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     

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 Unselective plasma exchange has been replaced by a variety of selective procedures.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.     

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.     

Activity of Free Radical Scavenging Enzymes in Red Cells and Plasma of Patients Undergoing Extracorporeal Low-Density Lipoprotein Apheresis

There is evidence that reactive oxygen species (ROSs) are generated in extracorporeal circuits. Free radical scavenging enzymes (FRSEs) such as glutathione reductase (GSSG-R), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) protect against the damaging effect of ROSs. The influence of extracorporeal treatment on FRSE activity was investigated in the plasma and red blood cells (RBCs) of 21 patients undergoing regular low-density lipoprotein (LDL) apheresis. The FRSEs GSSG-R, GSH-Px, and SOD were measured. Determinations were made before and after a single treatment. Because all apheresis patients suffered from coronary heart disease (CHD), 201 CHD patients and 90 individuals without CHD, neither group undergoing apheresis, served as controls. In apheresis patients, GSH-Px (33.9 ± 8.2 U/g Hb) and GSSG-R (7.6 ± 0.9 U/g Hb) activities were increased whereas SOD activity (5.4 ± 1.5 U/g Hb) was decreased in RBCs before a single treatment compared to controls. Plasma FRSEs of apheresis patients were not different from those of controls. There was no effect of a single treatment on FRSEs in RBCs. However, a significant decrease in plasma GSH-Px activity (209.9 ± 24.9 U/ml) due to the extracorporeal treatment was observed. These data show that long-term extracorporeal therapy with LDL apheresis modulates the activity of antioxidant enzymes in RBCs whereas a single treatment was without major effect on FRSE activity in RBCs and plasma, except for plasma GSH-Px.     

H.E.L.P. Apheresis Therapy in the Treatment of Severe Hypercholesterolemia: 10 Years of Clinical Experience

Abstract: In collaboration with B. Braun Melsungen AG, Germany, we were able to develop the heparin–mediated extracorporeal low–density lipoprotein (LDL) fibrinogen precipitation (H.E.L.P.) system and to introduce it into clinical use. The H.E.L.P. apheresis system is the most potent technique to reduce at the same time LDL, lipoprotein (a) (Lp[a]), and fibrinogen plasma concentrations if the physiological clearing mechanisms are insufficient and if diet and drugs fail to achieve a target concentration of 100 mg/dl LDL–cholesterol or lower, required for secondary prevention of coronary heart disease. The H.E.L.P. LDL apheresis system also improves plasma viscosity and microcirculation efficiently. The clinical experience with the H.E.L.P. system has proved its clinical utility; regression of coronary heart disease occurs, a decrease in events of coronary heart disease takes place, and acute as well as chronic impairment of microcirculation shows a remarkable improvement with H.E.L.P. therapy. For the future, the availability of this safe and efficient apheresis technique may help many patients who previously could not be treated adequately     

Low–Density Lipoprotein Adsorption for Arteriosclerotic Patients

Abstract: A wide variety of treatments is now available for arteriosclerosis obliterans (ASO) patients, not very successful in some cases. Low—density lipoprotein (LDL) apheresis using an extracorporeal adsorption column containing dextran sulfate cellulose beads was applied to control lipid levels intensively in ASO patients with accompanying drug—resistant hyperlipidemia. A series of the apheresis procedures had a remarkable impact on clinical symptoms and physiological findings with improvement in intermittent claudication observed in more than 80% of the patients. Improvements in plethysmogram and thermogram readings suggested an increased circulation in lower extremities in more than 80% of patients. In addition, the treatment improved blood rheology, as evidenced by a reduction in blood viscosity. In a follow—up study made by sending a questionnaire to previously treated patients, it was revealed that improvements in clinical symptoms were well maintained even after cessation of the treatment. In conclusion, LDL apheresis proved to be a useful therapeutic tool in ASO patients having elevated lipid levels     

Therapeutic apheresis in kidney diseases: an updated review

Besides conventional medical therapies, therapeutic apheresis has become an important adjunctive or alternative therapeutic option to immunosuppressive agents for primary or secondary kidney diseases and kidney transplantation. The available therapeutic apheresis techniques used in kidney diseases, including plasma exchange, double-filtration plasmapheresis, immunoadsorption, and low-density lipoprotein apheresis. Plasma exchange is still the leading extracorporeal therapy. Recently, growing evidence supports the potential benefits of double-filtration plasmapheresis and immunoadsorption for more specific and effective clearance of pathogenic antibodies with fewer side effects. However, more randomized controlled trials are still needed. Low-density lipoprotein apheresis is also an important supplementary therapy used in patients with recurrent focal segmental glomerulosclerosis. This review collects the latest evidence from recent studies, focuses on the specific advantages and disadvantages of these techniques, and compares the discrepancy among them to determine the optimal therapeutic regimens for certain kidney diseases.     

Hemorheological aspects of the Arvin therapy of acute thromboses of the magistral veins of the lower extremities

The rheologic blood properties were studied in patients with acute venous thrombosis during Arvin therapy. A marked correcting effect of the agent in removing the hemorheological disorders was demonstrated. It was found that the action of Arvin, linked with reduction of fibrinogen concentration, is attended by a decrease of blood viscosity, diminished aggregation of blood formed elements, and improvement of the functional condition of the microcirculatory bed during the whole course of treatment. The duration of the positive hemorheological effect of Arvin exceeds that in treatment by a complex of antithrombotic agents.     

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.     

Beyond dialysis: current and emerging blood purification techniques

Extracorporeal blood purification using various techniques and hardware is a major part of the modern day practice of clinical nephrology. Although the various modalities of hemodialysis and hemofiltration are the most commonly used extracorporeal therapies in clinical nephrology, blood purification using other techniques have become necessary to remove pathogenic, toxic, or waste substances not easily cleared by hemodialysis or hemofiltration due to factors such as molecular size, protein binding, and lipid solubility. The following review is an up to date summary of extracorporeal therapies, beyond hemodialysis and hemofiltration, in current clinical use as practiced by nephrologists and others in the United States and beyond. This comprises therapeutic apheresis (plasma exchange and cytapheresis), plasma adsorption, hemoperfusion, and the bio-artificial devices.     

Extracorporeal removal of anti-HLA antibodies in transplant candidates

We report on the results of a clinical trial in which 14 transplant candidates were treated with an extracorporeal immunoadsorption system using Protein A that selectively removes immunoglobulin from plasma; we also assessed the dynamics of anti-HLA antibody as a model of IgG removal and re-equilibration, as well as the clinical safety of the procedure. At the end of a treatment course, plasma IgG levels were reduced by 90% +/- 8% of control values (P less than 0.01). In contrast, albumin levels were reduced by only 15% (P less than 0.05). Specific cytotoxic anti-HLA antibody titers were reduced by approximately 18-fold. Panel reactivity was measured as the proportion of a 40-member cell donor panel killed by patients' serum in the presence of complement; in nine of the 14 patients, there was a significant reduction in this parameter (range, 23% to 87%). During the 4-week follow-up period, anti-HLA antibody titers returned to baseline levels. There were no remarkable changes observed in blood chemistries, nor were there any unanticipated adverse reactions seen in the patients treated. We conclude that selective extracorporeal immunoadsorption is a safe and effective way of removing IgG-type antibodies, with potential application to reduction of HLA antibodies in transplant candidates.     

A controlled trial of the effect of folate supplements on homocysteine, lipids and hemorheology in end-stage renal disease

Elevated plasma homocysteine (Hcy), dyslipidemia and hemorheological abnormalities all occur commonly in end-stage renal disease (ESRD) and are recognized risk factors for arteriosclerosis. To study the effect of folate supplementation on these factors we conducted a randomized controlled trial. Thirteen hemodialysis (HD) and 8 continuous ambulatory peritoneal dialysis (CAPD) patients received either 5 mg folic acid daily or placebo for 3 months. After 1 and 3 months, fasting blood samples were taken for Hcy, lipid profile, blood and plasma viscosity, red blood cell (RBC) osmotic fragility, plasma fibrinogen concentration and in vivo platelet aggregability. At baseline, the CAPD patients had a higher mean plasma fibrinogen concentration than the HD patients and they also tended to have higher mean plasma viscosity. Folate-treated patients showed marked increases in RBC folate and an average decrease in plasma Hcy concentration of 33%. Mean total cholesterol, LDL cholesterol and triglyceride concentrations decreased significantly in the CAPD patients who took folate. Folate had no significant effect on hemorheology. In conclusion, folate supplements in ESRD reduce plasma Hcy concentrations and may improve lipid profiles. In our patients, hemorheological abnormalities were more marked in patients on CAPD than in those on HD and were not improved by folate supplementation.     

Rheology of the cerebral circulation

Current concepts of brain perfusion focus on the importance of rheological factors in the determination of cerebral blood flow. Blood viscosity, a primary determinant of blood flow, increases as the shear rate (velocity gradient) decreases, thereby impeding cerebral perfusion. Hematocrit, erythrocyte aggregation, erythrocyte flexibility, platelet aggregation, and plasma viscosity differentially influence blood flow through the conductance vessels and microcirculation of the brain. In addition, the microcirculation is also affected by the Fahraeus effect, the inversion phenomenon, and the screening effect. Knowledge of these factors affecting blood flow provides a rationale for experimental and clinical rheological therapies in the treatment or prevention of acute focal cerebral ischemia.     

Échanges plasmatiques en néphrologie : techniques et indications

Plasma exchange is a non-selective apheresis technique that can be performed by filtration or centrifugation allowing rapid purification of high molecular weight pathogens. An immunosuppressive treatment is generally associated to reduce the rebound effect of the purified substance. Substitution solutes such as human albumin and macromolecules are needed to compensate for plasma extraction. Compensation by viro-attenuated plasma is reserved solely for the treatment of thrombotic microangiopathies or when there is a risk of bleeding, because this product is very allergenic and expensive. The treatment goal for a plasma exchange session should be between one and one and one-half times the patient's plasma volume estimated at 40 mL/kg body weight. The anticoagulation is best ensured by the citrate. Complications of plasma exchange are quite rare according to the French hemapheresis registry. The level of evidence of efficacy of plasma exchange in nephrology varies from one pathology to another. Main indications of plasma exchange in nephrology are Goodpasture syndrome, antineutrophil cytoplasmic antibody vasculitis when plasma creatinine is greater than 500 μmol/L, and thrombotic microangiopathies. During renal transplantation, plasma exchange may be proposed in the context of human leukocyte antigen (HLA) desensitization protocols or ABO-incompatible graft. After renal transplantation, plasma exchange is indicated as part of the treatment of acute humoral rejection or recurrent focal segmental glomerulosclerosis on the graft. Plasma exchanges are also proposed in the management of cryoglobulinemia or polyarteritis nodosa. Hemodialysis with membranes of very high permeability tends to replace plasma exchange for myeloma nephropathy. The benefit from plasma exchange has not been formally demonstrated for the treatment of severe lupus or antiphospholipid antibody syndrome. There is no indication of plasma exchange in the treatment of scleroderma or nephrogenic systemic fibrosis. More selective apheresis techniques such as immunoadsorption are currently proposed to replace plasma exchange.     

Low-density lipoprotein apheresis: principles and indications

Low-density lipoprotein (LDL) apheresis describes a group of apheresis techniques that selectively remove apolipoprotein B-containing lipoproteins producing an acute reduction in LDL-cholesterol (LDL-C). Six devices are available for the removal of LDL-C while sparing other important plasma components. The LDL-apheresis (LDL-A) is not routinely used for the treatment of hypercholesterolemia, which usually responds to medical management, but is used to treat familial hypercholesterolemia, an inherited metabolic abnormality resulting in premature death due to progressive coronary artery disease, and to treat patients who fail medical management. The mechanism of action of the available LDL-A devices, reactions that can occur with these treatments, and the role of this specialized apheresis technique in the treatment of hypercholesterolemia are described.     

Effect of surgical trauma on the rheological properties of the blood

The rheological properties of blood (viscosity, thrombocyte and erythrocyte aggregation activity, ability of erythrocytes for deformation) were studied in 49 patients subjected to surgical operation of different duration and volume of blood loss. It was found that a surgical trauma causes alterations in rheological properties of blood. The degree of hemorheological deviations was shown to correlate with the severity of surgery. In order to reduce the amount of postoperative complications in the patients it is necessary to investigate the main rheological parameters and their correction.     

Immunoadsorption onto protein A induces remission in severe systemic lupus erythematosus.

BACKGROUND: Reduction of pathological autoantibodies and circulating immune complexes can be useful in the treatment of autoimmune disease. Plasmapheresis has been shown to reduce autoantibody levels in systemic lupus erythematosus (SLE), but its effect on patients' outcome was not better compared with conventional immunosuppression in the past. AIM OF THE STUDY: Immunoadsorption as a selective extracorporeal immunoglobulin elimination technique was evaluated as rescue therapy in patients suffering from SLE. METHODS: Eight patients with severe, therapy-resistant SLE underwent immunoadsorption onto protein A sepharose without concomitant immunosuppressants. RESULTS: Remission of the disease was achieved in seven patients. Therapy had to be stopped in one patient because of side-effects. The best results were obtained when immunoadsorption was carried out daily, without supplementary intravenous immunoglobulin therapy. Oral cyclophosphamide for 3-6 months during follow-up was used to suppress relapse. Autoantibodies and circulating immune complexes were effectively eliminated regardless of their IgG subclass. CONCLUSION: Immunoadsorption onto protein A might be used as an extracorporeal treatment option in SLE when other therapies are ineffective.     

DALI apheresis in hyperlipidemic patients: biocompatibility, efficacy, and selectivity of direct adsorption of lipoproteins from whole blood

Recently, the first apheresis technique for direct adsorption of low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] from whole blood (DALI) was developed that does not require a prior plasma separation. That markedly simplifies the extracorporeal circuit. The aim of the present study was to test the acute biocompatibility, efficacy, and selectivity of DALI apheresis. In a prospective clinical study, 6 hypercholesterolemic patients suffering from angiographically proven atherosclerosis were treated 4 times each by DALI. 1.3 patient blood volumes were treated per session at blood flow rates of 60-80 ml/min using 750 or 1,000 ml of polyacrylate/polyacrylamide adsorber gel. The anticoagulation consisted of an initial heparin bolus followed by a citrate infusion. The sessions were clinically essentially uneventful. Mean corrected reductions of lipoproteins amounted to 65% for LDL-cholesterol, 54% for Lp(a), 28% for triglycerides, 1% for HDL-cholesterol, and 8% for fibrinogen. The selectivity of lipoprotein removal was high. Cell counts remained virtually unchanged and no signs of hemolysis or clotting were detected. Cell activation parameters elastase, beta-thromboglobulin, interleukin-1beta, and IL-6 showed no significant increase. Complement activation was negligible. There was significant, but clinically asymptomatic, bradykinin activation in the adsorber with mean maxima of 12,000 pg/ml in the efferent line at 1,000 ml of treated blood volume. In conclusion, DALI proved to be safe, selective, and efficient for the adsorption of LDL-C and Lp(a), which simplifies substantially the extracorporeal therapy in hypercholesterolemic patients.     

Comment mettre en place un plateau technique d’aphérèses

Many apheresis techniques can be performed in a blood-bank facility or a hemodialysis (HD) facility. However, it makes sense to perform apheresis in a hemodialysis facility as apheresis involves extra-corporeal circuits and because HD can be performed at the same time as apheresis (tandem procedure). Apheresis techniques comprise therapeutic plasma exchange, double-filtration plasmapheresis, and its derivative (rheopheresis and LDL-apheresis), and immunoadsorption (specific and semi-specific). We have setup an apheresis platform in our hospital that fulfills health recommendations. This process has involved financial investment and significant human resources, and has enabled us to network with different specialties (neurology, hematology, vascular medicine). We have setup protocols according to the type of pathology to be treated by apheresis, and to monitor clinical and biological data for each apheresis session. The main side effects of apheresis are a fall in blood pressure when a session is initiated, an increase in fluid overload, hypocalcemia, and the loss of some essential plasmatic factors. However, these side-effects are easily identified and can be properly managed in real time. Within two-years, we have performed 1845 apheresis sessions (134 patients). Of these, 66 received apheresis before and/or after kidney transplantation for ABO and/or HLA incompatibility (desensitization), for humoral rejection, or in the setting of relapsing focal-segmental glomerulosclerosis. Our patients’ outcomes have been similar to those reported in the literature. The other 68 patients had various conditions. Because our program is now well-established, we are currently forming a specialist center to train physicians and nurses in the various apheresis techniques/procedures.     

Estimation of total body fluid shifts between plasma and interstitium in man during extracorporeal circulation

Fluid transport between plasma and interstitium during extracorporeal circulation was studied in seven patients undergoing aortocoronary bypass grafting. The absolute shifts in plasma volume during hypothermia were determined as the difference between input and loss of fluid and the changes in blood volume. The change in haemoglobin concentration due to acute haemodilution when starting extracorporeal circulation was used to calculate the absolute blood and plasma volume. The Starling equation for exchange across the capillary wall was used to describe fluid shifts. The total fluid filtered during the 60- to 90-min period of extracorporeal circulation averaged 34.1 +/- 11.1 (s.d.) ml/min. The total body filtration coefficient from the Starling relationship averaged 0.046 +/- 0.012 ml/kg.mmHg.min (0.354 +/- 0.092 ml/kg.kPa.min). Haemodilution, reducing colloid osmotic pressure in plasma (COPP) by approximately 10 mmHg (1.3 kPa) will result in a loss of plasma fluid of around 2 1 per hour. When corrected for lower fluid viscosity due to hypothermia during extracorporeal circulation, CFC would be about 40% higher, and a filtered volume of nearly 3 1 in a normothermic 70-kg person would be expected. Crystalloid haemodilution for shorter periods of time does not produce excessive oedema and thus may be well tolerated.