Kidney International, Vol. 56, Suppl. 71 (1999), pp. S-248–S-250

Abnormalities in lipoprotein metabolism inhemodialysis patients

MICHAELA KONIGER, THOMAS QUASCHNING, CHRISTOPH WANNER, PETER SCHOLLMEYER,and ANNETTE KRAMER-GUTH

Department of Medicine, Division of Nephrology, University of Freiburg, Freiburg, and Department of Medicine,Division of Nephrology, University of Wurzburg, Wurzburg, Germany

Abnormalities in lipoprotein metabolism in hemodialysis pa- mained the most commonly reported cause of death.tients. Multiple factors contribute to the atherosclerotic pro-

Background. Patients on chronic hemodialysis treatment cess, but dyslipidemia, which is frequently found in pa-are at elevated atherogenic risk, and dyslipidemia appears to betients on HD, is one of the key factors in the initiationone of the major risk factors. However, most of these patientsand acceleration of atherosclerosis. Lipoprotein metabo-exhibit elevated serum triglycerides, whereas serum cholesterol

and low-density lipoprotein (LDL) cholesterol levels are in the lism is influenced by many determinants as the dialysisnormal range. This study was therefore designed to examine treatment itself, the use of heparin as anticoagulant, thethe influence of hypertriglyceridemia under the condition of

membrane material, and the underlying uremia [1]. Anhemodialysis and diabetes mellitus on LDL metabolism.atherogenic and typical lipoprotein profile can be de-Methods. LDL was isolated from healthy controls, hyper-

triglyceridemic diabetic patients, and nondiabetic hemodialysis tected consisting of hypertriglyceridemia with elevationpatients (N 5 30, 10 in each group), which were separated into of triglycerides in the very low-density lipoproteinsix subfractions by density gradient ultracentrifugation and (VLDL) and LDL density class, low high-density lipo-were characterized concerning lipid/protein composition, de-

protein (HDL) cholesterol and normal or only slightlygree of glycation, and oxidation. Uptake of 125I-labeled LDLelevated serum cholesterol levels [2]. In diabetic patientswas examined via LDL receptors of HepG2 cells and scavenger

receptors of mouse peritoneal macrophages. [non–insulin-dependent diabetes mellitus (NIDDM)] onResults. In hemodialysis patients, serum triglycerides were HD treatment, diabetes mellitus additionally impedes

significantly elevated, whereas cholesterol levels were withinlipoprotein metabolism by aggravation of hypertriglycer-the normal range. Triglyceride enrichment occurred in the veryidemia and further modification of lipoproteins. Thislow-density lipoprotein (VLDL) class and LDL class, and an

accumulation of a highly atherogenic small dense LDL subfrac- form of dyslipidemia, with LDL cholesterol levels in thetion could be detected predominantly in patients with non– normal range, may contribute to an elevated atherogenicinsulin-dependent diabetes mellitus. LDL of hemodialysis pa- risk, especially in the presence of diabetes mellitus. Intients also contained elevated levels of lipid peroxidation

this study, we therefore examined LDL metabolism un-products, which were even higher in diabetic patients. Alter-der the condition of HD treatment and diabetes mellitusations in composition, size, and configuration of LDL from

diabetic and nondiabetic patients on hemodialysis impaired and their potential impact on the pathogenesis of athero-LDL receptor-mediated degradation and enhanced the uptake sclerosis.of these modified LDL particles via nonsaturable scavengerreceptors.

Conclusion. Diminished LDL receptor-mediated uptake of METHODSmodified, triglyceride-rich, small dense LDL most likely leadsto accumulation of these lipoproteins in vivo, favoring the Low-density lipoprotein was isolated from plasma ofdevelopment of atherosclerotic lesions. Future clinical studies healthy controls (CO), hypertriglyceridemic diabeticmust demonstrate whether patients will benefit from reducing (NIDDM-HD) HD patients, and hypertriglyceridemicthese atherogenic particles by lipid-lowering intervention.

nondiabetic HD patients (HD) (N 5 30, 10 in eachgroup) by sequential ultracentrifugation. LDL was char-acterized concerning lipid/protein composition, distribu-Despite the tendency toward better survival in hemo-tion of LDL subfractions by density gradient centrifuga-dialysis (HD) patients, cardiovascular disease has re-tion [3], and glycation of apo B with the “Glycacor”enzyme immunoassay from Exocell (Philadelphia, PA,

Key words: diabetes mellitus, hypertriglyceridemia, LDL-subfractions. USA). Lipid peroxides in LDL and thiobarbituric acidreactive substances (TBARS) were determined [4]. Lag 1999 by the International Society of Nephrology

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Koniger et al: LDL metabolism in hemodialysis patients S-249

Table 1. Lipid distribution among various lipoprotein density classes in hemodialysis patients

Total LDL VLDL Total LDL VLDLChol Chol Chol TG TG TG

mmol /liter

CO 4.2060.75 2.56 60.54 0.23 60.13 0.87 60.38 0.14 60.02 0.58 60.38HD 5.3460.98a 3.2160.83 1.09 60.47a 3.3960.78a 0.5760.16a 2.4860.67a

NIDDM-HD 6.3760.16a 3.1960.73 2.20 61.71a 5.4263.24a 0.6860.23a 4.0163.57a

Abbreviations are: CO, controls (N 5 10); HD, hemodialysis patients (N 5 10); NIDDM-HD, hemodialysis patients with type 2 diabetes mellitus (N 5 10); Chol,cholesterol; TG, triglycerides. Data are given as mean 6 sem.

a P , 0.05 versus controls

time and diene formation [5] were measured to determinesusceptibility to oxididation of the different LDL prepara-tions. Uptake kinetics were performed with HepG2 cellsand mouse peritoneal macrophages by the method of Gold-stein, Basu, and Brown [6].

RESULTS

In our HD patients, elevated serum triglycerides andtriglyceride enrichment of VLDL and LDL were consis-tent findings. This was most pronounced in patients withdiabetes mellitus. In contrast, total cholesterol levelswere only slightly elevated (Table 1). Subfractionation ofLDL revealed that hypertriglyceridemia was associatedwith an atherogenic LDL subfraction pattern. The in-crease in LDL triglycerides was due to an accumulationof a triglyceride-rich large, buoyant fraction (LDL-1,density range, 1019 to 1031 kg/liter) and a small dense Fig. 1. Concentration-dependent degradation of 125I-labeled low-den-

sity lipoprotein (LDL) by cultures of HepG2 cells. LDL obtained fromfraction (LDL-6, density range, 1044 to 1060 kg/liter),healthy controls (open bars), LDL obtained from hemodialysis patientsboth subfractions known for their low affinity to the LDL (serum triglycerides . 2.28 mmol/liter, dotted bars), and LDL obtainedfrom hemodialysis patients with non–insulin-dependent diabetes melli-receptor and high atherogenicity. The largest enrichmenttus (serum triglycerides . 2.28 mmol/liter, hatched bars). Data arein LDL-6 was detected in the hypertriglyceridemic dia-given as mean 6 sem of 10 subjects in every group. All measurements

betic HD patients (HD, 73.6 6 4.6 mg/dl; NIDDM-HD, were carried out in triplicate. *P , 0.05 vs. controls.84.4 6 5.2 mg/dl vs. CO, 29.0 6 4.5 mg/dl, P , 0.01).

To identify modifications of LDL that may addition-ally reduce uptake via LDL receptor, especially in dia-

DISCUSSIONbetic patients, we measured the degree of glycation ofapo B of LDL and found elevated concentrations in the Hypertriglyceridemia, especially in combination withdiabetic patients (HD, 2.6 6 0.4%; NIDDM-HD, 4.7 6 diabetes mellitus, contributes to the elevated cardiovas-1.6% vs. CO, 2.5 6 0.4%, P , 0.05). Significant changes cular risk of HD patients. In this study, LDL, isolatedin lag time or diene formation could not be detected, from hypertriglyceridemic nondiabetic and diabetic HDbut lipid peroxides in LDL were significantly elevated, patients, exhibited impaired receptor specific uptake viaespecially in diabetic patients with higher concentrations the LDL receptor of HepG2 cells. LDL degradation wasof glycated apo B (HD, 0.058 6 0.028; NIDDM-HD, even more reduced if hypertriglyceridemia was aggra-0.158 6 0.126 vs. CO, 0.027 6 0.016 mmol/100 mg LDL vated by coexisting diabetes mellitus.protein, P , 0.05). Binding experiments with 125I-labeled In HD treatment and diabetes mellitus, a number ofLDL in HepG2 cells (Fig. 1) showed that these modified conditions are present, which may account for dimin-LDL were taken up by the LDL receptor of HepG2 cells ished cellular LDL metabolism: Independent of the etiol-with lower affinity than control LDL but were enhanced ogy, hypertriglyceridemia leads to prominent composi-taken up by scavenger receptors of macrophages. This tional and configurational changes of LDL particles [7].was most pronounced for LDL of hypertriglyceridemic Triglyceride-rich LDLs are smaller and denser particles

than control LDLs, and the alteration in the lipid-proteindiabetic patients.

Koniger et al: LDL metabolism in hemodialysis patientsS-250

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Reprint requests to Michaela Koniger, M.D., Department of Medi-tibility to in vitro oxidation among hypertriglyceridemic subjects:cine, Division of Nephrology, University of Freiburg, Hugstetterstr. 55,Normalization after clofibrate treatment. Arterioscler ThrombD-79106 Freiburg, Germany.13:712–719, 1993E-mail: koeniger@mm41.ukl.uni-freiburg.de