Oxidative stress during dialysis: effect on free radical scavenging enzyme (FRSE) activities and glutathione (GSH) concentration in granulocytes

Background. Living cells are protected by free radical scavenging enzymes against oxygen radical-mediated damage. It has been suggested that granulocytes are activated on the surface of dialyser membranes, resulting in the generation of free radicals. We have recently reported a lack of plasma lipid peroxidation and unchanged glutathione peroxidase (GSH-Px) as well as glutathione reductase (GSSG-R) activities in red blood cells of haemodialysis patients. However, because mature red cells are free of DNA and RNA, free radical scavenging enzymes (FRSE) cannot be regulated on the gene level in response to an acute oxidative stress. In contrast to erythrocytes, granulocytes are nucleated cells and FRSE protein concentrations can therefore be modulated. Methods. GSH-Px, GSSG-R, superoxide dismutase (SOD) activities and total glutathione (GSH) were determined spectrophotometrically using a Cobas Fara semi-automatic analyser in granulocytes of 31 healthy blood donors and in 28 patients with chronic renal failure (CRF) for more than 6 months before as well as immediately after a single dialysis treatment. Patients were treated either by haemodialysis (n=17) using low-flux polysulphone membranes or by haemofiltration (n=11) using high-flux polysulphone membranes. Results. Compared to healthy controls, SOD and GSSG-R activities were increased in granulocytes of HD and HF patients, GSH and GSH-Px were decreased before a single treatment. After dialysis SOD and GSH-PX activities were significantly induced by both HD and HF whereas GSSG-R activities and GSH were decreased. Conclusions. These results show that the enzymatic defence against oxygen radicals can be induced in granulocytes of patients undergoing regular dialysis treatment, whereas the non-enzymatic defence is compromised as shown by decreased GSH concentrations, both suggesting increased oxidative stress.     

Short–and Long–Term Effects on Serum Lipoproteins by Three Different Techniques of Apheresis

Abstract: Low–density lipoprotein (LDL) apheresis is applied in patients with coronary heart disease because of severe inherited forms of hypercholesterolemia, for which dietary and combined drug treatment cannot lower LDL cholesterol concentrations less than 130 mg/dl. The following article describes the changes in lipoprotein levels in a total of 19 patients undergoing weekly LDL apheresis. Immunoadsorption, operating with polyclonal antibodies against apolipoprotein B–100, was used in 6 patients. Five patients were put on heparin–induced extracorporeal LDL precipitation (HELP) therapy; 6 received dextran sulfate adsorption treatments. Under steady–state conditions a single treatment reduced LDL cholesterol by 149 ± 3 m/dl with immunoadsorption, 122 ± 2 mg/dl with HELP, and 124 ± 18 mg/dl with dextran sulfate adsorption. Lipoprotein (a) (Lp[a]) declined by 52 to 65%. Very low density lipoprotein (VLDL) cholesterol and VLDL triglycerides declined by 45 to 55% because of the activation of lipoprotein lipase and precipitation during the HELP procedure. In all procedures, there was a small reduction in the different high–density lipoprotein fractions, which had returned to normal after 24 h. The long–term HDL3 cholesterol levels increased significantly. During all procedures there was a decrease in the molar esterification rate of lecithin cholesterol acyltrans–ferase activity. All changes in lipid fractions were paralleled by changes in the corresponding apolipoprotein levels. It is concluded that all three techniques described are powerful tools capable of lowering LDL cholesterol in severe hereditary forms of hypercholesterolemia. In HELP and dextran sulfate adsorption, the amount of plasma is limited by the elimination of other plasma constituents. Immunoadsorption may thus be preferred in very severe forms of hypercholesterolemia.     

Lipid Peroxidation and Antioxidant Enzymes in CAPD Patients

The mechanisms of free-radical injury include reactions with proteins, nucleic acids, and polysaccharides; and covalent binding to membrane components and initiation of lipid peroxidation. Cells have developed antioxidant defense to prevent free-radical injury including superoxide dismutase (SOD) and glutathione peroxidase (GPx). Significantly higher concentrations of total malondialdehyde (MDA) in plasma (1.22 ± 0.42 vs. 0.64 ± 0.22 μimol/L, p < 0.0001) as well as erythrocytes (2.56 ± 1.28 vs. 1.03 ± 0.44 μmol/L, p < 0.0001) of the CAPD patients were found when compared to the control group. The free MDA in plasma and the erythrocytes do not differ significantly in continuous ambulatory peritoneal dialysis (CAPD) patients and the control group. A significantly lower activity of GPx in erythrocytes of CAPD patients (17.85 ± 2.63 U/g Hb vs. 23.26 ± 3.61 U/g Hb, p < 0.0001) was found when compdred to the control group, but the SOD activity in erythrocytes is not different (2272.36 ± 579.92 U/g Hb vs. 2347.13 ± 502.51 U/g Hg, NS). Our results show an increase of total MDA in erythrocytes and plasma. MDA is the product of lipid peroxidation with decreasing activity of GPx, which is capable of detoxifying peroxides. The activity of SOD did not change in CAPD patients. These results propose a possible role of free radicals with reduced antioxidant activity of GPx in CAPD patients and indicate that they could play some role in other pathological conditions such as atherogenesis and hemolysis.     

Contact activation in low-density lipoprotein apheresis systems

BACKGROUND: Anaphylactoid reactions due to contact activation have been observed in patients on ACE inhibitor therapy and hemodialysis with negatively charged dialysis membranes. Negatively charged surfaces are functional constituents of different LDL apheresis systems. Therefore, contact activation was investigated during LDL apheresis with three different systems: (i) heparin-induced extracorporeal LDL precipitation (HELP); (ii) dextran sulfate cellulose (DSC) columns; and (iii) modified polyacrylate gels (DALI) in a clinical setting. METHODS: 24 prevalent patients on regular LDL apheresis treatment were included in the study. Bradykinin, prekallikrein, and HMW kininogen were measured during a single LDL apheresis at different sites of the systems. RESULTS: LDL apheresis with DSC and DALI was associated with an extreme release of bradykinin after the passage of plasma or blood through the LDL adsorbers as well as with a decrease of prekallikrein and HMW kininogen during the course of the treatment. Bradykinin release exceeded the degradation capacity of the kininase II, since markedly elevated bradykinin concentrations were observed in the arterial line of the extracorporeal circuits of both systems. This was not associated with anaphylactoid reactions. In contrast to the treatments with DSC and DALI, the HELP system did not lead to any activation of the kallikrein-kinin system. CONCLUSION: From our data we conclude that angiotensin converting enzyme (ACE) inhibitors are contraindicated in patients on LDL apheresis with the DSC and the DALI system. Because the HELP system does not activate the kallikrein-kinin system, patients who need ACE inhibitors are predisposed for this LDL apheresis procedure.     

The effect of erythropoietin on the cellular defence mechanism of red blood cells in children with chronic renal failure

The glutathione redox system, haemoglobin (Hb) oxidation, the activity of antioxidant enzymes and the lipid peroxidation product malonyl dialdehyde (MDA) were studied in red blood cells (RBCs) during administration of recombinant human erythropoietin (rhEPO) over 12 weeks in ten children maintained on haemodialysis. A rapid increase in the reticulocyte count was accompanied by a slower rise in total Hb concentration. The mean level of oxidized glutathione (GSSG) increased from 13.2±5.3 nmol/g Hb to 56.7±15.8 nmol/g Hb 4 weeks after the start of rhEPO (P<0.001), followed by a fall to the basal value. Reduced glutathione (GSH) levels showed a smaller though constant elevation during rhEPO therapy (P<0.001). Before rhEPO treatment, incubation of RBCs for 1 h with acetylphenylhydrazine induced a decrease in GSH concentration compared with controls (P<0.001), which became more pronounced in the first few weeks of rhEPO therapy (P<0.001). In addition, the percentage of Hb derivatives (metHb and haemichrome) increased in the first 4 weeks of rhEPO therapy (P<0.001). Although there was no significant difference between the values obtained preEPO and during EPO treatment, MDA levels were continuously higher and superoxide dismutase, catalase and glutathione peroxidase concentrations were lower than in the controls (P<0.001). These results are compatible with oxidative damage to the RBCs in the early period of rhEPO therapy in children with end-stage renal failure. The GSH-GSSG system, as an important cellular defence mechanism of the RBCs, appears to be severely affected.     

Comparison of antioxidant enzyme activity in the internal spermatic vein and brachial veins of patients with infertile varicocele

AIM: Recent studies have shown that both oxidative and reductive stresses are present within the internal spermatic vein of patients with varicocele. The aim of this study was to compare the activities of antioxidant enzymes in the internal spermatic vein and brachial vein of patients with varicocele. METHODS: Fifteen primary infertile varicocele patients and ten normal-nonvaricocele-fertile control subjects participated in this study. The patients and subjects were first given a physical and color doppler examination, and then whole blood samples were drawn from the brachial vein and a dilated internal spermatic vein during surgery. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme activities were assessed by enzymatic methods, and the results were compared using the Mann-Whitney U test. RESULTS: The activity of SOD in the internal spermatic veins and brachial veins of patients with varicocele was 60.17 +/- 2.15 and 42.10 +/- 1.60 U/g protein, respectively; that of GSH-Px was 5.44 +/- 0.14 and 3.92 +/- 0.14 U/g protein, respectively. The results were statistically significant (P < 0.05). In the control group, the activity of SOD in the internal spermatic veins and brachial veins was 43.12 +/- 1.80 and 40.01 +/- 2.10 U/g protein, respectively; that of GSH-Px was 3.35 +/- 0.20 and 3.7 +/- 0.10 U/g protein, respectively (P > 0.05). CONCLUSIONS: Increased antioxidant enzyme activity in the internal spermatic vein may be due to increased oxidative stress in the internal spermatic vein: the increase in antioxidant enzyme activity may be a response to offset the toxic actions of reactive oxygen species. Further studies are needed to confirm this suggestion.     

Haemolysis in haemodialysis patients: evidence for impaired defence mechanisms against oxidative stress.

BACKGROUND: Uraemic patients have a decreased ability to withstand oxidative stress. It is postulated that their antioxidant capacity is reduced, yet the mechanism remains unclear. Recently 33 haemodialysis (HD) patients were exposed to chloramine contamination in the water supply. This led to haemolysis in 24 patients, while nine were unaffected. In the former group haemoglobin decreased from 11.7+/-1.1 to 8.5+/- 1.4 g/dl (P<0.0001) and returned to 11.4+/-0.9 g/dl (P<0.0001) following recovery. During haemolysis, haptoglobin was 38.4+/-10.6 vs 138.1+/-8.3 ng/dl (P<0.0001) following recovery. METHODS: To explore the factors affecting the severity of haemolysis we studied extracellular and intracellular anti-oxidant defence mechanisms 3 months after recovery. In 29 patients and 20 controls we determined plasma glutathione (GSH), and the erythrocyte enzymes glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rx), and superoxide dismutase (SOD). Serum malondialdehyde (MDA) was measured as a marker of oxidative stress. RESULTS: Plasma GSH was lower in patients as compared to controls (5.49+/-0.26 vs 7.4+/-0.5 micromol/l, P<0.005). There was an inverse correlation between GSH and the degree of haemolysis (r=-0.42, P<0.02). Patients had higher GSH-Rx (4.64+/-0.15 vs 3.97+/-0.12 U/gHb, P<0.02), lower GSH-Px (29. 7+/-1.85 vs 35.5+/-1.62 U/gHb, P<0.001), and similar SOD (0.63+/-0. 02 vs 0.51+/-0.02 U/mgHb) as compared to controls. There was no correlation between the enzyme levels and the degree of haemolysis. MDA was higher in patients (2.37+/-0.07 vs 0.97+/-0.1 nmol/ml, P<0. 0001). There was a correlation between MDA and the years patients were on HD (r=0.43, P<0.02). CONCLUSIONS: These data indicate that HD patients have an impaired anti-oxidant response, which may be attributed in part, to plasma GSH deficiency. Patients with the lowest plasma GSH levels are more susceptible to oxidative stress and consequent haemolysis.     

Oxidative stress status in adults with nephrotic syndrome

BACKGROUND: Excessive generation of reactive oxygen species is one of the incriminated mechanisms in the pathogenesis of progressive renal injury. The role of oxidant stress in acute and chronic glomerular diseases has been investigated through experimental and clinical studies. SUBJECTS, MATERIALS AND METHODS: In the present study, oxidative stress status in adult nephrotic patients was studied by determining plasma selenium levels, erythrocyte and plasma glutathione peroxidase (GSH-Px) activities, erythrocyte superoxide dismutase (Cu-Zn-SOD) activity, erythrocyte and plasma levels of malondialdehyde (MDA). RESULTS: Twenty adult nephrotic syndrome patients included into the study had lower activities of erythrocyte (17.17 +/- 2.29 U/gHb) and plasma (153.76 +/- 20.12 U/l) GSH-Px activities when compared the controls ( 27.05 +/- 7.30 U/gHb and 308.89 +/- 55.04 U/l for erythrocyte and plasma GSH-Px activities, respectively). They also had lower erythrocyte Cu-Zn-SOD activity (1896.30 +/-94.31 U/gHb) than that of the controls (2506.17 +/- 461.08 U/gHb). Erythrocyte (483.40 +/- 37.45 nmol/gHb in patients vs 210.35 +/- 55.55 nmol/gHb in controls) and plasma (4.84 +/- 0.65 nmol/ml in patients vs 2.03 +/- 0.41 nmol/ml in controls) levels of MDA were higher in patients. Plasma selenium levels of the patients (48.0 +/- 7.28 ng/ml) were lower than that of the controls (69.25 +/-5.80 ng/ml). CONCLUSION: In conclusion, these results obtained in adult nephrotic syndrome patients support the previous data indicating an abnormality in antioxidative system of nephrotic patients.     

LDL Hemoperfusion-A New Procedure for LDL Apheresis: First Clinical Application of an LDL Adsorber Compatible with Human Whole Blood

Abstract: To date, lipid apheresis procedures can remove low-density lipoprotein (LDL) cholesterol (LDL-C) only from plasma. Thus, initially plasma has to be separated from the blood cells, which increases the costs and complexity of the extracorporeal circuit. This paper describes the first clinical application of a new LDL adsorber that eliminates LDL directly from whole blood. The goal of this pilot study was to test the efficacy, safety, and feasibility of direct lipoprotein adsorption in patients. In a 2 center Phase II clinical trial, 12 hypercholesterolemic patients suffering from overt coronary or peripheral artery disease were treated once with LDL hemoperfusion. The new LDL adsorber (DALI, Fresenius, St. Wendel, Germany) contained 480 ml of polyacrylate coated polyacrylamide gel. The anticoagulation consisted of an initial heparin bolus followed by an acid citrate dextrose (ACD)-A infusion during the treatment. The processing of nearly 1 patient blood volume resulted in a reduction of LDL-C by 45 ± 8% and triglycerides by 23 ± 20%. HDL-C, fibrinogen, and cell counts were not significantly influenced. In a subgroup of 5 patients who exhibited elevated lipoprotein (a) (Lp[a]) levels, Lp(a) reduction was 43 ± 15% (all results corrected for plasma volume shifts). The sessions were clinically uneventful; the system was technically safe and easily handled. In conclusion, short-term LDL hemoperfusion by the DALI proved to be a safe, effective, and simple procedure for the treatment of patients suffering from symptomatic recalcitrant hypercholesterolemia. The present study represents a solid basis for the clinical long-term evaluation of this new technique in the future.     

维生素E对维持性血液透析患者静脉补铁诱导的氧化应激及脂代谢紊乱的影响

目的 探讨口服维生素E对静脉补铁诱导的氧化应激及脂质代谢紊乱的影响.方法 选择维持性血液透析合并肾性贫血患者40例,按随机数字表法分为静脉补铁组及静脉补铁+维生素E组,每组20例.健康对照组20名.静脉补铁组所有患者行血液透析治疗时由静脉输入100 mg蔗糖铁注射液,起始为每周2～3次,完成总剂量1000 mg后改为每周或2周1次,使患者的铁蛋白维持在100～300μg/L之间.静脉补铁+维生素E组:除按上述方法补铁外同时口服维生素E 200 mg,每日2次.两组患者同时每周使用促红素治疗(每周100～150 U/kg)并检测三组治疗前和补铁组、补铁+维生素E组治疗1、6个月血脂及氧化应激指标.结果 治疗1个月后,补铁组丙二醛(MDA)、终末氧化蛋白产物(AOPP)、总胆固醇(TCH),脂蛋白Lp(a)、载脂蛋白B(ApoB)含量与治疗前比较差异有统计学意义(P＜0.05);超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、ApoAl含量比较差异也有统计学意义(P＜0.05);而甘油三脂(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、极低密度脂蛋白(VLDL)比较则无明显变化.补铁+维生素E组TCH水平与补铁组比较差异有统计学意义(P＜0.05);而SOD、GSH-Px、AOPP、MDA、TG、LDL、HDL、VLDL载脂蛋白Al(ApoAl)、ApoB、Lp(a)比较差异均无统计学意义(P＞0.05).治疗6个月后,补铁+维生素E组SOD、GSH-Px、ApoAl与补铁组比较比较差异有统计学意义(P＜0.05);AOPP、MDA、TCH、Lp(a)、ApoB比较差异也有统计学意义(P＜0.05);而TG、LDL、HDL、VLDL则无明显变化(P＞0.05).结论 静脉补铁可以加重维持性血液透析患者体内的氧化应激水平及脂代谢紊乱.长时间口服维生素E可以改善维持性血液透析患者静脉补铁诱导的氧化应激及脂代谢紊乱.     

Effect of Nafamostat Mesilate on Bradykinin Generation and Hemodynamics During LDL Apheresis

Abstract: Dextran-sulfate (DS) cellulose used for low-density lipoprotein (LDL) apheresis seems to be a weak activator of the contact phase of the intrinsic coagulation pathway because the surface of this substance has negative charges. Heparin, a commonly used anticoagulant, has no effect on this process whereas the process is inhibited by a newly developed anticoagulant, nafamostat mesilate (NM). The effects on bradykinin generation were compared between heparin and NM. Five patients with severe hypercholesterolemia were treated with LDL apheresis using either heparin or NM on a different day. During apheresis with heparin, factor XII, high molecular weight kininogen, and prekallikrein were markedly decreased by passing through the DS column. A distinct generation of bradykinin was observed by passing plasma through the DS column, and this led to the rise of bradykinin levels from 12 ± 5 (mean ± SE) to 72 ± 14 pg/ml after treatment of 1,000 ml of plasma. NM suppressed almost completely the rise of bradykinin levels. Although blood pressure was apt to decrease during apheresis with heparin, there was no significant difference in blood pressure between heparin and NM. Since an angiotensin-converting enzyme inhibitor may lead to a marked rise in blood levels of bradykinin by suppressing its degradation, the use of NM is recommended for apheresis in patients taking this drug.     

Lipid peroxidation and antioxidant enzymes in children on maintenance dialysis

End-stage renal disease (ESRD) is associated with numerous complications, which may partly result from excessive amounts of reactive oxygen species and/or decreased antioxidant activity. The aim of the study was to evaluate lipid peroxidation (LP) in plasma and erythrocytes, erythrocyte antioxidant enzyme activity (superoxide dismutase, SOD; catalase, CAT; glutathione peroxidase, GSH-Px), and concentrations of Cu and Zn as cofactors of SOD and Se as a cofactor of GSH-Px in erythrocytes, plasma and in dialysis fluid in children with ESRD. In particular, we analyzed whether the modality of dialysis could modify oxidative stress parameters in children. To determine the influence of hemodialysis (HD) on oxidative stress, the measurements were also performed on HD children 20 min after the beginning of the dialysis session. Thirty-one patients participated in the study: group I with 10 children on continuous ambulatory peritoneal dialysis (CAPD), and group II with 21 on HD. The erythrocyte malondialdehyde concentrations (E-MDA), plasma MDA (P-MDA) and plasma organic hydroperoxide (OHP) in children from both groups were higher than in controls. E-MDA and P-MDA in HD before the session was lower compared to the values after 20 min of HD session (time T²⁰). The activity of SOD, GSH-Px, CAT, concentrations of erythrocyte and plasma Se, Cu, Zn were lower in children with ESRD than in controls. In the HD group, the activity of GSH-Px, CAT, and levels of trace elements in erythrocytes and in plasma were diminished at time T²⁰. In conclusion, increased oxidative stress occurs in children on maintenance dialysis, independent of dialysis modality. The activity of the enzymatic antioxidant defence system is highly reduced in red blood cells of pediatric dialysis patients. Children with ESRD exhibit lower trace element (Se, Cu, Zn) levels in plasma and erythrocytes as compared to healthy subjects. Oxidative stress is aggravated during every single HD session in children.     

Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia

Low-density lipoprotein (LDL) apheresis is an extracorporeal modality to lower LDL cholesterol. While most of the devices eliminate LDL particles from plasma, a recently introduced whole-blood perfusion column (DALI) adsorbs lipoproteins directly from whole blood. We investigated the efficacy and safety of a new whole-blood LDL apheresis system (Liposorber D) in 10 patients with severe hypercholesterolemia in a multicenter trial. In 93 LDL aphereses, the mean reduction in LDL cholesterol and lipoprotein(a) was 62.2 +/- 11.5% and 55.6 +/- 16.9%, respectively (P < 0.01). If hemodilution during apheresis was considered, the reductions were 58.0 +/- 10.9 and 55.3 +/- 10.9%, respectively (P < 0.01), while high-density lipoprotein (HDL) cholesterol did not change significantly. Three mild episodes of hypocalcemia and two mild episodes of arterial hypotension were observed; however, LDL apheresis could be continued in each case. In conclusion, the new whole-blood LDL apheresis with Liposorber D is a safe, simple, and useful modality to reduce LDL cholesterol and lipoprotein(a) in cardiovascular high-risk patients.     

Low–Density Lipoprotein Apheresis Versus Lipid Lowering Drugs in the Treatment of Severe Hypercholesterolemia: Four Years' Experience

Abstract: Elevated lipoprotein concentrations seem to be linked strongly in a dose dependent manner to an increased incidence of atherosclerosis. A total of 47 patients suffering from severe hyperlipidemia were matched to treatment with LDL apheresis (Baxter, Kaneka, Li–popak; 24 patients, aged 50.2 ±11.5 years), diet, and/or lipid–lowering drugs or with diet and lipid–lowering drugs only (23 patients, aged 48.8 ±11.8 years). After treatment periods of 49.8 ±13.4 months (apheresis group, 2,396 treatment sessions) and 38.6 ± 15.1 months (drug group), the ensuing results revealed significant differences (p <0.0001): –47.3% versus –12.1% for total cholesterol, –46.9% versus –21.8% for LDL, +8.4% versus +0.9% for HDL, –52.0% versus – 13.1% for the LDL/HDL ratio, –36.4% versus –16.2% for triglycerides, and –25.9% versus + 1.5% for lipoprotein (a). In the apheresis group, one patient died of myocardial infarction; in the drug group, there was one nonfatal myocardial infarction and the manifestation of coronary heart disease in 3 cases. There were no severe side effects in either group. All patients in the apheresis group responded to therapy. The present trial suggests that a continuing reduction in serum lipid concentrations may lower, in a dose dependent manner, the risk for development and progression of coronary heart disease. Regarding clinical and laboratory results, LDL apheresis seems to be safe, effective therapy for treatment of severe hyperlipidemia.     

Lipid Apheresis: From a Heroic Treatment to Routine Clinical Practice

Abstract: Lipid apheresis has developed from a heroic treatment into a routine clinical therapy and currently is the major indication for performing extracorporeal plasma therapy. Whereas it was once reserved for patients with homozygous familial hypercholesterolemia, today it has a place in the secondary prevention of severe coronary heart disease when low-density lipoprotein (LDL)-cholesterol levels exceed 150 mg/dl, despite conservative treatment, in any type of primary hypercholesterolemia. Unselective plasma exchange has been replaced by a variety of selective procedures. The efficacy of the treatment can be maximized by combining LDL apheresis with the use of cholesterol synthesis enzyme inhibitors. Clinical studies have shown that drastic cholesterol reduction can result in regression of coronary atherosclerosis as well as in reduced cardiac morbidity and mortality. Technical progress comprises improved selectivity, online regeneration of adsorbers, and LDL adsorption from whole blood. Recently, a new LDL hemoper-fusion procedure was successfully tested in a clinical pilot study; blood is passed directly over a lipid sorbent without prior plasma separation. If this system is demonstrated to be safe and effective in clinical Phase III trials, a further qualitative step in the rapid development of LDL apheresis will have been made.     

Development of Immunosorbents for apoB-Containing Lipoproteins Apheresis

Abstract: Three types of sorbents were developed for the specific removal of atherogenic apoB-containing low-density lipoprotein (LDL) and lipoprotein LDL(a) (Lp[a])from human plasma. Two sorbents contained monospecific sheep polyclonal or mouse monoclonal antibodies against human apoprotein B-100. The third one was intended for specific removal of Lp(a) and contains sheep antibodies against human Lp(a). Thirty patients were treated for up to 9 years by LDL apheresis with anti-LDL immunosorbents. A pilot study of Lp(a) apheresis with 3 patients was conducted during 3 years. The results showed that extracorporeal immunosorption is safe and effective for lowering LDL and Lp(a). These procedures may be used both for metabolic investigations and for studies on possible regression of atherosclerosis.     

State of the Art of Lipid Apheresis

Abstract: Currently, 5 different lipid apheresis procedures are available for routine clinical treatment of hy–percholesterolemic patients. Unselective plasma exchange is a technically simple extracorporeal circuit, but albumin substitution fluid must be used and there is no high–density lipoprotein (HDL) recovery. Semiselective double filtration with improved size selectivity because of a small–pore secondary filter combines good elimination of low–density lipoprotein (LDL), lipoprotein (a) (Lp[a]), and fibrinogen with adequate HDL recovery; modifications such as thermofiltration, predilution/backflush, or pulsatile flow have been proposed for the improvement of this system. Three highly selective procedures are basedon immunologic or electrostatic interactions: immunoad–sorption using anti–low–density lipoprotein (LDL) antibodies, chemoadsorption onto dextran sulfate, and hep–arin–induced LDL precipitation (HELP) apheresis. The features of each system are discussed critically. Lastly, two new developments, Lp(a) immunoadsorption and LDL hemoperfusion using a polyacrylate LDL adsorber compatible with whole blood, are described     

Assessment of Currently Available Low-Density Lipoprotein Apheresis Systems

Abstract: It has already been 10 years since the introduction of low-density lipoprotein (LDL) apheresis technologies. They have been established as technically and medically feasible for long-term treatment and economically acceptable, and their long-term treatment effects have been determined. Currently, there are efforts to develop more selective LDL removal systems. However, after 10 years of research, it is time to carefully review this strategy. The approach may have become too specific in light of the multiple macromolecules involved in the pathogenesis of atherosclerosis. In this paper, the six currently available LDL apheresis systems (plasma exchange, double filtration plasmapheresis, thermofiltration, LDL chemical adsorption (Kaneka system), LDL immunoadsorption, and the heparin-induced extracorporeal LDL precipitation [HELP] system) were reviewed and scored from various points of view such as effectiveness, simplicity, safety, and cost performance. Finally, each system was assessed from the global point of view in relation to the pathogenesis of lipid-related diseases.     

Assessment of oxidative stress in the early posttransplant period: comparison of cyclosporine A and tacrolimus-based regimens

BACKGROUND: Oxidative stress is one of the leading causes of cardiovascular morbidity and mortality in chronic kidney disease. Although it is clear that many metabolic abnormalities improve, the effects of kidney transplantation on oxidative state are obscure. METHODS: Twenty-three kidney transplant patients were included in the study. Eleven patients (mean age 27.9+/- 9.1 years) were treated with cyclosporine A (CsA) whereas 12 patients (mean age 22.4 +/- 3.4 years) were treated with tacrolimus. Twenty-three healthy subjects served as controls. None of the patients or controls suffered from diabetes mellitus or an acute infection at the time of the study. Plasma malondialdehyde (MDA), plasma selenium (Se), erythrocyte glutathione peroxidase (GSH-Px), erythrocyte superoxide dismutase (SOD), erythrocyte Zn (EZn), and erythrocyte Cu (ECu) levels were studied before and in the 1st, 3rd, 7th, 14th and 28th days after the transplantation. RESULTS: The GSH-Px, SOD, ECu, EZn and selenium levels were lower and MDA levels were higher in patients than controls before transplantation (p < 0.001 for all). MDA levels decreased and SOD, GSH-Px, ECu, EZn levels increased in parallel to the decrement of serum creatinine levels following the renal transplantation. No difference was found among the patients regarding the treatment regime. CONCLUSION: The study data suggest that the improvement in oxidative state parameters begins at the first day of renal transplantation and continues at the 28th posttransplant day in living donor transplantations.     

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.