DRUG THERAPY: SPECIAL CONSIDERATIONS IN DIALYSIS PATIENTS

Dyslipidemia in Dialysis Patients

Wajeh Y. Qunibi
Division of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio,
San Antonio, Texas

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-

fied and treated in an attempt to reduce the burden

of atherosclerosis in dialysis patients.
Dyslipidemia, defined as increased levels of serum
cholesterol and/or triglycerides, is a well-established
traditional risk factor for atherosclerotic CAD in
the general population and in patients with mild-tomoderate CKD, particularly those with nephroticrange proteinuria. Studies in the general population
have documented a direct, strong, and dose-dependent relationship between total cholesterol level and
CVD mortality. Moreover, the pathogenic role of
serum cholesterol as a risk factor in atherosclerotic
CVD was confirmed by several randomized clinical
trials (RCTs) which demonstrated that reductions in
total and LDL-C levels, primarily with statins, is
effective in reducing coronary artery events and
mortality (1013). Clinical trials have also shown
that lipid-lowering therapy is effective in reducing
the risk of atherosclerotic cardiovascular events in
the nondialyzed CKD population (14,15).
As dyslipidemia is also frequent in dialysis
patients and is believed to represent a major risk
for CAD (16), treatment with lipid-lowering agents
was considered a plausible strategy for reducing cardiovascular events in dialysis patients. Management
of dyslipidemia in dialysis patients followed the
guidelines recommended by the US National Cholesterol Education Program Adult Treatment Panel
III (ATP III) which base the initiation of treatment

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

and target LDL-cholesterol (LDL-C) level on the

projected 10-year risk for coronary artery event
such as myocardial infarction (MI) or coronary
death (17). According to these guidelines, LDL-C
should be reduced to <100 mg/dl in patients with a
projected 10-year risk of coronary artery event that
exceeds 20% such as those with CKD. However, as
will be discussed later, the underlying pathophysiology of CVD and the nature of atherosclerosis are
different in dialysis patients from that of the general
population. Understanding these differences may
help in designing a rational approach for the treatment of dyslipidemia in these patients.
Role of Atherosclerosis in Cardiovascular
Disease in Dialysis Patients
In patients with early stages of CKD, dyslipidemia
contributes significantly to the pathogenesis of atherosclerotic CAD (16). This process was thought to
be accelerated in chronic hemodialysis patients as
was initially described by Lindner et al. in 1974 (18).
Subsequently, Lowrie and Lew reported a U-shape
relationship between serum total cholesterol level
and the risk for all-cause mortality in dialysis
patients (19). Other large observational studies have
confirmed the negative relationship between serum
total or LDL-cholesterol and CVD in dialysis (20)
and nondialyzed CKD patients (21). In one study,
serum LDL-C < 70 mg/dl was strongly associated
with all-cause mortality risk, but black patients displayed a more conventional association between
high LDL-C and increased death risk (20). The high
risk associated with low cholesterol level was attributed to malnutrition and inflammation. Clarifying
this relationship further, Liu et al. reported that
hypercholesterolemia is an independent risk factor
for all-cause and CVD mortality in a subgroup of
ESRD patients without serologic evidence of inflammation or malnutrition (22). Given that statins
affect inflammation in addition to cholesterol level,
these authors stated that their findings support the
use of statins in preventing CVD in dialysis patients.
Effects of Stains in Patients with CKD
Observational Studies
Statins (3-hydroxy-3-methylglutaryl coenzyme A
reductase inhibitors) are highly effective for preventing CV morbidity and mortality in the general population, especially those at higher baseline CAD
risk (1012). In these patients, the reduction in mortality and in CAD events is proportional to the
reduction in LDL-C level. The Third Adult Treatment Panel of the National Cholesterol Education
Program recommended a target value of LDL-cholesterol of 70 mg/dl for individuals at very high risk
of CVD (23). Subgroup analyses of large trials in
the general population suggest that the benefit of
statin treatment is similar to, or even greater, in

patients with stage 3 CKD than that in individuals

with normal kidney function (24). Moreover, retrospective analyses of the U.S. Renal Data System
Dialysis Morbidity and Mortality Wave-2 study
showed that in incident hemodialysis or peritoneal
dialysis patients, statin therapy was associated with
a 32% decrease in total mortality and 37% decrease
in cardiovascular mortality (25). A similar decrease
in mortality associated with statin use was also
reported in prevalent dialysis patients enrolled in
Dialysis Outcomes and Practice Patterns Study
(DOPPS) (26).
However, there were no major randomized clinical trials that specifically examined the efficacy of
statins in improving survival and cardiovascular
events or on safety of these drugs in patients with
advanced CKD or in dialysis patients. Thus, the
Kidney Disease Dialysis Outcome Quality Initiative
(K/DOQI) guidelines stated that, in the absence of
strong evidence to the contrary, it is reasonable to
assume that statins will reduce LDL-C and thereby
atherosclerotic CVD in most patients with CKD.
Given the high mortality rate from CVD in CKD
patients, and based on results of studies in the general population as well as on observational studies
in CKD patients, the K/DOQI guidelines recommended a goal LDL-cholesterol <100 mg/dl in
patients with CKD, including those receiving maintenance dialysis (27).
Unfortunately, this approach proved to be controversial because an increased risk of CVD is seen in a
large proportion of dialysis patients irrespective of
whether their LDL-C levels were low, normal, or high.
This suggests that the accelerated atherosclerosis and
CVD in most dialysis patients may not be due to elevated LDL-C, and thus interventions that reduce CV
events in the general population may not be equally
effective in dialysis patients (28,29). Adding to this is
the concern about possible increased risk of rhabdomyolysis and liver function abnormalities due to statins in patients with decreased renal function.
To investigate the efficacy and safety of statins
and other lipid-lowering therapy in CKD patients,
three large RCTs and a number of meta-analyses
were conducted during the last 9 years with the aim
of ascertaining whether statins are beneficial, and
safe, in reducing CV risk and mortality from CVD
in dialysis patients (Table 1). A brief description of
each of these trial follows.
Randomized Placebo-Controlled Clinical
Trials
The 4D Study (Die Deutsche Diabetes Dialyse
Studie) was the first multicenter, double blind, placebo-controlled RCT that examined the effects of
lowering the level of LDL-C with statins on cardiovascular events and mortality in 1255 German hemodialysis patients with type 2 diabetes. Patients
were randomized to receive 20 mg of atorvastatin
daily or placebo (30). The primary end-point was a
composite of death from cardiac causes, fatal and

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

No reduced risk of the composite

primary end-point but significant
reduction in subgroup with
LDL-C > 145 mg/dl
2-fold increase in relative risk of
fatal stroke among those receiving
atorvastatin
No cases of rhabdomyolysis or
severe liver disease detected
in either group

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 reduced risk of mortality

or primary and secondary
end-points

No significant reduction in
major atherosclerotic events
in dialysis patients

Slight but significant increase

in hemorrhagic strokes in
diabetic patients receiving rosuvastatin
No increase in liver disease, or
rhabdomyolysis in rosuvastatin group

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

ticenter, double-blind, placebo-controlled RCT that

randomly assigned 2776 prevalent hemodialysis
patients to receive rosuvastatin 10 mg daily or placebo. The combined primary end-point was death
from cardiovascular causes, nonfatal myocardial
infarction, or nonfatal stroke. Secondary end-points
included death from all causes and individual cardiac and vascular events. Similar to the 4D study,
LDL-C levels decreased by 43% and total cholesterol levels decreased by 27% in the rosuvastatin
group. However, after a mean follow-up of
3.8 years, intent-to-treat analysis revealed no significant difference in the combined primary endpoint
between the rosuvastatin and the placebo groups
(hazard ratio (HR): 0.96; 95% CI: 0.841.11;
p = 0.59) or all-cause mortality (HR: 0.96; 95% CI:
0.861.07; p = 0.51). There was no increase in the
incidence of muscle-related adverse events, rhabdomyolysis, or liver disease in the rosuvastatin group
as compared with the placebo group but there was
a slight but significant increase in hemorrhagic
strokes in patients with diabetes who received rosuvastatin, which is consistent with the findings of the
4D study.
Again, this study was limited by a 50% dropout
of patients in each treatment group before study
completion which may have concealed the potential
benefit of statin therapy. Of note, the mean baseline
serum LDL-C was around 100 mg/dl. Moreover,
AURORA excluded patients who had received a
statin within the previous 6 months, a group that
represents 3540% of all dialysis population who
are likely to benefit the most from statins. Finally,
the study did not enroll patients who are younger
than 50 years old, a group that have higher cardiovascular risk and may potentially benefit from statin
therapy.
SHARP (Study of Heart and Renal Protection) is
the most recent trial. SHARP randomized 3023
dialysis patients (2527 on hemodialysis and 496 on
peritoneal dialysis) and 6247 CKD patients not
requiring dialysis to receive simvastatin 20 mg/day

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with ezetimibe 10 mg/day or placebo (33). None of

the patients had a history of MI or coronary artery
revascularization. After a median duration of follow-up of 4.9 years, the study showed a 17% reduction in major atherosclerotic events (RR: 0.83, 95%
CI: 0.740.94; log-rank p = 0.0021), 25% reduction
in nonhemorrhagic stroke (RR: 0.75, 95% CI: 0.60
0.94; p = 0.01), and 21% reduction in coronary
revascularization (RR: 0.79, 95% CI: 0.680.93;
p = 0.0036) among the simvastatin plus ezetimibetreated patients. Moreover, there was a nonsignificant 8% reduction in nonfatal MI or death from
CAD (RR: 0.92, 95% CI: 0.761.11; p = 0.37) in
the simvastatin and ezetimibe-treated group. However, there was no overall reduction in the risk of
all-cause mortality. SHARP did not find a significant reduction in major atherosclerotic events for
dialysis patients (RR: 0.90, 95% CI: 0.751.08)
compared with CKD patients not on dialysis (RR:
0.78, 95% CI: 0.670.91). Interestingly, the magnitude of reduction in LDL-C was greater in nondialysis CKD patients compared to dialysis patients
(37 mg/dl vs. 23 mg/dl, respectively).
Although the authors stated that there was not
good statistical evidence that the effects on major
atherosclerotic events differed between the dialysis
and nondialyzed CKD patients, it is believed that
SHARP did not have sufficient power to assess the
effects on major atherosclerotic events separately in
dialysis and nondialysis patients. It is possible that
the favorable results observed in the SHARP study
were largely related to the much larger number of
CKD patients not on dialysis enrolled in the study.
Similar to the 4D and AURORA trials, there was
no significant difference between the two treatment
groups with respect to the incidence of adverse
events such as myalgia, rhabdomyolysis, increased
transaminases, or hepatitis. One criticism of this
study has been the inclusion of 3 different groups of
patients; nondialysis CKD patients, hemodialysis
and peritoneal dialysis patients.
Meta-analysis of trials in chronic kidney disease
Despite the limitations of the above 3 trials, they
all have major strengths in being randomized, placebo-controlled trials and in enrolling large number
of patients. However, because of their limitations, it
would be difficult to generalize their results to all
dialysis patients.
A number of systematic reviews and meta-analyses pooled data from all available randomized clinical trials performed in CKD populations to allow
for sufficient power for assessing the treatment
effects of LDL-C lowering therapy in these patients.
In the first meta-analysis, Palmer and colleagues
(34) showed that statins significantly reduced allcause mortality and CV mortality in CKD patients
not on dialysis. However, they did not find a significant effect of statins on all-cause mortality (RR:
0.96; 95% CI: 0.881.04), cardiovascular mortality

(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

There are a multitude of reasons for the apparent

failure of these agents in reducing cardiovascular
events and mortality in the dialysis population. First,
the pathophysiology and spectrum of CVD in dialysis patients is markedly different compared to that in
the general population or even to earlier stages of
CKD (41). Besides atherosclerosis, these patients
may develop arterial stiffness, vascular calcification,
left ventricular hypertrophy, left ventricular diastolic
dysfunction, congestive cardiomyopathy, and sudden
cardiac death from arrhythmia. Lipid-lowering therapy would not be expected to have an impact on the
vast majority of these conditions.
It is well recognized that most of the deaths in
patients with CAD in the general population are
from MI (42), but only 12% of those in the 4D and
AURORA trials died of MI, while almost twice as
many died from sudden cardiac death (30,32). In
addition, death from noncardiac causes occurred in
20% and 25% in 4D and AURORA trials, respectively. Indeed, only 20% of the underlying causes of
CVD in dialysis patients are due to atherosclerotic
CAD (43). These findings suggest that the majority
of deaths in dialysis patients are not related to
CAD and thus would not be modifiable by statin or
other lipid-lowering therapy (42).
Second, although dialysis patients have a higher
prevalence of many of the traditional Framingham
risk factors for atherosclerosis such as older age,
hypertension, diabetes, obesity, inflammation, and
lipid abnormalities, these patients are also exposed
to uremia-related risk factors. These include anemia,
hyperphosphatemia, oxidative stress, inflammation,
and accumulation of the endogenous inhibitor of
nitric oxide (NO) synthase, asymmetric dimethylarginine (ADMA) which results in reduced NO synthesis and significantly contribute to CVD (Table 2).
Again, none of these factors is amenable to lipidTABLE 2. Risk factors for cardiovascular disease in dialysis
patients
Traditional Framingham risk factors:
Older age
Male sex
Hypertension
Diabetes
Obesity
Smoking
High LDL-cholesterol
Low HDL cholesterol
Physical inactivity
Genetic predisposition

Uremia-related risk factors:

Uremic milieu
Anemia
Abnormal mineral metabolism (Hyperphosphatemia,
calcium load and elevated PTH levels)
Dialysis vintage
Fluid overload
Oxidative stress
Malnutrition
Chronic inflammation (C-reactive protein and interleukin 6)
Increased asymmetric dimethylarginine (ADMA)

lowering therapy with statins and their management

requires specific therapy that is not expected to
impact dyslipidemia.
Third, the nature of atherosclerosis in dialysis
patients is different from that of the general population (44). Hypertriglyceridemia is present in approximately 50% of CKD patients but total serum
cholesterol and LDL-C are either normal or low,
whereas HDL-C is decreased due to reduced plasma
levels of apolipoprotein A-I, the principal apolipoprotein constituent of HDL-C. Moreover, LDL-C,
which is a major CVD risk factor for CAD in the
general population, may not be a good marker for
assessing cardiovascular risk in dialysis patients
because even those with low levels are still at a very
high risk of cardiovascular mortality. The explanation for this is that coexisting malnutrition and
inflammation may modify the relationship between
cholesterol and CVD. The prevalence of malnutrition and inflammation is higher than that of elevated cholesterol levels in dialysis patients (22).
Moreover, malnutrition and inflammation are more
important risk factors for CVD in dialysis patients
than high serum cholesterol level (4548). In the 4D
study, hs-CRP level was an important risk factor
associated with CVD events. However, in both the
4D and AURORA trials, statins, which have pleiotropic effects in reducing inflammation, were only
minimally effective in reducing the hs-CRP levels in
dialysis patients (30,32).
Fourth is the accumulation of the highly atherogenic lipoproteins which are not amenable to statin
therapy. In dialysis patients, decreased metabolism
of chylomicrons due to deficiency of lipoprotein
lipase, hepatic lipase and LDL receptor-related protein leads to accumulation of highly atherogenic
lipoproteins and their fragments such as very low
density lipoprotein (VLDL), small dense-LDL,
intermediate-density lipoproteins, oxidized LDL,
and lipoprotein (a) (4951) (Table 3). Moreover, the
inflammatory state in ESRD may lead to transformation of the protective HDL cholesterol to a proatherogenic inflammatory HDL (52). These
abnormalities are also not amenable to lipid-lowering therapy. Finally, hyperparathyroidism in
patients with ESRD may lead to accumulation of
calcium in the liver and other tissues and induces
deficiency of the enzymes involved in lipid metabolism such as lipoprotein lipase and hepatic lipase
(53). Despite these issues, it remains possible that
the lack of demonstrated benefit from statin therapy
in the recent RCTs in hemodialysis patients may, at
least in part, be due to limitations in the design and
or conduct of these trials as discussed above.
Adverse Effects of Statins in Dialysis Patients
Concern about the safety of statins in patients
with advanced CKD was based on the recognition
that a decrease in renal excretion of statin may
increase the risk of myopathy or rhabdomyolysis.

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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

Peritoneal dialysis patients

Very high
Commonly high
Commonly 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).

However, as discussed earlier, this notion has not

been confirmed in various clinical trials. In the
First United Kingdom Heart and Renal Protection
(UK-HARP-1) study, simvastatin use was not associated with an increased risk of abnormal liver function tests or creatine kinase elevation (54). Also, in
UK-HARP-II, simvastatin plus ezetimibe was not
associated with increased incidence of transaminitis
or creatine kinase elevation (55). Furthermore, data
from the recent 3 RCTs discussed above indicate
that the rate of statin-related adverse events is similar among patients with CKD and individuals from
the general population, and also not different from
those assigned to placebo. The exception is that a
higher risk of fatal stroke was reported from the 4D
(30) and in hemorrhagic stroke in AURORA (32).
Although in SHARP, significantly more patients in
the simvastatin plus ezetimibe discontinued the drug
due to myopathy than the placebo group, there was
no evidence for increased risk of rhabomyolysis or
liver dysfunction.
A review of the medical literature by an expert
panel concluded that statin therapy is safe in
patients with CKD (56). However, since pharmacokinetic studies suggest that the blood levels of
some statins may be increased in patients with
CKD, and that drug interactions may also increase
blood levels, dose adjustment should be considered. Atorvastatin and fluvastatin have the lowest
renal excretion (<2% and <6%, respectively), rosuvastatin has 10% urinary excretion, whereas simvastatin and pravastatin have higher urinary
excretion at 13% and 20%, respectively (57,58).
Atorvastatin, lovastatin, and simvastatin are all
metabolized by CYP-3A4 and thus are more prone
to have drugdrug interactions with macrolides,
azole antifungals, and nondihydropyridine calcium
channel blockers (59). However, except for lovastatin, it seems that no dose adjustments are
required for most of the lipid-lowering drugs for
reduced kidney function (56). KDIGO guidelines
recommend measuring levels of transaminases
before initiating statin therapy (60). However, further measurements are not necessary unless the
patient has suggestive symptoms. Given that statin-treated CKD patients are at higher risk of
adverse events when receiving concomitant fibrates,
the above report as well as the more recent KDI-

GO Work Group recommend against administering fibrates with statins in these patients.

What Should Nephrologists Do?

Collective evidence from RCTs and various metaanalyses argues against a significant benefit from
use of statins or other lipid-lowering agents in
reducing major cardiovascular events or mortality
in dialysis patients. Based on these results, the
Work Group of the KDIGO Clinical Practice
Guideline for Lipid Management in Chronic Kidney
Disease has issued the following guidelines for lipid
management in dialysis and CKD patients (60):
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, and triglycerides)
(1C). Although there is no direct evidence indicating that measurement of lipid status will
improve clinical outcomes, the KDIGO Work
Group recommend that patients with fasting triglyceride levels above 1000 mg/dl or LDL-C
levels above 190 mg/dl should be referred to a
specialist for further management (Table 4).
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 (not
graded). As higher cardiovascular risk and not
elevated LDL-C is now the primary indication
to initiate or adjust lipid-lowering treatment in
CKD patients, follow-up monitoring of LDL-C
(after an initial measurement) may not be
required for many patients. In the judgment of
the KDIGO Work Group, follow-up measurement of lipid levels should be reserved for
instances where the results would alter management such as assessment of adherence to statin
treatment; change in renal replacement therapy
modality or concern about the presence of new
secondary causes of dyslipidemia or to assess
10-year cardiovascular risk in patients aged
<50 years and not currently receiving a statin.
The group also recommends not measuring

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

Known coronary disease (myocardial infarction or coronary revascularization)

Diabetes mellitus
Prior ischemic stroke
Estimated 10-year incidence of coronary death or nonfatal
Myocardial infarction 410%

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

LDL-C in situations where the results likely

would not change management such as in
patients already receiving a statin. Also, since
clinical experience suggests that triglyceride levels >1000 mg/dl is rare in CKD patients, routine measurement of fasting triglycerides levels
is not recommended except in patients with
known severe hypertriglyceridemia.
3 In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination
not be initiated (2A). The KDIGO Work
Group recommend against using LDL-C levels
to identify CKD patients who should receive
cholesterol-lowering treatment. Rather, they
suggest focusing on the absolute risk of coro-

nary events and the evidence that such treatment is beneficial.

Summary and Recommendations

A proposed schema for treatment of dyslipidemia
in hemodialysis patients is shown in Fig. 1. Evidence from RCTs indicates that lipid-lowering
agents should not be initiated for primary prevention in dialysis patients, as recommended by KDIGO guidelines (60). However, this recommendation
may not be applicable to patients with high LDL-C
levels or those who have documented atherosclerotic

Treatment of dyslipidemia in ESRD patients

Incident dialysis patients

Patients already
receiving statin

Continue statins

Prevalent dialysis patients

Patients not
receiving statin

Patients prefer to
receive statin

Patients with low

LDL-C and no
recent MI or stroke

Patients with low

LDL-C and no
recent MI or stroke

Patients with LDL-C >

150 mg/dl or recent
MI or stroke

or
Patients with recent
MI or stroke

Start statins
Do not start statins

Start statins

Fig. 1. Schema for the treatment of dyslipidemia in ESRD patients.

Qunibi

CVD. The small percentage of patients with high

LDL-C levels in some of these trials suggests that
the potential benefits of statins in such patients were
not satisfactorily investigated. Thus, nephrologists
may be justified in initiating lipid-lowering therapy
for primary prevention in dialysis patients with
LDL-C level greater than 150 mg/dl and in maintaining therapy for secondary prevention in CKD
patients who were treated with these drugs before
initiating dialysis.
The KDIGO Work Group does not recommend
a specific on-treatment LDL-C target and thus does
not recommend adjusting the dose of statins based
on LDL-C levels. Statins have pleotropic effects,
particularly on inflammation and arterial stiffness,
which should be taken into consideration when
deciding on treatment with these drugs (61,62).
Finally, given that only 20% of cardiovascular
deaths in dialysis patients are due to atherosclerotic
CAD while the rest is due to arrhythmia, sudden
cardiac death or heart failure (43), it would be unrealistic to expect a dramatic reduction in cardiovascular events or mortality from statin monotherapy.
These patients are best managed by a multifaceted
approach designed to address the multitude of traditional as well as uremia-related risk factors for
CVD that are so prevalent in dialysis patients
including anemia, hypertension, malnutrition,
inflammation, abnormal mineral metabolism, and
dyslipidemia in selected patients.

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