lipoprotein metabolism and lipid management in chronic...

Disease of the Month

Lipoprotein Metabolism and Lipid Management in ChronicKidney Disease

Bonnie C.H. Kwan,* Florian Kronenberg, Srinivasan Beddhu, and Alfred K. Cheung

*Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Division ofNephrology & Hypertension and Dialysis Program, University of Utah, and Medical Service, Veterans Affairs SaltLake City Healthcare System, Salt Lake City, Utah; and Division of Genetic Epidemiology, Department of MedicalGenetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria

J Am Soc Nephrol 18: 12461261, 2007. doi: 10.1681/ASN.2006091006

D yslipidemia is an established cardiovascular (CV) riskfactor in the general population. In chronic kidney dis-ease (CKD), however, epidemiologic studies (13) andclinical trials (412) have raised uncertainties regarding the impactof dyslipidemia on clinical outcomes and, consequently, the opti-mal lipid profile. In this article, we review the pathophysiology ofdyslipidemia in CKD and dialysis patients and its association withclinical outcome and the effects of therapy and compare themwith those in the general population. Kidney transplant patientsare excluded from the discussion. Dyslipidemia is empiricallydefined here as plasma lipid and lipoproteins that are associatedwith adverse outcomes such as CV disease (CVD) in the generalpopulation. Whether this definition is justified in patients withCKD requires further investigations.

Normal Structure and Function ofLipoproteinsLipoproteins

Lipoproteins consist of lipids and proteins (known as apoli-poproteins [apo]), with the main function of transporting wa-ter-insoluble lipids such as cholesterol or triglycerides inplasma from the sites of absorption (gut) and/or synthesis(liver) to the sites of utilization (peripheral tissues) or process-ing. Besides contributing to the structure and the stability of themacromolecule, apolipoproteins control the metabolism of thelipoproteins by activation or inhibition of enzymes and inter-action with lipoprotein receptors. The major types of theplasma lipoproteins and their apolipoprotein components andphysiologic functions are briefly presented in Table 1.

Lipoprotein PathwaysIn the exogenous pathway (Figure 1), chylomicrons transport

dietary lipids that are absorbed from the intestine via the sys-temic circulation. Chylomicrons are triglyceride-rich and nor-mally catabolized within minutes by the endothelium-associ-ated lipoprotein lipase (LPL), thereby generating free fatty

acids (FFA), which are taken up by the liver, muscle, andadipose tissues. During this catabolic process, chylomicronsdiminish in size and become chylomicron remnants, which aretaken up by the liver via the low-density lipoprotein (LDL)receptor and the LDL receptorrelated protein (LRP).

In the endogenous pathway (Figure 1), the liver assemblesand secretes triglyceride-rich very low-density lipoprotein(VLDL) particles, which transport triglycerides from the liver toperipheral tissues. After hydrolysis of the triglycerides by LPL,the VLDL particles are reduced to intermediate-density li-poproteins (IDL), which can be taken up by the liver or can befurther hydrolyzed to LDL particles. During this conversion,the particles become depleted of triglycerides but retain con-siderable amounts of cholesterol (13).

LDL transports cholesterol primarily to hepatocytes but also toperipheral tissues. ApoB-100 is responsible for the recognition anduptake of LDL by the LDL receptor, which clears approximately60 to 80% of LDL in normal individuals. The remaining LDL isremoved by other specific receptors, such as LRP, or by scavengerreceptors (14). Oxidized LDL (ox-LDL) in particular can be takenup by scavenger receptors on macrophages and vascular smoothmuscle cells. When these macrophages become overloaded withcholesteryl esters, they transform into foam cells, which is a majorstep in the development of atherosclerosis (14). When LDL be-comes lipid depleted, small dense LDL (sdLDL) is generated,which has lower affinity for the LDL receptor but is more suscep-tible to oxidative modification. Thus, sdLDL are believed to bemore atherogenic than larger LDL particles (15).

High-density lipoprotein (HDL) plays an important role inreverse cholesterol transport, which shuttles cholesterol fromperipheral cells to the liver (16), an important step that relievesthe peripheral cells from cholesterol burden (Figure 1). HDLprecursor particles are secreted as disc-shaped structures by theliver and intestine and can absorb free cholesterol from cellmembranes, a process that is mediated by ATP binding cassettetransporter 1, apoA-I, and apoA-IV. ApoA-I is the major apo-lipoprotein of HDL and activates the enzyme lecithin:choles-terol acyltransferase (LCAT), which esterifies the accepted freecholesterol to allow more efficient packaging of the cholesterolfor transport. By acquisition of additional apolipoproteins, cho-lesteryl esters, and triglycerides, HDL3 particles are trans-

Published online ahead of print. Publication date available at www.jasn.org.

Address correspondence to: Dr. Alfred K. Cheung, Dialysis Program, 85 NorthMedical Drive East, University of Utah, Salt Lake City, UT 84112. Phone: 801-581-6427; Fax: 801-581-4750; E-mail: [email protected]

Copyright 2007 by the American Society of Nephrology ISSN: 1046-6673/1804-1246

formed into larger HDL2 particles (17). Reverse cholesterol trans-port can take three different routes. First, large HDL particles withmultiple copies of apoE can be taken up by the liver via the LDLreceptor (16). Second, the accumulated cholesteryl esters fromHDL can be selectively taken up by the liver mediated by scav-enger receptor B1 (18). This receptor is expressed primarily in liverand nonplacental steroidogenic tissues. Third, cholesteryl estersare transferred by the cholesteryl ester transfer protein from HDLto triglyceride-rich lipoproteins (16). Plasma HDL cholesterol lev-els are influenced by the complexity of these reverse cholesteroltransport processes. Disturbances in the concentrations of apopro-teins, function of enzymes, transport proteins, receptors, otherlipoproteins, and the clearance from plasma can have a majorimpact on the antiatherogenic properties of HDL.

Pathophysiology of Dyslipidemia in CKDand Dialysis

The spectrum of dyslipidemia in patients with CKD and dial-ysis patients is distinct from that of the general population. Itinvolves all lipoprotein classes and shows considerable variationsdepending on the stage of CKD (Table 2). There seems to be agradual shift to the uremic lipid profile as kidney function dete-riorates (19,20), which is further modified by concurrent illnessessuch as diabetes (21) and nephrotic syndrome (22). Apart fromquantitative differences, major qualitative changes in lipoproteinscan be observed, such as oxidization and modification to sdLDL,which render the particles more atherogenic.

HypertriglyceridemiaPlasma triglycerides start to increase in early stages of CKD

(Table 2) and show the highest concentrations in nephrotic syn-drome and in dialysis patients, especially those who are treatedwith peritoneal dialysis (PD). Plasma triglycerides are predomi-

nantly found in two types of lipoproteins in normal individuals.These are chylomicrons, which are assembled in the intestine forthe transport of dietary fatty acids, and VLDL, which are pro-duced in the liver for the transport of endogenous fatty acids(2325). The accumulation of triglycerides is the consequence ofboth a high production rate and a low fractional catabolic rate (24)(Figure 2). An increased production of triglyceride-rich lipopro-teins is possibly a consequence of impaired carbohydrate toler-ance and enhanced hepatic VLDL synthesis (26). The reducedfractional catabolic rate is likely due to the decreased activity oftwo endothelium-associated lipases, namely, LPL and hepatic tri-glyceride lipase, which have the primary physiologic function ofcleaving triglycerides into FFA for energy production or storage.The cause of the decreased lipase activities in uremia is thought tobe depletion of the enzyme pool induced by frequent hepariniza-tion in hemodialysis (HD) patients (27), an increase in the plasmaapoC-III/apoC-II ratio, and the presence of other lipase inhibitorsin plasma. ApoC-II is an activator of LPL, whereas apoC-III is aninhibitor of LPL. The increased apoC-III/apoC-II ratio is usuallydue to a disproportionate increase in plasma apoC-III (28). Theimpaired lipase activities in uremic plasma may also be caused bya decrease in LPL synthesis as a result of secondary hyperpara-thyroidism or suppressed insulin level (29).

Incomplete catabolism results in the accumulation of rem-nant particles (chylomicron remnants and IDL) that contributeto the heterogeneity of the plasma pool of triglyceride-richlipoproteins, with different sites of origin, sizes, compositions(30), and degrees of atherogenicity (31). These remnants are richin apoE, a ligand that is critical for the removal of the particlesfrom the circulation by binding to LRP and perhaps otherreceptors on the vascular wall (32). The arterial wall therefore isexposed to high plasma levels of remnant lipoproteins forprolonged durations, which may predispose to atherogenesis.

Table 1. Types of lipoproteins in normal plasmaa

Lipoprotein Physiologic FunctionRelative Content (%)b

ApolipoproteinscTG Ch Pl Pr

Chylomicron Transport of dietary TG from gut to peripheral tissue and liver 90 5 3 2 B-48, C-II, C-III, A-IV, EVLDL Transport of endogenous TG from liver to peripheral tissues 60 20 14 6 B-100, C-II, C-III, EIDL Intermediary of VLDL metabolism; usually present in small

concentrations in plasma but elevated in kidney failure20 40 22 18 B-100, E

LDL Transport of cholesterol from liver to peripheral tissues 7 50 22 21 B-100HDL Reverse transport of cholesterol from peripheral tissues to liver 5 25 26 44 A-I, A-II, A-IVLp(a) Unknown 5 45 20 26 apo(a), B-100

aapo, apolipoproteins; Ch, cholesterol; CKD, chronic kidney disease; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; Lp(a), Lipoprotein(a); Pl, phospholipids; Pr, proteins; TG, triglycerides.

bRelative content of TG, Ch, Pl, and Pr in the various plasma lipoproteins. Data are based on individuals without CKD.Lp(a) contains additionally 4% carbohydrates.

cOnly the major (apolipoproteins) or the ones with particular pathogenetic importance in uremia are presented for eachlipoprotein. ApoB is a ligand for cellular receptors for lipoprotein uptake. ApoC-II is an activator of lipoprotein lipase thathydrolyzes triglycerides, whereas apoC-III is an inhibitor of the lipases. ApoE is a ligand for hepatic receptors that mediatethe uptake of VLDL and IDL. ApoA-I is an activator of LCAT, which catalyzes the esterification and hence the reversetransport of cholesterol from periphery to liver. ApoA-IV is another activator of LCAT and lipoprotein lipase. ApoA-II is anactivator of another lipase, the hepatic lipase, which also hydrolyzes TG from lipoproteins. Increased apoC-III levels,decreased lipoprotein lipase activity, and low apoA-I and apoA-II levels are hallmarks of uremic dyslipidemia, resulting in theaccumulation of apoB-containing lipoproteins (e.g., IDL) and low levels of HDL cholesterol in plasma.

J Am Soc Nephrol 18: 12461261, 2007 Lipids in CKD 1247

High-Density LipoproteinPatients with CKD generally have reduced plasma HDL choles-

terol concentrations compared with nonuremic individuals (Table 2).Furthermore, the distribution of HDL subfractions is different. Be-cause of the low apo-AI level and decreased LCAT activity (see theLipoprotein Pathways section), the esterification of free cholesteroland hence the conversion of HDL3 to HDL2 are diminished in ure-mia. This decreased ability of the HDL particles to carry cholesterol

leads to an impairment in the reverse cholesterol transport fromperipheral cells to the liver, thereby burdening the vasculature withcholesterol and promoting atherosclerosis (3335).

Another important component of HDL is paraoxonase, anenzyme that inhibits the oxidation of LDL. Plasma paraoxonaseactivity is reduced in patients with CKD (36), thereby predis-posing the LDL and possibly also HDL particles to oxidation.Furthermore, infection-associated or uremia-associated inflam-

Figure 1. Major normal lipoprotein metabolic pathways. Refer to text for detailed explanation. Blue arrows refer to points of actionof the respective enzymes in blue. ABCA1, ATP binding cassette transporter 1; CE, cholesterol ester; CETP, cholesteryl estertransfer protein; FFA, free fatty acid; HTGL, hepatic triglyceride lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL-R, LDL receptor; Lp(a), lipoprotein(a); LPL, lipoprotein lipase; LRP, LDL-Rrelated protein; SRB1, scavenger receptor B1; TG, triglyceride. Illustration by Josh GramlingGramling Medical Illustration.

Table 2. Trend of changes in lipids, lipoproteins, and apoA-IV in various stages of CKDa

Parameter CKD 1 to 5 Nephrotic Syndrome Hemodialysis Peritoneal Dialysis

Total cholesterol m 11 72 1LDL cholesterol m 11 72 1HDL cholesterol 2 2 2 2NonHDL cholesterol m 11 72 1TG m 11 1 1Lp(a) m 11 1 11ApoA-I n m 2 2ApoA-IV m 1n 1 1ApoB m 11 72 1

aThese trends are derived from the composite of the literature. NonHDL cholesterol includes cholesterol in LDL, VLDL, IDL,and chylomicron and its remnant. Explanation of arrows: Normal (7), increased (1), markedly increased (_), and decreased (2)plasma levels compared with nonuremic indviduals; increasing (m) and decreasing (n) plasma levels with decreasing GFR.

1248 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 12461261, 2007

mation might convert HDL from an antioxidant into a pro-oxidant particle (37,38). All of these may contribute to athero-genesis in CKD.

Apolipoprotein A-IVApoA-IV is a 46-kDa glycoprotein that is synthesized primarily

in enterocytes of the small intestine. In vitro studies suggest thatapoA-IV might protect against atherosclerosis by promoting sev-eral steps in the reverse cholesterol transport pathway, whichremoves cholesterol from peripheral cells and directs the choles-terol to liver and steroidogenic organs for metabolism (3941).Specifically, apoA-IV activates LCAT (42,43) and modulates theactivation of LPL (44) as well as the protein-mediated transfer ofcholesteryl esters from HDL to LDL (45). Cross-sectional studieshave shown an inverse relationship between plasma apoA-IVlevels and presence of coronary artery disease in the generalpopulation (46,47) as well as in patients with CKD (20).

ApoA-IV has also been identified as a marker of primaryCKD, and its plasma levels are already increased when glomer-ular filtration rate (GFR) is still normal (Table 2) (20). Further-more, high plasma apoA-IV concentrations predicted, indepen-dent of baseline GFR, the progression of primary nondiabetickidney disease, defined as doubling of serum creatinine ornecessity of renal replacement therapy, during a prospective7-yr follow-up study (48). These findings were unexpected,given the physiologic functions in reverse cholesterol transportand the antioxidative properties of apoA-IV. The high apoA-IVlevels that were caused by the impairment of GFR are furthermodulated by nephrotic syndrome. Specifically, a tubular typeof proteinuria and severe proteinuria cause a decrease inplasma apoA-IV levels (49). These observations suggest that thehuman kidney is involved in apoA-IV metabolism, a hypothe-sis that is further supported by the presence of apoA-IV inkidney tubular cells (50). In dialysis patients, apoA-IV levels aretwice as high as in the general population (5154).

Low-Density LipoproteinElevated plasma LDL cholesterol concentration is common in

nephrotic syndrome but is not a typical feature of patients withadvanced CKD, especially those who are on HD (Table 2).There are, however, qualitative changes in LDL in patients withCKD and dialysis patients. The proportions of sdLDL and IDL,which are considered to be highly atherogenic, are increased.sdLDL is a subtype of LDL that has high propensity to pene-trate the vessel wall, becomes oxidized, and triggers the ath-erosclerotic process. IDL is an intermediate metabolite of VLDLthat is normally further degraded to LDL with the cleavage oftriglycerides by lipases (see the Hypertriglyceridemia section).Because of decreased hepatic triglyceride lipase activities in HDpatients, the conversion of IDL to LDL is impaired and IDLaccumulates in plasma (55). IDL and sdLDL have high affinityfor macrophages, which theoretically promote their entry intothe vascular wall to participate in the formation of foam cellsand atherosclerotic plaques (5659). The plasma levels of apoB,which is the major apolipoprotein of LDL and IDL, are stronglycorrelated with levels of these lipoproteins.

A vicious cycle has been suggested in uremia in which thedecreased catabolism of IDL and LDL leads to their increasedplasma residence time and further modification of the apoBcontained in these lipoproteins by oxidation, carbamylation,and glycation (60). These modifications lead to the reducedrecognition and binding of these lipoproteins to LDL receptorsand LRP in the liver and hence further reduction in plasmaclearance by this physiologic pathway. Using stable isotopetechniques, it was shown recently that the plasma residencetime of LDL and IDL is more than twice as long in HD patientsas in nonuremic individuals (Figure 3). This reduced catabolism,however, is masked by the decreased production of LDL, result-ing in near-normal plasma levels of LDL (60). In contrast to thedecreased clearance by the liver, there is an increased clearance ofthese altered lipoproteins via the scavenger pathway. ModifiedLDL particles, such as ox-LDL and malondialdehyde-modifiedLDL, are taken up by macrophages via binding to several cellsurface scavenger receptors. The accumulation of cholesterol leadsto the transformation of macrophages into foam cells in the vas-cular wall and contributes to atherogenesis (5659,61).

Lipoprotein(a)There is strong evidence that lipoprotein(a) [Lp(a)] is a risk

factor for CVD in the general population (62,63). Lp(a) is anLDL-like lipoprotein that consists of apo(a) that is covalentlybound to an LDL particle. Apo(a) shows a high homology withplasminogen and competes with this protein for binding to plas-minogen receptors, fibrinogen, and fibrin (64). Plasma Lp(a) con-centrations are strongly genetically determined by the apo(a)gene, which contains a heritable number of kringle-IV (K-IV)repeats. The number of K-IV repeats is the basis for the apo(a)K-IV repeat polymorphism (65). The molecular weight of apo(a)increases with the number of K-IV repeats, ranging from 300 to800 kDa, and is inversely related to the plasma Lp(a) concentra-tion. Thus, individuals with high molecular weight or large apo(a)isoforms have on average low plasma Lp(a) concentrations,whereas those with low molecular weight or small isoforms usu-

Figure 2. Pathophysiology of hypertriglyceridemia in uremia.Illustration by Josh GramlingGramling Medical Illustration.


ally exhibit high plasma Lp(a) concentrations. Depending on thepopulation under investigation, this association explains between30 and 70% of the variability in plasma Lp(a) levels.

In kidney disease, plasma Lp(a) levels are also influencedby GFR. In patients with large apo(a) isoforms but not thosewith small apo(a) isoforms, plasma Lp(a) levels begin toincrease in stage 1 CKD before GFR starts to decrease (19).This isoform-specific increase in plasma Lp(a) levels wasobserved in several but not all studies in non-nephroticpatients with CKD and HD patients (19,54,66 69). In con-trast, in patients with nephrotic syndrome (70,71) and PDpatients (54), increases in plasma Lp(a) levels occur in allapo(a) isoform groups, probably as a consequence of thepronounced protein loss and a subsequently increased pro-duction in the liver (72). After successful kidney transplan-tation, a decrease in plasma Lp(a) can be regularly observedin HD patients with large apo(a) isoforms (73,74) and in PDpatients with all apo(a) isoform groups (75). Thus, the ele-vation of Lp(a) in CKD is an acquired abnormality, mostlyinfluenced by the degree of proteinuria (19,71) and less bythe cause of kidney disease (54).

In vivo turnover studies using stable-isotope techniques recentlyelucidated the mechanism for the increased plasma Lp(a) levels inHD patients (76). The production rates of apo(a) and apoB, the twoapolipoproteins that are contained in Lp(a), were normal whencompared with control subjects with similar plasma Lp(a) concen-trations (Figure 3). The fractional catabolic rate of these apoli-poproteins, however, was significantly reduced compared withcontrol subjects. This resulted in a much longer residence time inplasma of almost 9 days for apo(a), compared with only 4.4 daysin control subjects. This decreased clearance is likely the result ofloss in kidney function in HD patients (76).

Malnutrition and inflammation have also been associatedwith high plasma Lp(a) levels in HD patients (68,69,77,78). Theelevation of plasma Lp(a), however, can even be observed inpatients with normal plasma C-reactive protein and/or normalplasma amyloid A levels (69). It therefore seems that inflam-mation only modifies Lp(a) concentrations but fails to explainthe apo(a) phenotype-specific elevation of plasma Lp(a).

In summary, the hallmarks of uremic dyslipidemia are hy-pertriglyceridemia; increased remnant lipoproteins (chylomi-cron remnants and IDL); reduced HDL cholesterol; and in-

Figure 3. Kinetic parameters of apolipoprotein B (apoB) in LDL, apoB in IDL, and apolipoprotein(a) [apo(a)] in Lp(a). Theconcentration, production rate, and residence time in plasma are presented for control subjects (light green) and HD patients (darkgreen). Each bar represents mean SEM. Data for LDL and IDL are derived from reference (60); data for Lp(a) are derived fromreference (76). Despite differences in the production rate and residence time, there were no statistically significant differences inplasma concentration of the three lipoprotein particles between HD patients and nonuremic control subjects. Illustration by JoshGramlingGramling Medical Illustration.


creased sdLDL, Lp(a), and apoA-IV. Elevated plasma LDLcholesterol level is not typical but can mostly be observed inpatients with nephrotic syndrome and PD patients.

Epidemiologic Association betweenDyslipidemia and CV Outcome in CKD

In the general population, high plasma concentrations of LDLcholesterol, low concentrations of HDL cholesterol, and to someextent high total triglyceride concentrations are associated withincreased atherosclerotic CV risk (79). In the dialysis populations,the preponderance of the literature, including cross-sectional(35,8082) and longitudinal (2,3,34,69,8390) studies, does notsupport a strong association between dyslipidemia and CVD (Ta-ble 3). This seemingly aberrant relationship may be due, in part, tothe approaches of dyslipidemia assessment. The precise contribu-tions of lipids to atherogenicity should probably be evaluatedlongitudinally using multiple measurements over time, becausethe plasma lipid patterns change substantially as kidney diseaseprogresses, as illustrated by the decline of plasma LDL levels fromthe nephrotic stage to the HD stage. Furthermore, the atherogenicpotential of dyslipidemia in CKD may depend more on the apo-lipoprotein than on lipid abnormalities and may not always berecognized by measurement of plasma lipids alone, as suggestedby Attman and Alaupovic (91). An additional caveat is that, inmany dialysis patients, CVD is caused or accentuated by other riskfactors, such as volume overload, medial calcification, and ar-rhythmogenicity, and may not necessarily be related to atheroscle-rosis.

Total CholesterolIn large administrative databases, the relationship between

plasma total cholesterol and mortality in HD patients has beenfound to be U-shaped (92,93). The group with total cholesterolbetween 200 and 250 mg/dl had the lowest risk for death,whereas those with levels 350 mg/dl had a relative risk of1.3-fold and those with levels 100 mg/dl had a relative risk of4.2-fold. The association between low total cholesterol and in-creased mortality, however, was reduced after statistical adjust-ment for plasma albumin levels. Subgroup analysis providesfurther insights into the potential effects of plasma total cho-lesterol on clinical outcomes. A recent study of 1167 HD pa-tients found that among those with low plasma albumin levels(3.5 to 3.9 g/dl), low plasma total cholesterol levels were alsoassociated with increased all-cause mortality. Among thosewith plasma albumin 4.5 g/dl, however, high plasma totalcholesterol levels were associated with increased mortality (1),as observed in the general population. This dichotomous rela-tionship was confirmed in the Choices for Healthy Outcomes inCaring for ESRD (CHOICE) study (84,94), which showed anonsignificant negative association of cardiovascular mortalitywith plasma total as well as nonHDL cholesterol levels in thepresence of inflammation and/or malnutrition (Figure 4); incontrast, there was a positive association between total andnonHDL cholesterol and mortality in the absence of inflam-mation or malnutrition. These observations are compatible withthe hypothesis that the inverse association of total cholesterollevels with mortality in dialysis patients is mediated by the

cholesterol-lowering effect of malnutrition and/or systemic in-flammation and not due to a protective effect of high choles-terol concentrations.

IDL CholesterolIn observational studies, high plasma IDL cholesterol levels

have been shown to be a risk factor independent of LDL cho-lesterol for coronary artery disease in the general population(95) and may also be a predictor for aortic atherosclerosis in HDpatients (96). As discussed, IDL cholesterol is often elevated inuremia. Unfortunately, the current clinical assays do not differ-entiate between LDL cholesterol and IDL cholesterol. There-fore, current clinical assays may not accurately assess the ath-erosclerotic burden of plasma cholesterol in uremia.

Lp(a) Concentrations and Apo(a) PolymorphismThe association of Lp(a) with atherosclerotic complications has

been investigated in numerous studies in dialysis patients. Theresults were inconsistent in prospective as well as in retrospectivestudies (Table 3) (3,85,97). This inconsistency might have beendue, at least in part, to the nonstandardized assay method forLp(a) in the past. When apo(a) phenotyping was performed inconjunction with plasma Lp(a) concentrations, however, an asso-ciation between the apo(a) K-IV repeat polymorphism and CVcomplications was consistently observed (3,35,85,97104) (Table3). A cross-sectional study in 607 HD patients showed an associ-ation between low molecular weight apo(a) phenotype with his-tory of coronary events (35). Two large prospective studies alsofound a clear association of the apo(a) polymorphism with coro-nary events and total mortality, respectively (3,85,97). Kronenberget al. (3) followed 440 HD patients for 5 yr and found a strongassociation between the low molecular weight apo(a) phenotypeand severe coronary events. In contrast, plasma Lp(a) in thosewith clinical events showed only a trend toward elevated levelsand did not reach statistical significance. Similarly, the CHOICEStudy recently reported small apo(a) isoforms to be associatedwith total mortality in an inception cohort of 800 incident dial-ysis patients who were followed for a median of 33.7 mo (85,97).In that study, Lp(a) concentrations were associated with CVevents (85) but not with total mortality (97).

ApolipoproteinsIn the general population, plasma apoA-IV was reported to

be lower in patients with CVD compared with control subjects,and this association was independent of HDL cholesterol andtriglyceride concentrations (46,47). Similarly, participants in theMild to Moderate Kidney Disease Study with CVD complica-tions also had lower apoA-IV levels than those without (20).More data in various stages of CKD are required to confirmthese findings.

Lipid Management in CKDLimitations of Clinical Lipid Assays in Uremia

In the general population, plasma levels of total, HDL, andLDL cholesterol as well as triglycerides are the parameters thatusually are measured clinically. As discussed, the total andLDL cholesterol levels are often normal in the CKD and HD


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TC

,tot

alch

oles

tero

l.


populations, but there are increased levels of sdLDL, IDL, andmodified (oxidized, glycated, or carbamylated) LDL that arepresumably more atherogenic. Similarly, the clinical assays donot differentiate among LDL and Lp(a) and its low molecularweight isoform, which are independent risk factors for athero-sclerotic disease and are often elevated in CKD. Clinical assaysfor HDL cholesterol also cannot capture the alterations in thedistribution of cholesterol subclasses with different antiathero-genic properties that are observed in CKD.

Recently, the use of nonHDL cholesterol, calculated as totalcholesterol minus HDL cholesterol, was suggested as an alterna-tive (105). NonHDL cholesterol includes and does not distin-guish among LDL cholesterol and subfractions that are consideredto be highly atherogenic, such as Lp(a) and lipoprotein remnantparticles. To date, there are insufficient data to establish the role ofnonHDL cholesterol for atherosclerosis risk assessment.

Drug Therapies for Dyslipidemia in CKDStatins. As in the general population, statins are very ef-

fective in lowering total and LDL cholesterol in uremic patients(12,106). The efficacy of statins in reducing CV events, however,may differ depending on the stage of CKD. In several random-ized, placebo-controlled trials of statins, post hoc analyses ofsubgroups with impaired kidney function have been per-formed (Table 4). In the Pravastatin Pooling Project (10), whichcombined data from three randomized trials, a total of 4991patients with stage 3 CKD were examined. These analysesshowed that 40 mg/d pravastatin was associated with a 23%reduction in the composite outcome of nonfatal myocardialinfarction, coronary mortality, and coronary revascularizationin stage 3 CKD over 5 yr. In a prespecified subgroup analysis of6517 patients with kidney dysfunction in the Anglo-Scandina-vian Cardiac Outcomes Trial (6),10 mg/d atorvastatin signifi-cantly reduced the risk for the primary composite end point of

nonfatal myocardial infarction and cardiac death by 39% over amedian of 3.3 yr. It should be noted that in both studies,individuals with known CVD or high CV risk were recruited;therefore, it is unclear whether these positive results are gen-eralizable to all patients with moderate CKD.

In a retrospective analysis of a registry of 3716 incidentdialysis patients, the use of statins at baseline was associatedwith a significant 36% reduction in CV and 32% reduction inall-cause mortality (107). This study, however, was limited bythe small number of patients who were on statins (n 362) andpossible selection bias. These findings were in general notconfirmed by the Die Deutsche Diabetes-Dialyse (4D) study, arandomized, controlled trial of 1255 HD patients with diabetes(12). In the 4D study, randomization to 20 mg/d atorvastatinresulted in the reduction in plasma LDL cholesterol levels by40%, compared with placebo (12). Despite this difference incholesterol, there were no statistically significant differences(8% reduction) between the groups in the primary compositeend point of cardiac death, stroke, or nonfatal myocardial in-farction. In the atorvastatin group, there was also an 18% de-crease in cardiac events (205 versus 246; P 0.03) but a two-foldincrease in fatal strokes (27 versus 13; P 0.04).

These results, along with the seemingly paradoxic epidemio-logic relationship between plasma cholesterol levels and mortality(12), have been interpreted by some to be rationales for abstainingfrom the use of statins in dialysis patients. Proponents of the useof statins in dialysis patients, however, point out that the 4D Studywas powered only to detect a 27% difference in the primary endpoint and not a more modest effect size of, for example, even 15%.Despite the two-fold increase in fatal stroke in the 4D Study, theabsolute number of events was small, compared with the numberof cardiac events, which seemed to respond favorably to atorva-statin. Moreover, approximately 15% of the patients in the placeboarm received a nonstudy statin, and 15% of the patients whoreceived atorvastatin required a dosage reduction to 10 mg/d.These drop-ins and dropouts might have resulted in the conver-gent trend in plasma LDL cholesterol levels between the twotreatment arms over time. Nonetheless, the time-averaged differ-ence in plasma LDL cholesterol was approximately 0.9 mmol/L,which was similar in magnitude to that observed in many statintrials with more positive clinical outcomes. Many CV events indialysis patients were due to arrhythmia or nonischemic cardio-myopathy, which might not be related to atherosclerosis andcould have diluted the potentially beneficial effects of statins.Finally, even though statins were effective in lowering plasmaLDL cholesterol, they have minimal effects on plasma triglycer-ides and HDL cholesterol and no effects on Lp(a). Because uremicdyslipidemia is characterized by these three components and notelevated LDL cholesterol, lowering of plasma LDL cholesterollevels in uremic patients might not produce substantial clinicalbenefits. Controversies notwithstanding, a reasonable conclusionfrom the 4D Study is that, in dialysis patients without very highplasma LDL cholesterol levels, the effect of statins on clinical outcomeis probably not large, but a modest effect cannot be ruled out.

There are two more large, ongoing, randomized trials usingstatins in patients with CKD. The Study of Heart and RenalProtection (SHARP) examines the effect of lowering plasma

Figure 4. Relative risk for all-cause mortality associated withplasma total cholesterol stratified by the presence or absence ofinflammation and/or malnutrition in the Choices for HealthyOutcomes in Caring for ESRD (CHOICE) study (84). Inflamma-tion and/or malnutrition was defined as the composite of plasmaalbumin 3.6 mg/dl, CRP 10 mg/L or IL-6 3.09 pg/ml (n 634). The remaining 189 patients were free of inflammation andmalnutrition. Illustration by Josh GramlingGramling Medical Illustra-tion.


Tab

le4.

Com

plet

edla

rge

stud

ies

onlip

idm

odif

icat

ion

inpa

tien

tsw

ith

CK

Da

Stud

yD

rug

Des

ign

Pati

ent

Cha

ract

eris

tics

No.

ofPa

tien

tsFo

llow

-Up

HR

(95%

CI)

ofO

utco

mes

Ran

dom

ized

tria

ls4D

(12)

Ato

rvas

tati

n20

mg/

dR

and

omiz

ed,d

oubl

e-bl

ind

,pla

cebo

-co

ntro

lled

,inv

esti

gato

r-in

itia

ted

Typ

e2

dia

bete

son

HD

2

yrw

ith

LD

Lch

oles

tero

l80

to19

0m

g/d

lan

dT

G

1000

mg/

dl

1255

4yr

0.92

(0.7

7to

1.10

)fo

rpr

imar

yen

dpo

int

(car

dia

cd

eath

,st

roke

,or

nonf

atal

MI)

;0.

82(0

.68

to0.

99)

for

seco

ndar

yen

dpo

int

(tot

ald

eath

,all

card

iac

orce

rebr

ovas

cula

rev

ents

)C

AR

E(1

1)Pr

avas

tati

n40

mg/

dP

ost

hoc

subg

roup

anal

ysis

ofin

vest

igat

or-i

niti

ated

,ra

ndom

ized

,dou

ble-

blin

d,p

lace

bo-

cont

rolle

dtr

ial

Prev

ious

MI

wit

hT

C

240

mg/

dl;

subg

roup

anal

ysis

ofpa

tien

tsw

ith

CrC

l

75m

l/m

inbu

tpl

asm

acr

eati

nine

1.

5ti

mes

uppe

rlim

itof

norm

al

1711

59m

o0.

72(0

.55

to0.

95)

for

prim

ary

end

poin

t(c

oron

ary

dea

thor

nonf

atal

MI)

;0.7

2(0

.59

to0.

88)

for

maj

orco

rona

ryev

ents

;0.8

1(0

.61

to1.

08)

for

tota

ld

eath

;0.6

2(0

.39

to1.

00)

for

stro

kePP

P(1

0)Pr

avas

tati

n40

mg/

dP

ost

hoc

subg

roup

anal

ysis

ofpo

oled

dat

afr

omth

ree

rand

omiz

ed,

dou

ble-

blin

d,p

lace

bo-

cont

rolle

dtr

ials

(WO

SCO

PS,C

AR

E,a

ndL

IPID

)

CK

Dst

age

3;W

OSC

OPS

stud

ied

prim

ary

prev

enti

onof

high

-ri

skpa

tien

tsw

ith

high

TC

;C

AR

Ean

dL

IPID

stud

ied

seco

ndar

ypr

even

tion

wit

hav

erag

eT

C

4491

5yr

0.77

(0.6

8to

0.86

)fo

rpr

imar

yen

dpo

int

(MI,

coro

nary

dea

th,o

rco

rona

ryre

vasc

ular

izat

ion)

;0.7

9(0

.71

to0.

88)

for

exte

nded

end

poin

t(p

rim

ary

end

poin

tor

stro

ke);

0.86

(0.7

4to

1.00

)fo

rto

tal

dea

thV

A-H

IT(9

)G

emfi

broz

il12

00m

g/d

Pos

tho

csu

bgro

upan

alys

isof

rand

omiz

ed,d

oubl

e-bl

ind

,pla

cebo

-co

ntro

lled

tria

l

Est

ablis

hed

coro

nary

dis

ease

wit

hH

DL

chol

este

rol

40

mg/

dl,

LD

Lch

oles

tero

l

140

mg/

dl,

and

TG

30

0m

g/d

l;su

bgro

upan

alys

isof

pati

ents

wit

hC

rCl

75

ml/

min

but

plas

ma

crea

tini

ne

2.0

mg/

dl

1046

5.3

yr0.

73(0

.56

to0.

96)

for

prim

ary

end

poin

t(c

oron

ary

dea

thor

nonf

atal

MI)

;0.7

4(0

.58

to0.

95)

for

coro

nary

dea

th,

nonf

atal

MI,

orst

roke

;0.8

5(0

.66

to1.

10)

for

coro

nary

reva

scul

ariz

atio

n;1.

03(0

.78

to1.

35)

for

tota

ld

eath

HPS

(7)

Sim

vast

atin

40m

g/d

Pres

peci

fied

subg

roup

anal

ysis

ofra

ndom

ized

,d

oubl

e-bl

ind

,pla

cebo

-co

ntro

lled

tria

l

Cor

onar

yor

othe

roc

clus

ive

arte

rial

dis

ease

ord

iabe

tes;

plas

ma

crea

tini

ne11

0to

200

m

ol/

Lfo

rw

omen

and

130

to20

0

mol

/L

for

men

1329

5yr

0.78

(sig

nifi

cant

lyd

iffe

rent

)fo

rfi

rst

maj

orva

scul

arev

ent

(inc

lud

ing

coro

nary

even

ts,s

trok

e,an

dre

vasc

ular

izat

ion)

LIP

S(8

)Fl

uvas

tati

n40

mg

twic

ed

aily

Pos

tho

csu

bgro

upan

alys

isof

rand

omiz

ed,p

lace

bo-

cont

rolle

dtr

ial

Aft

erfi

rst

succ

essf

ulpe

rcut

aneo

usco

rona

ryin

terv

enti

on;C

rCl

56

ml/

min

but

plas

ma

crea

tini

ne

1.8

mg/

dl

310

3.8

yr15

%ex

peri

ence

dca

rdia

cd

eath

,MI,

orre

-in

terv

enti

onun

rela

ted

tore

sten

osis

vers

us29

%in

plac

ebo

grou

p(P

0.

004)

ASC

OT

-LL

A(6

)A

torv

asta

tin

10m

g/d

Pres

peci

fied

subg

roup

anal

ysis

ofra

ndom

ized

,d

oubl

e-bl

ind

,pla

cebo

-co

ntro

lled

tria

l

Hyp

erte

nsio

nw

ith

thre

ead

dit

iona

lC

VD

risk

fact

ors,

TC

25

0m

g/d

lan

dpl

asm

acr

eati

nine

20

0

mol

/L

6517

3.3

yr0.

61(0

.44

to0.

84)

for

prim

ary

end

poin

t(n

onfa

tal

MI

orfa

tal

CH

D) (

Tab

leco

ntin

ues)


Tab

le4.

Con

tinu

ed

Hol

daa

set

al.

(5)

Fluv

asta

tin

Pos

tho

csu

bgro

upan

alys

isof

pool

edd

ata

from

30ra

ndom

ized

,dou

ble-

blin

dtr

ials

CrC

l

50m

l/m

in15

636

wk

to6

yr0.

83(0

.63

to1.

09)

for

card

iac

dea

th,n

onfa

tal

MI,

orco

rona

ryin

terv

enti

ons;

0.59

(0.4

0to

0.87

)fo

rca

rdia

cd

eath

orM

I;0.

78(0

.57

to1.

06)

for

tota

ld

eath

;0.8

7(0

.60

to1.

26)

for

nonc

ard

iac

dea

thFe

rram

osca

etal

.(4

)Se

vela

mer

Ran

dom

ized

tria

lco

mpa

ring

seve

lam

eror

calc

ium

acet

ate

Prev

alen

tH

D10

81

yrC

oron

ary

arte

rysc

ore

prog

ress

edsi

gnif

ican

tly

inca

lciu

m-t

reat

edpa

tien

tsbu

tno

tin

seve

lam

er-t

reat

edpa

tien

tsO

bse

rvat

ion

alst

ud

ies

USR

DS

(107

)St

atin

s,fi

brat

esR

etro

spec

tive

anal

ysis

ofex

isti

ngd

atab

ase

All

PDpa

tien

tsan

d20

%ra

ndom

sam

ple

ofal

lH

Dpa

tien

tsin

Uni

ted

Stat

es

3716

(sta

tin

36

2;fi

brat

e

78)

1996

tom

id-1

998

Stat

in:0

.68

(0.5

3to

0.86

)fo

rto

tal

dea

th;0

.63

(0.4

4to

0.91

)fo

rC

VD

dea

thfi

brat

e:1.

29(0

.85

to1.

95)

for

tota

ld

eath

;1.4

1(0

.79

to2.

51)

for

CV

Dd

eath

DO

PPS

(140

)St

atin

sR

etro

spec

tive

anal

ysis

ofex

isti

ngd

atab

ase

Prev

alen

tH

D73

65(s

tati

ns

11.8

%)

Thr

ough

mid

-20

010.

69(0

.60

to0.

79)

for

tota

ld

eath

;0.7

8(0

.62

to0.

98)

for

card

iac

even

ts;0

.77

(0.6

1to

0.97

)fo

rca

rdia

cd

eath

;0.5

6(0

.46

to0.

69)

for

nonc

ard

iac

dea

thW

inke

lmay

eret

al.(

141)

Stat

ins

Ret

rosp

ecti

vean

alys

isof

exis

ting

dat

abas

ePo

st-M

Id

ialy

sis

pati

ents

aged

65

yr49

4(s

tati

n

96)

1yr

0.97

(0.6

5to

1.45

)fo

rto

tal

dea

thG

EN

DIA

N(1

42)

Stat

ins

Pros

pect

ive

Prev

alen

tH

Dw

ith

type

2d

iabe

tes

irre

spec

tive

oflip

idle

vels

445

(sta

tin

12

2)4

yr0.

58(0

.34

to0.

99)

for

tota

ld

eath

aC

HD

,cor

onar

yhe

art

dis

ease

;CI,

conf

iden

cein

terv

al;C

rCl,

crea

tini

necl

eara

nce;

CV

D,c

ard

iova

scul

ard

isea

se;H

D,h

emod

ialy

sis;

HR

,haz

ard

rati

o;PD

,per

iton

eal

dia

lysi

s;4D

,Die

Deu

tsch

eD

iabe

tes-

Dia

lyse

Stud

y;C

AR

E,C

hole

ster

olan

dR

ecur

rent

Eve

nts

Tri

al;P

PP,P

rava

stat

inPo

olin

gPr

ojec

t;V

A-H

IT,V

eter

ans

Aff

airs

HD

LIn

terv

enti

onT

rial

;HPS

,Hea

rtPr

ojec

tion

Stud

y;L

IPS,

Les

col

Inte

rven

tion

Prev

enti

onSt

udy;

ASC

OT

-LL

A,A

nglo

-Sca

ndin

avia

nC

ard

iac

Out

com

esT

rial

:Lip

id-

Low

erin

g;U

SRD

S,U

nite

dSt

ates

Ren

alD

ata

Syst

em;D

OPP

S,D

ialy

sis

Out

com

esan

dPr

acti

cePa

tter

nsSt

udy;

GE

ND

IAN

,Gen

etic

and

Clin

ical

Pred

icto

rsof

Mor

bid

ity,

Mor

talit

y,an

dD

iabe

tic

Nep

hrop

athy

wit

hE

SRD

Ren

alD

isea

sein

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bete

sM

ellit

usT

ype

2.


cholesterol using the combination of simvastatin and ezetimibeon the primary prevention of heart disease and stroke. It aimsto recruit 6000 patients with CKD and plasma creatinine 1.7mg/dl (150 mol/L) in men and 1.5 mg/dl (130 mol/L)in women as well as 3000 patients who are on dialysis (108).There are no lipid inclusion criteria in this trial. The Study toEvaluate the Use of Rosuvastatin in Subjects on Regular He-modialysis: An Assessment of Survival and CardiovascularEvents (AURORA) Study examines the effect of rosuvastatin onthe incidence of heart attacks, strokes, and CV deaths in HDpatients both with and without diabetes, irrespective of base-line lipid levels (109,110).

Some investigators have raised the possibility of increasedincidence of adverse effects that are associated with the use ofstatins (e.g., liver damage and rhabdomyolysis in those withCKD or on dialysis [111,112]). This concern was not substanti-ated by the 4D study (12) and most other large studies (7,10,11).In contrast, the risk for myopathy in patients with CKD seemsto be increased when statins are used in combination withfibrates (113,114).

Fibrates. These agents are effective in reducing plasmatriglyceride concentrations and modestly increasing HDL cho-lesterol concentrations in the general population (115,116). Theuse of gemfibrozil was associated with a 20% reduction in CVevents in those with creatinine clearances of 30 to 75 ml/min(9). There are no data on the effects of fibrates on clinicaloutcomes in patients with CKD or HD patients. Evidence isstrong in support of an increased risk for myopathy that isassociated with this class of drug in patients with advancedGFR impairment (117,118).

Nicotinic Acids and Derivatives. Nicotinic acids may bethe most suitable drug that is available to produce a positiveimpact on uremic dyslipidemia. It is very effective in raisingplasma HDL cholesterol level and is the only drug available tolower plasma Lp(a) substantially (119). It reduces total triglyc-eride levels by 20 to 50% (120); lowers VLDL cholesterol andFFA; and shifts the sdLDL fraction to larger, more buoyantparticles (121). It also lowers plasma LDL cholesterol levels. Theimmediate-release formulations that were marketed earlier,however, were plagued by cutaneous flushing, pruritus, rashes,nausea, and gastrointestinal adverse effects. These adverse ef-fects are less often observed with the newer, extended-releaseformulations and are in many cases transient when they occur.The compliance of patients can be increased by the co-admin-istration of aspirin and gradual dosage escalation that decreasethe adverse effects (for details, see review [122]). In the generalpopulation, nicotinic acid has been shown to improve cardiacand cerebrovascular outcomes (123126). Studies that used nic-otinic acid in patients with CKD were mostly small with shortdurations of follow-up but showed the expected changes inlipid and lipoprotein profiles (122). No studies have examinedthe impact of nicotinic acid on CVD outcomes in patients withCKD or HD patients.

Sevelamer. This metal-free phosphate binder has also beenshown to reduce plasma total and LDL cholesterol concentra-tions by 18 to 22% and 30 to 37%, respectively, by acting as abile acid sequestrant (127). Whether this reduction in choles-

terol contributes to the decreased progression of coronary cal-cification (128) is unclear.

Antioxidants. Dialysis patients are generally in a state ofhigh oxidative stress. A beneficial effect of vitamin E on theoxidative susceptibility of LDL cholesterol in dialysis patientshas been shown (129131). Treatment with -tocopherol alsoresulted in partial normalization of malondialdehyde modifi-cations of LDL cholesterol in dialysis patients (132). Vitamin Emay also exert an additive or synergistic effect with statins. Ina 2 2 study in dialysis patients, treatment with atorvastatinwas found to be effective in lowering plasma total cholesterol,triglycerides, LDL cholesterol, apoB, and ox-LDL levels by 30 to40%, and the addition of -tocopherol to atorvastatin furtherreduced in vitro LDL oxidation (130). The Secondary Preventionwith Antioxidants of Cardiovascular Disease in Endstage RenalDisease (SPACE) trial suggested that vitamin E supplementa-tion lowered the incidence of major CV events in HD patientswithout significantly affecting total mortality (133). To date, theimpact of antioxidants on the clinical outcomes of patients withCKD and dialysis patients is not definitive and needs furtherclinical trials (134).

Other Therapies. When compared with high-flux modi-fied cellulosic membrane, HD using high-flux polysulfonemembranes was associated with a decrease in plasma totaltriglycerides by 10%, cholesterol in remnant particles by 21%,and ox-LDL by 15% (135). The underlying mechanisms of thesedifferences are unclear but might be related to potential differ-ences in dialysis membrane biocompatibility that affect inflam-matory responses and/or differences in the removal of plasmalipase inhibitory molecules.

Antioxidant effects can also be achieved in HD using avitamin Ecoated membrane dialyzer, which results in a sig-nificant reduction in ox-LDL or malondialdehyde-rich LDL andan attenuation of the increase in aortic calcification index after24 months (131). Lipid apheresis is very effective in loweringplasma LDL cholesterol and, depending on the technique, canalso lower plasma Lp(a), triglycerides, and fibrinogen (136).The effects of these extracorporeal therapies on clinical out-comes are uncertain.

Experimental Therapies. A number of novel therapeuticstrategies are in various stages of development for modulatinglipids and lipoproteins, including lipase gene transfer (137),apoA-I(Milano) infusion (138), and short interfering RNA forapoB (139). Although they are not ready for clinical use, thepotency and the specificities of these techniques for abnormal-ities that are characteristics of uremic dyslipidemia representintriguing promises.

ConclusionsThe optimal targets for plasma lipids in patients with CKD

and dialysis patients are unknown. The commonly used clinicalassays to measure triglycerides and total, LDL, and HDL cho-lesterol may not capture the clinically relevant lipid abnormal-ities of uremia, such as elevated Lp(a), IDL cholesterol, modi-fied LDL cholesterol, and alterations in HDL cholesterolsubfractions. Post hoc analyses of large clinical trials support thebeneficial effects of statins in early stages of CKD, whereas


there is a lack of data on the use of statins in stages 4 and 5CKD. Data in patients who are treated by PD as well as innondiabetic HD patients are too sparse to draw any conclusionon these subpopulations. Statins are generally ineffective incorrecting the elevated plasma concentrations of triglyceridesand Lp(a) as well as decreased plasma concentrations of HDLcholesterol, which are the major lipid abnormalities seen inuremia. Although there is a trend toward benefits, the 4D Studydid not provide definitive evidence for statins to improve CVoutcomes in HD patients with diabetes. Nicotinic acid deriva-tives and, to a lesser extent, fibrates may be more suitable totreat uremic dyslipidemia, but there are no studies on theefficacy of these agents to improve CV outcomes in CKD.

Nephrologists and primary care physicians should detectand treat dyslipidemia at early stages of CKD using the guide-lines developed for the general population. A great deal ofresearch is urgently needed to elucidate the relationship be-tween putatively atherogenic lipoproteins and clinical out-comes in advanced CKD. Targeting these lipoproteins may beimportant to decrease CVD in this population.

AcknowledgmentsThis work is partially supported by the US Department of Veterans

Affairs and Department of Medicine at the University of Utah; Depart-ment of Medicine & Therapeutics, The Chinese University of HongKong; Department of Medical Genetics, Molecular and Clinical Phar-macology at Innsbruck Medical University; and Genomics of Lipid-associated DisordersGOLD of the Austrian Genome Research Pro-gramme GEN-AU.

We thank Hans Dieplinger, Innsbruck Medical University, for criticalreading of the manuscript.

DisclosuresNone.

References1. Iseki K, Yamazato M, Tozawa M, Takishita S: Hypocholes-

terolemia is a significant predictor of death in a cohort ofchronic hemodialysis patients. Kidney Int 61: 18871893,2002

2. Degoulet P, Legrain M, Reach I, Aime F, Devries C, RojasP, Jacobs C: Mortality risk factors in patients treated bychronic hemodialysis. Report of the Diaphane collabora-tive study. Nephron 31: 103110, 1982

3. Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, AuingerM, Pribasnig A, Meisl T, Konig P, Dieplinger H: The lowmolecular weight apo(a) phenotype is an independent pre-dictor for coronary artery disease in hemodialysis patients: Aprospective follow-up. J Am Soc Nephrol 10: 10271036, 1999

4. Ferramosca E, Burke S, Chasan-Taber S, Ratti C, ChertowGM, Raggi P: Potential antiatherogenic and anti-inflamma-tory properties of sevelamer in maintenance hemodialysispatients. Am Heart J 149: 820825, 2005

5. Holdaas H, Wanner C, Abletshauser C, Gimpelewicz C,Isaacsohn J: The effect of fluvastatin on cardiac outcomesin patients with moderate to severe renal insufficiency: Apooled analysis of double-blind, randomized trials. IntJ Cardiol August 2, 2006 [epub ahead of print]

6. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G,

Caulfield M, Collins R, Kjeldsen SE, Kristinsson A,McInnes GT, Mehlsen J, Nieminen M, OBrien E, OstergrenJ: Prevention of coronary and stroke events with atorva-statin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes TrialLipid LoweringArm (ASCOT-LLA): A multicentre randomised controlledtrial. Lancet 361: 11491158, 2003

7. MRC/BHF Heart Protection Study of cholesterol loweringwith simvastatin in 20,536 high-risk individuals: A ran-domised placebo-controlled trial. Lancet 360: 722, 2002

8. Lemos PA, Serruys PW, de Feyter P, Mercado NF,Goedhart D, Saia F, Arampatzis CA, Soares PR, Ciccone M,Arquati M, Cortellaro M, Rutsch W, Legrand V: Long-termfluvastatin reduces the hazardous effect of renal impair-ment on four-year atherosclerotic outcomes (a LIPS sub-study). Am J Cardiol 95: 445451, 2005

9. Tonelli M, Collins D, Robins S, Bloomfield H, Curhan GC:Gemfibrozil for secondary prevention of cardiovascularevents in mild to moderate chronic renal insufficiency.Kidney Int 66: 11231130, 2004

10. Tonelli M, Isles C, Curhan GC, Tonkin A, Pfeffer MA,Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J,Craven T, West M: Effect of pravastatin on cardiovascularevents in people with chronic kidney disease. Circulation110: 15571563, 2004

11. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G: Prav-astatin for secondary prevention of cardiovascular eventsin persons with mild chronic renal insufficiency. Ann In-tern Med 138: 98104, 2003

12. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G,Ritz E: Atorvastatin in patients with type 2 diabetes mellitusundergoing hemodialysis. N Engl J Med 353: 238248, 2005

13. Eisenberg S, Bilheimer DW, Levy RI, Lindgren FT: On themetabolic conversion of human plasma very low densitylipoprotein to low density lipoprotein. Biochim Biophys Acta326: 361377, 1973

14. Brown MS, Goldstein JL: Lipoprotein metabolism in themacrophage: Implications for cholesterol deposition in ath-erosclerosis. Annu Rev Biochem 52: 223261, 1983

15. Austin MA, King MC, Vranizan KM, Krauss RM: Atherogeniclipoprotein phenotype. A proposed genetic marker for coronaryheart disease risk. Circulation 82: 495506, 1990

16. Bruce C, Chouinard RA Jr, Tall AR: Plasma lipid transferproteins, high-density lipoproteins, and reverse cholesteroltransport. Annu Rev Nutr 18: 297330, 1998

17. Dieplinger H, Zechner R, Kostner GM: The in vitro forma-tion of HDL2 during the action of LCAT: The role oftriglyceride-rich lipoproteins. J Lipid Res 26: 273282, 1985

18. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, KriegerM: Identification of scavenger receptor SR-BI as a high den-sity lipoprotein receptor. Science 271: 518520, 1996

19. Kronenberg F, Kuen E, Ritz E, Junker R, Konig P, Kraatz G,Lhotta K, Mann JF, Muller GA, Neyer U, Riegel W, Reigler P,Schwenger V, Von Eckardstein A: Lipoprotein(a) serum con-centrations and apolipoprotein(a) phenotypes in mild andmoderate renal failure. J Am Soc Nephrol 11: 105115, 2000

20. Kronenberg F, Kuen E, Ritz E, Konig P, Kraatz G, Lhotta K,Mann JF, Muller GA, Neyer U, Riegel W, Riegler P, Sch-wenger V, von Eckardstein A: Apolipoprotein A-IV serumconcentrations are elevated in patients with mild and mod-erate renal failure. J Am Soc Nephrol 13: 461469, 2002


21. Krentz AJ: Lipoprotein abnormalities and their conse-quences for patients with type 2 diabetes. Diabetes ObesMetab 5[Suppl 1]: S19S27, 2003

22. Kronenberg F: Dyslipidemia and nephrotic syndrome: Re-cent advances. J Ren Nutr 15: 195203, 2005

23. Savdie E, Gibson JC, Crawford GA, Simons LA, MahonyJF: Impaired plasma triglyceride clearance as a feature ofboth uremic and posttransplant triglyceridemia. Kidney Int18: 774782, 1980

24. Batista MC, Welty FK, Diffenderfer MR, Sarnak MJ,Schaefer EJ, Lamon-Fava S, Asztalos BF, Dolnikowski GG,Brousseau ME, Marsh JB: Apolipoprotein A-I, B-100, andB-48 metabolism in subjects with chronic kidney disease,obesity, and the metabolic syndrome. Metabolism 53: 12551261, 2004

25. Cattran DC, Fenton SS, Wilson DR, Steiner G: Defectivetriglyceride removal in lipemia associated with peritonealdialysis and haemodialysis. Ann Intern Med 85: 2933, 1976

26. Appel G: Lipid abnormalities in renal disease. Kidney Int39: 169183, 1991

27. Arnadottir M: Pathogenesis of dyslipoproteinemia in renalinsufficiency: The role of lipoprotein lipase and hepaticlipase. Scand J Clin Lab Invest 57: 111, 1997

28. Senti M, Romero R, Pedro-Botet J, Pelegri A, Nogues X,Rubies-Prat J: Lipoprotein abnormalities in hyperlipidemicand normolipidemic men on hemodialysis with chronicrenal failure. Kidney Int 41: 13941399, 1992

29. Cryer A: Tissue lipoprotein lipase activity and its action inlipoprotein metabolism. Int J Biochem 13: 525541, 1981

30. Brown MS, Goldstein JL: A receptor-mediated pathway forcholesterol homeostasis. Science 232: 3447, 1986

31. McNamara JR, Shah PK, Nakajima K, Cupples LA, WilsonPW, Ordovas JM, Schaefer EJ: Remnant-like particle (RLP)cholesterol is an independent cardiovascular disease riskfactor in women: results from the Framingham HeartStudy. Atherosclerosis 154: 229236, 2001

32. Leary ET, Wang T, Baker DJ, Cilla DD, Zhong J, WarnickGR, Nakajima K, Havel RJ: Evaluation of an immunosepa-ration method for quantitative measurement of remnant-like particle-cholesterol in serum and plasma. Clin Chem 44:24902498, 1998

33. Cheung AK, Wu LL, Kablitz C, Leypoldt JK: Atherogeniclipids and lipoproteins in hemodialysis patients. Am J Kid-ney Dis 22: 271276, 1993

34. Cressman MD, Heyka RJ, Paganini EP, ONeil J, SkibinskiCI, Hoff HF: Lipoprotein(a) is an independent risk factorfor cardiovascular disease in hemodialysis patients. Circu-lation 86: 475482, 1992

35. Koch M, Kutkuhn B, Trenkwalder E, Bach D, Grabensee B,Dieplinger H, Kronenberg F: Apolipoprotein B, fibrinogen,HDL cholesterol, and apolipoprotein(a) phenotypes pre-dict coronary artery disease in hemodialysis patients. J AmSoc Nephrol 8: 18891898, 1997

36. Dantoine TF, Debord J, Charmes JP, Merle L, Marquet P,Lachatre G, Leroux-Robert C: Decrease of serum paraoxo-nase activity in chronic renal failure. J Am Soc Nephrol 9:20822088, 1998

37. Navab M, Hama SY, Reddy ST, Ng CJ, Van Lenten BJ, LaksH, Fogelman AM: Oxidized lipids as mediators of coro-nary heart disease. Curr Opin Lipidol 13: 363372, 2002

38. Solakivi T, Jaakkola O, Salomaki A, Peltonen N, Metso S,Lehtimaki T, Jokela H, Nikkari ST: HDL enhances oxida-

tion of LDL in vitro in both men and women. Lipids HealthDis 4: 25, 2005

39. Steinmetz A, Barbaras R, Ghalim N, Clavey V, Fruchart JC,Ailhaud G: Human apolipoprotein A-IV binds to apoli-poprotein A-I/A-II receptor sites and promotes cholesterolefflux from adipose cells. J Biol Chem 265: 78597863, 1990

40. Stein O, Stein Y, Lefevre M, Roheim PS: The role of apoli-poprotein A-IV in reverse cholesterol transport studiedwith cultured cells and liposomes derived from an etheranalog of phosphatidylcholine. Biochim Biophys Acta 878:713, 1986

41. Dvorin E, Gorder NL, Benson DM, Gotto AM Jr: Apoli-poprotein A-IV. A determinant for binding and uptake ofhigh-density lipoproteins by rat hepatocytes. J Biol Chem261: 1571415718, 1986

42. Chen CH, Albers JJ: Activation of lecithin: cholesterol acyl-transferase by apolipoproteins E-2, E-3, and A-IV isolatedfrom human plasma. Biochim Biophys Acta 836: 279285, 1985

43. Steinmetz A, Utermann G: Activation of lecithin: Choles-terol acyltransferase by human apolipoprotein A-IV. J BiolChem 260: 22582264, 1985

44. Goldberg IJ, Scheraldi CA, Yacoub LK, Saxena U, BisgaierCL: Lipoprotein ApoC-II activation of lipoprotein lipase.Modulation by apolipoprotein A-IV. J Biol Chem 265: 42664272, 1990

45. Guyard-Dangremont V, Lagrost L, Gambert P: Compara-tive effects of purified apolipoproteins A-I, A-II, and A-IVon cholesteryl ester transfer protein activity. J Lipid Res 35:982992, 1994

46. Kronenberg F, Stuhlinger M, Trenkwalder E, GeethanjaliFS, Pachinger O, von Eckardstein A, Dieplinger H: Lowapolipoprotein A-IV plasma concentrations in men withcoronary artery disease. J Am Coll Cardiol 36: 751757, 2000

47. Warner MM, Guo J, Zhao Y: The relationship betweenplasma apolipoprotein A-IV levels and coronary heart dis-ease. Chin Med J (Engl) 114: 275279, 2001

48. Boes E, Fliser D, Ritz E, Konig P, Lhotta K, Mann JF, MullerGA, Neyer U, Riegel W, Riegler P, Kronenberg F: Apoli-poprotein A-IV predicts progression of chronic kidney dis-ease: The mild to moderate kidney disease study. J Am SocNephrol 17: 528536, 2006

49. Lingenhel A, Lhotta K, Neyer U, Heid IM, Rantner B,Kronenberg MF, Konig P, von Eckardstein A, Schober M,Dieplinger H, Kronenberg F: Role of the kidney in themetabolism of apolipoprotein A-IV: Influence of the typeof proteinuria. J Lipid Res 47: 20712079, 2006

50. Haiman M, Salvenmoser W, Scheiber K, Lingenhel A,Rudolph C, Schmitz G, Kronenberg F, Dieplinger H: Im-munohistochemical localization of apolipoprotein A-IV inhuman kidney tissue. Kidney Int 68: 11301136, 2005

51. Nestel PJ, Fidge NH, Tan MH: Increased lipoprotein-rem-nant formation in chronic renal failure. N Engl J Med 307:329333, 1982

52. Seishima M, Muto Y: An increased apo A-IV serum con-centration of patients with chronic renal failure on hemo-dialysis. Clin Chim Acta 167: 303311, 1987

53. Dieplinger H, Lobentanz EM, Konig P, Graf H, SandholzerC, Matthys E, Rosseneu M, Utermann G: Plasma apoli-poprotein A-IV metabolism in patients with chronic renaldisease. Eur J Clin Invest 22: 166174, 1992

54. Kronenberg F, Konig P, Neyer U, Auinger M, Pribasnig A,Lang U, Reitinger J, Pinter G, Utermann G, Dieplinger H:


Multicenter study of lipoprotein(a) and apolipoprotein(a)phenotypes in patients with end-stage renal disease treatedby hemodialysis or continuous ambulatory peritoneal di-alysis. J Am Soc Nephrol 6: 110120, 1995

55. Oi K, Hirano T, Sakai S, Kawaguchi Y, Hosoya T: Role ofhepatic lipase in intermediate-density lipoprotein andsmall, dense low-density lipoprotein formation in hemodi-alysis patients. Kidney Int Suppl 71: S227S228, 1999

56. Littlewood TD, Bennett MR: Apoptotic cell death in ath-erosclerosis. Curr Opin Lipidol 14: 469475, 2003

57. Stoneman VE, Bennett MR: Role of apoptosis in atheroscle-rosis and its therapeutic implications. Clin Sci (Lond) 107:343354, 2004

58. Kolodgie FD, Narula J, Haider N, Virmani R: Apoptosis inatherosclerosis. Does it contribute to plaque instability?Cardiol Clin 19: 127139, ix, 2001

59. Best PJ, Hasdai D, Sangiorgi G, Schwartz RS, Holmes DRJr, Simari RD, Lerman A: Apoptosis. Basic concepts andimplications in coronary artery disease. Arterioscler ThrombVasc Biol 19: 1422, 1999

60. Ikewaki K, Schaefer JR, Frischmann ME, Okubo K, HosoyaT, Mochizuki S, Dieplinger B, Trenkwalder E, Schweer H,Kronenberg F, Koenig P, Dieplinger H: Delayed in vivocatabolism of intermediate-density lipoprotein and low-density lipoprotein in hemodialysis patients as potentialcause of premature atherosclerosis. Arterioscler ThrombVasc Biol 25: 26152622, 2005

61. Moore KJ, Freeman MW: Scavenger receptors in athero-sclerosis: Beyond lipid uptake. Arterioscler Thromb Vasc Biol26: 17021711, 2006

62. Craig WY, Neveux LM, Palomaki GE, Cleveland MM,Haddow JE: Lipoprotein(a) as a risk factor for ischemicheart disease: Metaanalysis of prospective studies. ClinChem 44: 23012306, 1998

63. Dieplinger H, Kronenberg F: Genetics and metabolism oflipoprotein(a) and their clinical implications (Part 1). WienKlin Wochenschr 111: 520, 1999

64. Harpel PC, Gordon BR, Parker TS: Plasmin catalyzes bind-ing of lipoprotein (a) to immobilized fibrinogen and fibrin.Proc Natl Acad Sci U S A 86: 38473851, 1989

65. Utermann G: Lipoprotein(a). In: The Metabolic & MolecularBases of Inherited Disease, 8th Ed., edited by Scriver CR,Beaudet AL, Sly WS, Valle D, New York, McGraw-Hill,2000, pp 27532787

66. Dieplinger H, Lackner C, Kronenberg F, Sandholzer C,Lhotta K, Hoppichler F, Graf H, Konig P: Elevated plasmaconcentrations of lipoprotein(a) in patients with end-stagerenal disease are not related to the size polymorphism ofapolipoprotein(a). J Clin Invest 91: 397401, 1993

67. Milionis HJ, Elisaf MS, Tselepis A, Bairaktari E, KarabinaSA, Siamopoulos KC: Apolipoprotein(a) phenotypes andlipoprotein(a) concentrations in patients with renal failure.Am J Kidney Dis 33: 11001106, 1999

68. Stenvinkel P, Heimburger O, Tuck CH, Berglund L: Apo(a)-isoform size, nutritional status and inflammatory markers inchronic renal failure. Kidney Int 53: 13361342, 1998

69. Zimmermann J, Herrlinger S, Pruy A, Metzger T, WannerC: Inflammation enhances cardiovascular risk and mortal-ity in hemodialysis patients. Kidney Int 55: 648658, 1999

70. Wanner C, Rader D, Bartens W, Kramer J, Brewer HB,Schollmeyer P, Wieland H: Elevated plasma lipoprotein(a)

in patients with the nephrotic syndrome. Ann Intern Med119: 263269, 1993

71. Kronenberg F, Lingenhel A, Lhotta K, Rantner B, KronenbergMF, Konig P, Thiery J, Koch M, von Eckardstein A, DieplingerH: The apolipoprotein(a) size polymorphism is associated withnephrotic syndrome. Kidney Int 65: 606612, 2004

72. De Sain-Van Der Velden MG, Reijngoud DJ, Kaysen GA,Gadellaa MM, Voorbij H, Stellaard F, Koomans HA, Ra-belink TJ: Evidence for increased synthesis of lipopro-tein(a) in the nephrotic syndrome. J Am Soc Nephrol 9:14741481, 1998

73. Kronenberg F, Konig P, Lhotta K, Ofner D, Sandholzer C,Margreiter R, Dosch E, Utermann G, Dieplinger H: Apoli-poprotein(a) phenotype-associated decrease in lipopro-tein(a) plasma concentrations after renal transplantation.Arterioscler Thromb 14: 13991404, 1994

74. Kronenberg F, Lhotta K, Konig P, Margreiter R, DieplingerH, Utermann G: Apolipoprotein(a) isoform-specificchanges of lipoprotein(a) after kidney transplantation. EurJ Hum Genet 11: 693699, 2003

75. Kerschdorfer L, Konig P, Neyer U, Bosmuller C, Lhotta K,Auinger M, Hohenegger M, Riegler P, Margreiter R, Uter-mann G, Dieplinger H, Kronenberg F: Lipoprotein(a)plasma concentrations after renal transplantation: A pro-spective evaluation after 4 years of follow-up. Atheroscle-rosis 144: 381391, 1999

76. Frischmann KE, Kronenberg F, Trenkwalder E, Schafer J,Schweer H, Dieplinger B, Konig P, Ikewaki K, DieplingerH: In vivo turnover study demonstrates diminished clear-ance of lipoprotein(a) in hemodialysis patients. Kidney Int2007, in press

77. Kang DH, Yoon KI, Lee SW, Kang SW, Choi KH, Lee HY,Han DS: Impact of nutritional status on serum lipopro-tein(a) concentration in patients undergoing continuousambulatory peritoneal dialysis. Perit Dial Int 16[Suppl 1]:S241S245, 1996

78. Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U,Wang T, Berglund L, Jogestrand T: Strong association be-tween malnutrition, inflammation, and atherosclerosis inchronic renal failure. Kidney Int 55: 18991911, 1999

79. Wilson PW, DAgostino RB, Levy D, Belanger AM, Silber-shatz H, Kannel WB: Prediction of coronary heart diseaseusing risk factor categories. Circulation 97: 18371847, 1998

80. Stack AG, Bloembergen WE: Prevalence and clinical corre-lates of coronary artery disease among new dialysis pa-tients in the United States: A cross-sectional study. J AmSoc Nephrol 12: 15161523, 2001

81. Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, RoccoMV, Teehan BP, Levey AS: Atherosclerotic cardiovasculardisease risks in chronic hemodialysis patients. Kidney Int58: 353362, 2000

82. Guz G, Nurhan Ozdemir F, Sezer S, Isiklar I, Arat Z, TuranM, Haberal M: Effect of apolipoprotein E polymorphismon serum lipid, lipoproteins, and atherosclerosis in hemo-dialysis patients. Am J Kidney Dis 36: 826836, 2000

83. Iseki K, Fukiyama K: Predictors of stroke in patients receivingchronic hemodialysis. Kidney Int 50: 16721675, 1996

84. Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, FinkNE, Tracy RP, Powe NR, Klag MJ: Association betweencholesterol level and mortality in dialysis patients: Role ofinflammation and malnutrition. JAMA 291: 451459, 2004

85. Longenecker JC, Klag MJ, Marcovina SM, Liu YM, Jaar BG,


Powe NR, Fink NE, Levey AS, Coresh J: High lipopro-tein(a) levels and small apolipoprotein(a) size prospec-tively predict cardiovascular events in dialysis patients.J Am Soc Nephrol 16: 17941802, 2005

86. Koda Y, Nishi S, Suzuki M, Hirasawa Y: Lipoprotein(a) isa predictor for cardiovascular mortality of hemodialysispatients. Kidney Int Suppl 71: S251S253, 1999

87. Ohashi H, Oda H, Ohno M, Watanabe S, Sakata S: Lipopro-tein(a) as a risk factor for coronary artery disease in hemo-dialysis patients. Kidney Int Suppl 71: S242S244, 1999

88. Shoji T, Emoto M, Shinohara K, Kakiya R, Tsujimoto Y, Kishi-moto H, Ishimura E, Tabata T, Nishizawa Y: Diabetes mellitus,aortic stiffness, and cardiovascular mortality in end-stage renaldisease. J Am Soc Nephrol 12: 21172124, 2001

89. Hocher B, Ziebig R, Altermann C, Krause R, Asmus G,Richter CM, Slowinski T, Sinha P, Neumayer HH: Differ-ent impact of biomarkers as mortality predictors amongdiabetic and nondiabetic patients undergoing hemodialy-sis. J Am Soc Nephrol 14: 23292337, 2003

90. Schwaiger JP, Lamina C, Neyer U, Konig P, Kathrein H,Sturm W, Lhotta K, Grochenig E, Dieplinger H, Kronen-berg F: Carotid plaques and their predictive value forcardiovascular disease and all-cause mortality in hemodi-alysis patients considering renal transplantation: A decadefollow-up. Am J Kidney Dis 47: 888897, 2006

91. Attman PO, Alaupovic P: Lipid and apolipoprotein pro-files of uremic dyslipoproteinemia: Relation to renal func-tion and dialysis. Nephron 57: 401410, 1991

92. Lowrie EG, Lew NL: Commonly measured laboratory vari-ables in hemodialysis patients: Relationships among themand to death risk. Semin Nephrol 12: 276283, 1992

93. Lowrie EG, Lew NL: Death risk in hemodialysis patients:The predictive value of commonly measured variables andan evaluation of death rate differences between facilities.Am J Kidney Dis 15: 458482, 1990

94. Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, MartinA, Klag MJ: Traditional cardiovascular disease risk factors indialysis patients compared with the general population: TheCHOICE Study. J Am Soc Nephrol 13: 19181927, 2002

95. Tatami R, Mabuchi H, Ueda K, Ueda R, Haba T, KametaniT, Ito S, Koizumi J, Ohta M, Miyamoto S, Nakayama A,Kanaya H, Oiwake H, Genda A, Takeda R: Intermediate-density lipoprotein and cholesterol-rich very low densitylipoprotein in angiographically determined coronary ar-tery disease. Circulation 64: 11741184, 1981

96. Shoji T, Nishizawa Y, Kawagishi T, Kawasaki K, TaniwakiH, Tabata T, Inoue T, Morii H: Intermediate-density li-poprotein as an independent risk factor for aortic athero-sclerosis in hemodialysis patients. J Am Soc Nephrol 9:12771284, 1998

97. Longenecker JC, Klag MJ, Marcovina SM, Powe NR, FinkNE, Giaculli F, Coresh J: Small apolipoprotein(a) size pre-dicts mortality in end-stage renal disease: The CHOICEstudy. Circulation 106: 28122818, 2002

98. Auguet T, Senti M, Rubies-Prat J, Pelegri A, Pedro-Botet J,Nogues X, Romero R: Serum lipoprotein(a) concentrationin patients with chronic renal failure receiving haemodi-alysis: Influence of apolipoprotein (a) genetic polymor-phism. Nephrol Dial Transplant 8: 10991103, 1993

99. Kronenberg F, Kathrein H, Konig P, Neyer U, Sturm W,Lhotta K, Grochenig E, Utermann G, Dieplinger H: Apoli-poprotein(a) phenotypes predict the risk for carotid ath-

erosclerosis in patients with end-stage renal disease. Arte-rioscler Thromb 14: 14051411, 1994

100. Wanner C, Bartens W, Walz G, Nauck M, Schollmeyer P:Protein loss and genetic polymorphism of apolipopro-tein(a) modulate serum lipoprotein(a) in CAPD patients.Nephrol Dial Transplant 10: 7581, 1995

101. Emanuele E, Lusignani LS, Peros E, Montagna G,DAngelo A, Montagna L, Geroldi D: Lipoprotein(a)-asso-ciated atherothrombotic risk in hemodialysis patients. Am JNephrol 24: 221229, 2004

102. Iliescu EA, Marcovina SM, Morton AR, Lam M, Koschinsky ML:Apolipoprotein(a) phenotype and lipoprotein(a) level predictperitoneal dialysis patient mortality. Perit Dial Int 22: 492499,2002

103. Webb AT, Reaveley DA, ODonnell M, OConnor B, SeedM, Brown EA: Lipids and lipoprotein(a) as risk factors forvascular disease in patients on renal replacement therapy.Nephrol Dial Transplant 10: 354357, 1995

104. Gazzaruso C, Bonetti G, Garzaniti A, Pini G, Ragazzoni A,Bianchi C, Jucci A, Buscaglia P, Geroldi D: Increasedplasma concentrations of lipoprotein(a) for every pheno-type of apolipoprotein(a) in patients with chronic renalfailure treated by hemodialysis. Nutr Metab Cardiovasc Dis6: 203210, 1996

105. K/DOQI clinical practice guidelines for management ofdyslipidemias in patients with kidney disease. Am J KidneyDis 41: S1S91, 2003

106. Lins RL, Matthys KE, Billiouw JM, Dratwa M, Dupont P,Lameire NH, Peeters PC, Stolear JC, Tielemans C, Maes B,Verpooten GA, Ducobu J, Carpentier YA: Lipid and apo-protein changes during atorvastatin up-titration in hemo-dialysis patients with hypercholesterolemia: A placebo-controlled study. Clin Nephrol 62: 287294, 2004

107. Seliger SL, Weiss NS, Gillen DL, Kestenbaum B, Ball A,Sherrard DJ, Stehman-Breen CO: HMG-CoA reductase in-hibitors are associated with reduced mortality in ESRDpatients. Kidney Int 61: 297304, 2002

108. Baigent C, Landry M: Study of Heart and Renal Protection(SHARP). Kidney Int Suppl S207S210, 2003

109. Fellstrom B, Zannad F, Schmieder R, Holdaas H, Jardine A, RoseH, Wilpshaar W: Effect of rosuvastatin on outcomes in chronichaemodialysis patients: Design and rationale of the AURORAstudy. Curr Control Trials Cardiovasc Med 6: 9, 2005

110. Fellstrom BC, Holdaas H, Jardine AG: Why do we need a statintrial in hemodialysis patients? Kidney Int Suppl S204S206, 2003

111. Schech S, Graham D, Staffa J, Andrade SE, Grenade LL,Burgess M, Blough D, Stergachis A, Chan KA, Platt R,Shatin D: Risk factors for statin-associated rhabdomyoly-sis. Pharmacoepidemiol Drug Saf 16: 352358, 2006

112. Thompson PD, Clarkson P, Karas RH: Statin-associatedmyopathy. JAMA 289: 16811690, 2003

113. Ballantyne CM, Corsini A, Davidson MH, Holdaas H,Jacobson TA, Leitersdorf E, Marz W, Reckless JP, Stein EA:Risk for myopathy with statin therapy in high-risk pa-tients. Arch Intern Med 163: 553564, 2003

114. Shek A, Ferrill MJ: Statin-fibrate combination therapy. AnnPharmacother 35: 908917, 2001

115. Knopp RH, Brown WV, Dujovne CA, Farquhar JW,Feldman EB, Goldberg AC, Grundy SM, Lasser NL, Mel-lies MJ, Palmer RH, et al.: Effects of fenofibrate on plasmalipoproteins in hypercholesterolemia and combined hyper-lipidemia. Am J Med 83: 5059, 1987


116. Grundy SM, Vega GL: Fibric acids: Effects on lipids andlipoprotein metabolism. Am J Med 83: 920, 1987

117. Knopp RH: Drug treatment of lipid disorders. N Engl J Med341: 498511, 1999

118. Schonfeld G: The effects of fibrates on lipoprotein and hemo-static coronary risk factors. Atherosclerosis 111: 161174, 1994

119. Carlson LA, Hamsten A, Asplund A: Pronounced lowering ofserum levels of lipoprotein Lp(a) in hyperlipidaemic subjectstreated with nicotinic acid. J Intern Med 226: 271276, 1989

120. McKenney J: New perspectives on the use of niacin in thetreatment of lipid disorders. Arch Intern Med 164: 697705,2004

121. Superko HR, Krauss RM: Differential effects of nicotinicacid in subjects with different LDL subclass patterns. Ath-erosclerosis 95: 6976, 1992

122. Kronenberg F: Epidemiology, pathophysiology and thera-peutic implications of lipoprotein(a) in kidney disease. Ex-pert Rev Cardiovasc Ther 2: 729743, 2004

123. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA:Arterial Biology for the Investigation of the TreatmentEffects of Reducing Cholesterol (ARBITER) 2: A double-blind, placebo-controlled study of extended-release niacinon atherosclerosis progression in secondary prevention pa-tients treated with statins. Circulation 110: 35123517, 2004

124. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L,Prineas RJ, Friedewald W: Fifteen year mortality in Coro-nary Drug Project patients: Long-term benefit with niacin.J Am Coll Cardiol 8: 12451255, 1986

125. Carlson LA, Rosenhamer G: Reduction of mortality in theStockholm Ischaemic Heart Disease Secondary PreventionStudy by combined treatment with clofibrate and nicotinicacid. Acta Med Scand 223: 405418, 1988

126. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC,Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P,Frohlich J, Albers JJ: Simvastatin and niacin, antioxidantvitamins, or the combination for the prevention of coro-nary disease. N Engl J Med 345: 15831592, 2001

127. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates theprogression of coronary and aortic calcification in hemo-dialysis patients. Kidney Int 62: 245252, 2002

128. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J,Dreisbach A, Raggi P: Effects of sevelamer and calcium oncoronary artery calcification in patients new to hemodial-ysis. Kidney Int 68: 18151824, 2005

129. Islam KN, OByrne D, Devaraj S, Palmer B, Gr

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