Low-density lipoprotein subfraction profiles in chronic renal failure

Background: Small low-density lipoprotein (LDL) particle size, a newly recognized risk factor for cardiovascular disease in the general population, is frequently associated with hypertriglyceridaemia, the predominant plasma lipid abnormality present in uraemia. Methods: Plasma lipids and LDL subfraction profiles were examined in 33 non-dialysed patients with chronic renal failure (predial), 40 patients on continuous ambulatory peritoneal dialysis (CAPD), 42 haemodialysis patients (HD), 47 renal transplant recipients (RTR), and 44 controls. LDL subfractions separated by gel electrophoresis were scored by densitometric analysis (higher scores indicate profiles comprising smaller particles). Results: All groups with renal failure had significantly elevated (mean±SD) LDL scores (predial 1.36±0.6, CAPD 1.71±0.9, HD 1.68±0.9, RTR 1.92±0.8 vs control 0.87±0.4, all P<0.001), this being the only lipid abnormality detected in the predialysis patients. In CAPD and HD patients, LDL scores were associated with serum triglyceride (r=0.81, P<0.0001 and r=0.70, P<0.01 respectively), cholesterol (r=0.55, P<0.001 and r=0.49, P<0.01) and HDL-cholesterol (r=-0.43, P<0.01 and r=-0.51, P<0.01), whilst no such relationship was seen in the predialysis and RTR groups, suggesting that other factors were important. Conclusions: The presence of small LDL particles appears to be an early and unexplained feature of the uraemic dyslipidaemia. This abnormality persists after renal transplantation and may represent an important atherogenic risk factor. Key words: LD subfractions; renal failure; transplants      

Symptomatic antiproteinuric treatment decreases serum lipoprotein (a) concentration in patients with glomerular proteinuria

Elevated serum levels of the atherogenic and thrombogenic lipoprotein(a) (Lp(a)) have been recognized as a feature of the nephroticsyndrome associated hyperlipidaemia. To examine a possible relationshipbetween serum Lp(a) concentration and proteinuria, serum albumin,or blood pressure, we studied nine patients with nephrotic-rangeproteinuria both at baseline and after various forms of antihypertensiveand antiproteinuric treatment. In fixed order, patients receivedconventional antihypertensive treatment (either -methyldopaor clonidine), subsequently ACE-inhibition therapy (lisinopril),ACE inhibition combined with an NSAID (indomethacin), and finallyNSAID plus conventional antihypertensive therapy. Measurementswere performed at the end of each 2-month study period. When compared to controls (n = 29), proteinuric patients beforetreatment showed increased levels of total cholesterol, very-lowand low-density lipoprotein (VLDL + LDL) cholesterol, triglyceridesand apolipo-protein B (apoB), while high-density lipoprotein(HDL) HDL cholesterol was lower. Lp(a) was significantly higherin patients (107 (95% CI: 55–208) mg/l) as compared tocontrols (25 (13–49) mg/l, P<0.01). Conventional antihypertensivetreatment did not reduce proteinuria, while Lp(a) remained unaffected.ACE-inhibitor treatment lowered proteinuria, raised serum albumin,while La(a) tended to fall (– 11 ±8%). Additionof an NSAID induced a further fall in proteinuria and a risein serum albumin. Lp(a) now fell by 40±5% from baselinevalues (P<0.01). Both serum total, HDL and VLDL + LDL cholesterolfell significantly. Finally, during subsequent single therapywith NSAID most parameters, including proteinuria and Lp(a),returned towards values obtained during single therapy withACE inhibition. Multiple regression analysis showed a strongrelation of Lp(a) with the amount of proteinuria (P = 0.001),while serum albu-min did not independently contribute to Lp(a)levels (P = 0.2). In conclusion, effective symptomatic antiproteinuric treatmentdecreases serum Lp(a) levels in patients with glomerular proteinuria.Our data suggests that renal protein leakage plays a more importantrole in the metabolic regulation of this lipoprotein than serumalbumin level, and that antiproteinuric treatment may be ofbenefit in reducing the increased risk of thrombosis and atherosclerosisobserved in this patient category.     

Protein and lipid metabolism in nephrotic infants on peritoneal dialysis after nephrectomy

Congenital nephrotic syndrome of the Finnish type (CNF) is associated with protein deficiency despite substantial protein supplementation in the nephrotic state before nephrectomy. Different protein intakes (2.5 vs. 3.7 g/kg per day) in hypoproteinaemic children on continuous cycling peritoneal dialysis (CCPD) were studied. Lipids were also measured to determine whether severe atherogenic abnormalities seen during nephrosis improved after nephrectomy. Growth was normal or became normal with both protein intakes. Serum pre-albumin and transferrin concentrations became normal. Total protein (57±3.0 vs. reference limits 60–75 g/l) and albumin (28±5.0 vs. reference limits 30–50 g/l) concentrations improved but remained below normal, even with the higher protein intake. Muscle mass determined by measuring femoral quadriceps muscle thickness using ultrasound was markedly reduced in all patients at nephrectomy. It improved (P<0.05) in all but 2 patients who had several bacterial infections, but reached normal level in only 3 patients within 6 months. Plasma total, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) triglyceride concentrations decreased (P<0.05,P<0.05 andP<0.01, respectively) and VLDL, LDL and high-density lipoprotein (HDL) particles contained less triglyceride than in the nephrotic state. HDL cholesterol concentrations increased by 28% [0.58±0.22 mmol/l during nephrosis, 0.81±0.21 mmol/l on CCPD after nephrectomy (P<0.05)] but remained below the level of 1.38±0.75 mmol/l in normal controls (P<0.001). If compared with controls there were still significant abnormalities in lipoprotein concentrations on CCPD. Hence, a protein intake of 2.5 g/kg per day representing 140% of the recommended dietary allowance is sufficient to maintain normal growth and improve nutritional and protein status in CNF patients on CCPD. Although lipid levels improved they remained abnormal.     

Influence of low molecular weight heparin compared to conventional heparin for anticoagulation during haemodialysis on low density lipoprotein subclasses.

BACKGROUND: In haemodialysis (HD) patients, low density lipoprotein (LDL) particle distribution is characterized by a higher proportion of more atherogenic dense LDL. Though clinical studies showed favourable effects of low molecular weight (LMW) heparin compared to standard heparin on triglycerides (TG) and cholesterol (CH) in HD patients with hypertriglyceridaemia, it is not known if LMW heparin influences LDL subfraction pattern. Thus, the aim of this pilot study was to investigate if a switch to LMW heparin influences LDL subfractions and apolipoproteins. METHODS: Ten outpatients with fasting TG >230 mg/dl in the chronic HD programme on heparin for anticoagulation (AC) were switched to dalteparin (80 IU/kg body weight as a bolus). Blood samples were drawn for CH, TG, LDL-CH, HDL-CH, apolipoproteins (apo), very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and LDL subclasses at the beginning and after 12 months of therapy. Lipoproteins were isolated by preparative ultracentrifugation. Total LDL were fractionated into six density classes by equilibrium density gradient ultracentrifugation [(density in kg/l): LDL-1 1.019-1.031, LDL-2 1.031-1.034, LDL-3 1.034-1.037, LDL-4 1.037-1.040, LDL-5 1.040-1.044, LDL-6 1.045-1.063]. CH and TG were determined enzymatically, apolipoproteins by turbidimetry. RESULTS: In eight patients suitable for evaluation cholesterol decreased from 241 to 202 (P<0.05) and TG from 557 to 278 mg/dl (P<0.01), whereas LDL-CH and HDL-CH did not change significantly. A 28.2% decrease of VLDL (P<0.01) and a 19.3% decrease of IDL (P<0.05) paralleled by a significant drop of apoB were observed. Buoyant LDL subclasses increased (LDL-2, +34.3% and LDL-3, +20.3%) whereas dense LDL (LDL-5, -13.4% and LDL-6, -33.1%) decreased (P<0.05 for LDL-6). The ratio of buoyant LDL to dense LDL increased from 0.46+/-0.28 to 0.72+/-0.33 (P<0.05). CONCLUSION: In hypertriglyceridaemic HD patients, dalteparin improved metabolism of TG-rich lipoproteins, increased buoyant LDL and decreased potentially atherogenic dense LDL. Preservation of lipoprotein lipase by LMW heparin may be a possible mechanism to explain our findings.     

Significant Changes in the Lipid-Lipoprotein Status of Premenopausal Morbidly Obese Females following Gastric Bypass Surgery

The morbidly obese premenopausal female may be more dyslipoproteinemic and at greater risk for developing coronary heart disease than her lean or less seriously obese counterparts. The purpose of the present study was to examine the effects of weight loss with Roux-en-Y gastric bypass surgery on the lipid-lipoprotein status of morbidly obese, premenopausal females. Anthropometrics and blood samples for lipid-lipoprotein analyses were obtained before surgery and 6 - 12 months post-operatively. Following surgery, patients lost 30% of their initial body weight, along with a 40% decline (p < 0.01) in total triglyceride and a 20% decrease (p < 0.01) in total cholesterol. Levels of cholesterol in the high density lipoprotein (HDL) fraction were unaffected by weight loss, but there was a significant (p < 0.05) increase in the proportion of HDL in its more buoyant and anti-atherogenic form, i.e. HDL-L. The apolipoprotein B-containing lipoproteins, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL), were reduced up to 70% following surgery. There were no significant changes in VLDL or IDL particle composition, i.e. cholesterol/triglyceride, cholesterol/protein, but there was a significant (p < 0.01) increase in the ratio of cholesterol/apolipoprotein B in LDL, suggesting a shift from the small, dense atherogenic LDL to a larger, less atherogenic particle. We conclude that weight loss following gastric bypass surgery markedly improves the lipid-lipoprotein status of morbidly obese premenopausal females and, thereby, significantly reduces the risk of coronary disease.     

Effects of two low-flux cellulose acetate dialysers on plasma lipids and lipoproteins-a cross-over trial

Background: Studies have shown a beneficial effect of high-flux dialysis on lipids, lipoproteins and lipoprotein lipase (Lpl) activity. This has been attributed to improved clearance of Lpl-inhibitory molecules of middle molecular weight, but differences in flux or biocompatibility have not been addressed. We conducted a blinded cross-over trial of two cellulose acetate dialysers (AN140, Althin medical Inc. and CA210, Baxter Inc.) of similar flux (11 ml/h/mmHg transmembrane pressure) but with different clearances of larger molecules [AN140 sieving coefficient at mol. wt 11 000 Da ({beta}2-microglobulin) 0.6; CA210 sieving coefficient negligible]. Methods: Sixteen patients were divided into two groups to receive dialysis with AN140 for 1 week followed by CA210 or vice versa. Before and after the third dialysis with each membrane, plasma lipid and lipoprotein concentrations were measured. Post-dialysis post-heparin lipase activity was measured in six patients. Results: Fifteen patients completed the study. No difference between dialysers was found for apolipoprotein (apo) A1, B or total cholesterol measurements. The rise in triglyceride post-dialysis was attenuated by AN140 (rise 0.05±0.4 mmol/l vs CA210 0.44±0.54 mmol/l, P=0.03), while high density lipoprotein (HDL) cholesterol was increased by AN140 (rise 0.18±0.12 mmol/l vs CA210 0.06±0.14 mmol/l, P<0.02). ApoE rose with AN140 during dialysis but declined with CA210 (1.10±1.06 mg/dl and -0.77±0.63 mg/dl, P=0.002) as did apoCIII (HDL) (AN140 rise 1.33±2.06 mg/dl; CA210 fall -0.67±0.73 mg/dl, P=0.001). Lpl activity, measured in six patients, tended to be higher for AN140 (45.3±10.5 mmol FFA/ml plasma/h vs CA 210 (37.2±7.9 mmol FFA/ml plasma/h) (P=0.16). Conclusions: We conclude that low-flux dialysis using a cellulose acetate membrane with good clearance of higher molecular weight molecules may be associated with beneficial changes in plasma lipids and lipoproteins.     

Bariatric Surgery Improves Atherogenic LDL Profile by Triglyceride Reduction

Background  Small dense low-density lipoprotein (LDL) are atherogenic particles frequently observed in obese patients. Fatty acids modulate LDL. Objective of this study was to determine the relations between plasma phospholipid fatty acid composition and the presence of small dense LDL particles in morbidly obese patients treated with laparoscopic gastric banding (LAGB). Methods  Small dense LDL, plasma lipids, lipoproteins, apoproteins, and phospholipid fatty acid composition (a marker of dietary fatty acid intake) were quantified before and 12 months after surgery in four men and 11 women who were morbidly obese and (BMI > 40 kg/m²) eligible for surgery, consecutively treated with LAGB at the Department of Medical and Surgical Sciences of the University of Padova. Results  BMI was 48.3 ± 4.8 kg/m² before and 36.1 ± 5.5 kg/m² after LAGB. Plasma triglycerides and apoprotein E levels significantly decreased, while HDL cholesterol significantly increased after LAGB. A reduction of small dense LDL with an increase of LDL relative flotation (0.34 ± 0.04 before vs 0.38 ± 0.03 after LAGB, p < 0.001) was also observed. These modifications were neither related to weight reduction nor to changes in phospholipid fatty acid composition, but they were associated to triglyceride reduction, which explained 76.7% of the LDL relative flotation variation. Conclusion  Weight loss obtained by LAGB in morbidly obese subjects was accompanied by triglyceride reduction, high-density lipoprotein increase, and an improvement of the atherogenic LDL profile. Triglyceride reduction, but not the extent of weight loss or dietary fatty acid modifications, is the determinant of modifications of LDL physical properties in these patients.     

Low-density lipoprotein subfraction profiles in dialysis patients

Summary: Uraemic dyslipidaemia is a major risk factor for cardiovascular disease in end-stage renal failure patients. In patients without renal failure, high levels and qualitative abnormalities of low-density lipoprotein (LDL) are known to be atherogenic. Recently, LDL subfraction analysis has associated premature coronary artery disease with a high prevalence of small, dense LDL particles characterizing the LDL subclass phenotype B. We therefore examined the lipid profiles, LDL subfraction distribution and phenotypes in our population of haemodialysis (HD; n = 30) and peritoneal dialysis patients (PD; n = 17), and compared them to 40 asymptomatic, non-uraemic volunteers. Dialysis patients had significantly higher triglyceride and VLDL cholesterol concentrations and lower HDL cholesterol and smaller LDL peak particle diameters. PD patients had significantly higher total cholesterol, glycated haemoglobin and fasting blood glucose levels with smaller LDL peak particle diameters (24.4 [0.1] vs 24.8 [0.1 nm] than HD. Both groups showed significant negative correlations between plasma triglyceride and LDL peak particle diameter, and positive correlations between HDL cholesterol and LDL peak particle diameter. All the PD patients expressed the B phenotype (LDL peak diameter ± 25.5 nm) compared to 73% of HD patients. This study demonstrates that HD and especially PD patients have atherogenic lipid profiles which are associated with a predominance of small dense LDL particles and the highly atherogenic LDL subclass phenotype B.     

Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease

Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P: < 0.01), triglyceride (14%, P: < 0.05), LDL cholesterol (LDL-C; 23%, P: < 0.01), total LDL (18%, P: < 0.01), and LDLIII concentration (27% P: < 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r(2) = 34%, P: < 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P: < 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% (P: < 0.01). HDL-C (19%, P: < 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r(2) = 67%, P: < 0.001; RLP cholesterol r(2) = 58%, P: < 0.005). Serum creatinine increased with fenofibrate treatment (14%, P: < 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 +/- 85 mg/dl after cerivastatin treatment and 133 +/- 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.     

The atherogenic lipoprotein profile associated with obesity and insulin resistance is largely attributable to intra-abdominal fat

Obesity and insulin resistance are both associated with an atherogenic lipoprotein profile. We examined the effect of insulin sensitivity and central adiposity on lipoproteins in 196 individuals (75 men and 121 women) with an average age of 52.7 years. Subjects were subdivided into three groups based on BMI and their insulin sensitivity index (S(I)): lean insulin sensitive (n = 65), lean insulin resistant (n = 73), and obese insulin resistant (n = 58). This categorization revealed that both obesity and insulin resistance determined the lipoprotein profile. In addition, the insulin-resistant groups had increased central adiposity. Increasing intra-abdominal fat (IAF) area, quantified by computed tomography scan and decreasing S(I), were important determinants of an atherogenic profile, marked by increased triglycerides, LDL cholesterol, and apolipoprotein B and decreased HDL cholesterol and LDL buoyancy (Rf). Density gradient ultracentrifugation (DGUC) revealed that in subjects who had more IAF and were more insulin resistant, the cholesterol content was increased in VLDL, intermediate-density lipoprotein (IDL), and dense LDL fractions whereas it was reduced in HDL fractions. Multiple linear regression analysis of the relation between the cholesterol content of each DGUC fraction as the dependent variable and IAF and S(I) as independent variables revealed that the cholesterol concentration in the fractions corresponding to VLDL, IDL, dense LDL, and HDL was associated with IAF, and that S(I) additionally contributed independently to VLDL, but not to IDL, LDL, or HDL. Thus an atherogenic lipoprotein profile appears to be the result primarily of an increase in IAF, perhaps via insulin resistance.     

Increase in Serum Magnesium Level in Haemodialysis Patients Receiving Sevelamer Hydrochloride

Background: Clinical studies have shown that sevelamer hydrochloride improves lipid profiles and attenuates the progression of the cardiovascular calcifications in haemodialysis patients. It is known that both of these properties are associated with increased magnesium levels. The effect of sevelamer on serum magnesium level is not well documented. The aim of this study was to determine the effects of sevelamer treatment on serum magnesium in haemodialysis patients and to assess the association of magnesium levels with lipid profiles and intact parathyroid hormone (iPTH). Methods: Phosphate binders were discontinued during a two week washout period. Forty-seven patients, whose serum phosphate was greater than 6.0 mg/dl at the end of washout, received sevelamer hydrochloride for eight weeks. The patients were then washed off sevelamer for another two weeks. Results: Mean serum phosphorus concentration declined from 7.5 ± 1.3 to 6.4 ± 1.2 mg/dl (P < 0.001), mean serum magnesium levels increased from 2.75 ± 0.35 to 2.90 ± 0.41 mg/dl (P < 0.001) and median serum iPTH levels decreased from 297 to 213 pg/ml (P=0.001) during the eight weeks of sevelamer treatment. After the two week post-treatment washout phosphorus levels increased to 7.3 ± 1.3 mg/dl (P < 0.001), magnesium levels were reduced to 2.77 ± 0.39 mg/dl (P < 0.001) and iPTH levels increased to 240 pg/ml (P=0.012). No change was observed in serum calcium levels during the sevelamer treatment period and the subsequent washout period. The mean decline in total and low density lipoprotein (LDL) cholesterol during sevelamer treatment was 16.3 and 28.3 (P < 0.001), respectively. The mean increase in high density lipoprotein (HDL) cholesterol and in apolipoprotein A1 was 2.9 ± 5.8 mg/dl (P=0.004) and 6.8 ± 11.1 mg/dl (P=0.001), respectively. Multivariate analysis showed that the rise in serum magnesium concentration significantly correlated with reductions in iPTH levels (r=−0.40, P=0.016), but did not have any significant correlation with the changes in lipid profiles. Conclusions: Our findings indicate that patients on haemodialysis receiving sevelamer have a significant increase in serum magnesium concentrations. This increase in serum magnesium is associated with reduction in iPTH levels. The changes in lipid profiles of these patients however are not related to changes in serum magnesium levels.     

Patients with nephrotic-range proteinuria have apolipoprotein C and E deficient VLDL1

BACKGROUND: Impaired very low-density lipoprotein (VLDL) clearance contributes to dyslipidemia in nephrotic-range proteinuria. VLDL can be subdivided into large light VLDL1 (Sf 60 to 400) and smaller, denser VLDL2 (Sf 20 to 60). In nephrotic-range proteinuria, the clearance of VLDL1 is delayed. VLDL1 lipolysis is influenced by apolipoprotein CII (apoCII) and apoCIII, whereas apoE regulates receptor-mediated clearance. METHODS: To ascertain whether impaired VLDL1 clearance was related to a deficiency in apolipoproteins on VLDL1, we measured VLDL subfraction concentrations and VLDL1 apolipoprotein and lipid compositions in 27 patients with glomerular disease and urinary albumin> 2 g/24 h along with 27 age- and sex-matched controls. RESULTS: Proteinuric patients had increased plasma VLDL1, VLDL2, apoCII, apoCIII (all P < 0.001), and apoE concentration (P < 0.002). Patients appeared to have smaller VLDL1 particles, as assessed by triglyceride per particle (median + interquartile range, moles per VLDL1 particle): patients, 4.9 (3.0 to 7.9) x103; controls, 7.0 (4.6 to 15.7) x103, P < 0.05, with reduced apoCII, 4.2 (3.1 to 8.2) versus 9.9 (7.4 to 23.2), P < 0.0004; apoCIII, 16.6 (9.1 to 27.2) versus 29.3 (18.5 to 69.4), P < 0.02; and apoE content, 0.17 (0.08 to 0.44) versus 0.48 (0.31 to 1. 31), P < 0.006. The VLDL1 surface free cholesterol to phospholipid results were increased in proteinuric patients (0.55 +/- 0.17 vs. 0. 40 +/- 0.18, P < 0.002, all mean +/- SD). For all patients, VLDL1 apoCII, apoCIII, and apoE contents per particle were related to particle size (apoCII, r2 = 61.5%, P < 0.001; apoCIII, r2 = 75.8%, P < 0.001; apoE, r2 = 58.2%, P < 0.001) and inversely to the free cholesterol to phospholipid ratio (apoCII, r2 = 41.6%, P < 0.001; apoCIII, r2 = 38.8%, P < 0.001; apoE, r2 = 11.7%, P < 0.05). Multivariate analysis suggested that the relative lack of apoCII and apoCIII on patients VLDL1 was related to smaller particle size and increased free cholesterol:phospholipid (FC:PL) ratio. Particle size but not free cholesterol determined the apoE content of VLDL1. CONCLUSIONS: We postulate that impaired VLDL1 clearance in nephrotic-range proteinuria results from the appearance of particles deficient in apoCII, apoCIII, and apoE. VLDL1 apoC deficiency is associated with the formation of smaller particles with a high FC:PL ratio, and is likely to cause inefficient lipolysis. VLDL1 apoE deficiency is associated with smaller VLDL1 particles but not altered VLDL1 surface lipid content, and may reduce receptor-mediated clearance of this lipoprotein.     

Sevelamer hydrochloride: an effective phosphate binder in dialyzed children

This pilot study was designed to evaluate the efficacy and acceptability of sevelamer hydrochloride as a phosphate binder in pediatric patients treated with dialysis. A 6-month open-label trial of sevelamer hydrochloride (Renagel) was initiated in 17 patients, aged 11.8±3.7 years, undergoing hemodialysis (n=3) or peritoneal dialysis (n=14). Following a 2-week washout period of the phosphate binders, serum phosphorus increased from 5.2±1.3 mg/dl to 7.5±2.2 mg/dl (P<0.0002). After initiation of therapy with sevelamer hydrochloride, serum phosphorus levels decreased to 6.2±1.2 mg/dl (P<0.01) during the first 8 weeks and final values were 6.3±1.5 mg/dl. Serum calcium concentration decreased during the washout period from 9.4±0.9 mg/dl to 8.9±1.5 mg/dl (P<0.01); values remained unchanged thereafter. The serum calcium-phosphorus ion product decreased during the first 8 weeks and values did not change subsequently. Serum bicarbonate, parathyroid hormone, total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, and triglyceride levels did not change. The initial prescribed dose of sevelamer hydrochloride was 121±50 mg/kg (4.5±5 g/day) and the final prescribed dose was 163±46 mg/kg (6.7±2.4 g/day). Sevelamer hydrochloride was well tolerated and without adverse effects related to the drug.     

Hydrochlorothiazide treatment of children with hypercalciuria: effects and side effects

Urinary excretion of calcium and the changes in serum cholesterol fractions were investigated in 15 children with renal hypercalciuria, following 3-month hydrochlorothiazide (HCT) treatment (daily dose 1 mg/kg). Urinary calcium excretion (expressed as the ratio of calcium to creatinine) reached its lowest value after 2 weeks. It was still below the initial value at the end of the 3rd month of treatment (0.84±0.06, 0.29±0.03 and 0.6±0.09 mmol/mmol, respectively). A significant rise in the total serum cholesterol level (4.64±0.23 vs. 4.25±0.18 mmol/l before treatment,P<0.01) and the lowdensity lipoprotein (LDL)-cholesterol fraction (2.6±0.24 vs. 2.31±0.31 before treatment,P<0.01) was observed at the end of the 3rd month, while high-density lipoprotein (HDL)-cholesterol was slightly decreased. A significant elevation of the LDL/HDL ratio was also observed (from 1.76±0.17 to 2.2±0.17,P<0.001), indicating an increase in the atherogenic cholesterol fractions. The risks and benefits of the thiazide therapy should be considered before starting long-term treatment of children with hypercalciuria and haematuria or renal stone disease.     

Low-density lipoprotein (LDL) apheresis reduces atherogenic and oxidative markers in uremic patients with hyperlipidemia

Uremic patients with hyperlipidemia are classified at high atherogenic risk due to oxidative stress induced by regular hemodialysis process (hemoincompatibility) and a high level of oxidized low-density lipoprotein (ox-LDL). This study aimed to investigate whether LDL apheresis was capable of reducing oxidative and atherogenic markers in uremic patients with hyperlipidemia. We found that oxidative metabolites (methylquanidine, dityrosine, and ox-LDL) and atherogenic markers (lipoprotein (a), LDL, and LDL/HDL ratio) were significantly reduced (P < 0.05) after LDL apheresis. On the other hand, plasma total antioxidant status (TAS) was not influenced after LDL apheresis. Our results suggest that LDL apheresis reduces oxidative and atherogenic markers and do not influence plasma TAS in uremic patients with hyperlipidemia. This may lead to a decreased risk of atherosclerosis in these patients. However, supplementation of dietary proteins may be necessary because of the removal of some “useful” proteins (e.g., albumin and globulin) after LDL apheresis.     

Does long-term treatment of renal anaemia with recombinant erythropoietin influence oxidative stress in haemodialysed patients?

Background. Patients with end-stage renal failure undergoing haemodialysis (HD) are exposed to oxidative stress. Increased levels of malondialdehyde (MDA) were demonstrated in plasma of uraemic patients, indicating accelerated lipid peroxidation (LPO) as a consequence of multiple pathogenetic factors. The aim of our investigation was to examine the role of renal anaemia in oxidative stress in HD patients. Methods. MDA and 4-hydroxynonenal (HNE) were measured in three groups of patients undergoing HD: group I comprised eight patients with a blood haemoglobin (Hb) <10 g/dl (mean Hb=8.1±1.3 g/dl), and group II were eight patients with a Hb <10 g/dl (mean Hb=12.4±1.9 g/dl); none of these 16 patients had been treated with human recombinant erythropoietin (rHuEpo). Group III comprised 27 patients with a mean Hb of 10.5±1.6 g/dl after long-term rHuEpo treatment. Results. Mean plasma concentrations of both MDA and HNE were significantly higher (P<0.0001) in all 43 HD patients than in 20 healthy controls (MDA 2.85±0.25 vs 0.37± &mgr;M, HNE 0.32± vs 0.10±0.01 &mgr;M). Comprising the three groups, it was shown that HD patients with a Hb <10 g/dl had significantly higher plasma levels of LPO products (MDA 3.81±0.86 &mgr;M, HNE 0.45±0.07 &mgr;M) than HD patients with a Hb > 10 g/dl (MDA 2.77±0.58 &mgr;M, HNE 0.25±0.05 &mgr;M), and than HD patients treated with rHuEpo (MDA 2.50±0.12 &mgr;M, HNE 0.29±0.03 &mgr;M). Furthermore, an inverse correlation between plasma concentration of LPO products and haemoglobin levels was seen (r=0.62, P<0.0001). Conclusion. Radical generation in HD patients might be caused in part by renal anemia itself. Treatment with rHuEpo may decrease radical generation effectively in HD patients due to the increase in the number of red blood cells and blood haemoglobin concentration. Keywords: erythropoietin; haemodialysis; HNE; lipid peroxidation; MDA; renal anaemia      

Metabolism of apolipoprotein B-containing lipoproteins in subjects with nephrotic-range proteinuria

Although hyperlipidemia is a well recognized complication of the nephrotic syndrome, the precise disturbances of lipoprotein metabolism which cause the elevated plasma lipid and lipoprotein concentrations have not been clearly defined in humans. This study examines the metabolism of apolipoprotein B-containing lipoproteins in patients with nephrotic-range proteinuria and in healthy controls. Two radioiodinated tracers of very low density lipoproteins (VLDL1, Sf60 to 400, and VLDL2, Sf20 to 60), were used to trace the metabolism of apolipoprotein B through the delipidation cascade from very low density lipoproteins (VLDL) to low density lipoproteins (LDL). The data from the apoB specific radioactivity curves and the pool sizes of apoB in four subfractions were analyzed by a multicompartmental modeling procedure using the SAAM 30 program. The main findings in the nephrotic group were: 1.) a consistent decrease in the fractional rate of apoB transfer from VLDL1----VLDL2 (median values-nephrotic 0.92 pools/day vs. controls 3.66, P less than 0.02) and from VLDL2----IDL (1.49 vs. 2.74, P less than 0.05); 2.) increased secretion of apoB into VLDL2 (14.5 mg/kg/day vs. 4.2, P less than 0.02); 3.) a trend towards decreased removal of IDL and LDL attributable to a defect in LDL receptor-mediated removal as previously shown (Metabolism 39:187-192, 1990). These findings suggest that catabolic defects of the apo B-containing lipoproteins are as important as increased hepatic synthesis in the pathogenesis of nephrotic hyperlipidemia in humans.     

ApoE polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in NIDDM?

Background: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) present with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patient hyperglycaemia. The role of lipid abnormalities in this matter remains debated. Methods: We studied the prevalence of nephropathy (N+=urinary albumin excretion rate (UAE) >20 mg/d) in 134 Caucasian NIDDM patients ranked according to alipoprotein E (apoE) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n=1) was excluded from the analysis. Results: The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P <0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI=0.35-0.80). Both groups were comparable in terms of age (55±11 vs 57±11 years), diabetes duration (15 ±9vs 14±10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n=94). Conclusions: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with NIDDM argues for a role for LDL in the development of human nephropathy in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in NIDDM patients.     

Effect of increasing serum albumin on haemostatic factors synthesized in the liver in CAPD patients

Background. This study was performed to evaluate the relationship between serum albumin and plasma concentration of haemostatic factors and the effect of raising serum albumin on haemostatic factors synthesized in the liver in CAPD patients. Methods. We measured blood levels of albumin, fibrinogen, factor II, factor VII, protein C, free protein S, plasminogen, &agr;2-antiplasmin and antithrombin III in 103 CAPD patients and 30 normal controls. Twenty-two patients with albumin lt;3.5 g/dl were divided into two groups. In the experimental group (n = 11), haemostatic factors and albumin were measured before, after repeated infusion of 20% albumin 100 ml three times per week for 2 weeks, and 4 weeks after withdrawal of albumin infusion. The same parameters were measured in the control group (n = 11) which did not receive albumin infusion. C-reactive protein and haematocrit were followed in both groups as an indicator of acute phase reactant and an indirect measure of volume status. Results. CAPD patients as a whole had lower albumin and higher fibrinogen and factor VII than normal controls. A significant inverse correlation was present between fibrinogen and albumin (r = -0.27, P <0.01). Albumin in the experimental group increased from 2.7 ± 0.4 to 3.5 ± 0.6 g/l at the end of its repeated infusion and haematocrit decreased from 26.6 ± 4.4 to 24.9 ± 5.2%. Fibrinogen and factor VII decreased significantly, even after correction for haematocrit (624 ± 96 vs 556 ± 91 mg/dl, 160 ± 36 vs 121 ± 44%, P <0.05). Four weeks after withdrawal of albumin infusion, serum albumin decreased to 2.7 ± 0.5 g/dl, whereas fibrinogen and factor VII increased to 619 ± 78 mg/dl and 158 ± 32%, respectively (P &;lt;0.05). Albumin, haematocrit and haemostatic factors in the control group did not change. CRP was stable during the study period in both groups. Conclusion. These findings indicate that hypoalbuminaemia is an important trigger factor in the elevation of fibrinogen, and possibly factor VII, in CAPD patients. Keywords: albumin; CAPD; factor VII; fibrinogen      

Effect of different membranes on amino-acid losses during haemodialysis

Background: We analysed amino-acid losses during haemodialysis, their influence on plasma amino-acid concentration, and their possible effects on nutritional state. Methods: Five patients were dialysed with three membranes: cuprophan (CUP), polysulphone (PS), and polyacrylonitrile AN69 (PAN). We compared anthropometric and biochemical parameters after 6 months in patients dialysed with CUP respect to patients with PAN. Results: Total losses of amino acids were higher with PAN than with PS and CUP (6.1±2.3 vs 3.8±1.3, P <0.05, and 3.7±1.3 g/session, P <0.01 respectively). Losses of essential amino acids (EAA) and non-essential amino acids (NEAA) were also higher with PAN respect to PS and CUP (1.8±0.8 vs 1±0.3 and 0.8±0.3, and 4.3±1.6 vs 2.8±1 and 2.9±1.1 g/session, P <0.05). The percentage reduction for plasma EAA and NEAA were lower with CUP respect to PS and PAN (11±5% and 20±14% vs 25±10% and 33±11%, and 30±11% and 25±17% respectively, P <0.05). There was no difference in the nutritional state between patients with CUP and PAN. However, plasma valine in patients with PAN was lower than in those with CUP (1.88±0.12 vs 2.13±0.32 mg/dl) and almost reached statistical significance. Conclusions: New synthetic membranes are advantageous with respect to conventional ones, but a disadvantage is the higher amino-acid losses, especially with polyacrylonitrile. Long-term studies are necessary to evaluate the impact of amino-acid losses on nutritional state in patients dialysed with these membranes.