Post-prandial lipoprotein metabolism in nephrotic syndrome

Post-prandial lipaemia was investigated in a group of nine subjects with nephrotic syndrome by following the concentrations of triglyceride and retinyl palmitate in the d < 1.006 g ml-1 fraction of plasma after a standard oral fat load containing vitamin A. Lipoprotein lipase and hepatic triglyceride lipase activities were measured in post-heparin plasma. Subjects with other renal disease but insignificant proteinuria acted as controls. The time course of the lipaemic response was similar in both groups although individual patients demonstrated a prolonged lipaemia. Overall, there were no significant differences in the rise in triglyceride at 6 h (nephrotic--median 2.53 mmol l-1; range 0.87-4.76 vs. control 1.88; 0.38-4.12, P = 0.34), the peak concentration of retinyl palmitate (nephrotic 0.87 mg dl-1; 0.27-2.16 vs. control 0.65; 0.24-1.89, P = 0.97) or the areas under the curve from 0-24 h for triglyceride (nephrotic 10.5 mmol. h l-1; 2.9-43.6 vs. control 9.7; 4.3-27.0, P = 1.0) or retinyl palmitate (5.5 mg.h dl-1; 1.0-23.4 vs. 4.3; 1.5-12.4, P = 0.7). At baseline, the particles in the d < 1.006 g ml-1 fraction of plasma from nephrotic subjects had a higher free cholesterol:phospholipid ratio but this difference was no longer apparent 6 h after the test meal. There were no differences in total heparin-releasable lipase, lipoprotein lipase or hepatic triglyceride lipase activities between the two groups. These data suggest that impaired clearance of chylomicrons is not a major contributor to nephrotic hyperlipidaemia in man.     

Low-density lipoprotein metabolism and its association to plasma lipoprotein(a) in the nephrotic syndrome

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low-density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 ± 6.4 vs. 13.1 ± 0.3 mg kg^–1 day^–1; P  < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 ± 0.04 vs. 0.33 ± 0.008 pools day^–1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB-FCR. Serum albumin was inversely correlated with the LDL apoB production rate ( R  = –0.82; P  < 0.05). Plasma lipoprotien (a) [Lp(a)] levels were significantly ( P  < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate ( R  = 0.90; P  < 0.01), VLDL-cholesterol ( R  = 0.95; P  < 0.001) and VLDL-triglycerides ( R  = 0.80; P  < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor-mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.     

儿童肾病综合征患者血浆氧化低密度脂蛋白及其免疫复合物水平

目的分析儿童肾病综合征（NS）患儿血浆氧化低密度脂蛋白（ox-LDL）及其免疫复合物（LDL-IC）水平的变化。方法采用酶联免疫吸附试验（ELISA）分别测定106例活动期儿童NS患儿、42例恢复期儿童NS患儿和155名健康对照者ox-LDL和LDL-IC水平,同时对受检者血脂水平进行检测。结果恢复期及活动期NS患儿的ox-LDL水平均高于对照组（P〈0.05、P〈0.01）,且活动期高于恢复期（P〈0.01）;活动期NS患儿LDL-IC水平高于恢复期NS患儿和对照组（P〈0.01）。NS患儿ox-LDL、LDL-IC分别与总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）和尿素（Urea）呈正相关,与白蛋白（A lb）呈负相关。活动期NS患儿经类固醇治疗后,A lb水平升高,ox-LDL、LDL-IC、TC、TG和LDL-C水平下降。结论 NS患儿ox-LDL及LDL-IC水平明显升高,可能参与动脉粥样硬化的发生、发展过程。     

儿童肾病综合征患者血浆氧化低密度脂蛋白及其免疫复合物水平

目的分析儿童肾病综合征(NS)患儿血浆氧化低密度脂蛋白(ox-LDL)及其免疫复合物(LDL-IC)水平的变化。方法采用酶联免疫吸附试验(ELISA)分别测定106例活动期儿童NS患儿、42例恢复期儿童NS患儿和155名健康对照者ox-LDL和LDL-IC水平,同时对受检者血脂水平进行检测。结果恢复期及活动期NS患儿的ox-LDL水平均高于对照组(P<0.05、P<0.01),且活动期高于恢复期(P<0.01);活动期NS患儿LDL-IC水平高于恢复期NS患儿和对照组(P<0.01)。NS患儿ox-LDL、LDL-IC分别与总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和尿素(Urea)呈正相关,与白蛋白(A lb)呈负相关。活动期NS患儿经类固醇治疗后,A lb水平升高,ox-LDL、LDL-IC、TC、TG和LDL-C水平下降。结论 NS患儿ox-LDL及LDL-IC水平明显升高,可能参与动脉粥样硬化的发生、发展过程。     

Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.

Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population.     

Elevated oxidized low-density lipoprotein concentrations in postmenopausal women with the metabolic syndrome

BackgroundLow-density lipoprotein cholesterol (LDL-C) and oxidized low-density lipoprotein (ox-LDL) are probably associated with atherosclerosis and coronary artery disease. The influence of LDL-C and ox-LDL on metabolic syndrome among healthy, postmenopausal women has not been well studied. The aim of this study was to assess the association between LDL-C, ox-LDL, and metabolic syndrome in postmenopausal women.MethodsThe study design was a cross-sectional study. A total of 1309 postmenopausal women (355 with metabolic syndrome and 954 without metabolic syndrome) aged 60–79 years were included. Lipid profiles, glucose, ox-LDL, adiponectin, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α concentrations were measured.ResultsPlasma ox-LDL levels were higher in subjects with metabolic syndrome, when compared without metabolic syndrome subjects. A multiple linear regression analysis revealed that ox-LDL was significantly associated with high-density lipoprotein cholesterol, LDL-C, triglycerides, and adiponectin. After a multivariable adjustment, the odds ratios for the second, third, and fourth quartiles of ox-LDL in metabolic syndrome compared with the lowest quartile were 1.76 (95% confidence interval [CI], 1.15–2.70), 2.45 (95% CI, 1.58–3.79), and 3.98 (95% CI, 2.52–6.28), respectively. LDL levels were not significantly associated with metabolic syndrome.ConclusionsOx-LDL concentration was associated with metabolic syndrome in postmenopausal women. These findings suggest that high ox-LDL levels are associated with high cardiovascular risk in postmenopausal women with metabolic syndrome.     

Effects of atorvastatin and simvastatin on low-density lipoprotein subfraction profile, low-density lipoprotein oxidizability, and antibodies to oxidized low-density lipoprotein in relation to carotid intima media thickness in familial hypercholesterolemia.

BACKGROUND: Little is known about the effects of statins on the quality of circulating low-density lipoprotein (LDL) in relation to atherosclerosis progression. METHODS: In a double-blind, randomized trial of 325 patients with familial hypercholesterolemia (FH), we assessed the effects of high-dose atorvastatin (80 mg) and conventional-dose simvastatin (40 mg) on LDL subfraction profile (n = 289), LDL oxidizability (n = 121), and circulating autoantibodies to oxidized LDL (n = 220). Progression of atherosclerosis was measured by carotid intima media thickness (IMT) (n = 325). RESULTS: At baseline, the patients showed an intermediate LDL subfraction profile composed of three LDL subfractions (LDL1, LDL2, LDL3), with LDL2 as the predominant subfraction. A strong negative correlation was found between plasma triglycerides and the LDL subfraction profile (r = -.64, p = .000). Both plasma levels of triglycerides and small dense LDL3 correlated weakly with baseline IMT (r = .11, p = .04 and r = .15, p = .01, respectively; n = 289). No association was found between baseline IMT and oxidation parameters or circulating antibodies to oxidized LDL. Atorvastatin reduced triglycerides, LDL cholesterol, and all LDL subfractions to a greater extent than did simvastatin and led to regression of carotid IMT. However, LDL subfraction pattern and plasma levels of autoantibodies to oxidized LDL remained unchanged in both treatment groups, and LDL oxidizability increased minimally to a similar extent in both groups. Significant treatment differences were found for the rate of in vitro oxidation of LDL and the amount of dienes formed during in vitro oxidation of LDL, which both decreased more following atorvastatin than after simvastatin. CONCLUSION: Change of IMT after statin treatment was associated with baseline IMT (r = .41), LDL cholesterol (r = -.20), and the amount of dienes formed during in vitro oxidation of LOL (r = .28) but not with plasma levels of antibodies to oxidized LDL, in vitro LDL oxidizability, and LDL subfraction profile.     

A case of nephrotic syndrome due to lupus nephritis which was controlled with low-density lipoprotein apheresis.

Our report discusses a 29 year old female patient with nephrotic syndrome due to lupus nephritis, biopsy-proven World Health Organization classification Types IVb and V that was controlled with low-density lipoprotein (LDL) apheresis. She was initially treated with steroid therapy, including methylprednisolone pulse therapy, and the serological activity of her systemic lupus erythematosus was suppressed. However, her nephrotic state, accompanied by severe hyperlipidemia, persisted despite the steroid therapy. Since we could not obtain her consent to administer immunosuppressants such as cyclophosphamide, we tried to treat her using LDL apheresis (LDL-A). We found that her urine protein excretion, hyperlipidemia, hypoalbuminemia, and renal function improved following the initiation of LDL-A. This suggests that LDL-A may be an effective therapy for nephrotic syndrome due to lupus nephritis through short-term amelioration of hyperlipidemia.     

Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations

BACKGROUND: Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol-lowering drug simvastatin has an extensive first-pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40-mg dose of simvastatin was administered orally. Plasma concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography-ion spray tandem mass spectrometry method. RESULTS: Rifampin decreased the total area under the plasma concentration-time curve of simvastatin and simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both simvastatin and simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half-life of simvastatin or simvastatin acid. CONCLUSIONS: Rifampin greatly decreases the plasma concentrations of simvastatin and simvastatin acid. Because the elimination half-life of simvastatin was not affected by rifampin, induction of the CYP3A4-mediated first-pass metabolism of simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterol-lowering efficacy of simvastatin.     

The metabolism in vivo and in vitro of plasma low-density lipoprotein from a subject with inherited hypercholesterolaemia.

1. The metabolism in vivo and in vitro of an abnormal low-density lipoprotein (LDL) obtained from a patient with an inherited form of hypercholesterolaemia was compared with that of LDL obtained from a normal subject. 2. The rates of turnover of the apoprotein of the two types of LDL in a normal subject, and their uptake and catabolism by normal lymphocytes in vitro, were similar. 3. It is concluded that the abnormal behaviour of the patient's LDL may not be due to an abnormality in the apoprotein component.     

Calcium and phosphorus metabolism in nephrotic syndrome.

Calcium and phosphorus balance studies were performed on 13 nephrotic patients and eight patients during clinical remission of the nephrotic syndrome. Marked impairment of intestinal absorption of calcium was found among nephrotic patients, in eight of whom faecal calcium equalled or exceeded dietary calcium. The mean faecal:dietary calcium ratio of nephrotic patients, 1-06 +/- 0-23 (SD), was significantly higher (p less than 0-005) than that of patients in remission, 0-58 +/- 0-21 (SD). The mean 24-hour urinary excretion of calcium of nephrotic patients, 0-68 +/- 0-68 (SD) mmol, was significantly lower (p less than 0-005) than that of patients in remission, 3-02 +/- 1-91 (SD) mmol. Calciferol administered to three nephrotic patients in the dosage of 1.25 mg per day did not significantly influence intestinal absorption or renal excretion of calcium. There was no difference between the two groups of patients in intestinal absorption or renal excretion of phosphorus; there was net intestinal absorption in all subjects. Quantitative bone histology was studied in seven of the nephrotic patients. None had osteomalacia or osteitis fibrosa, while only one had evidence of mild osteoporosis.     

Circulating malondialdehyde-modified low-density lipoprotein is strongly associated with very small low-density lipoprotein cholesterol concentrations in healthy men

BACKGROUND: Despite the importance of oxidized LDL and small LDL particles as atherogenic lipoproteins, the relationship between oxidized LDL and the distributions of size subclasses of lipoproteins is not fully proved. We investigated the relationship of circulating malondialdehyde-modified (MDA)-LDL, an oxidized form of LDL, and lipoprotein subclasses in healthy men. METHODS: The study group consisted of a total of 170 healthy Japanese men (55+/-9 y). Plasma cholesterol concentrations in major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RESULTS: In univariate analysis, body mass index, waist circumference, blood pressure, white blood cell count, C-reactive protein, uric acid, fasting insulin, HOMA-IR, total cholesterol, triglycerides, each VLDL subclass cholesterol, each LDL subclass cholesterol, small HDL cholesterol, and very small HDL cholesterol were positively correlated with MDA-LDL, whereas adiponectin and large HDL cholesterol were inversely correlated with MDA-LDL. In stepwise multiple regression analysis, very small LDL cholesterol, medium VLDL cholesterol, very small HDL cholesterol, small HDL cholesterol, and systolic blood pressure were identified as independent determinants of MDA-LDL (R(2)=0.718, p<0.0001). CONCLUSIONS: Circulating MDA-LDL concentrations are strongly associated with very small LDL cholesterol concentrations in healthy men. HDL size heterogeneity has a biphasic effect on MDA-LDL.     

Oxidized low-density lipoprotein reduces plasma coagulation in vitro

Oxidation of low-density lipoprotein (LDL) was shown to occur in vivo and involved lipid peroxidation and apolipoprotein modification. We studied the effect of oxidized-LDL (Ox-LDL) on plasma coagulation by measuring prothrombin time (PT) and partial thromboplastin time (PTT) following the addition of Ox-LDL to normal plasma. Ox-LDL, but not native LDL, caused prolongation of PT and PTT by 30% in a dose- and time-dependent pattern. This effect was also shown to be present following lipoprotein delipidation, suggesting that it was the apolipoprotein fraction of Ox-LDL, but not its lipid fraction, that was responsible for the prolongation of PT and PTT. This was further substantiated since similar effect could be obtained by adding LDL treated with trinitrobenzenesulphonic acid to block the lysine groups, as occurs in oxidized LDL. Ox-LDL, unlike LDL, was found to reduce plasma ionized calcium by 33%. Moreover, adding calcium ions to Ox-LDL negated its effect on PT and PTT, suggesting that Ox-LDL apolipoprotein may influence coagulation by binding calcium ions.