Dyslipidemia in
Hemodialysis Patients
Turki Banamah
Consultant Transplant nephrology
King Abdulaziz medical city
Jeddah
Objectives
• Definition of dyslipidemia in Hemodialysis
Patient.
• Normal Structure and Function of
Lipoproteins.
• Pathophysiology of Dyslipidemia in CKD
and Dialysis.
• Is Lipid Control Necessary in Hemodialysis
Patients?
• Analyze the recent clinical trial
• Conclusion
• Dyslipidemia is an established cardiovascular
(CV) risk factor in the general population.
• In chronic kidney disease (CKD), however,
epidemiologic studies and clinical trials have
raised uncertainties regarding the impact of
dyslipidemia on clinical outcomes and,
consequently, the optimal lipid profile.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• Dyslipidemia is empirically defined as
plasma lipid and lipoproteins that are
associated with adverse outcomes such as CV
disease (CVD) in the general population.
• Whether this definition is justified in patients
with CKD requires further investigations.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
Normal Structure and Function of
Lipoproteins
• Lipoproteins consist of lipids and proteins
(known as apolipoproteins [apo]), with the
main function of transporting waterinsoluble lipids such as cholesterol or
triglycerides in plasma from the sites of
absorption (gut) and/or synthesis (liver) to
the sites of utilization (peripheral tissues) or
processing.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• Besides contributing to the structure and the
stability of the macromolecule, Apo
lipoproteins control the metabolism of the
lipoproteins by activation or inhibition of
enzymes and interaction with lipoprotein
receptors.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
Pathophysiology of Dyslipidemia in CKD
and Dialysis
• The spectrum of dyslipidemia in patients
with CKD and dialysis patients is distinct
from that of the general population.
• It involves all lipoprotein classes and shows
considerable variations depending on the
stage of CKD.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• There seems to be a gradual shift to the
uremic lipid profile as kidney function
deteriorates.
• Apart from quantitative differences, major
qualitative changes in lipoproteins can be
observed, such as oxidization and
modification to sdLDL, which render the
particles more atherogenic.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
Hypertriglyceridemia
• Plasma triglycerides are predominantly
found in two types of lipoproteins in normal
individuals.
• These are chylomicrons, which are assembled
in the intestine for the transport of dietary
fatty acids, and VLDL, which are produced in
the liver for the transport of endogenous fatty
acids.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• The accumulation of triglycerides is the
consequence of both a high production rate
and a low fractional catabolic rate .
• The reduced fractional catabolic rate is likely
due to the decreased activity of two
endothelium-associated lipases, namely, LPL
and hepatic triglyceride lipase, which have
the primary physiologic function of cleaving
triglycerides into FFA for energy production
or storage.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• The cause of the decreased lipase activities in
uremia is thought to be depletion of the
enzyme pool induced by frequent
heparinization in hemodialysis (HD) patients
• An increase in the plasma apoC-III/apoC-II
ratio, and the presence of other lipase
inhibitors in plasma.
• ApoC-II is an activator of LPL, whereas
apoC-III is an inhibitor of LPL.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• The increased apoC-III/apoC-II ratio is
usually due to a disproportionate increase in
plasma apoC-III .
• The impaired lipase activities in uremic
plasma may also be caused by a decrease in
LPL synthesis as a result of secondary
hyperparathyroidism or suppressed insulin
level .
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
High-Density Lipoprotein
• Patients with CKD generally have reduced
plasma HDL cholesterol concentrations
compared with nonuremic individuals
Because of the low apo-AI level and
decreased LCAT activity , the esterification of
free cholesterol and hence the conversion of
HDL3 to HDL2 are diminished in uremia.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• In summary, the hallmarks of uremic
dyslipidemia are hypertriglyceridemia;
increased remnant lipoproteins (chylomicron
remnants and IDL); reduced HDL cholesterol;
and in-creased sdLDL, Lp(a), and apoA-IV.
• Elevated plasma LDL cholesterol level is not
typical but can mostly be observed in patients
with Nephrotic syndrome and PD patients.
J Am Soc Nephrol 18: 1246–1261, 2007. doi:
10.1681/ASN.2006091006
• Is Lipid Control Necessary in
Hemodialysis Patients?
Clin J Am Soc Nephrol 4: S95–S101, 2009. doi:
10.2215/CJN.04780709
Observational Studies of
Hypercholesterolemia in the Dialysis
Population
• Chronic kidney disease (CKD) represents a
very wide spectrum of GFRs and proteinuria,
associated with highly variable rates and risk
factors for cardiovascular events.
• The coronary risk factors for individuals with
stage 1 or 2 CKD are generally quite similar to
those without kidney disease .
Clin J Am Soc Nephrol 4: S95–S101, 2009. doi:
10.2215/CJN.04780709
• In contrast, a number of epidemiologic
studies and a few randomized clinical trials
have shown unconventional associations of
cardiovascular risk factors with clinical
outcomes in long-term dialysis patients.
• The first large observational study relating
serum cholesterol levels and clinical
outcomes was published in the early 1990s,
based on the database of National Medical .
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 15: 458–482, 1990
• In that study, a U-shape relationship
between serum total cholesterol level and the
risk for all-cause mortality was observed,
with the lowest risk found in the category
with cholesterol levels between 200 and 250
mg/dl.
• Cholesterol levels between 250 and 300
mg/dl seemed to be associated with a modest
increase in mortality risk, but the subgroup
with cholesterol levels 100 mg/dl had a threefold increase in mortality risk after
adjustment for case mix.
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 15: 458–482, 1990
• (CHOICE) Study by Liu et al. is compatible
with this hypothesis.
• In that analysis, 823 incident dialysis patients
were classified by the presence or absence of
inflammation and/or malnutrition (defined
as low serum albumin levels or elevated
serum levels of C-reactive protein or IL-6).
• An increase in baseline serum cholesterol
level was associated with a decreased risk for
all-cause mortality in the entire CHOICE
cohort.
Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink
NE, Tracy RP, Powe NR, Klag MJ: Association between
cholesterol level and mortality in dialysis patients: Role of
inflammation and malnutrition. JAMA 291: 451–459, 2004
• Recent randomized trials
Die Deutsche Diabetes Dialyse Studie (4D) targeted German
patients who had type 2 diabetes and ESRD and were on
long-term hemodialysis
• A multicenter, randomized, double-blind,
prospective study of 1255 subjects with type 2
diabetes mellitus receiving maintenance
hemodialysis who were randomly assigned to
receive 20 mg of atorvastatin per day or
matching placebo.
• The primary end point was a composite of
death from cardiac causes, nonfatal
myocardial infarction, and stroke.
• Secondary end points included death from all
causes and all cardiac and cerebrovascular
events combined.
Die Deutsche Diabetes Dialyse Studie (4D) targeted German
patients who had type 2 diabetes and ESRD and were on
long-term hemodialysis
• There are several potential interpretations of
this seemingly negative result.
• First, LDL cholesterol may not be important
in the pathogenesis of cardiovascular disease
in dialysis patients.
• Second it could mean that atherosclerosis is
not a major cause of cardiovascular death.
• The most common causes of cardiac death
listed in the US Renal Data System and the
Hemodialysis (HEMO) Study were sudden
death, arrhythmia, and unknown.
Die Deutsche Diabetes Dialyse Studie (4D) targeted German
patients who had type 2 diabetes and ESRD and were on
long-term hemodialysis
• A third potential explanation is that statins
are, in fact, effective in decreasing
cardiovascular events in dialysis patients
with diabetes, but the sample size of the 4D
Study was not sufficiently large to detect the
modest effect.
Die Deutsche Diabetes Dialyse Studie (4D) targeted German
patients who had type 2 diabetes and ESRD and were on
long-term hemodialysis
• A post hoc analysis was conducted of the 4D
(Die Deutsche Diabetes Dialyze) study to
investigate whether LDL-cholesterol at
baseline is predictive of cardiovascular events
and whether the effect of atorvastatin on
clinical outcomes depends on LDLcholesterol at baseline.
• Atorvastatin significantly reduced the rates of
adverse outcomes in the highest quartile of
LDL-cholesterol (145 mg/dl, 3.76 mmol/L).
Die Deutsche Diabetes Dialyse Studie (4D) targeted German
patients who had type 2 diabetes and ESRD and were on
long-term hemodialysis
• In patients with type 2 diabetes mellitus
undergoing hemodialysis, atorvastatin
significantly reduces the risk of fatal and
nonfatal cardiac events and death from any
cause if pretreatment LDL-cholesterol is 145
mg/dl (3.76 mmol/L).
Die Deutsche Diabetes Dialyse Studie (4D) targeted German
patients who had type 2 diabetes and ESRD and were on
long-term hemodialysis
A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an
Assessment of survival and cardiovascular events (AURORA)
• An international, multicenter, randomized,
double-blind, prospective trial involving 2776
patients, 50 to 80 years of age, who were
undergoing maintenance hemodialysis.
• Randomly assigned 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.
A study to evaluate the Use of Rosuvastatin in subjects On
Regular hemodialysis: an
Assessment of survival and cardiovascular events (AURORA)
• The major differences in the study design
between AURORA and the 4D Study are as
follows:
• (1) The AURORA enrolled approximately
twice as many patients as the 4D Study.
• (2) approximately 74% of the AURORA
patients did not have diabetes, whereas the
4D Study targeted patients with diabetes
exclusively
• (3) the 4D study was more generalizable
from the age standpoint; the lower age limit
of the 4D study was 18 yr, whereas the lower
age limit of AURORA was 50 yr.
• Despite these differences, the remarkable
similarity between these two trials was the
apparent lack of efficacy for statins to
decrease cardiovascular events in the longterm hemodialysis population.
• A post-hoc analysis of 731 diabetic patients
from AURORA also showed no difference in
the composite outcome or in the risk of stroke
• There was a 32 percent reduction in cardiac
events (including cardiac death and nonfatal
MI) among diabetic patients assigned to
receive rosuvastatin (n = 388) compared with
placebo (n = 343) (HR 1.68, 95% CI 0.51-0.90) .
• The Study of Heart and Renal Protection
(SHARP) trial.
• In this study, 9270 patients with CKD with
no history of myocardial infarction or
coronary revascularization were randomized
to simvastatin/ ezetimibe or placebo.
• The study included 3023 patients undergoing
dialysis at study entry, and 2000 additional
patients reached ESRD during the course of
the study.
• The intervention resulted in a net decrease in
LDL cholesterol of 35 mg/dl, and over a
median follow-up of 4.9 years, a 17% lower
risk for atherosclerotic vascular events
(nonfatal myocardial infarction, coronary
death, ischemic stroke, arterial
revascularization)
• There was no reduction in either overall or
cardiovascular mortality.
• Only one-quarter of all vascular deaths were
classified as being secondary to
atherosclerosis .
Recommendation
• In the dialysis population, approximately 60
percent of all cardiac deaths are presumably
due to sudden death or arrhythmias.
• We agree with the 2013 KDIGO guidelines
that suggest that statin therapy be continued
in patients who are already receiving statins
or a statin/ezetimibe combination at the time
of initiation of dialysis.
• if statin therapy is administered to dialysis
patients, the following goals are reasonable,
although they have not been validated in
dialysis patients:
• A serum LDL-cholesterol of
<100 mg/dL (<2.6 mmol/L)
• A non-high-density lipoprotein (HDL)cholesterol concentration (ie, total minus
HDL-cholesterol) of
<130 mg/dL (<3.36 mmol/L) in patients who
have already achieved the target LDLcholesterol level, but have fasting
triglycerides ≥200 mg/dL (≥2.26 mmol/L).
• Diabetic individuals with higher LDL
cholesterol may have the greatest benefit with
statin therapy (eg,
>190 mg/dL [4.9 mmol/L])
• Although some authers suggest to start any
diabetic patient on dialysis with high
cholestrol on statin .
Thanks