 studies with 8289 participants
concluded that statins had little or no benefit on
major cardiovascular events, all-cause mortality, cardiovascular mortality and MI and uncertain effects
on stroke in adults treated with dialysis despite clinically relevant reductions in serum cholesterol levels.
Finally, Hou and colleagues reported the results of
their meta-analysis of 31 trials that provided data for
48,429 patients with CKD (38). Their results showed
that statin therapy produced a 23% risk reduction
for major cardiovascular events, an 18% reduction
for coronary events, and 8% reduction in cardiovascular or all-cause deaths, but had no significant effect
on stroke. The observed beneficial effects appeared
to be smaller in patients with advanced kidney disease and those requiring dialysis. Interestingly, experience from a Japanese dialysis population that had
lesser degrees of inflammation and a different lipoprotein particle pattern have indicated that statins
may be helpful (39,40).
Why Lipid-Lowering Therapies are not
Effective in Dialysis Patients?
Statins are remarkably effective in reducing the
risk of atherosclerotic cardiovascular events in the
general population, particularly those with preexisting CAD. Thus, it would be reasonable to assume
that they will be at least equally effective in the population that are at even greater risk of CAD such as
CKD patients including those who are receiving
maintenance dialysis. Unfortunately, as discussed
above, there is no definitive evidence from RCTs to
indicate that statins or other lipidlowering therapies
are as effective in reducing cardiovascular risk in dialysis patients as in the general population or even
those with nondialysis CKD patients.
HYPERLIPIDEMIA IN ESRD
Qunibi
TABLE 3. Lists the various lipid abnormalities in nondialyzed CKD patients and dialysis patients
Triglycerides
Total cholesterol
LDL-C
HDL-C
VLDL
Small dense-LDL
IDL cholesterol
Lp (a)
CKD stages 14
Hemodialysis patients
Normal or high
High, normal or low
High, normal or low
Normal or low
High
High
High
High
High
Normal, low or rarely high
Normal, low or rarely high
Low
High
High
High
High
CKD, chronic kidney disease; LDL, low density lipoprotein; HDL, high density lipoprotein; VLDL, very low density lipoprotein;
IDL, intermediate dense lipoprotein; Lp (a), Lipoprotein (a).
GO Work Group recommend against administering fibrates with statins in these patients.
HYPERLIPIDEMIA IN ESRD
TABLE 4. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease (CKD) patients
Grade
Assessment of lipid status in adults with CKD
1C
1.1: In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplantation),
we recommend evaluation with a lipid profile (total cholesterol, LDL-cholesterol, HDL cholesterol, triglycerides)
Not graded 1.2: In adults with CKD (including those treated with chronic dialysis or kidney transplantation), follow-up measurement
of lipid levels is not required for the majority of patients
Pharmacological cholesterol-lowering treatment in adults
1A
2.1.1: In adults aged 50 years with eGFR <60 ml/min per 1.73 m2 but not treated with chronic dialysis or kidney
transplantation (GFR categories G3aG5), we recommend treatment with a statin or statin/ezetimibe combination
1B
2.1.2: In adults aged 50 years with CKD and eGFR 60 ml/min per 1.73 m2 (GFR categories G1G2), we recommend
treatment with a statin
2A
2.2: In adults aged 1849 years with CKD but not treated with chronic dialysis or kidney transplantation, we suggest
statin treatment in people with one or more of the following (2A):
2B
2C
2D
2.3.1: In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated
In adult kidney transplant recipients, we suggest treatment with a statin
2.3.2: In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest
that these agents be continued
5.1: In adults with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia,
we suggest that therapeutic lifestyle changes be implemented
Patients already
receiving statin
Continue statins
Patients not
receiving statin
Patients prefer to
receive statin
or
Patients with recent
MI or stroke
Start statins
Do not start statins
Start statins
Qunibi
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