Document 10763

Peritoneal Dialysis International, Vol. 26, pp. 523–539
Printed in Canada. All rights reserved.
0896-8608/06 $3.00 + .00
Copyright © 2006 International Society for Peritoneal Dialysis
Sabin Shurraw1 and Marcello Tonelli1,2,3
Dyslipidemia is a potent cardiovascular (CV) risk factor
in the general population. Elevated low-density lipoprotein
cholesterol (LDL-C) and/or low high-density lipoprotein
(HDL-C) are well-established CV risk factors, but more precise determinants of risk include increased apoprotein B
(ApoB), lipoprotein(a) [Lp(a)], intermediate and very lowdensity lipoprotein (IDL-C, VLDL-C; “remnant particles”),
and small dense LDL particles. Lipoprotein metabolism is
altered in association with declining glomerular filtration
rate such that patients with non dialysis-dependent chronic
kidney disease (CKD) have lower levels of HDL-C, higher triglyceride, ApoB, remnant IDL-C, remnant VLDL-C, and Lp(a),
and a greater proportion of oxidized LDL-C. Similar abnormalities are prevalent in hemodialysis (HD) patients, who
often manifest proatherogenic changes in LDL-C in the absence of increased levels. Patients treated with peritoneal
dialysis (PD) have a similar but more severe dyslipidemia
compared to HD patients due to stimulation of hepatic lipoprotein synthesis by glucose absorption from dialysate,
increased insulin levels, and selective protein loss in the
dialysate analogous to the nephrotic syndrome. In the dialysis-dependent CKD population, total cholesterol is directly associated with increased mortality after controlling
for the presence of malnutrition–inflammation.
Treatment with statins reduces CV mortality in the general population by approximately one third, irrespective of
baseline LDL-C or prior CV events. Statins have similar, if
not greater, efficacy in altering the lipid profile in patients
with dialysis-dependent CKD (HD and PD) compared to those
with normal renal function, and are well tolerated in CKD
≤≤ mg/day atorvastatin or
patients at moderate doses (≤
Correspondence to: M. Tonelli, Division of Nephrology, University of Alberta, 7-129 Clinical Science Building, 8440 112
Street, Edmonton, Alberta, T6G 2G3 Canada.
[email protected]
Received 29 March 2006; accepted 15 June 2006.
simvastatin). Statins reduce C-reactive protein as well as
lipid moieties such as ApoB, remnants IDL and VLDL-C, and
oxidized and small dense LDL-C fraction. Large observational studies demonstrate that statin treatment is independently associated with a 30% – 50% mortality reduction
in patients with dialysis-dependent CKD (similar between
HD- and PD-treated patients). One recent randomized controlled trial evaluated the ability of statin treatment to reduce mortality in type II diabetics treated with HD (“4D”);
the primary end point of death from cardiac cause, myocardial infarction, and stroke was not significantly reduced.
However, results of this trial may not apply to other endstage renal disease populations. Two ongoing randomized
controlled trials (SHARP and AURORA) are underway evaluating the effect of statins on CV events and death in patients with CKD (including patients treated with HD and
PD). Recruitment to future trials should be given a high
priority by nephrologists and, until more data are available,
consideration should be given to following published guidelines for the treatment of dyslipidemia in CKD. Additional
consideration could be given to treating all dialysis patients
felt to be at risk of CV disease (irrespective of cholesterol
level), given the safety and potential efficacy of statins.
This is especially relevant in patients treated with PD, given
their more atherogenic lipid profile and the lack of randomized controlled trials in this population.
Perit Dial Int 2006; 26:523–539
KEY WORDS: HMG-CoA reductase inhibitor; statin;
chronic kidney disease; hemodialysis.
he tremendous burden of cardiovascular (CV) morbidity and mortality in hemodialysis (HD) and peritoneal
dialysis (PD) patients has been well documented (1,2).
Dyslipidemia contributes significantly to CV death in
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Division of Nephrology1 and Division of Critical Care Medicine,2 University of Alberta;
Institute of Health Economics,3 Edmonton, Alberta, Canada
Lipids [triglycerides (TGs) and cholesterol] are insoluble in plasma and must therefore associate with
phospholipid and apoproteins (also referred to as
apolipoproteins) to form dissolvable particles called lipoproteins. Apoproteins function not only as lipid carriers, but may possess enzymatic activity and may serve
as cofactors for other enzymes or as ligands for receptors in various tissues. Five classes of apoprotein exist:
ApoA to ApoE, with several subclasses within each. The
most important subclasses are ApoA-I (activator of lecithin cholesterol acyltransferase), ApoB-100 [promotes
low- density lipoprotein (LDL) uptake by LDL-receptor],
ApoB-48 (promotes chylomicron binding to remnant
liver receptors), and ApoC-III (inhibits lipoprotein lipase). Lipoproteins are categorized by their density,
which is directly proportional to their ratio of protein to
lipid and to the ratio of cholesterol to TG (Figure 1). Each
lipoprotein contains a unique array of apoproteins that
allow the particle to carry out its specific physiological
Dyslipidemia is a key contributor to atherosclerosis
when kidney function is normal. The detrimental effect
of high LDL and/or low high-density lipoprotein (HDL)
cholesterol (LDL-C; HDL-C) on CV risk is well established
from early studies of dietary cholesterol on atheroscle524
Figure 1 — Major classes of lipoproteins with predominant
apoprotein components. Small, dense, low-density lipoprotein
(LDL) and lipoprotein(a) [Lp(a)] may be more atherogenic. A
subset of LDL contains a unique apoprotein, Apo(a), which is
covalently bound to ApoB-100; this complex is called
lipoprotein(a), or Lp(a). TG = triglyceride; VLDL = very lowdensity lipoprotein; IDL = intermediate-density lipoprotein;
HDL = high-density lipoprotein.
rotic progression in animal models, and by large epidemiological studies (4). Apoprotein B-containing lipoproteins are key to the atherosclerotic process and include
not only cholesterol-rich LDL and lipoprotein(a) [Lp(a)],
but also TG-rich very low-density lipoprotein (VLDL) and
intermediate-density lipoprotein (IDL). Apoprotein Bcontaining lipoproteins can initiate atherosclerosis by
infiltrating the subendothelial space of the arterial wall,
where they are sequestered by ionic interactions and
subsequently oxidized. LDL-C is a heterogeneous group
of lipoproteins; for a given serum LDL concentration,
there may be a small number of large particles, or a large
number of small, dense, cholesterol-poor particles. The
size and shape of the latter particles allow them to more
easily pass through the endothelial barrier and bind with
stronger affinity to the subendothelial matrix (5), perhaps explaining why predominance of this small dense
LDL is associated with increased CV risk (6,7). Since each
LDL particle contains one ApoB lipoprotein, ApoB levels
may be useful for refining risk estimation within a given
stratum of LDL-C level. Oxidized LDL can be taken up by
macrophages, which then become cholesterol-laden
foam cells that form fatty streaks (8). Foam cells and
oxidized LDL in turn play a direct role in the progression
of atherosclerosis and plaque rupture (9).
Elevated Lp(a) is an independent CV risk factor in most
but not all studies. A meta-analysis of 27 prospective
studies showed that an elevated baseline Lp(a) (top
tertile versus bottom) independently increased the
10-year risk of a coronary event by 70% (10). The in-
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patients with normal renal function, and cholesterol lowering with statins is effective for primary or secondary
prevention of CV disease (3). If pharmacological treatment even modestly lowers the risk of CV events in patients with end-stage renal disease (ESRD), the overall
benefit in this high-risk group would be substantial.
However, the relation between dyslipidemia and CV risk
in patients with renal disease is less clear than in those
with normal renal function, as is the efficacy of statins
for preventing CV risk.
This article reviews the physiology of lipoprotein metabolism, the effect of lipoproteins on atherosclerosis,
and how statins might interact with these processes. A
review of the literature pertaining to dyslipidemia,
statins, and CV risk will follow, discussing patients with
normal renal function, non dialysis-dependent chronic
kidney disease (CKD), and ESRD in turn, with special
emphasis on issues relating to PD.
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In contrast to other lipoproteins, increasing levels of
HDL independently reduce CV risk in humans in a graded
fashion (17). One important protective mechanism may
be HDL’s ability to remove cholesterol from atherosclerotic plaques and cells (reverse cholesterol transport),
a process mediated by ApoA-I, the predominant
apoprotein in HDL (18). Other potential mechanisms may
include a direct antioxidant effect, maintenance of blood
viscosity by promotion of er ythrocyte membrane
deformability, maintenance of endothelial function, and
prevention of the transbilayer shift of anionic phospholipids to the outside surface of erythrocytes (thereby
impeding their ability to activate the coagulation cascade) (19,20).
The relationship between total cholesterol (TC) and
mortality is clearly illustrated in an analysis of 356 222
men screened for the Multiple Risk Factor Intervention
prospective cohort study (21). At the 6-year analysis, a
continuous graded relation between initial TC and sub-
sequent death from coronary artery disease was evident.
The age-adjusted relative risk (RR) of death in quintiles
2 through 5 of TC, compared to the lowest cholesterol
quintile, was 1.29, 1.73, 2.21, and 3.42, respectively.
Similar findings were found in a recent case-control study
involving approximately 15 000 persons in 52 countries
(22). About half the population’s attributable risk of first
myocardial infarction in both men and women was attributed to dyslipidemia (defined as an elevated ApoB/
ApoA-I ratio).
Lipoprotein metabolism appears to be substantially
influenced by the severity of renal dysfunction and proteinuria. HDL-C, TC, and LDL-C decrease with declining
glomerular filtration rate (GFR) and, on average, are
similar or lower in people with stage 3–5 CKD than in the
general population (23). The prevalence of various “nontraditional” CV risk factors was studied in a cross-sectional analysis of 16 471 NHANES III participants,
stratified by estimated GFR > 90, 60 – 89, and 15 –
59 mL/minute (24). After adjustment for age, sex, and
race, mean ApoA-I (found mostly in HDL) was lower and
ApoB higher at lower GFR. This clustering of low HDL-C
with elevated ApoB and Lp(a) characterizes the more
atherogenic lipid profile of CKD.
Patients with CKD have elevated TG, including the
atherogenic TG-rich ApoB-containing VLDL and IDL
(25), due perhaps to decreased activity of hepatic TG
lipase and peripheral lipoprotein lipase. These abnormalities in turn may be due to an inhibitory effect of
hyperparathyroidism (26), calcium accumulation in islet cells resulting in impaired insulin action (27), elevated ApoC-III which acts as a direct lipase inhibitor,
or a putative circulating inhibitor detected in uremic
plasma (28).
Although elevated LDL-C is not a characteristic feature of CKD, serum LDL-C levels may underestimate the
atherogenic effect of LDL in CKD for several reasons.
First, patients with CKD may have a greater proportion
of LDL-C existing in the more atherogenic oxidized form
(29,30). Second, routine LDL-C measurement does not
measure the subfraction that exists as the more atherogenic Lp(a) particle. Although most studies have focused
on elevated Lp(a) levels in the ESRD population, it is
likely that levels are also increased in non-dialysis CKD
(31). Furthermore, there is an increase in the small,
dense LDL-C phenotype in patients with non dialysisdependent CKD versus healthy controls (32). Multiple
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creased risk was similar when studies that exclusively
involved patients with vascular disease were excluded.
Lipoprotein(a) may promote atherosclerosis by inhibiting fibrinolysis via competition with plasminogen binding sites (11), promoting oxidation of LDL (12), and
recruiting monocytes into the vessel wall (13).
The independent relation between serum TG levels and
CV risk is controversial, since this association is potentially confounded by low HDL-C (14). A more precise determinant of risk than TG levels may be VLDL particles,
which have a large TG component. A prospective casecontrol substudy of the Cholesterol and Recurrent Events
(CARE) study found, by direct measurements, that plasma
VLDL and ApoC-III (found in VLDL and LDL) levels were
independently associated with increased coronary risk;
whereas, overall, TG itself did not increase risk (14). NonHDL cholesterol (TC-HDL) may be used in clinical practice as a simple and accurate estimate of VLDL and IDL;
this parameter may be a more powerful predictor of CV
mortality than LDL-C alone (15). These TG-rich “remnant
particles” may mediate atherosclerosis by ApoC-III’s direct inhibition of VLDL lipolysis preventing its clearance
from the plasma, or by direct effects on plasma viscosity
(16). Thus, hypertriglyceridemia in itself may be atherogenic only in specific circumstances where VLDL and IDL
metabolism is altered.
Few data describe the contribution of dyslipidemia toward CV morbidity and mortality in the non-dialysis CKD
population. Although one could extrapolate from data
in the general population, the pathophysiology of CV disease in CKD may be influenced by other factors, such as
the effect of anemia, uremic toxins, increased calcium
intake, abnormal mineral metabolism, malnutrition/inflammation, and proteinuria (39–42). Thus, it is plausible that dyslipidemia per se contributes differently to
overall risk in the setting of CKD, especially at lower levels of GFR.
A recent study of 14856 participants with no coronary
disease at baseline examined the contribution of various risk factors toward CV mortality in the non-dialysis
CKD population over a mean follow-up period of 10.5
years (43). In this prospective cohort study, the presence and severity of dyslipidemia was associated with
future CV events to a similar degree among those with
normal renal function (Modification of Diet in Renal Disease GFR > 90 mL/min) compared to those with mild and
moderate-to-severe CKD (GFR 60 – 89 and 15 – 59 mL/
min, respectively) (Figure 2). The authors predicted that,
for every 1.1 mmol/L (1 SD) reduction in TC, there would
be a 19.7% reduction in associated incident CV events.
This compared favorably to their predicted 18% reduction associated with a systolic blood pressure reduction
of 20 mmHg. Although this study shows that dyslipidemia
is associated with excess CV risk in patients with non dialysis-dependent CKD, it does not demonstrate that
treatment of dyslipidemia reduces CV mortality in this
Patients treated with HD typically have relatively normal TC and LDL-C accompanied by high TG and low HDL,
similar to CKD patients who are not dialysis dependent.
Approximately 20% – 40% of chronic HD patients have
elevated TGs and reduced HDL-C (44–46). In a cross-sectional analysis of 1047 HD patients from the United States
Renal Data System (USRDS) Wave II study, 28% of patients had TG > 2.26 mmol/L, and 57% had non-HDL cholesterol > 3.36 mmol/L. The apoprotein profile in HD
patients is also similar to that of patients with less severe renal failure: moderately increased ApoB and ApoE,
significantly increased in ApoC-III, and depressed ApoA-I
and ApoA-II (47). The increase in ApoB is accounted for
by TG-rich ApoB-containing lipoproteins in the VLDL and
IDL range, as opposed to cholesterol-rich LDL (48). Increased VLDL and IDL is likely due to diminished activity
of lipoprotein lipase, as in patients with non dialysisdependent CKD (49). In a study of 183 HD patients on no
cholesterol medications, approximately one third were
found to have increased plasma level of CETP, which may
contribute to the low level of HDL-C found in this population (50).
Hemodialysis patients can also have an atherogenic
lipid profile in the absence of hyperlipidemia per se, as
shown by a study that compared 210 chronic HD patients
to 223 age- and sex-matched healthy controls (51). The
HD group had lower TC than controls (4.44 vs 5.33, p <
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studies have shown small dense LDL-C to be a strong independent predictor of coronary artery disease (7). Finally, the lower levels of HDL-C in CKD may exaggerate
the pathogenic effect of lower-density lipoproteins for
any given level of LDL-C.
The dyslipidemia in CKD patients with nephrotic
syndrome is distinct from that in patients with non-nephrotic CKD. From a quantitative standpoint, both hypercholesterolemia and hypertriglyceridemia (by
definition) are common in the nephrotic syndrome
(23,33). Nephrotic patients typically have significantly
elevated levels of all ApoB-containing lipoproteins, including VLDL, IDL, and LDL, as well as normal or slightly
depressed HDL, although the mechanisms for these abnormalities are not completely elucidated. Early work
suggested enhanced lipoprotein synthesis as the major
mechanism, but more recent studies suggest an important role for decreased catabolism. Delipidation from
TG-rich VLDL to IDL to LDL is impaired (the degree of impairment positively correlating with the amount of proteinuria), with a trend toward slightly increased hepatic
ApoB production (34). Delipidation is carried out via lipoprotein lipase and hepatic lipase; level of an activator
cofactor protein required for this enzymatic activity may
be decreased due to its loss in the urine (35). Low HDL-C
may be secondary to increased activity of cholesteryl
ester transfer protein (CETP) (36). This enzyme facilitates
clearance of HDL-C from the circulation by transferring
cholesterol ester from HDL to ApoB-containing lipoproteins, which are then taken up by the liver. Patients with
nephrotic syndrome also appear to have slower LDL clearance, mediated by decreased hepatic LDL receptor function (37). Finally, the levels of Lp(a) are almost uniformly
and severely elevated: one study found median Lp(a) in
nephrotic patients to be about 7 times higher than in
healthy controls, and 5 times higher than in patients with
CKD and minimal proteinuria (38).
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Relative Risk of Major Coronary Event
Total Cholesterol (Quartile)
Triglyceride (Quartile)
0.0001) and higher TG (1.30 vs 1.10, p < 0.0006). Compared with controls, the HD patients also had higher
VLDL-C (0.89 vs 0.57 mmol/L) and IDL-C (0.40 vs
0.18 mmol/L), and lower HDL-C (1.01 vs 1.39 mmol/L)
and LDL-C (2.12 vs 2.81 mmol/L); p < 0.0001 for all comparisons. These differences remained significant when
groups were compared on the basis of similar TG and TC
levels. Despite lower mean LDL-C in the HD patients, their
cholesterol/TG ratio was significantly decreased (2.8 vs
4.10, p < 0.00001), reflecting a preponderance of small
dense LDL (52). Other studies have shown that HD patients tend to have elevated Lp(a) and oxidized LDL-C,
even if LDL-C levels are relatively normal (32,53–55).
In summary, the dyslipidemia in HD is similar to that
in the non dialysis-dependent CKD population, characterized by relatively normal TC and LDL-C, elevated TG,
and low HDL-C. While these quantitative abnormalities
may themselves contribute to atherosclerosis and CV
mortality, the qualitative forms of dyslipidemia of HD
patients may also play a role.
Peritoneal dialysis patients also exhibit a form of “uremic dyslipidemia,” but the lipid profile in this group is
more overtly abnormal than in HD patients. Multiple
cross-sectional studies demonstrate higher TC, LDL-C,
and TG in PD patients compared to HD patients (48,56–
60). One study compared 31 patients on continuous ambulatory peritoneal dialysis (CAPD), 30 patients treated
with HD, and 27 healthy controls. Compared to HD, patients treated with CAPD had significantly higher mean
TC (6.8 vs 5.1 mmol/L, p < 0.001), LDL-C (4.6 vs 3.2, p <
0.001), VLDL-C (1 vs 0.7, p < 0.05), and TG (2.3 vs 1.5,
p < 0.01), with a nonsignificant difference in HDL (1.1
vs 1.3 in HD, p = NS) (48). Atherogenic ApoB was 47%
higher in CAPD compared to HD patients (p < 0.001), and
CAPD patients had both a higher TG-rich ApoB fraction
(mainly VLDL, IDL) and a higher cholesterol-rich ApoB
fraction (LDL) than HD patients.
Further data supporting the concept of a more atherogenic lipid profile in CAPD were provided by a large
multicenter cross-sectional study that compared 564 HD
patients with 168 CAPD patients (53). Compared to HD,
patients treated with CAPD had higher TC (6.0 vs
4.8 mmol/L), LDL-C (4.0 vs 3.0 mmol/L), TC/HDL-C ratio
(7.0 vs 5.5), TG (2.1 vs 1.8 mmol/L), and Lp(a) (1.2 vs
0.9 µmol/L); p < 0.001 for all comparisons. HDL-C was
similar between groups (0.95 in CAPD vs 0.97 mmol/L in
HD, p = NS). There were twice as many CAPD than HD patients with a TC > 5.2 mmol/L (67% vs 34%), and 1.7
times as many with a TG > 4.7 mmol/L (47% vs 28%).
Approximately half of CAPD patients, compared to only
a quarter of HD patients, possessed three or more dyslipidemic risk factors (elevated LDL-C, TC, Lp(a), or low
HDL-C). However, PD patients were more than twice as
likely to have diabetes mellitus, which may have accounted for some of these differences. Patients treated
with PD, like those on HD, have increased specific activity of CETP, which may contribute to the low HDL-C and
increased ApoB-containing lipoproteins observed in this
population (61,62).
Other qualitative lipid abnormalities may further
contribute to the CV risk of CAPD patients. For example,
Lp(a) is elevated to an even greater degree than in HD
patients. Analysis of data from the 702 HD and CAPD
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Figure 2 — Relationship of total cholesterol and triglyceride levels with major coronary events in 17898 participants followed for
10.5 years. The Figure shows that participants with increased total cholesterol or triglyceride suffered more coronary events
irrespective of baseline estimated glomerular filtration rate (GFR). Data from Muntner et al. (43).
Data describing the association between dyslipidemia
and death in dialysis patients may seem contradictory.
For instance, large cross-sectional studies have found
no association between baseline TC or TG and CV disease
in dialysis patients (72,73), and two prospective studies
in HD patients showed no association between baseline
TG, TC, LDL-C, or HDL-C and future atherosclerotic events
(74,75). In contrast, several cross-sectional studies of
HD patients have shown dyslipidemia to be positively
associated with coronary artery disease or death
(76–78), as has a prospective study that followed 412
patients (317 HD, 95 PD) for 9 years (77). Finally, some
studies have shown a paradoxical (inverse) relation between cholesterol levels and mortality in HD patients
(79–82), or both HD and PD patients (83).
To make sense of this seemingly conflicting data, one
must consider the potential role of malnutrition/inflammation on mortality. In a retrospective study of 12000
HD patients in 1995, the relation between TC and death
took the form of a U-shaped curve, which appeared more
linear after adjustment for serum albumin (80). This apparently paradoxical relation may be wholly or partially
due to increased mortality among patients with evidence
of inflammation/malnutrition, which typically results in
lower cholesterol levels (41). Alternatively, it may result
from “reverse causation,” wherein coexisting CV disease
leads to inflammation/malnutrition, and thus lowers
cholesterol level.
Two large prospective studies help to clarify this issue.
In a prospective report of 1167 Japanese HD patients,
low cholesterol was found to be independently associated with higher C-reactive protein (CRP) and mortality
at 10 years in those with low albumin (79). However, in
the subgroup of patients with albumin >45 g/L, high
cholesterol was associated with increased mortality. A
second prospective study performed in the USA followed
823 patients starting HD (80%) or PD (20%) for a median of 2.4 years (84). Patients were classified by the
presence or absence of inflammation and/or malnutrition at baseline, based on serum levels of albumin
(<36 g/L: <10th percentile in the general population),
CRP (>10 mg/L: >90th percentile), or interleukin-6
(>3.09 pg/mL: >75th percentile). An increment in baseline TC of 1 mmol/L decreased all-cause mortality in the
presence of inflammation/malnutrition [relative hazard
(RH) 0.89, 0.84 – 0.95], but in the absence of inflammation/malnutrition, there was a strong, positive,
graded relation of TC with all-cause mortality (RH 1.32,
1.07 – 1.63) and CV mortality (RH 1.41, 1.04 – 1.89) (Figure 3). These studies both demonstrate that hypercholesterolemia is a risk factor for all-cause and CV mortality
in patients with ESRD, but the association can be masked
by concomitant inflammation and/or malnutrition.
As in the general population, Lp(a) has been positively
associated with atherosclerotic CV disease in HD patients
(42,74,85,86). This was best demonstrated in a study of
390 HD patients and 105 normal controls who had baseline Lp(a) measured and were then prospectively followed for 28 months (85). Lipoprotein(a) level was twice
as high in HD patients compared to controls and was independently associated with CV death. There are few data
describing the effect of other, less traditional, lipid risk
factors (such as small dense LDL, oxidized LDL, and VLDL/
IDL) on mortality in dialysis patients.
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patients in the aforementioned cross-sectional study revealed that 34% of HD patients and 42% of CAPD patients
had serum Lp(a) greater than the 75th percentile of the
healthy control group (>0.92 µmol/L, p < 0.005 for HD
vs PD) (63). Mean Lp(a) was 0.82 µmol/L in HD patients
and 1.25 µmol/L in CAPD patients, versus 0.64 µmol/L
in controls (p < 0.005 for comparisons of patients to controls). Finally, small dense LDL-C (32,64) and oxidized
LDL-C (55,65) are increased to a greater extent in CAPD
patients compared to HD patients.
Several mechanisms have been proposed to explain
the more atherogenic lipid profile in patients undergoing PD. It has been suggested that absorption of glucose from the dialysate solution may stimulate hepatic
lipoprotein synthesis (66), or increase insulin levels and
thus TG synthesis (67). Consistent with this is the observation that the lipid profile improves when the overnight
dwell is switched from a dextrose-based solution to icodextrin (68). The daily loss of protein in the dialysate
solution may also promote dyslipidemia by mechanisms
similar to those relating to protein loss in the nephrotic
syndrome. Finally, smaller sized proteins, including various lipoproteins, are preferentially lost due to peritoneal sieving; for example, HDL is lost at a rate equivalent
to 34% of its daily synthetic rate, while ApoB-containing lipoprotein loss is negligible (69–71).
In summary, patients on PD typically have more severe dyslipidemia than those on HD, as reflected by increased TG, ApoB-containing VLDL and IDL, TC, LDL-C,
Lp(a), and small dense LDL-C with a persistently low level
of HDL-C. Although it is plausible that these apparent
differences are due to PD per se, this association may be
partially confounded by other characteristics related to
selection of dialytic modality. Regardless of the etiology,
it is indisputable that PD patients commonly have a
highly atherogenic lipid profile.
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spective studies, 20% of dialysis patients enrolled in the
largest prospective study were receiving PD (84). These
data are consistent with the hypothesis that hypercholesterolemia is equally deleterious to patients treated
with HD and PD. Since (as mentioned above) dyslipidemia
is more prevalent in PD patients, this suggests that the
population-attributable risk (i.e., the proportion of CV
events that are due to dyslipidemia) may be higher compared to the HD population. However, whether pharmacological treatment of dyslipidemia will reduce CV risk
in dialysis patients will require specific study.
Mortality rate per 100 patients
Cholesterol (mg/dL)
Figure 3 — 823 patients starting hemodialysis (80%) or peritoneal dialysis (20%) were classified according to the presence (heavy dotted lines) or absence (light dotted lines) of
malnutrition/inflammation at baseline. Total cholesterol is
positively associated with all-cause (upper panel) and cardiovascular-specific (lower panel) mortality in patients without
evidence of inflammation/malnutrition. Control: solid line.
Adapted from Liu et al. (84).
Statins compete with HMG-CoA for binding at the active site of the enzyme HMG-CoA reductase (96). Binding blocks the rate-limiting step of hepatic cholesterol
biosynthesis, leading to enhanced surface expression
and subsequent recycling of LDL receptors (97). The end
result is a pronounced reduction in serum LDL-C, ranging from 30% to 60% depending on the potency and dose
of the particular statin (98). Statins also shift the LDL
profile away from the more atherogenic small dense form
toward the larger, less dense and less atherogenic subtype (16). The effect of statins on other lipids is less
marked, with HDL-C typically increasing 2% – 10%, and
TG reduction ranging between 8% and 26% (99).
In addition to directly improving the lipid profile,
statins also exert a number of lipid-independent (“pleiotropic”) effects, including improvement in endothelial
dysfunction by reducing endothelial permeability to LDL
and enhancing vasodilatory response, a blunted inflammatory response, and reduced expression of endothelial
adhesion molecules, antioxidant activity, and stabilization of atherosclerotic plaques (100). However, the clinical significance of these effects remains to be determined.
The majority of the aforementioned studies examined
the relation between the serum lipid profile and CV
events or death in HD patients. However, a similar relation between low cholesterol, malnutrition, and increased mortality in PD patients has been reported (46,
87,88), and a few retrospective studies also demonstrated an association between CV mortality and
dyslipidemia in PD patients (89–92). There are also observational data confirming the association of elevated
Lp(a) with atherosclerotic disease or death in CAPD patients (93–95). Although none of these were large pro-
Four landmark randomized controlled trials (RCTs)
published in the past decade demonstrate the benefits
of statins in people with known coronary disease who
were selected from the general population (101–104)
(Table 1). Together, these trials clearly show that statins
reduce the risk of CV death by 22% – 42% and all-cause
mortality by 22% – 30%, in this population with acceptably low adverse events rates. In selected patients, aggressive lipid-lowering with higher doses of statin
appears to further reduce CV event rates, but leads to
slightly increased medication-related toxicity (104).
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Mortality rate per 100 patients
Cholesterol (mg/dL)
SEPTEMBER 2006 – VOL. 26, NO. 5
Landmark Randomized Controlled Trials of Statin Therapy in the General Population
Study (Ref.)
Population/(total n) (years)
Secondary prevention trials
4S (101)
Previous angina/MI
TC: >5.5
Age: 35–70 (n=4444)
LIPID (102)
Recent ACS
TC: 4–7
Age: 31–75 (n=9014)
CARE (103)
Previous MI; TC<6.2
Age: 21–75 (n=4159)
TNT (104)
Stable CAD
LDL: <3.4 (n=10001)
High risk: MI,
TC: >3.5
Age: 40–80 (n=20576)
Primary prevention trials
Male only
TC: >7
Age: 45–64 (n=6595)
AFCAPS (106)
HDL: M: <1.16, F: <1.22
Average LDL & TC
Age 45–73
(n=6605; 15% female)
ASCOT (107)
≥3 CAD risk factors
& HTN; TC: <6.5
Age 40–79 (n=10305)
20–40 mg/day
40 mg/day
40 mg/day
80 mg/dayb
40 mg/day
40 mg/day
20–40 mg/day
10 mg/day
reduction in ACMc
(control vs statind)
4.9→3.2 Death: 0.70 (0.58–0.85)
CV death: 0.58 (0.46–
(11.5% vs 8.2%)
3.9→2.9 Death: 0.78 (0.69–0.87)
CV death: 0.76 (0.65–
(14.1% vs 11%)
3.6→2.5 CV death or MI:
0.76 (0.64–0.91)
2.6→2.0 CV death, MI, stroke
resuscitation after
arrest: 0.78 (0.69–0.89)
3.3→2.3 Death: 0.87 (0.81–0.94)
Vascular death: 0.83
(14.7% vs 12.9%)
CV death or nonfatal
MI: 0.69 (0.57–0.83)
3.9→3.0 MI, unstable angina,
or sudden cardiac
death: 0.63 (0.50–0.79)
3.4→2.3 CV death or nonfatal
MI: 0.64 (0.50–0.83)
(4.1 vs 3.2%)
(trial stopped
MI = myocardial infarction; TC = total cholesterol; ACS = acute coronary syndrome; CAD = coronary artery disease; LDL = lowdensity lipoprotein cholesterol; PVD = peripheral vascular disease; DM = diabetes mellitus; HTN = hypertension; HDL = high-density lipoprotein cholesterol; CI = confidence interval; CV = cardiovascular; ACM = all-cause mortality.
a In HPS, 2/3 of enrolled patients had known CAD, thus this was largely a trial of secondary prevention.
b Control group received atorvastatin 10 mg/day.
c Bold = 1° end point.
d p < 0.001 for statin treatment versus control unless otherwise specified.
Findings from three major primary prevention trials are
consistent with those in secondary prevention, although
absolute risk reductions tend to be smaller given the
lower event rates (105–107). The largest statin trial published to date (HPS; see Table 1) enrolled patients with
or at high risk for CV events (with and without coronary
disease at baseline) who had a broad range of serum TC
values (3.5 mmol/L and higher) (108). Since the RR reduction due to statin therapy was similar regardless of
baseline LDL-C or prior CV events, results of this trial suggest that overall CV risk is the best determinant of benefit from statins, rather than individual factors, such as
cholesterol level. Given the high CV event rates in renal
populations, this implies that CKD and ESRD patients
would be particularly likely to benefit from statins.
Post hoc analyses of several, large, randomized, placebo-controlled statin trials compared the effect of
statins on CV outcomes in persons with and without renal
insufficiency (Table 2) (107–109). In all three analyses,
the RR reduction associated with statin therapy was simi-
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HPSa (108)
∆ mean LDL
(mmol/L) Relative riskc (95% CI)
SEPTEMBER 2006 – VOL. 26, NO. 5
Effect of Statins on Cardiovascular Outcomes in Patients with Non Dialysis-Dependent
Chronic Kidney Disease (Post Hoc Subgroup Analyses of Major Statin Trials)
Renal function
(mL/min or µmol/L)
Patients in
subgroup Duration
Tonelli et al. (109)a CG-GFR: 30–59.99
CG–GFR: 60–89.99
12 333
CG-GFR: ≥90
ASCOT (107)
3.9→2.7 CV death, MI, CABG, or
PTCA: 0.77 (0.68–0.86) (16.8% vs 14.5%)
Death: 0.86 (0.74 – 1)
4.3→3.1 CV death, MI, CABG, or
PTCA: 0.76 (0.70–0.83)
Death: 0.76 (0.66–0.87)
4.3→3.2 CV death, MI, CABG, or
PTCA: 0.78 (0.55–0.94)
Death: 0.93 (0.68–1.28)
CV death or nonfatal
10 mg/day
MI: 0.61 (0.44–0.84)
CV death or nonfatal
MI: 0.70 (0.45–1.04)
Major vascular event:
40 mg/day
0.77 (0.67–0.87)c
Major vascular event:
0.86 (0.83–0.89)c
CG-GFR = Cockroft–Gault estimated glomerular filtration rate; Cr = creatinine; LDL = low-density lipoprotein cholesterol; CI =
confidence interval; CV = cardiovascular; MI = myocardial infarction; CABG = coronary artery bypass graft; PTCA = percutaneous
transluminal coronary angioplasty; ACM = all-cause mortality.
a Analysis of data from WOS-COPS, LIPID, and CARE trials.
b Bold = 1° end point.
c Relative risk rather than hazard ratio.
lar in patients with and without CKD, and medicationrelated toxicity was no higher among those with impaired
kidney function. However, due to the higher event rates
in people with CKD, the absolute risk reduction due to
statin treatment was markedly higher in the presence of
impaired kidney function. Although these results are
consistent with those from the general population, it is
important to note that very few of these patients (<1%)
had stage 4 CKD, and none were dialysis dependent. In
addition, it is uncertain whether these patients are representative of those seen in nephrologists’ offices, given
the inclusion criteria of the randomized trials. Therefore, definitive evidence of the benefits of statins in
stage 2 – 3 CKD must await the results of RCTs conducted
specifically in this patient population (discussed below).
There have been seven published RCTs determining
statins to be safe and efficacious in the treatment of
dyslipidemia in both HD and PD patients (Table 3)
(110–116). Overall, these studies show that statins reduce TC and LDL-C by 18% – 33% and 20% – 43% respectively, increase HDL-C from 0 to +7%, and decrease TG
from nonsignificant to –40%. These changes are similar
to those observed in patients with normal renal function in the major statin trials. With the doses used (generally not exceeding 20 mg of simvastatin or
atorvastatin), there were no statistically significant differences in adverse events (including patient symptoms
or elevation in creatine kinase or liver enzymes) between
statin and placebo/control arms in any of the trials. Although the effect of statin on cholesterol levels was not
statistically different between the three groups studied
in the UK-HARP trial (dialysis patients, non dialysis-dependent CKD, and renal transplant; total n = 448) (114),
the much larger number of patients studied in a pooled
analysis of three pravastatin trials (n = 19727) showed
that LDL-C was lowered to a significantly greater extent
in participants with stage 3 CKD, compared to those with
normal kidney function (109). A Cochrane meta-analysis of 6 RCTs was performed in 2004 that included some
of the trials listed in Table 3, as well as abstracts (117).
In their pooled analysis, statin treatment for at least
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HPS (108)
Approx. 5 Pravastatin
40 mg/day
Serum Cr:
M: 130–200, F: 110–200
Serum Cr:
M: <130, F: <110
Serum Cr:
M: 130–200, F: 110–200
Serum Cr:
19 207
M: <130, F: <110
Likelihood of reaching Absolute reduc∆ mean LDL clinical end pointb
tion in ACM
(mmol/L) [hazard ratio (95% CI)] (control vs statin)
SEPTEMBER 2006 – VOL. 26, NO. 5
Randomized Controlled Trials of Statins in Dialysis Patients: Efficacy and Safety
Wanner et al. (110)
4 years
20 mg/day
619 statin
636 placebo
N/R –42c,d N/R N/R
Chang et al. (111)
2 months
Harris et al. (112)
4 months
20 mg/day
10–20 mg/day
31 statin
31 control
82 statin
94 placebo
–41b +3 –41b
+3 –3 +2
–40c +7c –14
–9 –3 +11
16 statin
5–20 (median 10) 7 placebo
22 statin
11 placebo
38 statin
20 mg/day
35 placebo
–36c 0
–33c –5
–9 –3
–20c +2c
Saltissi et al. (113)
CAPD (n=23) 6 months
HD (n=33)
Baigent et al. (114)a CAPD (n=39)
HD (n=34)
Robson et al. (115)
Lins et al. (116)
1 year
CAPD (n=47) 6 months
HD (n=60)
3 months
10 mg/day
10–40 mg/day
Patients in %∆ %∆ %∆ %∆
each arm (n) TC LDL HDL TG
24 statin
29 placebo
23 statin
19 placebo
–19c –24c 0 –11c
–8 –9 –5 –3
–33c –43c –1 –12c
–3 –8 –12 +21
Adverse eventse
Myalgias: s: 7, c: 5
↑CK 3–5×: s: 11, c: 3
↑CK >5×: s: 1, c: 1
↑ALT: s: 5, c: 1
None related to
Pain: s: 4, c: 0
↑CK: s: 5, c: 3
↑ALT: s: 1, c: 1
s=c for symptoms
↑CK: s: 1, c: 1
s=c for symptoms
↑CK/ALT: s: 0, c: 0
Myalgias: s: 65, c: 59
↑CK: s: 2, c: 3
↑ALT: s: 4, c: 2
Myalgias: s: 1, c: 0
CK/ALT: no ∆
Myalgias: s: 3, c: 1
↑CK: s: 0, c: 0
↑ALT: s: 1, c: 0
HD = hemodialysis; PD = peritoneal dialysis; CAPD = continuous ambulatory PD; TC = total cholesterol; N/R = data not reported;
LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; TG = triglycerides; CK = creatine kinase;
ALT = alanine aminotransferase.
a UK-HARP I included 448 CKD patients: 242 non-dialysis, 73 dialysis (combined analysis of CAPD+HD), 133 transplant.
b Statistically significant percent change from baseline (p < 0.01).
c Statistically significant difference in percent change for statin versus placebo (p < 0.05).
d Change in LDL-C as reported after 4 weeks of treatment.
e s: n = number in statin group; c: n = number in control group.
12 weeks lowered TC by 1.4 mmol/L (1.7 in CAPD vs 1.4
in HD), LDL-C by 1.4 mmol/L (2.0 in CAPD vs 1.2 in HD),
and TG by 0.4 mmol/L (0.5 mmol/L in CAPD vs nonsignif icant decrease in HD), and raised HDL-C by
0.13 mmol/L (nonsignificant in CAPD vs 0.13 in HD).
Apolipoprotein B and remnant lipoproteins VLDL and
IDL are similarly reduced with statin treatment in patients undergoing PD or HD (116,118,119). Conversely,
statin treatment has little effect on Lp(a) concentration
in patients with ESRD, as in patients with normal renal
function (113). Treatment with statins lowers CRP in patients with normal renal function, independent of lipid
lowering (120). Studies in HD patients confirm that
statins retain many pleiotropic effects, including reducing CRP (by approximately half) and increasing serum
albumin, decreasing oxidized LDL-C, and shifting LDL-C
from the small dense to the larger, buoyant, less atherogenic form (116,121–123). Although it is tempting to
speculate that these pleiotropic effects are clinically
beneficial (especially given the frequency of inflammation/malnutrition in ESRD), this remains to be proven.
Two observational studies demonstrated that statin
use in the ESRD population was independently associated with reduced mortality. The first study analyzed
data from 3716 incident patients enrolled in the USRDS
Dialysis Morbidity and Mortality Wave II cohort, which
included all patients starting PD and a 20% random
sample of patients starting HD in the United States during 1996 to 1997 (124). Of the total cohort, only 362
(approximately 10%) were using statins at the start of
dialysis. Statin use was independently associated with a
32% reduction in total mortality [adjusted RR = 0.68,
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HD or PD
SEPTEMBER 2006 – VOL. 26, NO. 5
cerebrovascular events or total mortality. The authors
concluded that the apparent lack of benefit with statin
treatment in HD patients could be due to nontraditional
pathogenic pathways contributing to CV disease, making statin therapy unhelpful when postponed until dialysis is required.
The available data are consistent with this hypothesis, but consideration of some of this study’s unique
characteristics is worthwhile. First, as with most RCTs,
the study population was highly specific (prevalent diabetic HD patients), and therefore findings may not be
generalizable to all dialysis patients. Second, 15% of
patients receiving atorvastatin required a dose reduction to 10 mg/day (as specified in the protocol if LDL-C
in follow-up was <1.3 mmol/L); after 2 years of study,
16.6% of the atorvastatin users who remained alive and
free of a primary event discontinued therapy altogether,
and 15% of patients receiving placebo eventually received non-study statins. These factors probably led to
the decreasing difference in LDL-C between atorvastatin
and placebo groups over time, which may have reduced
power to show a beneficial effect. Third, since many CV
events in dialysis patients are due to sudden death (perhaps due to electrolyte abnormalities) (126–128) or to
cardiomyopathy (perhaps from chronic extracellular fluid
volume overload) (128,129), it is possible that a beneficial effect of statin therapy on atherosclerotic events
might have been diluted. Although a relative risk reduction of 8% is not usually of major clinical significance,
the high CV event rate in this patient population means
that such a benefit, if it exists, would translate into a
favorable absolute risk reduction of 1.7%. All of these
factors point to the need to perform additional randomized trials of statins in dialysis patients.
Two subsequent large RCTs evaluating statin use in
patients with ESRD commenced in 2003 and are currently
underway. A Study to Evaluate the Use of Rosuvastatin
in Subjects on Regular Hemodialysis (AURORA) has randomized 2700 patients from 190 sites in Australia,
Canada, and Europe to rosuvastatin 10 mg/day or placebo. End points will be time to death from any cause
and time to major CV event (nonfatal stroke, nonfatal
myocardial infarction, or CV death). Results are expected
in approximately 2 years. The multinational Study of
Heart and Renal Protection (SHARP) will include about
9000 patients with CKD (3000 on PD or HD at randomization) and will compare the effect of simvastatin
20 mg/day plus ezetimibe 10 mg/day versus placebo on
the end point of fatal and nonfatal cardiac events, fatal
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95% confidence interval (CI) 0.54 – 0.87] and 37% lower
CV-specific mortality (RR = 0.64, 95% CI 0.45 – 0.91).
This result was similar in PD and HD treated patients.
Fibrate use was not associated with a lower risk of allcause or CV-specific death. In patients with preexisting
CV disease, statin use was associated with an even greater
reduction in CV mortality of 50% (RR = 0.50, 95% CI
0.32 – 0.79). The second observational study analyzed
data from 7365 prevalent HD patients enrolled in the
multinational Dialysis Outcomes and Practice Patterns
Study (DOPPS) (125). In multivariate analysis, statin
users had a 31% lower adjusted risk of all-cause mortality than nonusers [hazard ratio (HR) = 0.69, 95% CI
0.60 – 0.79], a 23% reduction in CV-specific mortality
(HR = 0.77, 95% CI 0.61 – 0.97), and a 44% reduction in
non-cardiac mortality (HR = 0.56, 95% CI 0.46 – 0.69).
Although these findings support the hypothesis that
statins reduce mortality in both PD and HD patients, the
possibility of residual confounding remains, given that
statin therapy was not randomly assigned.
The sole RCT designed to establish if statins reduce
mortality in dialysis patients was recently published
(Die Deutsche Diabetes Dialyse Studie: “4D”) (110). This
was a rigorously conducted double-blind study of 1255
German HD patients with type II diabetes, comparing
atorvastatin 20 mg/day with placebo on the composite
primary outcome of death from cardiac causes, nonfatal myocardial infarction, and stroke. Adult patients
were included if they had received HD for <2 years,
had LDL-C between 2.1 and 4.9 mmol/L, and TG
<11.3 mmol/L. The study had 90% power to detect a 27%
reduction in the primary end point, and analysis was intention-to-treat. Baseline characteristics of the two
patient groups were similar, including lipid profile
(TC 5.7 mmol/L, LDL-C 3.3 mmol/L, HDL-C 0.93 mmol/L,
TG 2.9 mmol/L in each group). During a median followup of 4 years, the primary end point was reached by
38.2% of patients randomized to placebo, versus 36.5%
in those in the atorvastatin group, with no significant
difference between groups (RR due to atorvastatin use
0.92, 95% CI 0.77 – 1.10, p = 0.37). Of the individual
components of the composite primary end point, death
from cardiac causes was of borderline statistical significance (RR = 0.81, 95% CI 0.64 – 1.03, p = 0.08) but was
offset by an unexpected increase in fatal strokes in the
atorvastatin group (RR of fatal stroke 2.03, 95% CI
1.05 – 3.93, p = 0.04). Of the secondary end points, atorvastatin significantly reduced the incidence of combined
cardiac events (death from cardiac cause, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty) by 18% (RR
0.82, 95% CI 0.68 – 0.99, p = 0.03) but not combined
Figure 4 — 2003 K/DOQI guidelines for the treatment of
dyslipidemia in patients with dialysis-dependent chronic kidney disease. All units are mmol/L. TG = triglyceride; TLC = therapeutic lifestyle change; LDL = low-density lipoprotein
cholesterol; HDL = high-density lipoprotein cholesterol.
Adapted from K/DOQI, National Kidney Foundation (130).
Note: If LDL is 2.6 – 3.4 mmol/L, consider a trial of therapeutic lifestyle change before initiating pharmacotherapy.
Dyslipidemia is quantitatively and qualitatively different in patients with CKD compared to those with normal
renal function, but is associated with adverse outcomes
regardless of kidney function after accounting for malnutrition and inflammation. While multiple RCTs have
demonstrated statins to reduce all-cause and CV mortality in patients with normal renal function, only post
hoc subgroup analyses support their use in patients with
non dialysis-dependent CKD, and the sole randomized
trial conducted in dialysis patients found no evidence of
benefit. Two additional randomized trials of statin
therapy in dialysis patients are underway, and results
from these studies should help to clarify the role of
statins in this population. In the interim, following practice guidelines for treatment of dyslipidemia in dialysis
patients appears reasonable.
1.Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of
cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32(5 Suppl 3):S112–19.
2.Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic
kidney disease and the risks of death, cardiovascular
events, and hospitalization. N Engl J Med 2004; 351(13):
3.Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total
mortality. An overview of randomized trials. JAMA 1997;
4.LaRosa JH. National Cholesterol Education Program: Report of the expert panel on the detection, evaluation, and
treatment of high blood cholesterol in adults. J Occup Med
1988; 30(10):826–9.
5.Hurt-Camejo E, Olsson U, Wiklund O, Bondjers G, Camejo
G. Cellular consequences of the association of apoB lipoproteins with proteoglycans. Potential contribution to
atherogenesis. Arterioscler Thromb Vasc Biol 1997; 17(6):
6.Griffin BA, Minihane AM, Furlonger N, Chapman C, Murphy
M, Williams D, et al. Inter-relationships between small,
dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects. Clin Sci (Lond)
1999; 97(3):269–76.
7. Gardner CD, Fortmann SP, Krauss RM. Association of small
low-density lipoprotein particles with the incidence of
coronary artery disease in men and women. JAMA 1996;
8.Iuliano L, Mauriello A, Sbarigia E, Spagnoli LG, Violi F.
Radiolabeled native low-density lipoprotein injected into
patients with carotid stenosis accumulates in macro-
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and nonfatal cerebrovascular events, or revascularization among the various subgroups. Patients are eligible if their physician feels that statins are not clearly
indicated or contraindicated, and if they have no prior
history of myocardial infarction. SHARP will be adequately powered to evaluate the effects of therapy on
dialysis and CKD patients separately; as of December
2005, 2190 dialysis patients (376 of whom are on PD)
had been randomized.
The current uncertainty about the benefit of statins
in patients with advanced CKD may be clarified once the
results of the SHARP and/or AURORA trial are published.
In the meantime, clinicians can be reassured that statins
reduce LDL-C and raise HDL-C without evidence of harm
in dialysis patients, and may yet be shown to improve
clinically meaningful outcomes.
For patients who are not candidates for enrollment
into SHARP, and until results from AURORA and SHARP
become available, we recommend that the current
K/DOQI recommendations for treatment of dyslipidemia
in PD patients be followed (Figure 4) (130). Additional
consideration could be given to treating all dialysis patients felt to be at risk of CV disease (regardless of serum
cholesterol levels, as in the HPS study), but it is important to recognize that these suggestions are not supported by evidence. Given the current uncertainty,
discussions between physicians and ESRD patients about
the decision to prescribe statins in ESRD should focus
on patient preferences as well as potential risks and benefits. Finally, given the increased risk of rhabdomyolysis,
fibrates should not be co-administered with statins to
dialysis patients.
SEPTEMBER 2006 – VOL. 26, NO. 5
SEPTEMBER 2006 – VOL. 26, NO. 5
23.Kasiske BL. Hyperlipidemia in patients with chronic renal
disease. Am J Kidney Dis 1998; 32(5 Suppl 3):S142–56.
24.Muntner P, Hamm LL, Kusek JW, Chen J, Whelton PK, He J.
The prevalence of nontraditional risk factors for coronary
heart disease in patients with chronic kidney disease. Ann
Intern Med 2004; 140(1):9–17.
25.Attman PO, Knight-Gibson C, Tavella M, Samuelsson O,
Alaupovic P. The compositional abnormalities of lipoproteins in diabetic renal failure. Nephrol Dial Transplant 1998;
26.Nishizawa Y, Shoji T, Kawagishi T, Morii H. Atherosclerosis
in uremia: possible roles of hyperparathyroidism and intermediate density lipoprotein accumulation. Kidney Int
Suppl 1997; 62:S90–2.
27.Arnadottir M, Nilsson-Ehle P. Has parathyroid hormone
any influence on lipid metabolism in chronic renal failure? Nephrol Dial Transplant 1995; 10(12):2381–2.
28.Cheung AK, Parker CJ, Ren K, Iverius PH. Increased lipase
inhibition in uremia: identification of pre-beta-HDL as a
major inhibitor in normal and uremic plasma. Kidney Int
1996; 49(5):1360–71.
29.Heeringa P, Tervaert JW. Role of oxidized low-density lipoprotein in renal disease. Curr Opin Nephrol Hypertens
2002; 11(3):287–93.
30.Kasahara J, Kobayashi K, Maeshima Y, Yamasaki Y, Yasuda
T, Matsuura E, et al. Clinical significance of serum oxidized
low-density lipoprotein/beta2-glycoprotein I complexes
in patients with chronic renal diseases. Nephron Clin Pract
2004; 98(1):c15–24.
31.Kimak E, Solski J. ApoA- and apoB-containing lipoproteins
and Lp(a) concentration in non-dialyzed patients with
chronic renal failure. Ren Fail 2002; 24(4):485–92.
32.Deighan CJ, Caslake MJ, McConnell M, Boulton-Jones JM,
Packard CJ. Atherogenic lipoprotein phenotype in endstage renal failure: origin and extent of small dense lowdensity lipoprotein formation. Am J Kidney Dis 2000;
33.Radhakrishnan J, Appel AS, Valeri A, Appel GB. The nephrotic syndrome, lipids, and risk factors for cardiovascular
disease. Am J Kidney Dis 1993; 22(1):135–42.
34.Demant T, Mathes C, Gutlich K, Bedynek A, Steinhauer HB,
Bosch T, et al. A simultaneous study of the metabolism of
apolipoprotein B and albumin in nephrotic patients.
Kidney Int 1998; 54(6):2064–80.
35.Staprans I, Felts JM, Couser WG. Glycosaminoglycans and
chylomicron metabolism in control and nephrotic rats.
Metabolism 1987; 36(5):496–501.
36.Subbaiah PV, Rodby RA. Abnormal acyltransferase activities and accelerated cholesteryl ester transfer in patients
with nephrotic syndrome. Metabolism 1994; 43(9):
37.Warwick GL, Caslake MJ, Boulton-Jones JM, Dagen M,
Packard CJ, Shepherd J. Low-density lipoprotein metabolism in the nephrotic syndrome. Metabolism 1990;
Downloaded from by guest on June 9, 2014
phages of atherosclerotic plaque: effect of vitamin E
supplementation. Circulation 2000; 101(11):1249–54.
9.Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum
JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med
1989; 320(14):915–24.
10.Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary
heart disease. Meta-analysis of prospective studies.
Circulation 2000; 102(10):1082–5.
11.Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding, and plasminogen activation.
Arteriosclerosis 1990; 10(2):240–5.
12.Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon
RJ, Kornman KS, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 2005;
13.Poon M, Zhang X, Dunsky KG, Taubman MB, Harpel PC.
Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation 1997;
14.Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B,
Stampfer MJ, et al. VLDL, apolipoproteins B, CIII, and E,
and risk of recurrent coronary events in the Cholesterol
and Recurrent Events (CARE) trial. Circulation 2000;
15.Cui Y, Blumenthal RS, Flaws JA, Whiteman MK, Langenberg
P, Bachorik PS, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001; 161(11):1413–19.
16.Otvos JD, Shalaurova I, Freedman DS, Rosenson RS. Effects of pravastatin treatment on lipoprotein subclass profiles and particle size in the PLAC-I trial. Atherosclerosis
2002; 160(1):41–8.
17.Castelli WP. Cardiovascular disease and multifactorial risk:
challenge of the 1980s. Am Heart J 1983; 106(5 Pt 2):
18.Benoit P, Emmanuel F, Caillaud JM, Bassinet L, Castro G,
Gallix P, et al. Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models.
Circulation 1999; 99(1):105–10.
19.Tall AR. Plasma high density lipoproteins. Metabolism and
relationship to atherogenesis. J Clin Invest 1990; 86(2):
20.Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and
its apolipoproteins: an idea whose time for testing is coming, part I. Circulation 2001; 104(19):2376–83.
21.Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from
coronary heart disease continuous and graded? Findings
in 356,222 primary screenees of the Multiple Risk Factor
Intervention Trial (MRFIT). JAMA 1986; 256(20):2823–8.
22.Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F,
et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the
INTERHEART study): case-control study. Lancet 2004;
52.Coresh J, Kwiterovich PO Jr, Smith HH, Bachorik PS. Association of plasma triglyceride concentration and LDL
particle diameter, density, and chemical composition with
premature coronary artery disease in men and women.
J Lipid Res 1993; 34(10):1687–97.
53.Kronenberg F, Lingenhel A, Neyer U, Lhotta K, Konig P,
Auinger M, et al. Prevalence of dyslipidemic risk factors
in hemodialysis and CAPD patients. Kidney Int Suppl 2003;
54.Maggi E, Bellazzi R, Gazo A, Seccia M, Bellomo G. Autoantibodies against oxidatively-modified LDL in uremic patients undergoing dialysis. Kidney Int 1994; 46(3):
55.Maggi E, Bellazzi R, Falaschi F, Frattoni A, Perani G, Finardi
G, et al. Enhanced LDL oxidation in uremic patients: an
additional mechanism for accelerated atherosclerosis?
Kidney Int 1994; 45(3):876–83.
56.Shoji T, Nishizawa Y, Nishitani H, Yamakawa M, Morii H.
Roles of hypoalbuminemia and lipoprotein lipase on
hyperlipoproteinemia in continuous ambulatory peritoneal dialysis. Metabolism 1991; 40(10):1002–8.
57. Horkko S, Huttunen K, Laara E, Kervinen K, Kesaniemi YA.
Effects of three treatment modes on plasma lipids and
lipoproteins in uraemic patients. Ann Med 1994; 26(4):
58.Llopart R, Donate T, Oliva JA, Roda M, Rousaud F, GonzalezSastre F, et al. Triglyceride-rich lipoprotein abnormalities
in CAPD-treated patients. Nephrol Dial Transplant 1995;
59.Siamopoulos KC, Elisaf MS, Bairaktari HT, Pappas MB,
Sferopoulos GD, Nikolakakis NG. Lipid parameters including lipoprotein (a) in patients undergoing CAPD and hemodialysis. Perit Dial Int 1995; 15(8):342–7.
60.Moberly JB, Attman PO, Samuelsson O, Johansson AC,
Knight-Gibson C, Alaupovic P. Alterations in lipoprotein
composition in peritoneal dialysis patients. Perit Dial Int
2002; 22(2):220–8.
61.Tanaka Y, Matsuyama T, Ishikura K, Hataya H, Ikeda M,
Honda M. Cholesterol ester transfer protein in children
on peritoneal dialysis. Perit Dial Int 2004; 24(3):281–6.
62.Asayama K, Hayashibe H, Mishiku Y, Honda M, Ito H,
Nakazawa S. Increased activity of plasma cholesteryl ester
transfer protein in children with end-stage renal disease
receiving continuous ambulatory peritoneal dialysis.
Nephron 1996; 72(2):231–6.
63.Kronenberg F, Konig P, Neyer U, Auinger M, Pribasnig A,
Lang U, et al. Multicenter study of lipoprotein(a) and
apolipoprotein(a) phenotypes in patients with end-stage
renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 1995; 6(1):
64.O’Neal D, Lee P, Murphy B, Best J. Low-density lipoprotein particle size distribution in end-stage renal disease
treated with hemodialysis or peritoneal dialysis. Am J
Kidney Dis 1996; 27(1):84–91.
Downloaded from by guest on June 9, 2014
38.Stenvinkel P, Berglund L, Heimburger O, Pettersson E,
Alvestrand A. Lipoprotein(a) in nephrotic syndrome.
Kidney Int 1993; 44(5):1116–23.
39.Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate
product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31(4):
40.Vaziri ND, Gonzales EC, Wang J, Said S. Blood coagulation, fibrinolytic, and inhibitory proteins in end-stage
renal disease: effect of hemodialysis. Am J Kidney Dis
1994; 23(6):828–35.
41.Coresh J, Longenecker JC, Miller ER, 3rd, Young HJ, Klag
MJ. Epidemiology of cardiovascular risk factors in chronic
renal disease. J Am Soc Nephrol 1998; 9(12 Suppl):S24–30.
42.Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner
C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55(2):
43.Muntner P, He J, Astor BC, Folsom AR, Coresh J. Traditional
and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the Atherosclerosis Risk in Communities Study. J Am Soc Nephrol
2005; 16(2):529–38.
44.Avram MM, Fein PA, Antignani A, Mittman N, Mushnick RA,
Lustig AR, et al. Cholesterol and lipid disturbances in renal
disease: the natural history of uremic dyslipidemia and
the impact of hemodialysis and continuous ambulatory
peritoneal dialysis. Am J Med 1989; 87(5N):55N–60N.
45.Sniderman A, Cianflone K, Kwiterovich PO Jr, Hutchinson
T, Barre P, Prichard S. Hyperapobetalipoproteinemia: the
major dyslipoproteinemia in patients with chronic renal
failure treated with chronic ambulatory peritoneal dialysis. Atherosclerosis 1987; 65(3):257–64.
46.Avram MM, Goldwasser P, Burrell DE, Antignani A, Fein PA,
Mittman N. The uremic dyslipidemia: a cross-sectional and
longitudinal study. Am J Kidney Dis 1992; 20(4):324–35.
47. Attman PO, Samuelsson O, Johansson AC, Moberly JB,
Alaupovic P. Dialysis modalities and dyslipidemia. Kidney
Int Suppl 2003; 84:S110–12.
48.Attman PO, Samuelsson OG, Moberly J, Johansson AC,
Ljungman S, Weiss LG, et al. Apolipoprotein B-containing
lipoproteins in renal failure: the relation to mode of dialysis. Kidney Int 1999; 55(4):1536–42.
49.Lee DM, Knight-Gibson C, Samuelsson O, Attman PO, Wang
CS, Alaupovic P. Lipoprotein particle abnormalities and
the impaired lipolysis in renal insufficiency. Kidney Int
2002; 61(1):209–18.
50.Kimura H, Miyazaki R, Imura T, Masunaga S, Suzuki S, Gejyo
F, et al. Hepatic lipase mutation may reduce vascular disease prevalence in hemodialysis patients with high CETP
levels. Kidney Int 2003; 64(5):1829–37.
51.Shoji T, Nishizawa Y, Kawagishi T, Tanaka M, Kawasaki K,
Tabata T, et al. Atherogenic lipoprotein changes in the
absence of hyperlipidemia in patients with chronic renal
failure treated by hemodialysis. Atherosclerosis 1997;
SEPTEMBER 2006 – VOL. 26, NO. 5
SEPTEMBER 2006 – VOL. 26, NO. 5
(non-HDL-C) as a predictor of cardiovascular mortality in
patients with end-stage renal disease. Kidney Int Suppl
2003; 84:S117–20.
79.Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of
chronic hemodialysis patients. Kidney Int 2002; 61(5):
80.Lowrie EG, Lew NL. Death risk in hemodialysis patients:
the predictive value of commonly measured variables and
an evaluation of death rate differences between facilities.
Am J Kidney Dis 1990; 15(5):458–82.
81.Degoulet P, Legrain M, Reach I, Aime F, Devries C, Rojas P,
et al. Mortality risk factors in patients treated by chronic
hemodialysis. Report of the Diaphane collaborative study.
Nephron 1982; 31(2):103–10.
82.Kalantar-Zadeh K, Kopple JD, Block G, Humphreys MH. A
malnutrition-inflammation score is correlated with morbidity and mortality in maintenance hemodialysis patients. Am J Kidney Dis 2001; 38(6):1251–63.
83.Avram MM, Bonomini LV, Sreedhara R, Mittman N. Predictive value of nutritional markers (albumin, creatinine,
cholesterol, and hematocrit) for patients on dialysis for
up to 30 years. Am J Kidney Dis 1996; 28(6):910–17.
84.Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink
NE, et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004; 291(4):451–9.
85.Koda Y, Nishi S, Suzuki M, Hirasawa Y. Lipoprotein(a) is a
predictor for cardiovascular mortality of hemodialysis
patients. Kidney Int Suppl 1999; 71:S251–3.
86.Fujisawa M, Haramaki R, Miyazaki H, Imaizumi T, Okuda S.
Role of lipoprotein (a) and TGF-beta 1 in atherosclerosis
of hemodialysis patients. J Am Soc Nephrol 2000; 11(10):
87.Piccoli GB, Quarello F, Salomone M, Iadarola GM, Funaro
L, Marciello A, et al. Are serum albumin and cholesterol
reliable outcome markers in elderly dialysis patients?
Nephrol Dial Transplant 1995; 10(Suppl 6):72–7.
88.Sreedhara R, Avram MM, Blanco M, Batish R, Avram MM,
Mittman N. Prealbumin is the best nutritional predictor
of survival in hemodialysis and peritoneal dialysis. Am J
Kidney Dis 1996; 28(6):937–42.
89.Webb AT, Brown EA. Prevalence of symptomatic arterial
disease and risk factors for its development in patients
on continuous ambulatory peritoneal dialysis. Perit Dial
Int 1993; 13(Suppl 2):S406–8.
90.Pollock CA, Ibels LS, Caterson RJ, Mahony JF, Waugh DA,
Cocksedge B. Continuous ambulatory peritoneal dialysis.
Eight years of experience at a single center. Medicine (Baltimore) 1989; 68(5):293–308.
91.Gault MH, Longerich L, Prabhakaran V, Purchase L. Ischemic heart disease, serum cholesterol, and apolipoproteins in CAPD. ASAIO Trans 1991; 37(3):M513–M514.
92.Gamba G, Mejia JL, Saldivar S, Pena JC, Correa-Rotter R.
Death risk in CAPD patients. The predictive value of the
initial clinical and laboratory variables. Nephron 1993;
Downloaded from by guest on June 9, 2014
65.Futatsuyama M, Oiwa T, Komatsu Y. Correlation between
oxidized low-density lipoprotein and other factors in patients on peritoneal dialysis. Adv Perit Dial 2002; 18:
66.Johansson AC, Samuelsson O, Attman PO, Haraldsson B,
Moberly J, Knight-Gibson C, et al. Dyslipidemia in peritoneal dialysis—relation to dialytic variables. Perit Dial Int
2000; 20(3):306–14.
67.Lindholm B, Norbeck HE. Serum lipids and lipoproteins
during continuous ambulatory peritoneal dialysis. Acta
Med Scand 1986; 220(2):143–51.
68.Bredie SJ, Bosch FH, Demacker PN, Stalenhoef AF, van
Leusen R. Effects of peritoneal dialysis with an overnight
icodextrin dwell on parameters of glucose and lipid metabolism. Perit Dial Int 2001; 21(3):275–81.
69.Kagan A, Bar-Khayim Y, Schafer Z, Fainaru M. Kinetics of
peritoneal protein loss during CAPD: II. Lipoprotein leakage and its impact on plasma lipid levels. Kidney Int 1990;
70.Fein PA, Fletcher D, Antignani A, Goldwasser P, Jorden A,
Lustig A, et al. Variability of peritoneal clearances for apolipoprotein and its relationship to susceptibility for atherosclerotic changes in CAPD. Adv Perit Dial 1989; 5:
71.Steele J, Billington T, Janus E, Moran J. Lipids, lipoproteins and apolipoproteins A-I and B and apolipoprotein
losses in continuous ambulatory peritoneal dialysis.
Atherosclerosis 1989; 79(1):47–50.
72.Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco
MV, et al. Atherosclerotic cardiovascular disease risks in
chronic hemodialysis patients. Kidney Int 2000; 58(1):
73.Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: a cross-sectional study.
J Am Soc Nephrol 2001; 12(7):1516–23.
74.Cressman MD, Heyka RJ, Paganini EP, O’Neil J, Skibinski
CI, Hoff HF. Lipoprotein(a) is an independent risk factor
for cardiovascular disease in hemodialysis patients.
Circulation 1992; 86(2):475–82.
75.Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, Auinger
M, Pribasnig A, et al. The low molecular weight apo(a)
phenotype is an independent predictor for coronary artery disease in hemodialysis patients: a prospective follow-up. J Am Soc Nephrol 1999; 10(5):1027–36.
76.Hahn R, Oette K, Mondorf H, Finke K, Sieberth HG. Analysis of cardiovascular risk factors in chronic hemodialysis
patients with special attention to the hyperlipoproteinemias. Atherosclerosis 1983; 48(3):279–88.
77.Koch M, Kutkuhn B, Grabensee B, Ritz E. Apolipoprotein
A, fibrinogen, age, and history of stroke are predictors of
death in dialysed diabetic patients: a prospective study
in 412 subjects. Nephrol Dial Transplant 1997; 12(12):
78.Nishizawa Y, Shoji T, Kakiya R, Tsujimoto Y, Tabata T,
Ishimura E, et al. Non-high-density lipoprotein cholesterol
J Med 1995; 333(20):1301–7.
106.Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR,
Beere PA, et al. Primary prevention of acute coronary
events with lovastatin in men and women with average
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/
Texas Coronary Atherosclerosis Prevention Study. JAMA
1998; 279(20):1615–22.
107. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G,
Caulfield M, et al. Prevention of coronary and stroke events
with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations,
in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid
Lowering Arm (ASCOT-LLA): a multicentre randomised
controlled trial. Lancet 2003; 361(9364):1149–58.
108.MRC/BHF Heart Protection Study of cholesterol lowering
with simvastatin in 20,536 high-risk individuals: a
randomised placebo-controlled trial. Lancet 2002; 360
109.Tonelli M, Isles C, Curhan GC, Tonkin A, Pfeffer MA, Shepherd J, et al. Effect of pravastatin on cardiovascular events
in people with chronic kidney disease. Circulation 2004;
110. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G,
et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353(3):
111. Chang JW, Yang WS, Min WK, Lee SK, Park JS, Kim SB. Effects of simvastatin on high-sensitivity C-reactive protein
and serum albumin in hemodialysis patients. Am J Kidney
Dis 2002; 39(6):1213–17.
112.Harris KP, Wheeler DC, Chong CC. A placebo-controlled trial
examining atorvastatin in dyslipidemic patients undergoing CAPD. Kidney Int 2002; 61(4):1469–74.
113.Saltissi D, Morgan C, Rigby RJ, Westhuyzen J. Safety and
efficacy of simvastatin in hypercholesterolemic patients
undergoing chronic renal dialysis. Am J Kidney Dis 2002;
114.Baigent C, Landray M, Leaper C, Altmann P, Armitage J,
Baxter A, et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and
safety of simvastatin and safety of low-dose aspirin in
chronic kidney disease. Am J Kidney Dis 2005; 45(3):
115.Robson R, Collins J, Johnson R, Kitching R, Searle M,
Walker R, et al. Effects of simvastatin and enalapril on
serum lipoprotein concentrations and left ventricular
mass in patients on dialysis. The Perfect Study Collaborative Group. J Nephrol 1997; 10(1):33–40.
116.Lins RL, Matthys KE, Billiouw JM, Dratwa M, Dupont P,
Lameire NH, et al. Lipid and apoprotein changes during
atorvastatin up-titration in hemodialysis patients with
hypercholesterolemia: a placebo-controlled study. Clin
Nephrol 2004; 62(4):287–94.
117. Navaneethan SD, Shrivastava R. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database
Syst Rev 2004; 4:CD004289.
Downloaded from by guest on June 9, 2014
93.Iliescu EA, Marcovina SM, Morton AR, Lam M, Koschinsky
ML. Apolipoprotein(a) phenotype and lipoprotein(a) level
predict peritoneal dialysis patient mortality. Perit Dial Int
2002; 22(4):492–9.
94.Ohkuma T, Minagawa T, Takada N, Ohno M, Oda H, Ohashi
H. C-reactive protein, lipoprotein(a), homocysteine, and
male sex contribute to carotid atherosclerosis in peritoneal dialysis patients. Am J Kidney Dis 2003; 42(2):
95.Avram MM, Sreedhara R, Patel N, Chattopadhyay J, Thu T,
Fein P. Is an elevated level of serum lipoprotein (a) a risk
factor for cardiovascular disease in CAPD patients? Adv
Perit Dial 1996; 12:266–71.
96.Istvan ES, Deisenhofer J. Structural mechanism for statin
inhibition of HMG-CoA reductase. Science 2001; 292
97. Ness GC, Zhao Z, Lopez D. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation. Arch Biochem Biophys 1996;
98.Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin,
pravastatin, lovastatin, and fluvastatin in patients with
hypercholesterolemia (the CURVES study). Am J Cardiol
1998; 81(5):582–7.
99.Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM,
Miller E, et al. Comparison of the efficacy and safety of
rosuvastatin versus atorvastatin, simvastatin, and
pravastatin across doses (STELLAR* Trial). Am J Cardiol
2003; 92(2):152–60.
100.Vaughan CJ, Gotto AM Jr, Basson CT. The evolving role of
statins in the management of atherosclerosis. J Am Coll
Cardiol 2000; 35(1):1–10.
101.Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344(8934):
102.Prevention of cardiovascular events and death with
pravastatin in patients with coronary heart disease and a
broad range of initial cholesterol levels. The Long-Term
Intervention with Pravastatin in Ischaemic Disease
(LIPID) Study Group. N Engl J Med 1998; 339(19):1349–57.
103.Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford
JD, Cole TG, et al. The effect of pravastatin on coronary
events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events
Trial investigators. N Engl J Med 1996; 335(14):1001–9.
104.LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P,
Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J
Med 2005; 352(14):1425–35.
105.Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR,
MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
West of Scotland Coronary Prevention Study Group. N Engl
SEPTEMBER 2006 – VOL. 26, NO. 5
SEPTEMBER 2006 – VOL. 26, NO. 5
124.Seliger SL, Weiss NS, Gillen DL, Kestenbaum B, Ball A,
Sherrard DJ, et al. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney
Int 2002; 61(1):297–304.
125.Mason NA, Bailie GR, Satayathum S, Bragg-Gresham JL,
Akiba T, Akizawa T, et al. HMG-coenzyme A reductase
inhibitor use is associated with mortality reduction in hemodialysis patients. Am J Kidney Dis 2005; 45(1):119–26.
126.Herzog CA. How to manage the renal patient with coronary heart disease: the agony and the ecstasy of opinionbased medicine. J Am Soc Nephrol 2003; 14(10):2556–72.
127. Karnik JA, Young BS, Lew NL, Herget M, Dubinsky C,
Lazarus JM, et al. Cardiac arrest and sudden death in dialysis units. Kidney Int 2001; 60(1):350–7.
128.United States Renal Data System. USRDS 2001 Annual Data
Report: Atlas of End-Stage Renal Disease in the United
States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2001.
129.London GM, Marchais SJ, Metivier F, Guerin AP. Cardiovascular risk in end-stage renal disease: vascular aspects.
Nephrol Dial Transplant 2000; 15(Suppl 5):97–104.
130.K/DOQI clinical practice guidelines for management of
dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003; 41(4 Suppl 3):I–IV, S1–91.
Downloaded from by guest on June 9, 2014
118.Nishizawa Y, Shoji T, Emoto M, Kawasaki K, Konishi T,
Tabata T, et al. Reduction of intermediate density lipoprotein by pravastatin in hemo- and peritoneal dialysis patients. Clin Nephrol 1995; 43(4):268–77.
119.Nishizawa Y, Shoji T, Tabata T, Inoue T, Morii H. Effects of
lipid-lowering drugs on intermediate-density lipoprotein
in uremic patients. Kidney Int Suppl 1999; 71:S134–6.
120.Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin
therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial
and cohort study. JAMA 2001; 286(1):64–70.
121.Ikejiri A, Hirano T, Murayama S, Yoshino G, Gushiken N,
Hyodo T, et al. Effects of atorvastatin on triglyceride-rich
lipoproteins, low-density lipoprotein subclass, and C-reactive protein in hemodialysis patients. Metabolism 2004;
122.Vernaglione L, Cristofano C, Muscogiuri P, Chimienti S.
Does atorvastatin influence serum C-reactive protein levels in patients on long-term hemodialysis? Am J Kidney
Dis 2004; 43(3):471–8.
123.van den Akker JM, Bredie SJ, Diepenveen SH, van Tits LJ,
Stalenhoef AF, van Leusen R. Atorvastatin and simvastatin
in patients on hemodialysis: effects on lipoproteins, Creactive protein and in vivo oxidized LDL. J Nephrol 2003;