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      Compositional Lipoprotein Changes and Low-Density Lipoprotein Susceptibility to Oxidation in Chronic Renal Failure Patients with Heavy Proteinuria

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          Background: There are limited data regarding qualitative lipoprotein abnormalities in undialysed uremic patients without proteinuria. In this report, we focused on lipoprotein changes observed in uremic patients with proteinuria as well as on the susceptibility of low-density lipoprotein (LDL) of these patients to oxidative modification in vitro. Methods: 20 patients with chronic renal failure [serum creatinine >1.6 mg/dl (141.4 µmol/l)], but not yet on renal replacement therapy, and with heavy proteinuria (>2 g/24 h), and 18 age- and sex-matched healthy individuals participated in the study. In both patients and controls, venous blood was collected for determination of serum lipid and lipoprotein levels, lipoprotein subfraction profile and chemical composition, as well as the susceptibility of LDL subfractions to oxidation. Results: Patients exhibited a more atherogenic lipid profile compared with the control population. Furthermore, the total very LDL + intermediate-density lipoprotein mass was increased in patients compared with controls, while this subfraction was triglyceride enriched in uremic patients. The total LDL concentration was significantly higher in patients compared with controls due mainly to an increase in the mass of all lipoprotein subfractions. It is noteworthy that the mass of small dense LDL was significantly elevated in patients compared with controls (135 ± 12 vs. 115 ± 11 mg/dl, p = 0.01), an increase which was more pronounced in hypertriglyceridemic patients. Furthermore, the subfraction high-density lipoprotein-2 mass was significantly lower in uremic patients compared with controls. Finally, no significant differences in the lag time, the rate of oxidation and the relative electrophoretic mobility values in each LDL subfraction between the two groups were observed. Conclusion: We conclude that uremic patients with heavy proteinuria exhibit compositional lipoprotein changes that are less marked than those observed in nonuremic patients with nephrotic syndrome. However, there is no evidence that circulating LDL isolated from these patients is more susceptible to oxidation in vitro than lipoprotein isolated from age- and gender-matched controls.

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          Most cited references 6

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          A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.

          To test whether a predominance of small, dense low-density lipoprotein (LDL) particles and elevated triglyceride levels are independent risk factors for myocardial infarction (MI). Nested case-control study with prospectively collected samples. Prospective cohort study. Blood samples were collected at baseline (85% nonfasting samples) from 14916 men aged 40 to 84 years in the Physicians' Health Study. Myocardial infarction diagnosed during 7 years of follow-up. Cases (n=266) had a significantly smaller LDL diameter (mean [SD], 25.6 [0.9] nm) than did controls (n=308) matched on age and smoking (mean [SD], 25.9 [8] nm; P<.001). Cases also had higher median triglyceride levels (1.90 vs 1.49 mmol/L [168 vs 132 mg/dL]; P<.001). The LDL diameter had a high inverse correlation with triglyceride level (r=-0.71), and a high direct correlation with high-density lipoprotein cholesterol (HDL-C) level (r=0.60). We observed a significant multiplicative interaction between triglyceride and total cholesterol (TC) levels (P=.01). After simultaneous adjustment for lipids and a variety of coronary risk factors, LDL particle diameter was no longer a statistically significant risk indicator, with a relative risk (RR) of 1.09 (95% confidence interval [CI], 0.85-1.40) per 0.8-nm decrease. However, triglyceride level remained significant with an RR of 1.40 (95% CI, 1.10-1.77) per 1.13 mmol/L (100-mg/dL) increase. The association between triglyceride level and MI risk appeared linear across the distribution; men in the highest quintile had a risk about 2.5 times that of those in the lowest quintile. The TC level, but not HDL-C level, also remained significant, with an RR of 1.80 (95% CI, 1.44-2.26) per 1.03-mmol/L (40-mg/dL) increase. These findings indicate that nonfasting triglyceride levels appear to be a strong and independent predictor of future risk of MI, particularly when the total cholesterol level is also elevated. In contrast, LDL particle diameter is associated with risk of MI, but not after adjustment for triglyceride level. Increased triglyceride level, small LDL particle diameter, and decreased HDL-C levels appear to reflect underlying metabolic perturbations with adverse consequences for risk of MI; elevated triglyceride levels may help identify high-risk individuals.
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            The atherogenic lipoprotein phenotype: small dense LDL and lipoprotein remnants in nephrotic range proteinuria.

             C. Deighan (2001)
            The dyslipidaemia in nephrotic-range proteinuria is believed to contribute to the increased atherogenesis associated with the condition. Excess small dense low density lipoprotein (LDLIII) contributes to this risk. Lipoprotein remnants (RLP) may also be implicated but have not been studied in this population. We measured the plasma concentration of low density lipoprotein (LDL) subfractions (by density gradient ultracentrifugation), RLP (by immunoaffinity gel), very low density lipoprotein (VLDL) subfractions, post heparin lipases and cholesteryl ester transfer protein (CETP) activity in 27 patients with glomerular disease and albuminuria >2.0g. These were compared with 27 age and sex matched controls. Proteinuric patients had increased LDLIII concentration (patients 182 (84:267) vs. controls 31 (27:62); P<0.0001) with reduced lighter LDLI (36 (24:43) vs 69 (46:101); P<0.0005) and LDLII (124 (79:220) vs 178 (129:236); P<0.04, all mg/dl, median+interquartile range). RLP-cholesterol (RLP-C) and triglyceride (RLP-TG) were increased in proteinuric patients (RLP-C 18.9 (11.0:26.9) vs 7.7 (6.0:8.8); P<0.0001, RLP-TG 35.8 (11.8:54.7) vs. 7.2 (4.3:10.0); P<0.0001, all mg/dl). Increased LDLIII and RLP were independent of renal function. VLDL(1) and VLDL(2) concentrations were increased by 258 and 260% (both P<0.0001). CETP activity was increased by 46% (P<0.005). Lipoprotein and hepatic lipase activities did not differ from control values. LDLIII concentration (r(2)=45.7%, P<0.001), RLP-C (r(2)=85.2%, P<0.001) and RLP-TG (r(2)=87.5%, P<0.001) all correlated positively with plasma triglyceride. Moreover, increased LDLIII was associated with both RLP-C (r(2)=31.3%, P<0.002) and RLP-TG (r(2)=33.6%, P<0.002). Excess LDLIII and RLP are present in nephrotic-range proteinuria and add to the spectrum of cardiovascular risk factors present in proteinuric patients. Increases in LDLIII and RLP are closely related to plasma triglyceride. The association between excess RLP and LDLIII suggests that RLP contribute to the increased atherogenicity attributed to the atherogenic lipoprotein phenotype.
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              Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women

               C Gardner (1996)

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                November 2003
                17 November 2004
                : 95
                : 3
                : c77-c83
                Departments of aChemistry, Laboratory of Biochemistry, bNephrology and cInternal Medicine, and dLaboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece
                74320 Nephron Clin Pract 2003;95:c77–c83
                © 2003 S. Karger AG, Basel

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                Tables: 6, References: 34, Pages: 1
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