Abnormalities in uremic lipoprotein metabolism and its impact on cardiovascular disease

doi:10.1053/ajkd.2001.27384

American Journal of Kidney Diseases

Volume 38, Issue 4, Supplement, October 2001, Pages S14-S19

https://doi.org/10.1053/ajkd.2001.27384 Get rights and content

Abstract

Patients with end-stage renal disease (ESRD) suffer from a secondary form of complex dyslipidemia consisting of both quantitative and qualitative abnormalities in serum lipoproteins resulting from alterations in lipoprotein metabolism and composition. The prominant features of uremic dyslipidemia are an increase in serum triglyceride levels (due to elevated very low density lipoprotein [VLDL]-remnants and intermediate-density lipoprotein [IDL]) and low high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein (LDL) cholesterol often is normal, but the cholesterol may originate from the atherogenic small and dense LDL subclass (sdLDL). The apolipoprotein B (apoB)-containing part of the lipoprotein may undergo modifications (enzymatic- and advanced glycation end-product [AGE]-peptide modification, oxidation, or glycosilation). Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote prolonged circulation. While LDL particles undergo a vicious cycle of accumulation and modification, reverse cholesterol transport is also impaired due to low lecithin:cholesterol acyltransferase (LCAT) and paraoxonase activity. Therefore, discoid HDL particles are structurally altered and hepatic cholesterol clearance is limited. The composition of HDL may also be altered during states of inflammation. The contribution of this complex and atherogenic form of dyslipidemia to cardiovascular disease in patients with renal disease is unclear at present. Most studies are negative in demonstrating the predictive power of serum lipids for the development of cardiovascular disease. This is most likely due to interference with deteriorating aspects of the activated acute-phase response. Nevertheless, patients with renal disease belong to a very high cardiovascular risk group and dyslipidemia should most likely be subjected to sufficient lipid-lowering therapy in most patients. Because it is also still unclear whether we have available therapies with sufficient impact on LDL size, remnant lipoprotein-lowering, and restoration of HDL function, we urgently need the results from large scale intervention trials such as the 4D-trial and the CHORUS study. © 2001 by the National Kidney Foundation, Inc.

Section snippets

Significance of apolipoprotein B (apoB)-containing lipoproteins in atherosclerosis

In ESRD, serum triglycerides are elevated due to the enhanced production and accumulation of triglyceride-rich lipoproteins such as very low density lipoproteins (VLDL; Fig 1).[4], [5] Correspondingly, components of triglyceride-rich lipoproteins such as apoB, apoC-llI, and apoE, exhibit elevated serum levels in end-stage renal failure.⁶

In the Monitored Atherosclerosis Regression Study (MARS), a number of correlations were found between these markers of accumulated apoB-containing lipoproteins

High-density lipoprotein (HDL)-metabolism

Uremia is considered to be a state of activated acute-phase response. High serum concentrations of interleukin-6 and C-reactive protein (CRP) predict future all-cause and cardiovascular mortality in hemodialysis patients.[11], [12] In this microinflammatory milieu, a number of acute-phase proteins [eg, fibrinogen and lipoprotein(a) {Lp(a)}], known predictors of CAD in hemodialysis patients,¹³ are elevated in plasma. On the other hand, a number of antiatherogenic factors are diminished, among

Modification and accumulation of lipoproteins: a ″vicious cycle”

In addition to quantitative changes of lipoprotein particles, several compositional and qualitative lipoprotein changes have been demonstrated to occur in ESRD, including modification of the apoB moiety such as oxidation, carbamoylation, and glycation or transformation by advanced glycation end-products (AGEs). Modified lipoproteins are not readily recognized by their respective receptors.¹⁷ They may exhibit an increased half life by remaining in the circulation until they are taken up by

Differences in atherogenicity among lipoprotein subclasses

The best known example for elevated atherosclerotic risk of a distinct lipoprotein subclass is small dense LDL, which confers at least a 3-fold higher risk compared with large LDL.²⁴ Patients with diabetic nephropathy and especially hyper-triglyceridemic diabetics on hemodialysis²⁵ accumulate large amounts of small dense LDL. Small dense LDL promote atherosclerotic processes²⁶ and increase the risk for myocardial infarction²⁷ and coronary artery disease in general.[28], [29], [30], [31]

Lp(a)

Lp(a), identified as an independent risk factor for atherosclerotic cardiovascular disease, was found to be consistently elevated in a considerable proportion of patients with proteinuria or ESRD. Plasma concentrations of Lp(a) are highly inheritable and are mainly determined by a size polymorphism of apo(a). In patients with proteinuria, with the nephrotic syndrome, or on dialysis, however, elevation of Lp(a) is not only related to size polymorphism of apo(a). Lp(a) concentrations in plasma

Effects of modified lipoproteins on oxidant stress, endothelial function, and apoptosis

An impairment of endothelial function is considered to be the first step in the pathogenesis of atherosclerosis. Pathophysiological conditions associated with impaired endothelial function include, among others, hypercholesterolemia³⁷ and diabetes mellitus.³⁸ Suggested mechanisms underlying the effects of lipoproteins have in common that oxidative modification of the lipoprotein is considered to be a prerequisite for endothelial damage.³⁹ Therefore, elevated oxidative stress in ESRD is

Cholesteryl ester transfer protein (CETP) gene mutation, lecithin-cholesteryl acyltansferase (LCAT), and vascular disease

As noted above, among hemodialysis patients, a decreased HDL cholesterol concentration is the most commonly observed abnormality of lipid metabolism and apparently is a risk factor for vascular disease. This form of dyslipidemia may arise from reduced activity of lipoprotein lipase, LCAT, and/or hepatic triglyceride lipase.

Hemodialysis patients have also been reported to have decreased rates of cholesterol ester transfer from HDL, which indicates impaired reverse cholesterol transport. A common

Rationale for lipid lowering treatment in ESRD

The quantities of abnormal lipoprotein particles in uremia and their associated coronary heart disease are underestimated by conventional cholesterol measurement. Therefore, a specific strategy based on LDL cholesterol, HDL cholesterol, and triglycerides has to be developed for renal patients to identify those with a high cardiovascular risk in which lipid-lowering treatment is mandatory. The absolute risk of patients on dialysis with type 2 diabetes dying from cardiovascular disease usually

Conclusion

Combined hyperlipidemia (elevated cholesterol and triglycerides) with a low HDL cholesterol level reflects a probably more atherogenic condition than does isolated elevation of LDL cholesterol. Individuals with elevated triglycerides are observed to have higher risk lipoprotein subclass profiles, which are even more aggravated if diabetes mellitus is the underlying disease. Lipoprotein particles, which are abnormally composed, may remain in the circulation for prolonged periods of time and are

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Abnormalities in uremic lipoprotein metabolism and its impact on cardiovascular disease

Abstract

Section snippets

Significance of apolipoprotein B (apoB)-containing lipoproteins in atherosclerosis

High-density lipoprotein (HDL)-metabolism

Modification and accumulation of lipoproteins: a ″vicious cycle”

Differences in atherogenicity among lipoprotein subclasses

Lp(a)

Effects of modified lipoproteins on oxidant stress, endothelial function, and apoptosis

Cholesteryl ester transfer protein (CETP) gene mutation, lecithin-cholesteryl acyltansferase (LCAT), and vascular disease

Rationale for lipid lowering treatment in ESRD

Conclusion

Am J Kidney Dis

Atherosclerosis

Kidney Int

Am J Kidney Dis

Lancet

Am Heart J

Atherosclerosis

Atherosclerosis

Kidney Int

Kidney Int Suppl

Am J Kidney Dis

Glomerular macrophages and the mesangial proliferative response in the experimental nephrotic syndrome

Am J Pathol

Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis

Kidney Int Suppl

Endothelial function in proteinuric renal disease

Kidney Int

Abnormal lipid and apolipoprotein composition of major lipoprotein density classes in patients with chronic renal failure

Nephrol Dial Transplant

Progression of renal failure: Role of apolipoprotein B-containing lipoproteins

Kidney Int Suppl

The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results

Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression

Arterioscler Thromb Vasc Biol

Intermediate density lipoproteins as an independent risk factor for aortic atherosclerosis in hemodialysis patients

J Am Soc Nephrol

Apolipoprotein B, fibrinogen, HDL cholesterol, and apolipoprotein(a) phenotypes predict coronary artery disease in hemodialysis patients

J Am Soc Nephrol

Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year follow-up of 8000 men

Arterioscler Thromb Vasc Biol

A cholesteryl ester transfer protein gene mutation and vascular disease in dialysis patients

J Am Soc Nephrol

The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group

N Engl J Med