Disease of the Month

Lipoprotein Metabolism and Lipid Management in Chronic Kidney Disease

Bonnie C.H. Kwan, Florian Kronenberg, Srinivasan Beddhu and Alfred K. Cheung
JASN April 2007, 18 (4) 1246-1261; DOI: https://doi.org/10.1681/ASN.2006091006

Dyslipidemia is an established cardiovascular (CV) risk factor in the general population. In chronic kidney disease (CKD), however, epidemiologic studies (1–3) and clinical trials (4–12) have raised uncertainties regarding the impact of dyslipidemia on clinical outcomes and, consequently, the optimal lipid profile. In this article, we review the pathophysiology of dyslipidemia in CKD and dialysis patients and its association with clinical outcome and the effects of therapy and compare them with those in the general population. Kidney transplant patients are excluded from the discussion. Dyslipidemia is empirically defined here as plasma lipid and lipoproteins that are associated with adverse outcomes such as CV disease (CVD) in the general population. Whether this definition is justified in patients with CKD requires further investigations.

Normal Structure and Function of Lipoproteins

Lipoproteins

Lipoproteins consist of lipids and proteins (known as apolipoproteins [apo]), with the main function of transporting water-insoluble lipids such as cholesterol or triglycerides in plasma from the sites of absorption (gut) and/or synthesis (liver) to the sites of utilization (peripheral tissues) or processing. Besides contributing to the structure and the stability of the macromolecule, apolipoproteins control the metabolism of the lipoproteins by activation or inhibition of enzymes and interaction with lipoprotein receptors. The major types of the plasma lipoproteins and their apolipoprotein components and physiologic functions are briefly presented in Table 1.

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Table 1.

Types of lipoproteins in normal plasmaa

Lipoprotein Pathways

In the exogenous pathway (Figure 1), chylomicrons transport dietary lipids that are absorbed from the intestine via the systemic circulation. Chylomicrons are triglyceride-rich and normally catabolized within minutes by the endothelium-associated lipoprotein lipase (LPL), thereby generating free fatty acids (FFA), which are taken up by the liver, muscle, and adipose tissues. During this catabolic process, chylomicrons diminish in size and become chylomicron remnants, which are taken up by the liver via the low-density lipoprotein (LDL) receptor and the LDL receptor–related protein (LRP).

Figure 1.
Figure 1.

Major normal lipoprotein metabolic pathways. Refer to text for detailed explanation. Blue arrows refer to points of action of the respective enzymes in blue. ABCA1, ATP binding cassette transporter 1; CE, cholesterol ester; CETP, cholesteryl ester transfer 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-R–related protein; SR B1, scavenger receptor B1; TG, triglyceride. Illustration by Josh Gramling—Gramling Medical Illustration.

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

LDL transports cholesterol primarily to hepatocytes but also to peripheral tissues. ApoB-100 is responsible for the recognition and uptake of LDL by the LDL receptor, which clears approximately 60 to 80% of LDL in normal individuals. The remaining LDL is removed by other specific receptors, such as LRP, or by scavenger receptors (14). Oxidized LDL (ox-LDL) in particular can be taken up by scavenger receptors on macrophages and vascular smooth muscle cells. When these macrophages become overloaded with cholesteryl esters, they transform into foam cells, which is a major step in the development of atherosclerosis (14). When LDL becomes lipid depleted, small dense LDL (sdLDL) is generated, which has lower affinity for the LDL receptor but is more susceptible to oxidative modification. Thus, sdLDL are believed to be more atherogenic than larger LDL particles (15).

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport, which shuttles cholesterol from peripheral cells to the liver (16), an important step that relieves the peripheral cells from cholesterol burden (Figure 1). HDL precursor particles are secreted as disc-shaped structures by the liver and intestine and can absorb free cholesterol from cell membranes, a process that is mediated by ATP binding cassette transporter 1, apoA-I, and apoA-IV. ApoA-I is the major apolipoprotein of HDL and activates the enzyme lecithin:cholesterol acyltransferase (LCAT), which esterifies the accepted free cholesterol to allow more efficient packaging of the cholesterol for transport. By acquisition of additional apolipoproteins, cholesteryl esters, and triglycerides, HDL3 particles are transformed into larger HDL2 particles (17). Reverse cholesterol transport can take three different routes. First, large HDL particles with multiple copies of apoE can be taken up by the liver via the LDL receptor (16). Second, the accumulated cholesteryl esters from HDL can be selectively taken up by the liver mediated by scavenger receptor B1 (18). This receptor is expressed primarily in liver and nonplacental steroidogenic tissues. Third, cholesteryl esters are transferred by the cholesteryl ester transfer protein from HDL to triglyceride-rich lipoproteins (16). Plasma HDL cholesterol levels are influenced by the complexity of these reverse cholesterol transport processes. Disturbances in the concentrations of apoproteins, function of enzymes, transport proteins, receptors, other lipoproteins, and the clearance from plasma can have a major impact on the antiatherogenic properties of HDL.

Pathophysiology of Dyslipidemia in CKD and Dialysis

The spectrum of dyslipidemia in patients with CKD and dialysis patients is distinct from that of the general population. It involves all lipoprotein classes and shows considerable variations depending on the stage of CKD (Table 2). There seems to be a gradual shift to the uremic lipid profile as kidney function deteriorates (19,20), which is further modified by concurrent illnesses such as diabetes (21) and nephrotic syndrome (22). Apart from quantitative differences, major qualitative changes in lipoproteins can be observed, such as oxidization and modification to sdLDL, which render the particles more atherogenic.

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Table 2.

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

Hypertriglyceridemia

Plasma triglycerides start to increase in early stages of CKD (Table 2) and show the highest concentrations in nephrotic syndrome and in dialysis patients, especially those who are treated with peritoneal dialysis (PD). Plasma triglycerides are predominantly found in two types of lipoproteins in normal individuals. These are chylomicrons, which are assembled in the intestine for the transport of dietary fatty acids, and VLDL, which are produced in the liver for the transport of endogenous fatty acids (23–25). The accumulation of triglycerides is the consequence of both a high production rate and a low fractional catabolic rate (24) (Figure 2). An increased production of triglyceride-rich lipoproteins is possibly a consequence of impaired carbohydrate tolerance and enhanced hepatic VLDL synthesis (26). The reduced fractional catabolic rate is likely due to the decreased activity of two endothelium-associated lipases, namely, LPL and hepatic triglyceride lipase, which have the primary physiologic function of cleaving triglycerides into FFA for energy production or storage. The cause of the decreased lipase activities in uremia is thought to be depletion of the enzyme pool induced by frequent heparinization in hemodialysis (HD) patients (27), an increase in the plasma apoC-III/apoC-II ratio, and the presence of other lipase inhibitors in plasma. ApoC-II is an activator of LPL, whereas apoC-III is an inhibitor of LPL. The increased apoC-III/apoC-II ratio is usually due to a disproportionate increase in plasma apoC-III (28). The impaired lipase activities in uremic plasma may also be caused by a decrease in LPL synthesis as a result of secondary hyperparathyroidism or suppressed insulin level (29).

Figure 2.
Figure 2.

Pathophysiology of hypertriglyceridemia in uremia. Illustration by Josh Gramling—Gramling Medical Illustration.

Incomplete catabolism results in the accumulation of remnant particles (chylomicron remnants and IDL) that contribute to the heterogeneity of the plasma pool of triglyceride-rich lipoproteins, with different sites of origin, sizes, compositions (30), and degrees of atherogenicity (31). These remnants are rich in apoE, a ligand that is critical for the removal of the particles from the circulation by binding to LRP and perhaps other receptors on the vascular wall (32). The arterial wall therefore is exposed to high plasma levels of remnant lipoproteins for prolonged durations, which may predispose to atherogenesis.

High-Density Lipoprotein

Patients with CKD generally have reduced plasma HDL cholesterol concentrations compared with nonuremic individuals (Table 2). Furthermore, the distribution of HDL subfractions is different. Because of the low apo-AI level and decreased LCAT activity (see the Lipoprotein Pathways section), the esterification of free cholesterol and hence the conversion of HDL3 to HDL2 are diminished in uremia. This decreased ability of the HDL particles to carry cholesterol leads to an impairment in the reverse cholesterol transport from peripheral cells to the liver, thereby burdening the vasculature with cholesterol and promoting atherosclerosis (33–35).

Another important component of HDL is paraoxonase, an enzyme that inhibits the oxidation of LDL. Plasma paraoxonase activity is reduced in patients with CKD (36), thereby predisposing the LDL and possibly also HDL particles to oxidation. Furthermore, infection-associated or uremia-associated inflammation might convert HDL from an antioxidant into a pro-oxidant particle (37,38). All of these may contribute to atherogenesis in CKD.

Apolipoprotein A-IV

ApoA-IV is a 46-kDa glycoprotein that is synthesized primarily in enterocytes of the small intestine. In vitro studies suggest that apoA-IV might protect against atherosclerosis by promoting several steps in the reverse cholesterol transport pathway, which removes cholesterol from peripheral cells and directs the cholesterol to liver and steroidogenic organs for metabolism (39–41). Specifically, apoA-IV activates LCAT (42,43) and modulates the activation of LPL (44) as well as the protein-mediated transfer of cholesteryl esters from HDL to LDL (45). Cross-sectional studies have shown an inverse relationship between plasma apoA-IV levels and presence of coronary artery disease in the general population (46,47) as well as in patients with CKD (20).

ApoA-IV has also been identified as a marker of primary CKD, and its plasma levels are already increased when glomerular filtration rate (GFR) is still normal (Table 2) (20). Furthermore, high plasma apoA-IV concentrations predicted, independent of baseline GFR, the progression of primary nondiabetic kidney disease, defined as doubling of serum creatinine or necessity of renal replacement therapy, during a prospective 7-yr follow-up study (48). These findings were unexpected, given the physiologic functions in reverse cholesterol transport and the antioxidative properties of apoA-IV. The high apoA-IV levels that were caused by the impairment of GFR are further modulated by nephrotic syndrome. Specifically, a tubular type of proteinuria and severe proteinuria cause a decrease in plasma apoA-IV levels (49). These observations suggest that the human kidney is involved in apoA-IV metabolism, a hypothesis that is further supported by the presence of apoA-IV in kidney tubular cells (50). In dialysis patients, apoA-IV levels are twice as high as in the general population (51–54).

Low-Density Lipoprotein

Elevated plasma LDL cholesterol concentration is common in nephrotic syndrome but is not a typical feature of patients with advanced CKD, especially those who are on HD (Table 2). There are, however, qualitative changes in LDL in patients with CKD 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 penetrate the vessel wall, becomes oxidized, and triggers the atherosclerotic process. IDL is an intermediate metabolite of VLDL that is normally further degraded to LDL with the cleavage of triglycerides by lipases (see the Hypertriglyceridemia section). Because of decreased hepatic triglyceride lipase activities in HD patients, the conversion of IDL to LDL is impaired and IDL accumulates in plasma (55). IDL and sdLDL have high affinity for macrophages, which theoretically promote their entry into the vascular wall to participate in the formation of foam cells and atherosclerotic plaques (56–59). The plasma levels of apoB, which is the major apolipoprotein of LDL and IDL, are strongly correlated with levels of these lipoproteins.

A vicious cycle has been suggested in uremia in which the decreased catabolism of IDL and LDL leads to their increased plasma residence time and further modification of the apoB contained in these lipoproteins by oxidation, carbamylation, and glycation (60). These modifications lead to the reduced recognition and binding of these lipoproteins to LDL receptors and LRP in the liver and hence further reduction in plasma clearance by this physiologic pathway. Using stable isotope techniques, it was shown recently that the plasma residence time of LDL and IDL is more than twice as long in HD patients as in nonuremic individuals (Figure 3). This reduced catabolism, however, is masked by the decreased production of LDL, resulting in near-normal plasma levels of LDL (60). In contrast to the decreased clearance by the liver, there is an increased clearance of these altered lipoproteins via the scavenger pathway. Modified LDL particles, such as ox-LDL and malondialdehyde-modified LDL, are taken up by macrophages via binding to several cell surface scavenger receptors. The accumulation of cholesterol leads to the transformation of macrophages into foam cells in the vascular wall and contributes to atherogenesis (56–59,61).

Figure 3.
Figure 3.

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

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 an LDL-like lipoprotein that consists of apo(a) that is covalently bound to an LDL particle. Apo(a) shows a high homology with plasminogen and competes with this protein for binding to plasminogen receptors, fibrinogen, and fibrin (64). Plasma Lp(a) concentrations 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 to >800 kDa, and is inversely related to the plasma Lp(a) concentration. 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 usually exhibit high plasma Lp(a) concentrations. Depending on the population under investigation, this association explains between 30 and 70% of the variability in plasma Lp(a) levels.

In kidney disease, plasma Lp(a) levels are also influenced by GFR. In patients with large apo(a) isoforms but not those with small apo(a) isoforms, plasma Lp(a) levels begin to increase in stage 1 CKD before GFR starts to decrease (19). This isoform-specific increase in plasma Lp(a) levels was observed in several but not all studies in non-nephrotic patients with CKD and HD patients (19,54,66–69). In contrast, in patients with nephrotic syndrome (70,71) and PD patients (54), increases in plasma Lp(a) levels occur in all apo(a) isoform groups, probably as a consequence of the pronounced protein loss and a subsequently increased production in the liver (72). After successful kidney transplantation, a decrease in plasma Lp(a) can be regularly observed in HD patients with large apo(a) isoforms (73,74) and in PD patients with all apo(a) isoform groups (75). Thus, the elevation of Lp(a) in CKD is an acquired abnormality, mostly influenced by the degree of proteinuria (19,71) and less by the cause of kidney disease (54).

In vivo turnover studies using stable-isotope techniques recently elucidated the mechanism for the increased plasma Lp(a) levels in HD patients (76). The production rates of apo(a) and apoB, the two apolipoproteins that are contained in Lp(a), were normal when compared with control subjects with similar plasma Lp(a) concentrations (Figure 3). The fractional catabolic rate of these apolipoproteins, however, was significantly reduced compared with control subjects. This resulted in a much longer residence time in plasma of almost 9 days for apo(a), compared with only 4.4 days in control subjects. This decreased clearance is likely the result of loss in kidney function in HD patients (76).

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

In summary, the hallmarks of uremic dyslipidemia are hypertriglyceridemia; increased remnant lipoproteins (chylomicron remnants and IDL); reduced HDL cholesterol; and increased sdLDL, Lp(a), and apoA-IV. Elevated plasma LDL cholesterol level is not typical but can mostly be observed in patients with nephrotic syndrome and PD patients.

Epidemiologic Association between Dyslipidemia and CV Outcome in CKD

In the general population, high plasma concentrations of LDL cholesterol, low concentrations of HDL cholesterol, and to some extent high total triglyceride concentrations are associated with increased atherosclerotic CV risk (79). In the dialysis populations, the preponderance of the literature, including cross-sectional (35,80–82) and longitudinal (2,3,34,69,83–90) studies, does not support a strong association between dyslipidemia and CVD (Table 3). This seemingly aberrant relationship may be due, in part, to the approaches of dyslipidemia assessment. The precise contributions of lipids to atherogenicity should probably be evaluated longitudinally using multiple measurements over time, because the plasma lipid patterns change substantially as kidney disease progresses, as illustrated by the decline of plasma LDL levels from the nephrotic stage to the HD stage. Furthermore, the atherogenic potential of dyslipidemia in CKD may depend more on the apolipoprotein than on lipid abnormalities and may not always be recognized by measurement of plasma lipids alone, as suggested by Attman and Alaupovic (91). An additional caveat is that, in many dialysis patients, CVD is caused or accentuated by other risk factors, such as volume overload, medial calcification, and arrhythmogenicity, and may not necessarily be related to atherosclerosis.

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Table 3.

Association of dyslipidemia and clinical outcomes in dialysis patientsa

Total Cholesterol

In large administrative databases, the relationship between plasma total cholesterol and mortality in HD patients has been found to be U-shaped (92,93). The group with total cholesterol between 200 and 250 mg/dl had the lowest risk for death, whereas those with levels >350 mg/dl had a relative risk of 1.3-fold and those with levels <100 mg/dl had a relative risk of 4.2-fold. The association between low total cholesterol and increased mortality, however, was reduced after statistical adjustment for plasma albumin levels. Subgroup analysis provides further insights into the potential effects of plasma total cholesterol on clinical outcomes. A recent study of 1167 HD patients found that among those with low plasma albumin levels (3.5 to 3.9 g/dl), low plasma total cholesterol levels were also associated with increased all-cause mortality. Among those with plasma albumin >4.5 g/dl, however, high plasma total cholesterol levels were associated with increased mortality (1), as observed in the general population. This dichotomous relationship was confirmed in the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study (84,94), which showed a nonsignificant negative association of cardiovascular mortality with plasma total as well as non–HDL cholesterol levels in the presence of inflammation and/or malnutrition (Figure 4); in contrast, there was a positive association between total and non–HDL cholesterol and mortality in the absence of inflammation or malnutrition. These observations are compatible with the hypothesis that the inverse association of total cholesterol levels with mortality in dialysis patients is mediated by the cholesterol-lowering effect of malnutrition and/or systemic inflammation and not due to a protective effect of high cholesterol concentrations.

Figure 4.
Figure 4.

Relative risk for all-cause mortality associated with plasma total cholesterol stratified by the presence or absence of inflammation and/or malnutrition in the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study (84). Inflammation and/or malnutrition was defined as the composite of plasma albumin <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 and malnutrition. Illustration by Josh Gramling—Gramling Medical Illustration.

IDL Cholesterol

In observational studies, high plasma IDL cholesterol levels have been shown to be a risk factor independent of LDL cholesterol for coronary artery disease in the general population (95) and may also be a predictor for aortic atherosclerosis in HD patients (96). As discussed, IDL cholesterol is often elevated in uremia. Unfortunately, the current clinical assays do not differentiate between LDL cholesterol and IDL cholesterol. Therefore, current clinical assays may not accurately assess the atherosclerotic burden of plasma cholesterol in uremia.

Lp(a) Concentrations and Apo(a) Polymorphism

The association of Lp(a) with atherosclerotic complications has been investigated in numerous studies in dialysis patients. The results were inconsistent in prospective as well as in retrospective studies (Table 3) (3,85,97). This inconsistency might have been due, at least in part, to the nonstandardized assay method for Lp(a) in the past. When apo(a) phenotyping was performed in conjunction with plasma Lp(a) concentrations, however, an association between the apo(a) K-IV repeat polymorphism and CV complications was consistently observed (3,35,85,97–104) (Table 3). A cross-sectional study in 607 HD patients showed an association between low molecular weight apo(a) phenotype with history of coronary events (35). Two large prospective studies also found a clear association of the apo(a) polymorphism with coronary events and total mortality, respectively (3,85,97). Kronenberg et al. (3) followed 440 HD patients for 5 yr and found a strong association between the low molecular weight apo(a) phenotype and severe coronary events. In contrast, plasma Lp(a) in those with clinical events showed only a trend toward elevated levels and did not reach statistical significance. Similarly, the CHOICE Study recently reported small apo(a) isoforms to be associated with total mortality in an inception cohort of >800 incident dialysis patients who were followed for a median of 33.7 mo (85,97). In that study, Lp(a) concentrations were associated with CV events (85) but not with total mortality (97).

Apolipoproteins

In 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 and triglyceride concentrations (46,47). Similarly, participants in the Mild to Moderate Kidney Disease Study with CVD complications also had lower apoA-IV levels than those without (20). More data in various stages of CKD are required to confirm these findings.

Lipid Management in CKD

Limitations of Clinical Lipid Assays in Uremia

In the general population, plasma levels of total, HDL, and LDL cholesterol as well as triglycerides are the parameters that usually are measured clinically. As discussed, the total and LDL cholesterol levels are often normal in the CKD and HD populations, but there are increased levels of sdLDL, IDL, and modified (oxidized, glycated, or carbamylated) LDL that are presumably more atherogenic. Similarly, the clinical assays do not differentiate among LDL and Lp(a) and its low molecular weight isoform, which are independent risk factors for atherosclerotic disease and are often elevated in CKD. Clinical assays for HDL cholesterol also cannot capture the alterations in the distribution of cholesterol subclasses with different antiatherogenic properties that are observed in CKD.

Recently, the use of non–HDL cholesterol, calculated as total cholesterol minus HDL cholesterol, was suggested as an alternative (105). Non–HDL cholesterol includes and does not distinguish among LDL cholesterol and subfractions that are considered to be highly atherogenic, such as Lp(a) and lipoprotein remnant particles. To date, there are insufficient data to establish the role of non–HDL cholesterol for atherosclerosis risk assessment.

Drug Therapies for Dyslipidemia in CKD

Statins.

As in the general population, statins are very effective 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 randomized, placebo-controlled trials of statins, post hoc analyses of subgroups with impaired kidney function have been performed (Table 4). In the Pravastatin Pooling Project (10), which combined data from three randomized trials, a total of 4991 patients with stage 3 CKD were examined. These analyses showed that 40 mg/d pravastatin was associated with a 23% reduction in the composite outcome of nonfatal myocardial infarction, coronary mortality, and coronary revascularization in stage 3 CKD over 5 yr. In a prespecified subgroup analysis of 6517 patients with kidney dysfunction in the Anglo-Scandinavian Cardiac Outcomes Trial (6),10 mg/d atorvastatin significantly reduced the risk for the primary composite end point of nonfatal myocardial infarction and cardiac death by 39% over a median 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 generalizable to all patients with moderate CKD.

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Table 4.

Completed large studies on lipid modification in patients with CKDa

In a retrospective analysis of a registry of 3716 incident dialysis patients, the use of statins at baseline was associated with a significant 36% reduction in CV and 32% reduction in all-cause mortality (107). This study, however, was limited by the small number of patients who were on statins (n = 362) and possible selection bias. These findings were in general not confirmed by the Die Deutsche Diabetes-Dialyse (4D) study, a randomized, controlled trial of 1255 HD patients with diabetes (12). In the 4D study, randomization to 20 mg/d atorvastatin resulted in the reduction in plasma LDL cholesterol levels by 40%, compared with placebo (12). Despite this difference in cholesterol, there were no statistically significant differences (8% reduction) between the groups in the primary composite end point of cardiac death, stroke, or nonfatal myocardial infarction. In the atorvastatin group, there was also an 18% decrease in cardiac events (205 versus 246; P = 0.03) but a two-fold increase in fatal strokes (27 versus 13; P = 0.04).

These results, along with the seemingly paradoxic epidemiologic relationship between plasma cholesterol levels and mortality (12), have been interpreted by some to be rationales for abstaining from the use of statins in dialysis patients. Proponents of the use of statins in dialysis patients, however, point out that the 4D Study was powered only to detect a 27% difference in the primary end point and not a more modest effect size of, for example, even 15%. Despite the two-fold increase in fatal stroke in the 4D Study, the absolute number of events was small, compared with the number of cardiac events, which seemed to respond favorably to atorvastatin. Moreover, approximately 15% of the patients in the placebo arm received a nonstudy statin, and 15% of the patients who received atorvastatin required a dosage reduction to 10 mg/d. These drop-ins and dropouts might have resulted in the convergent trend in plasma LDL cholesterol levels between the two treatment arms over time. Nonetheless, the time-averaged difference in plasma LDL cholesterol was approximately 0.9 mmol/L, which was similar in magnitude to that observed in many statin trials with more positive clinical outcomes. Many CV events in dialysis patients were due to arrhythmia or nonischemic cardiomyopathy, which might not be related to atherosclerosis and could have diluted the potentially beneficial effects of statins. Finally, even though statins were effective in lowering plasma LDL cholesterol, they have minimal effects on plasma triglycerides and HDL cholesterol and no effects on Lp(a). Because uremic dyslipidemia is characterized by these three components and not elevated LDL cholesterol, lowering of plasma LDL cholesterol levels in uremic patients might not produce substantial clinical benefits. Controversies notwithstanding, a reasonable conclusion from the 4D Study is that, in dialysis patients without very high plasma LDL cholesterol levels, the effect of statins on clinical outcome is probably not large, but a modest effect cannot be ruled out.

There are two more large, ongoing, randomized trials using statins in patients with CKD. The Study of Heart and Renal Protection (SHARP) examines the effect of lowering plasma cholesterol using the combination of simvastatin and ezetimibe on the primary prevention of heart disease and stroke. It aims to recruit 6000 patients with CKD and plasma creatinine ≥1.7 mg/dl (150 μmol/L) in men and ≥1.5 mg/dl (130 μmol/L) in women as well as 3000 patients who are on dialysis (108). There are no lipid inclusion criteria in this trial. The Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) Study examines the effect of rosuvastatin on the incidence of heart attacks, strokes, and CV deaths in HD patients both with and without diabetes, irrespective of baseline lipid levels (109,110).

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

Fibrates.

These agents are effective in reducing plasma triglyceride concentrations and modestly increasing HDL cholesterol concentrations in the general population (115,116). The use of gemfibrozil was associated with a 20% reduction in CV events in those with creatinine clearances of 30 to 75 ml/min (9). There are no data on the effects of fibrates on clinical outcomes in patients with CKD or HD patients. Evidence is strong in support of an increased risk for myopathy that is associated with this class of drug in patients with advanced GFR impairment (117,118).

Nicotinic Acids and Derivatives.

Nicotinic acids may be the most suitable drug that is available to produce a positive impact on uremic dyslipidemia. It is very effective in raising plasma HDL cholesterol level and is the only drug available to lower plasma Lp(a) substantially (119). It reduces total triglyceride levels by 20 to 50% (120); lowers VLDL cholesterol and FFA; and shifts the sdLDL fraction to larger, more buoyant particles (121). It also lowers plasma LDL cholesterol levels. The immediate-release formulations that were marketed earlier, however, were plagued by cutaneous flushing, pruritus, rashes, nausea, and gastrointestinal adverse effects. These adverse effects are less often observed with the newer, extended-release formulations and are in many cases transient when they occur. The compliance of patients can be increased by the co-administration of aspirin and gradual dosage escalation that decrease the adverse effects (for details, see review [122]). In the general population, nicotinic acid has been shown to improve cardiac and cerebrovascular outcomes (123–126). Studies that used nicotinic acid in patients with CKD were mostly small with short durations of follow-up but showed the expected changes in lipid and lipoprotein profiles (122). No studies have examined the impact of nicotinic acid on CVD outcomes in patients with CKD or HD patients.

Sevelamer.

This metal-free phosphate binder has also been shown to reduce plasma total and LDL cholesterol concentrations by 18 to 22% and 30 to 37%, respectively, by acting as a bile acid sequestrant (127). Whether this reduction in cholesterol contributes to the decreased progression of coronary calcification (128) is unclear.

Antioxidants.

Dialysis patients are generally in a state of high oxidative stress. A beneficial effect of vitamin E on the oxidative susceptibility of LDL cholesterol in dialysis patients has been shown (129–131). Treatment with α-tocopherol also resulted in partial normalization of malondialdehyde modifications of LDL cholesterol in dialysis patients (132). Vitamin E may also exert an additive or synergistic effect with statins. In a 2 × 2 study in dialysis patients, treatment with atorvastatin was found to be effective in lowering plasma total cholesterol, triglycerides, LDL cholesterol, apoB, and ox-LDL levels by 30 to 40%, and the addition of α-tocopherol to atorvastatin further reduced in vitro LDL oxidation (130). The Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) trial suggested that vitamin E supplementation lowered the incidence of major CV events in HD patients without significantly affecting total mortality (133). To date, the impact of antioxidants on the clinical outcomes of patients with CKD and dialysis patients is not definitive and needs further clinical trials (134).

Other Therapies.

When compared with high-flux modified cellulosic membrane, HD using high-flux polysulfone membranes was associated with a decrease in plasma total triglycerides by 10%, cholesterol in remnant particles by 21%, and ox-LDL by 15% (135). The underlying mechanisms of these differences are unclear but might be related to potential differences in dialysis membrane biocompatibility that affect inflammatory responses and/or differences in the removal of plasma lipase inhibitory molecules.

Antioxidant effects can also be achieved in HD using a vitamin E–coated membrane dialyzer, which results in a significant reduction in ox-LDL or malondialdehyde-rich LDL and an attenuation of the increase in aortic calcification index after 24 months (131). Lipid apheresis is very effective in lowering plasma LDL cholesterol and, depending on the technique, can also lower plasma Lp(a), triglycerides, and fibrinogen (136). The effects of these extracorporeal therapies on clinical outcomes are uncertain.

Experimental Therapies.

A number of novel therapeutic strategies are in various stages of development for modulating lipids and lipoproteins, including lipase gene transfer (137), apoA-I(Milano) infusion (138), and short interfering RNA for apoB (139). Although they are not ready for clinical use, the potency and the specificities of these techniques for abnormalities that are characteristics of uremic dyslipidemia represent intriguing promises.

Conclusions

The optimal targets for plasma lipids in patients with CKD and dialysis patients are unknown. The commonly used clinical assays to measure triglycerides and total, LDL, and HDL cholesterol may not capture the clinically relevant lipid abnormalities of uremia, such as elevated Lp(a), IDL cholesterol, modified LDL cholesterol, and alterations in HDL cholesterol subfractions. Post hoc analyses of large clinical trials support the beneficial effects of statins in early stages of CKD, whereas there is a lack of data on the use of statins in stages 4 and 5 CKD. Data in patients who are treated by PD as well as in nondiabetic HD patients are too sparse to draw any conclusion on these subpopulations. Statins are generally ineffective in correcting the elevated plasma concentrations of triglycerides and Lp(a) as well as decreased plasma concentrations of HDL cholesterol, which are the major lipid abnormalities seen in uremia. Although there is a trend toward benefits, the 4D Study did not provide definitive evidence for statins to improve CV outcomes in HD patients with diabetes. Nicotinic acid derivatives and, to a lesser extent, fibrates may be more suitable to treat uremic dyslipidemia, but there are no studies on the efficacy of these agents to improve CV outcomes in CKD.

Nephrologists and primary care physicians should detect and treat dyslipidemia at early stages of CKD using the guidelines developed for the general population. A great deal of research is urgently needed to elucidate the relationship between putatively atherogenic lipoproteins and clinical outcomes in advanced CKD. Targeting these lipoproteins may be important to decrease CVD in this population.

Disclosures

None.

Acknowledgments

This work is partially supported by the US Department of Veterans Affairs and Department of Medicine at the University of Utah; Department of Medicine & Therapeutics, The Chinese University of Hong Kong; Department of Medical Genetics, Molecular and Clinical Pharmacology at Innsbruck Medical University; and “Genomics of Lipid-associated Disorders—GOLD” of the Austrian Genome Research Programme GEN-AU.

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

Footnotes

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

References

  1. ↵
    Iseki K, Yamazato M, Tozawa M, Takishita S: Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 61 : 1887 –1893, 2002
    OpenUrlCrossRefPubMed
  2. ↵
    Degoulet P, Legrain M, Reach I, Aime F, Devries C, Rojas P, Jacobs C: Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron 31 : 103 –110, 1982
    OpenUrlCrossRefPubMed
  3. ↵
    Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, Auinger M, Pribasnig A, Meisl T, Konig P, Dieplinger H: The low molecular weight apo(a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: A prospective follow-up. J Am Soc Nephrol 10 : 1027 –1036, 1999
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Ferramosca E, Burke S, Chasan-Taber S, Ratti C, Chertow GM, Raggi P: Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J 149 : 820 –825, 2005
    OpenUrlCrossRefPubMed
  5. Holdaas H, Wanner C, Abletshauser C, Gimpelewicz C, Isaacsohn J: The effect of fluvastatin on cardiac outcomes in patients with moderate to severe renal insufficiency: A pooled analysis of double-blind, randomized trials. Int J 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, O'Brien E, Ostergren J: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet 361 : 1149 –1158, 2003
    OpenUrlCrossRefPubMed
  7. ↵
    MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 360 : 7 –22, 2002
    OpenUrlCrossRefPubMed
  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-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy). Am J Cardiol 95 : 445 –451, 2005
    OpenUrlCrossRefPubMed
  9. ↵
    Tonelli M, Collins D, Robins S, Bloomfield H, Curhan GC: Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int 66 : 1123 –1130, 2004
    OpenUrlCrossRefPubMed
  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 cardiovascular events in people with chronic kidney disease. Circulation 110 : 1557 –1563, 2004
  11. ↵
    Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G: Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 138 : 98 –104, 2003
    OpenUrlCrossRefPubMed
  12. ↵
    Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353 : 238 –248, 2005
    OpenUrlCrossRefPubMed
  13. ↵
    Eisenberg S, Bilheimer DW, Levy RI, Lindgren FT: On the metabolic conversion of human plasma very low density lipoprotein to low density lipoprotein. Biochim Biophys Acta 326 : 361 –377, 1973
    OpenUrlPubMed
  14. ↵
    Brown MS, Goldstein JL: Lipoprotein metabolism in the macrophage: Implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 52 : 223 –261, 1983
    OpenUrlCrossRefPubMed
  15. ↵
    Austin MA, King MC, Vranizan KM, Krauss RM: Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 82 : 495 –506, 1990
  16. ↵
    Bruce C, Chouinard RA Jr, Tall AR: Plasma lipid transfer proteins, high-density lipoproteins, and reverse cholesterol transport. Annu Rev Nutr 18 : 297 –330, 1998
    OpenUrlCrossRefPubMed
  17. ↵
    Dieplinger H, Zechner R, Kostner GM: The in vitro formation of HDL2 during the action of LCAT: The role of triglyceride-rich lipoproteins. J Lipid Res 26 : 273 –282, 1985
    OpenUrlAbstract
  18. ↵
    Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M: Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271 : 518 –520, 1996
    OpenUrlAbstract
  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 concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol 11 : 105 –115, 2000
    OpenUrlAbstract/FREE Full Text
  20. ↵
    Kronenberg F, Kuen E, Ritz E, Konig P, Kraatz G, Lhotta K, Mann JF, Muller GA, Neyer U, Riegel W, Riegler P, Schwenger V, von Eckardstein A: Apolipoprotein A-IV serum concentrations are elevated in patients with mild and moderate renal failure. J Am Soc Nephrol 13 : 461 –469, 2002
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Krentz AJ: Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. Diabetes Obes Metab 5[Suppl 1] : S19 –S27, 2003
  22. ↵
    Kronenberg F: Dyslipidemia and nephrotic syndrome: Recent advances. J Ren Nutr 15 : 195 –203, 2005
    OpenUrlCrossRefPubMed
  23. ↵
    Savdie E, Gibson JC, Crawford GA, Simons LA, Mahony JF: Impaired plasma triglyceride clearance as a feature of both uremic and posttransplant triglyceridemia. Kidney Int 18 : 774 –782, 1980
    OpenUrlPubMed
  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, and B-48 metabolism in subjects with chronic kidney disease, obesity, and the metabolic syndrome. Metabolism 53 : 1255 –1261, 2004
    OpenUrlCrossRefPubMed
  25. ↵
    Cattran DC, Fenton SS, Wilson DR, Steiner G: Defective triglyceride removal in lipemia associated with peritoneal dialysis and haemodialysis. Ann Intern Med 85 : 29 –33, 1976
    OpenUrlCrossRefPubMed
  26. ↵
    Appel G: Lipid abnormalities in renal disease. Kidney Int 39 : 169 –183, 1991
    OpenUrlPubMed
  27. ↵
    Arnadottir M: Pathogenesis of dyslipoproteinemia in renal insufficiency: The role of lipoprotein lipase and hepatic lipase. Scand J Clin Lab Invest 57 : 1 –11, 1997
    OpenUrlPubMed
  28. ↵
    Senti M, Romero R, Pedro-Botet J, Pelegri A, Nogues X, Rubies-Prat J: Lipoprotein abnormalities in hyperlipidemic and normolipidemic men on hemodialysis with chronic renal failure. Kidney Int 41 : 1394 –1399, 1992
    OpenUrlPubMed
  29. ↵
    Cryer A: Tissue lipoprotein lipase activity and its action in lipoprotein metabolism. Int J Biochem 13 : 525 –541, 1981
    OpenUrlCrossRefPubMed
  30. ↵
    Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science 232 : 34 –47, 1986
    OpenUrlFREE Full Text
  31. ↵
    McNamara JR, Shah PK, Nakajima K, Cupples LA, Wilson PW, Ordovas JM, Schaefer EJ: Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study. Atherosclerosis 154 : 229 –236, 2001
    OpenUrlCrossRefPubMed
  32. ↵
    Leary ET, Wang T, Baker DJ, Cilla DD, Zhong J, Warnick GR, Nakajima K, Havel RJ: Evaluation of an immunoseparation method for quantitative measurement of remnant-like particle-cholesterol in serum and plasma. Clin Chem 44 : 2490 –2498, 1998
    OpenUrlAbstract/FREE Full Text
  33. ↵
    Cheung AK, Wu LL, Kablitz C, Leypoldt JK: Atherogenic lipids and lipoproteins in hemodialysis patients. Am J Kidney Dis 22 : 271 –276, 1993
    OpenUrlPubMed
  34. ↵
    Cressman MD, Heyka RJ, Paganini EP, O'Neil J, Skibinski CI, Hoff HF: Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients. Circulation 86 : 475 –482, 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 predict coronary artery disease in hemodialysis patients. J Am Soc Nephrol 8 : 1889 –1898, 1997
    OpenUrlAbstract
  36. ↵
    Dantoine TF, Debord J, Charmes JP, Merle L, Marquet P, Lachatre G, Leroux-Robert C: Decrease of serum paraoxonase activity in chronic renal failure. J Am Soc Nephrol 9 : 2082 –2088, 1998
    OpenUrlAbstract
  37. ↵
    Navab M, Hama SY, Reddy ST, Ng CJ, Van Lenten BJ, Laks H, Fogelman AM: Oxidized lipids as mediators of coronary heart disease. Curr Opin Lipidol 13 : 363 –372, 2002
    OpenUrlCrossRefPubMed
  38. ↵
    Solakivi T, Jaakkola O, Salomaki A, Peltonen N, Metso S, Lehtimaki T, Jokela H, Nikkari ST: HDL enhances oxidation of LDL in vitro in both men and women. Lipids Health Dis 4 : 25 , 2005
    OpenUrlCrossRefPubMed
  39. ↵
    Steinmetz A, Barbaras R, Ghalim N, Clavey V, Fruchart JC, Ailhaud G: Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells. J Biol Chem 265 : 7859 –7863, 1990
    OpenUrlAbstract/FREE Full Text
  40. Stein O, Stein Y, Lefevre M, Roheim PS: The role of apolipoprotein A-IV in reverse cholesterol transport studied with cultured cells and liposomes derived from an ether analog of phosphatidylcholine. Biochim Biophys Acta 878 : 7 –13, 1986
    OpenUrlPubMed
  41. ↵
    Dvorin E, Gorder NL, Benson DM, Gotto AM Jr: Apolipoprotein A-IV. A determinant for binding and uptake of high-density lipoproteins by rat hepatocytes. J Biol Chem 261 : 15714 –15718, 1986
    OpenUrlAbstract/FREE Full Text
  42. ↵
    Chen CH, Albers JJ: Activation of lecithin: cholesterol acyltransferase by apolipoproteins E-2, E-3, and A-IV isolated from human plasma. Biochim Biophys Acta 836 : 279 –285, 1985
    OpenUrlPubMed
  43. ↵
    Steinmetz A, Utermann G: Activation of lecithin: Cholesterol acyltransferase by human apolipoprotein A-IV. J Biol Chem 260 : 2258 –2264, 1985
    OpenUrlAbstract/FREE Full Text
  44. ↵
    Goldberg IJ, Scheraldi CA, Yacoub LK, Saxena U, Bisgaier CL: Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV. J Biol Chem 265 : 4266 –4272, 1990
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Guyard-Dangremont V, Lagrost L, Gambert P: Comparative effects of purified apolipoproteins A-I, A-II, and A-IV on cholesteryl ester transfer protein activity. J Lipid Res 35 : 982 –992, 1994
    OpenUrlAbstract
  46. ↵
    Kronenberg F, Stuhlinger M, Trenkwalder E, Geethanjali FS, Pachinger O, von Eckardstein A, Dieplinger H: Low apolipoprotein A-IV plasma concentrations in men with coronary artery disease. J Am Coll Cardiol 36 : 751 –757, 2000
    OpenUrlCrossRefPubMed
  47. ↵
    Warner MM, Guo J, Zhao Y: The relationship between plasma apolipoprotein A-IV levels and coronary heart disease. Chin Med J (Engl) 114 : 275 –279, 2001
  48. ↵
    Boes E, Fliser D, Ritz E, Konig P, Lhotta K, Mann JF, Muller GA, Neyer U, Riegel W, Riegler P, Kronenberg F: Apolipoprotein A-IV predicts progression of chronic kidney disease: The mild to moderate kidney disease study. J Am Soc Nephrol 17 : 528 –536, 2006
    OpenUrlAbstract/FREE Full Text
  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 the metabolism of apolipoprotein A-IV: Influence of the type of proteinuria. J Lipid Res 47 : 2071 –2079, 2006
    OpenUrlAbstract/FREE Full Text
  50. ↵
    Haiman M, Salvenmoser W, Scheiber K, Lingenhel A, Rudolph C, Schmitz G, Kronenberg F, Dieplinger H: Immunohistochemical localization of apolipoprotein A-IV in human kidney tissue. Kidney Int 68 : 1130 –1136, 2005
    OpenUrlCrossRefPubMed
  51. ↵
    Nestel PJ, Fidge NH, Tan MH: Increased lipoprotein-remnant formation in chronic renal failure. N Engl J Med 307 : 329 –333, 1982
    OpenUrlPubMed
  52. Seishima M, Muto Y: An increased apo A-IV serum concentration of patients with chronic renal failure on hemodialysis. Clin Chim Acta 167 : 303 –311, 1987
    OpenUrlCrossRefPubMed
  53. Dieplinger H, Lobentanz EM, Konig P, Graf H, Sandholzer C, Matthys E, Rosseneu M, Utermann G: Plasma apolipoprotein A-IV metabolism in patients with chronic renal disease. Eur J Clin Invest 22 : 166 –174, 1992
    OpenUrlPubMed
  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 treated by hemodialysis or continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 6 : 110 –120, 1995
    OpenUrlAbstract
  55. ↵
    Oi K, Hirano T, Sakai S, Kawaguchi Y, Hosoya T: Role of hepatic lipase in intermediate-density lipoprotein and small, dense low-density lipoprotein formation in hemodialysis patients. Kidney Int Suppl 71 : S227 –S228, 1999
    OpenUrlCrossRefPubMed
  56. ↵
    Littlewood TD, Bennett MR: Apoptotic cell death in atherosclerosis. Curr Opin Lipidol 14 : 469 –475, 2003
    OpenUrlCrossRefPubMed
  57. Stoneman VE, Bennett MR: Role of apoptosis in atherosclerosis and its therapeutic implications. Clin Sci (Lond) 107 : 343 –354, 2004
    OpenUrlAbstract/FREE Full Text
  58. Kolodgie FD, Narula J, Haider N, Virmani R: Apoptosis in atherosclerosis. Does it contribute to plaque instability? Cardiol Clin 19 : 127 –139, ix, 2001
    OpenUrlCrossRefPubMed
  59. ↵
    Best PJ, Hasdai D, Sangiorgi G, Schwartz RS, Holmes DR Jr, Simari RD, Lerman A: Apoptosis. Basic concepts and implications in coronary artery disease. Arterioscler Thromb Vasc Biol 19 : 14 –22, 1999
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Ikewaki K, Schaefer JR, Frischmann ME, Okubo K, Hosoya T, Mochizuki S, Dieplinger B, Trenkwalder E, Schweer H, Kronenberg F, Koenig P, Dieplinger H: Delayed in vivo catabolism of intermediate-density lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler Thromb Vasc Biol 25 : 2615 –2622, 2005
    OpenUrlAbstract/FREE Full Text
  61. ↵
    Moore KJ, Freeman MW: Scavenger receptors in atherosclerosis: Beyond lipid uptake. Arterioscler Thromb Vasc Biol 26 : 1702 –1711, 2006
    OpenUrlAbstract/FREE Full Text
  62. ↵
    Craig WY, Neveux LM, Palomaki GE, Cleveland MM, Haddow JE: Lipoprotein(a) as a risk factor for ischemic heart disease: Metaanalysis of prospective studies. Clin Chem 44 : 2301 –2306, 1998
    OpenUrlAbstract/FREE Full Text
  63. ↵
    Dieplinger H, Kronenberg F: Genetics and metabolism of lipoprotein(a) and their clinical implications (Part 1). Wien Klin Wochenschr 111 : 5 –20, 1999
    OpenUrlPubMed
  64. ↵
    Harpel PC, Gordon BR, Parker TS: Plasmin catalyzes binding of lipoprotein (a) to immobilized fibrinogen and fibrin. Proc Natl Acad Sci U S A 86 : 3847 –3851, 1989
    OpenUrlAbstract/FREE Full Text
  65. ↵
    Utermann G: Lipoprotein(a). In: The Metabolic & Molecular Bases of Inherited Disease, 8th Ed., edited by Scriver CR, Beaudet AL, Sly WS, Valle D, New York, McGraw-Hill, 2000 , pp 2753 –2787
  66. ↵
    Dieplinger H, Lackner C, Kronenberg F, Sandholzer C, Lhotta K, Hoppichler F, Graf H, Konig P: Elevated plasma concentrations of lipoprotein(a) in patients with end-stage renal disease are not related to the size polymorphism of apolipoprotein(a). J Clin Invest 91 : 397 –401, 1993
    OpenUrlPubMed
  67. Milionis HJ, Elisaf MS, Tselepis A, Bairaktari E, Karabina SA, Siamopoulos KC: Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure. Am J Kidney Dis 33 : 1100 –1106, 1999
    OpenUrlPubMed
  68. ↵
    Stenvinkel P, Heimburger O, Tuck CH, Berglund L: Apo(a)-isoform size, nutritional status and inflammatory markers in chronic renal failure. Kidney Int 53 : 1336 –1342, 1998
    OpenUrlCrossRefPubMed
  69. ↵
    Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55 : 648 –658, 1999
    OpenUrlCrossRefPubMed
  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 Med 119 : 263 –269, 1993
    OpenUrlCrossRefPubMed
  71. ↵
    Kronenberg F, Lingenhel A, Lhotta K, Rantner B, Kronenberg MF, Konig P, Thiery J, Koch M, von Eckardstein A, Dieplinger H: The apolipoprotein(a) size polymorphism is associated with nephrotic syndrome. Kidney Int 65 : 606 –612, 2004
    OpenUrlCrossRefPubMed
  72. ↵
    De Sain-Van Der Velden MG, Reijngoud DJ, Kaysen GA, Gadellaa MM, Voorbij H, Stellaard F, Koomans HA, Rabelink TJ: Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome. J Am Soc Nephrol 9 : 1474 –1481, 1998
    OpenUrlAbstract
  73. ↵
    Kronenberg F, Konig P, Lhotta K, Ofner D, Sandholzer C, Margreiter R, Dosch E, Utermann G, Dieplinger H: Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation. Arterioscler Thromb 14 : 1399 –1404, 1994
    OpenUrlAbstract/FREE Full Text
  74. ↵
    Kronenberg F, Lhotta K, Konig P, Margreiter R, Dieplinger H, Utermann G: Apolipoprotein(a) isoform-specific changes of lipoprotein(a) after kidney transplantation. Eur J Hum Genet 11 : 693 –699, 2003
    OpenUrlCrossRefPubMed
  75. ↵
    Kerschdorfer L, Konig P, Neyer U, Bosmuller C, Lhotta K, Auinger M, Hohenegger M, Riegler P, Margreiter R, Utermann G, Dieplinger H, Kronenberg F: Lipoprotein(a) plasma concentrations after renal transplantation: A prospective evaluation after 4 years of follow-up. Atherosclerosis 144 : 381 –391, 1999
    OpenUrlCrossRefPubMed
  76. ↵
    Frischmann KE, Kronenberg F, Trenkwalder E, Schafer J, Schweer H, Dieplinger B, Konig P, Ikewaki K, Dieplinger H: In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients. Kidney Int 2007 , in press
  77. ↵
    Kang DH, Yoon KI, Lee SW, Kang SW, Choi KH, Lee HY, Han DS: Impact of nutritional status on serum lipoprotein(a) concentration in patients undergoing continuous ambulatory peritoneal dialysis. Perit Dial Int 16[Suppl 1] : S241 –S245, 1996
  78. ↵
    Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L, Jogestrand T: Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 55 : 1899 –1911, 1999
    OpenUrlCrossRefPubMed
  79. ↵
    Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB: Prediction of coronary heart disease using risk factor categories. Circulation 97 : 1837 –1847, 1998
  80. ↵
    Stack AG, Bloembergen WE: Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: A cross-sectional study. J Am Soc Nephrol 12 : 1516 –1523, 2001
    OpenUrlAbstract/FREE Full Text
  81. Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco MV, Teehan BP, Levey AS: Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 58 : 353 –362, 2000
    OpenUrlCrossRefPubMed
  82. ↵
    Guz G, Nurhan Ozdemir F, Sezer S, Isiklar I, Arat Z, Turan M, Haberal M: Effect of apolipoprotein E polymorphism on serum lipid, lipoproteins, and atherosclerosis in hemodialysis patients. Am J Kidney Dis 36 : 826 –836, 2000
    OpenUrlPubMed
  83. ↵
    Iseki K, Fukiyama K: Predictors of stroke in patients receiving chronic hemodialysis. Kidney Int 50 : 1672 –1675, 1996
    OpenUrlPubMed
  84. ↵
    Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink NE, Tracy RP, Powe NR, Klag MJ: Association between cholesterol level and mortality in dialysis patients: Role of inflammation and malnutrition. JAMA 291 : 451 –459, 2004
    OpenUrlCrossRefPubMed
  85. ↵
    Longenecker JC, Klag MJ, Marcovina SM, Liu YM, Jaar BG, Powe NR, Fink NE, Levey AS, Coresh J: High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients. J Am Soc Nephrol 16 : 1794 –1802, 2005
    OpenUrlAbstract/FREE Full Text
  86. Koda Y, Nishi S, Suzuki M, Hirasawa Y: Lipoprotein(a) is a predictor for cardiovascular mortality of hemodialysis patients. Kidney Int Suppl 71 : S251 –S253, 1999
    OpenUrlCrossRefPubMed
  87. Ohashi H, Oda H, Ohno M, Watanabe S, Sakata S: Lipoprotein(a) as a risk factor for coronary artery disease in hemodialysis patients. Kidney Int Suppl 71 : S242 –S244, 1999
    OpenUrlPubMed
  88. Shoji T, Emoto M, Shinohara K, Kakiya R, Tsujimoto Y, Kishimoto H, Ishimura E, Tabata T, Nishizawa Y: Diabetes mellitus, aortic stiffness, and cardiovascular mortality in end-stage renal disease. J Am Soc Nephrol 12 : 2117 –2124, 2001
    OpenUrlAbstract/FREE Full Text
  89. Hocher B, Ziebig R, Altermann C, Krause R, Asmus G, Richter CM, Slowinski T, Sinha P, Neumayer HH: Different impact of biomarkers as mortality predictors among diabetic and nondiabetic patients undergoing hemodialysis. J Am Soc Nephrol 14 : 2329 –2337, 2003
    OpenUrlAbstract/FREE Full Text
  90. ↵
    Schwaiger JP, Lamina C, Neyer U, Konig P, Kathrein H, Sturm W, Lhotta K, Grochenig E, Dieplinger H, Kronenberg F: Carotid plaques and their predictive value for cardiovascular disease and all-cause mortality in hemodialysis patients considering renal transplantation: A decade follow-up. Am J Kidney Dis 47 : 888 –897, 2006
    OpenUrlCrossRefPubMed
  91. ↵
    Attman PO, Alaupovic P: Lipid and apolipoprotein profiles of uremic dyslipoproteinemia: Relation to renal function and dialysis. Nephron 57 : 401 –410, 1991
    OpenUrlPubMed
  92. ↵
    Lowrie EG, Lew NL: Commonly measured laboratory variables in hemodialysis patients: Relationships among them and to death risk. Semin Nephrol 12 : 276 –283, 1992
    OpenUrlPubMed
  93. ↵
    Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15 : 458 –482, 1990
    OpenUrlCrossRefPubMed
  94. ↵
    Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, Klag MJ: Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: The CHOICE Study. J Am Soc Nephrol 13 : 1918 –1927, 2002
    OpenUrlAbstract/FREE Full Text
  95. ↵
    Tatami R, Mabuchi H, Ueda K, Ueda R, Haba T, Kametani T, 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 density lipoprotein in angiographically determined coronary artery disease. Circulation 64 : 1174 –1184, 1981
  96. ↵
    Shoji T, Nishizawa Y, Kawagishi T, Kawasaki K, Taniwaki H, Tabata T, Inoue T, Morii H: Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 9 : 1277 –1284, 1998
    OpenUrlAbstract
  97. ↵
    Longenecker JC, Klag MJ, Marcovina SM, Powe NR, Fink NE, Giaculli F, Coresh J: Small apolipoprotein(a) size predicts mortality in end-stage renal disease: The CHOICE study. Circulation 106 : 2812 –2818, 2002
  98. Auguet T, Senti M, Rubies-Prat J, Pelegri A, Pedro-Botet J, Nogues X, Romero R: Serum lipoprotein(a) concentration in patients with chronic renal failure receiving haemodialysis: Influence of apolipoprotein (a) genetic polymorphism. Nephrol Dial Transplant 8 : 1099 –1103, 1993
    OpenUrlAbstract/FREE Full Text
  99. Kronenberg F, Kathrein H, Konig P, Neyer U, Sturm W, Lhotta K, Grochenig E, Utermann G, Dieplinger H: Apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease. Arterioscler Thromb 14 : 1405 –1411, 1994
    OpenUrlAbstract/FREE Full Text
  100. Wanner C, Bartens W, Walz G, Nauck M, Schollmeyer P: Protein loss and genetic polymorphism of apolipoprotein(a) modulate serum lipoprotein(a) in CAPD patients. Nephrol Dial Transplant 10 : 75 –81, 1995
    OpenUrlAbstract/FREE Full Text
  101. Emanuele E, Lusignani LS, Peros E, Montagna G, D'Angelo A, Montagna L, Geroldi D: Lipoprotein(a)-associated atherothrombotic risk in hemodialysis patients. Am J Nephrol 24 : 221 –229, 2004
    OpenUrlCrossRefPubMed
  102. Iliescu EA, Marcovina SM, Morton AR, Lam M, Koschinsky ML: Apolipoprotein(a) phenotype and lipoprotein(a) level predict peritoneal dialysis patient mortality. Perit Dial Int 22 : 492 –499, 2002
    OpenUrlAbstract/FREE Full Text
  103. Webb AT, Reaveley DA, O'Donnell M, O'Connor B, Seed M, Brown EA: Lipids and lipoprotein(a) as risk factors for vascular disease in patients on renal replacement therapy. Nephrol Dial Transplant 10 : 354 –357, 1995
    OpenUrlAbstract/FREE Full Text
  104. ↵
    Gazzaruso C, Bonetti G, Garzaniti A, Pini G, Ragazzoni A, Bianchi C, Jucci A, Buscaglia P, Geroldi D: Increased plasma concentrations of lipoprotein(a) for every phenotype of apolipoprotein(a) in patients with chronic renal failure treated by hemodialysis. Nutr Metab Cardiovasc Dis 6 : 203 –210, 1996
  105. ↵
    K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 41 : S1 –S91, 2003
    OpenUrlPubMed
  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 apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: A placebo-controlled study. Clin Nephrol 62 : 287 –294, 2004
    OpenUrlPubMed
  107. ↵
    Seliger SL, Weiss NS, Gillen DL, Kestenbaum B, Ball A, Sherrard DJ, Stehman-Breen CO: HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 61 : 297 –304, 2002
    OpenUrlCrossRefPubMed
  108. ↵
    Baigent C, Landry M: Study of Heart and Renal Protection (SHARP). Kidney Int Suppl S207 –S210, 2003
  109. ↵
    Fellstrom B, Zannad F, Schmieder R, Holdaas H, Jardine A, Rose H, Wilpshaar W: Effect of rosuvastatin on outcomes in chronic haemodialysis patients: Design and rationale of the AURORA study. Curr Control Trials Cardiovasc Med 6 : 9 , 2005
  110. ↵
    Fellstrom BC, Holdaas H, Jardine AG: Why do we need a statin trial in hemodialysis patients? Kidney Int Suppl S204 –S206, 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 rhabdomyolysis. Pharmacoepidemiol Drug Saf 16 : 352 –358, 2006
  112. ↵
    Thompson PD, Clarkson P, Karas RH: Statin-associated myopathy. JAMA 289 : 1681 –1690, 2003
    OpenUrlCrossRefPubMed
  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 patients. Arch Intern Med 163 : 553 –564, 2003
    OpenUrlCrossRefPubMed
  114. ↵
    Shek A, Ferrill MJ: Statin-fibrate combination therapy. Ann Pharmacother 35 : 908 –917, 2001
    OpenUrlAbstract/FREE Full Text
  115. ↵
    Knopp RH, Brown WV, Dujovne CA, Farquhar JW, Feldman EB, Goldberg AC, Grundy SM, Lasser NL, Mellies MJ, Palmer RH, et al.: Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. Am J Med 83 : 50 –59, 1987
    OpenUrlPubMed
  116. ↵
    Grundy SM, Vega GL: Fibric acids: Effects on lipids and lipoprotein metabolism. Am J Med 83 : 9 –20, 1987
    OpenUrlPubMed
  117. ↵
    Knopp RH: Drug treatment of lipid disorders. N Engl J Med 341 : 498 –511, 1999
    OpenUrlCrossRefPubMed
  118. ↵
    Schonfeld G: The effects of fibrates on lipoprotein and hemostatic coronary risk factors. Atherosclerosis 111 : 161 –174, 1994
    OpenUrlCrossRefPubMed
  119. ↵
    Carlson LA, Hamsten A, Asplund A: Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med 226 : 271 –276, 1989
    OpenUrlCrossRefPubMed
  120. ↵
    McKenney J: New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med 164 : 697 –705, 2004
    OpenUrlCrossRefPubMed
  121. ↵
    Superko HR, Krauss RM: Differential effects of nicotinic acid in subjects with different LDL subclass patterns. Atherosclerosis 95 : 69 –76, 1992
    OpenUrlCrossRefPubMed
  122. ↵
    Kronenberg F: Epidemiology, pathophysiology and therapeutic implications of lipoprotein(a) in kidney disease. Expert Rev Cardiovasc Ther 2 : 729 –743, 2004
    OpenUrlCrossRefPubMed
  123. ↵
    Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 110 : 3512 –3517, 2004
  124. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W: Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J Am Coll Cardiol 8 : 1245 –1255, 1986
    OpenUrlCrossRefPubMed
  125. Carlson LA, Rosenhamer G: Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 223 : 405 –418, 1988
    OpenUrlPubMed
  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, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345 : 1583 –1592, 2001
    OpenUrlCrossRefPubMed
  127. ↵
    Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62 : 245 –252, 2002
    OpenUrlCrossRefPubMed
  128. ↵
    Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, Raggi P: Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 68 : 1815 –1824, 2005
    OpenUrlCrossRefPubMed
  129. ↵
    Islam KN, O'Byrne D, Devaraj S, Palmer B, Grundy SM, Jialal I: Alpha-tocopherol supplementation decreases the oxidative susceptibility of LDL in renal failure patients on dialysis therapy. Atherosclerosis 150 : 217 –224, 2000
    OpenUrlCrossRefPubMed
  130. ↵
    Diepeveen SH, Verhoeven GW, Van Der Palen J, Dikkeschei LD, Van Tits LJ, Kolsters G, Offerman JJ, Bilo HJ, Stalenhoef AF: Effects of atorvastatin and vitamin E on lipoproteins and oxidative stress in dialysis patients: A randomised-controlled trial. J Intern Med 257 : 438 –445, 2005
    OpenUrlCrossRefPubMed
  131. ↵
    Mune M, Yukawa S, Kishino M, Otani H, Kimura K, Nishikawa O, Takahashi T, Kodama N, Saika Y, Yamada Y: Effect of vitamin E on lipid metabolism and atherosclerosis in ESRD patients. Kidney Int Suppl 71 : S126 –S129, 1999
    OpenUrlPubMed
  132. ↵
    Yukawa S, Hibino A, Maeda T, Mimura K, Yukawa A, Maeda A, Kishino M, Sonobe M, Mune M, Yamada Y, et al.: Effect of alpha-tocopherol on in vitro and in vivo metabolism of low-density lipoproteins in haemodialysis patients. Nephrol Dial Transplant 10[Suppl 3] : 1 –3, 1995
  133. ↵
    Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS: Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE): Randomised placebo-controlled trial. Lancet 356 : 1213 –1218, 2000
    OpenUrlCrossRefPubMed
  134. ↵
    Mann JF, Lonn EM, Yi Q, Gerstein HC, Hoogwerf BJ, Pogue J, Bosch J, Dagenais GR, Yusuf S: Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: Results of the HOPE study. Kidney Int 65 : 1375 –1380, 2004
    OpenUrlCrossRefPubMed
  135. ↵
    Wanner C, Bahner U, Mattern R, Lang D, Passlick-Deetjen J: Effect of dialysis flux and membrane material on dyslipidaemia and inflammation in haemodialysis patients. Nephrol Dial Transplant 19 : 2570 –2575, 2004
    OpenUrlAbstract/FREE Full Text
  136. ↵
    Bosch T, Gahr S, Belschner U, Schaefer C, Lennertz A, Rammo J: Direct adsorption of low-density lipoprotein by DALI-LDL-apheresis: Results of a prospective long-term multicenter follow-up covering 12,291 sessions. Ther Apher Dial 10 : 210 –218, 2006
    OpenUrlCrossRefPubMed
  137. ↵
    Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D, Ross CJ, Hayden MR, Bakker AC, Dijkhuizen P, Hermens WT, Twisk J, Stroes E, Kastelein JJ, Kuivenhoven JA, Meulenberg JM: Gene therapy for lipoprotein lipase deficiency: Working toward clinical application. Hum Gene Ther 16 : 1276 –1286, 2005
    OpenUrlCrossRefPubMed
  138. ↵
    Fazio S, Linton MF: Apolipoprotein AI as therapy for atherosclerosis: Does the future of preventive cardiology include weekly injections of the HDL protein? Mol Interv 3 : 436 –440, 2003
    OpenUrlCrossRefPubMed
  139. ↵
    Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Rohl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoharan M, Vornlocher HP: Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432 : 173 –178, 2004
    OpenUrlCrossRefPubMed
  140. Mason NA, Bailie GR, Satayathum S, Bragg-Gresham JL, Akiba T, Akizawa T, Combe C, Rayner HC, Saito A, Gillespie BW, Young EW: HMG-coenzyme a reductase inhibitor use is associated with mortality reduction in hemodialysis patients. Am J Kidney Dis 45 : 119 –126, 2005
    OpenUrlCrossRefPubMed
  141. Winkelmayer WC, Charytan DM, Levin R, Avorn J: Poor short-term survival and low use of cardiovascular medications in elderly dialysis patients after acute myocardial infarction. Am J Kidney Dis 47 : 301 –308, 2006
    OpenUrlCrossRefPubMed
  142. Gotz AK, Boger CA, Hirschmann C, Schmitz G, Riegger GA, Kramer BK: Effect of HMG-CoA-reductase inhibitors on survival in type 2 diabetes patients with end stage diabetic nephropathy. Eur J Med Res 10 : 155 –160, 2005
    OpenUrlPubMed
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Lipoprotein Metabolism and Lipid Management in Chronic Kidney Disease
Bonnie C.H. Kwan, Florian Kronenberg, Srinivasan Beddhu, Alfred K. Cheung
JASN Apr 2007, 18 (4) 1246-1261; DOI: 10.1681/ASN.2006091006
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