lipoprotein metabolism and lipid management in chronic...
TRANSCRIPT
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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
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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
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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.
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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.
J Am Soc Nephrol 18: 12461261, 2007 Lipids in CKD 1249
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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.
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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
J Am Soc Nephrol 18: 12461261, 2007 Lipids in CKD 1251
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Tab
le3.
Ass
ocia
tion
ofd
yslip
idem
iaan
dcl
inic
alou
tcom
esin
dia
lysi
spa
tien
tsa
Stud
ybN
Out
com
eH
igh
TCH
igh
LDL
Cho
lest
erol
Low
HD
LC
hole
ster
olH
igh
TGH
igh
Lp(a
)
LMW
Apo
(a)
Isof
orm
s
Long
itudi
nals
tudi
esIs
ekie
tal.,
1996
(83)
1491
Inci
dent
stro
ke7
7D
egou
lete
tal.,
1982
(2)
1453
Car
diov
ascu
lar
and
all-c
ause
mor
talit
y2
7
CH
OIC
ESt
udy
(84,
85)
833
Car
diov
ascu
lar
and
all-c
ause
mor
talit
y2
inpr
esen
ceof
infla
mm
atio
n/m
alnu
triti
on;1
inab
senc
eof
infla
mm
atio
n/m
alnu
triti
onC
HO
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Stud
y(8
4,85
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cide
ntfa
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hero
scle
rotic
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ents
11
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.,19
99(3
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ents
77
27
71
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al.,
(86)
390
Car
diov
ascu
lar
mor
talit
y1
Zim
mer
man
net
al.,
1999
(69)
280
Car
diov
ascu
lar
and
all-c
ause
mor
talit
y7
77
77
Oha
shie
tal.,
1999
(87)
268
Car
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lar
mor
talit
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71
Shoj
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5C
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7
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.,20
03(8
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5C
ardi
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dal
l-cau
sem
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72
7
Schw
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al.,
2006
(90)
165
Car
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even
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77
77
1
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.,19
92(3
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rotic
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77
77
1
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7
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al.,
1997
(35)
607
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tory
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50
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ryar
tery
sten
osis
77
27
71
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ung
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ory
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vasc
ular
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ts7
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00(8
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9C
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tery
intim
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edia
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77
77
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77
72
771
1
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res
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sed
(1),
unch
ange
d(7
)or
dec
reas
ed(2
)as
soci
ated
wit
hth
ein
dic
ated
dys
lipid
emia
.LM
W,l
owm
olec
ular
wei
ght;
TC
,tot
alch
oles
tero
l.
1252 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 12461261, 2007
-
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.
J Am Soc Nephrol 18: 12461261, 2007 Lipids in CKD 1253
-
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)
1254 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 12461261, 2007
-
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
Dia
bete
sM
ellit
usT
ype
2.
J Am Soc Nephrol 18: 12461261, 2007 Lipids in CKD 1255
-
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
1256 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 12461261, 2007
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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.
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