Low-density Lipoprotein Apheresis Systems Research Articles

LDL Apheresis and Inflammation – Implications for Atherosclerosis

Low-density lipoprotein (LDL) apheresis is an extracorporeal treatment modality used in high-risk patients when LDL cholesterol levels cannot be reduced adequately with medication. The treatment is highly effective, but could be affected by potential unwanted effects on pro- and anti-inflammatory biomarkers. In this paper, we review the literature regarding the effect of LDL apheresis on pro- and anti-inflammatory biomarkers important in atherosclerosis, also as patients in LDL apheresis have high risk for atherosclerotic complications. We discuss the effect of LDL apheresis on complement, cytokines and finally a group of other selected pro- and anti-inflammatory biomarkers. The complement system is affected by LDL apheresis, and there are differences between different LDL apheresis systems. The plasma separation columns seem to trigger the formation of proinflammatory complement factors including C3a and C5a, while the same anaphylatoxins are adsorbed by the LDL apheresis columns, however, to varying degree. Proinflammatory cytokines are to some extent adsorbed by the LDL apheresis columns, while some of the anti-inflammatory cytokines increase during treatment. Finally, we discuss the effect of apheresis on different biomarkers including C-reactive protein, fibrinogen, adhesion molecules, myeloperoxidase and HDL cholesterol. In conclusion, even if there are differences between pro- and anti-inflammatory biomarkers during LDL apheresis, the consequences for the patients are largely unknown and larger studies need to be performed. Preferably, they should be comparing the effect of different LDL apheresis columns on the total inflammatory profile, and this should be related to clinical endpoints.

Complement profile and activation mechanisms by different LDL apheresis systems

Extracorporeal removal of low-density lipoprotein (LDL) cholesterol by means of selective LDL apheresis is indicated in otherwise uncontrolled familial hypercholesterolemia. During blood–biomaterial interaction other constituents than the LDL particles are affected, including the complement system. We set up an ex vivo model in which human whole blood was passed through an LDL apheresis system with one of three different apheresis columns: whole blood adsorption, plasma adsorption and plasma filtration. The concentrations of complement activation products revealed distinctly different patterns of activation and adsorption by the different systems. Evaluated as the final common terminal complement complex (TCC) the whole blood system was inert, in contrast to the plasma systems, which generated substantial and equal amounts of TCC. Initial classical pathway activation was revealed equally for both plasma systems as increases in the C1rs–C1inh complex and C4d. Alternative pathway activation (Bb) was most pronounced for the plasma adsorption system. Although the anaphylatoxins (C3a and C5a) were equally generated by the two plasma separation systems, they were efficiently adsorbed to the plasma adsorption column before the “outlet”, whereas they were left free in the plasma in the filtration system. Consequently, during blood–biomaterial interaction in LDL apheresis the complement system is modulated in different manners depending on the device composition.

Treatment of Hyperlipidemia With a Modified Low Density Lipoprotein Apheresis System With Dextran Sulfate

Many low density lipoprotein (LDL) apheresis systems have been applied to patients with hyperlipidemia, but these systems usually work on the basis of complicated equipment and the cost of treatment is expensive. In order to achieve effective treatment of hyperlipidemia at a lower cost, we developed a new LDL apheresis system with dextran sulfate (LAS-DS). In this study, 50 patients with hyperlipidemia were treated 120 times with the new LAS-DS. In each treatment, 600 +/- 100 mL of plasma (equal to approximately 25% of the total plasma of patients) was collected by apheresis, and DS solution and calcium chloride solution were added into the collected plasma as LDL absorber and catalyzer, respectively. DS selectively binds LDL cholesterol (LDL-C) under the catalysis of calcium ion and the LDL-C-DS complex is removed by centrifugation. The treated plasma was transfused back into the patients and the excessive calcium in the plasma was removed by the cation exchange column integrated in the transfusion set. After treatment with our new system, the acute mean LDL-C reduction was 97% in the apheresis plasma of hyperlipidemia patients. The corresponding reduction was 55.2% and 69.4% for total cholesterol and total triglyceride. There were insignificant reductions of high density lipoprotein cholesterol (HDL-C) and albumin. The new LDL apheresis system with DS that we developed is very simple to operate without relying on complicated equipment, and it can achieve significant clinical results at a much lower cost compared with existing systems. Based on this study we think the new system can provide a safe, effective and much cheaper means for the treatment of hyperlipidemia patients.

Dextran‐sulfate‐adsorption of atherosclerotic lipoproteins from whole blood or separated plasma for lipid‐apheresis—Comparison of performance characteristics with DALI and lipidfiltration

For many years dextran sulfate adsorption (DSA) treatment of separated plasma has been an established technology for low-density lipoprotein (LDL)-elimination. Recently a system for the treatment of whole blood based on DSA was introduced into clinical practice. To further characterize DSA treatment of whole blood, the performance characteristics of both DSA modalities were compared at two investigational sites with two alternative LDL apheresis systems being already in routine clinical use. In prospective cross-over design, DSA whole blood treatment was compared with a whole blood polyacrylate LDL adsorption system (DALI) in one study group. DSA for plasma treatment was compared with Lipidfiltration in cross-over design in a second study group. In total, 12 patients on chronic LDL apheresis received 169 treatments. Six patients were treated twice with whole blood polyacrylate adsorption and twice with whole blood DSA. LDL-cholesterol (74.9-78.0%) and lipoprotein (a) (72.1-73.3%) were reduced by both with equal efficacy. DSA achieved a significantly higher reduction rate of fibrinogen. Another six patients were treated eight times with DSA plasma adsorption followed by 16 Lipidfiltration treatments. LDL-cholesterol (67.0-70.2%) and lipoprotein (a) (69.2-73.7%) were reduced by both with equal efficacy. Fibrinogen was eliminated more efficiently by Lipidfiltration (50.2 vs. 38.5%). DSA proved to be a safe and effective in both treatment modes, for plasma as well as for whole blood. At the discretion of the apheresis specialist, depending upon the status of national approval, DSA of whole blood complements the armamentarium of powerful modalities for extracorporeal elimination of atherosclerotic lipoproteins to meet specific individual, medical, or logistic needs.

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.

2P-0591 Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia

2P-0591 Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia

Lipid reductions by low-density lipoprotein apheresis: A comparison of three systems

There are currently three established low-density lipoprotein (LDL) apheresis systems: immunoadsorption, heparin-induced extracorporeal LDL precipitation (HELP), and dextran sulfate. We treated the same patient with all three systems and compared the lipid reductions achieved. A total of 135 consecutive treatments were studied, 57 with immunoadsorption, followed by 30 with HELP and 48 with dextran sulfate adsorption. The mean plasma volume (mean ± SD) treated was 4.9 ± 0.05, 3.08 ± 0.091, and 3.39 ± 0.71 L, respectively. The LDL-cholesterol (LDL-C) reduction was 75.5% ± 7.4%, 61.6% ± 5.1%, and 57.1% ± 12.4%, respectively (P < .001 for immunoadsorption v HELP and dextran sulfate). The mean removal efficiency (mass removed/plasma volume treated) for LDL-C was 1.0 ± 0.12, 1.42 ± 0.25, and 1.15 ± 0.21 g/L, respectively (P < .001 for HELP v immunoadsorption and dextran sulfate). The mean LDL-C plasma concentration before apheresis was 199 ± 23.9, 201 ± 25.7, and 186 ± 28 mg/dL, respectively (P < .001 for dextran sulfate adsorption v immunoadsorption and HELP). Among the three LDL apheresis systems, immunoadsorption caused the greatest percent reduction in LDL-C, while HELP eliminated LDL-C from the plasma most efficiently. Dextran sulfate was similar to HELP in terms of LDL-C reduction, and its removal efficiency was similar to immunoadsorption. Dextran sulfate was also associated with the lowest pretreatment plasma LDL-C concentration. Copyright © 2000 by W.B. Saunders Company

Development of selective low-density lipoprotein (LDL) apheresis system: immobilized polyanion as LDL-specific adsorption for LDL apheresis system. 1996.

Abstract: Guest Editor's Introduction: The binding site of the human LDL receptor is rich in anionic amino acids, and interacts with apolipoprotein‐B by the electrostatic force. Therefore, anionic ligands could be used for the selective adsorption of LDL without HDL adsorption. Based upon this concept, Kaneka Co. developed LDL adsorbent. The adsorbent named Loposorber consists of microporous cellulose beads which immobilized dextrane sulfate with a molecular weight of several thousands. This paper describes the basic study for the selection of polyanions, in vitro adsorption characteristics, and the references of initial clinical applications. This paper was printed in Artificial Organs, vol. 20, page 922–929 (1996), and reprinted here with permission.Low‐density lipoprotein (LDL) is widely recognized as one of the major risk factors for developing coronary heart diseases. Despite intensive development of LDL‐lowering drugs, there still exist those patients with refractory hyperlipidemia whose plasma LDL levels are not sufficiently lowered by drugs. LDL apheresis, direct removal of plasma LDL from circulating blood, is thought to be the most promising treatment for such refractory patients. Various techniques, such as the use of an immunoadsorbent utilizing an anti‐LDL antibody, have been used in an attempt to achieve the selective removal of LDL. However, none were widely used because of complications, poor selectivity, and so forth. To establish a safe and effective LDL apheresis system, we chose a synthetic affinity adsorbent as the LDL‐removing device. Synthetic polyanion compounds were used as the affinity ligands for LDL adsorbent to simulate the anion‐rich sequence of LDL binding sites in the human LDL receptor. Among various polyanion compounds, those polyanions with sulfate or sulfonate groups and hydrophilic backbone were found to have a strong affinity for LDL. In contrast, polyanions with carboxyl groups showed poor affinity. Dextran sulfate (DS) was selected as the affinity ligand of LDL adsorbent for its high affinity and low toxicity. The influence of its charge density and molecular weight on its affinity for LDL was suitable. The affinity rapidly increased as the charge density increased, then, reached a constant value. Little affinity was found for either the DS monomer (glucose sulfate) or DS with a molecular weight higher than 104 daltons whereas DS with molecular weights in the midrange showed strong affinity. DS with a midrange molecular weight was immobilized on cellulose hard gel to give LDL adsorbent clinical application. The adsorbent demonstrated an excellent selectivity for LDL and very low density lipoprotein (VLDL) in vitro. Adsorption of high‐density lipoprotein and major plasma proteins was almost negligible. Additional study of the LDL‐binding mechanism revealed that DS directly interacts with positively charged sites on LDL, which demonstrates that the nature of the interaction is the same as that of the LDL receptor. An LDL adsorption column (Liposorber) packed with an LDL adsorbent and polysulfone hollow‐fiber plasma separator (Sulflux) was developed as an efficient LDL apheresis system. Clinical investigation proved that this system is capable of intensively lowering the plasma LDL level without affecting major plasma components.

Improved Coronary Risk Assessment With Electron Beam Computed Tomography in an Asymptomatic Female With Familial Hypercholesterolemia

Improved Coronary Risk Assessment With Electron Beam Computed Tomography in an Asymptomatic Female With Familial Hypercholesterolemia

Lipoprotein(a) stimulates growth of human mesangial cells and induces activation of phospholipase C via pertussis toxin-sensitive G proteins

Renal disease is commonly associated with hyperlipidemia and correlates with glomerular accumulation of atherogenic lipoproteins, for example, lipoprotein(a) [Lp(a)], and mesangial hypercellularity. Specific binding of Lp(a) to mesangial cells and induction of c-myc and c-fos expression has been demonstrated. Therefore, in this study, we investigated a possible growth stimulatory effect and mode of action of Lp(a) in human mesangial cells. Lp(a) was purified from the regenerate fluid of a dextran sulfate column-based low-density lipoprotein apheresis system. Human mesangial cells were isolated by a sequential sieving technique from patients undergoing tumor nephrectomy. DNA synthesis was measured by [3H]-thymidine incorporation. The intracellular calcium concentration ([Ca2+]i) was determined by Fura 2-fluorescence, and inositol 1,4,5-trisphosphate (1,4,5-IP3) concentration was measured by a radioreceptor assay. The data show that Lp(a) bound to the cells with a Kd of 17.0 micrograms/ml and increased DNA synthesis and cell proliferation. Lp(a) caused a rapid increase in 1,4,5-IP3 and [Ca2+]i via a pertussis toxin-sensitive mechanism. The phospholipase C (PLC) inhibitor U73122 abolished Lp(a)-induced cell proliferation. In contrast, vasopressin-induced increase in 1,4,5-IP3 and [Ca2+]i was pertussis toxin insensitive. This study revealed that Lp(a) stimulates growth of human mesangial cells. Lp(a)-induced signaling involves binding to a receptor and stimulation of PLC via Gi proteins. Stimulation of PLC appears to be essential for the growth stimulatory effect of Lp(a). Whether these effects of Lp(a) contribute to the pathophysiology of renal disease needs to be determined.

Development of selective low-density lipoprotein (LDL) apheresis system: immobilized polyanion as LDL-specific adsorption for LDL apheresis system.

Low-density lipoprotein (LDL) is widely recognized as one of the major risk factors for developing coronary heart diseases. Despite intensive development of LDL-lowering drugs, there still exist those patients with refractory hyperlipidemia whose plasma LDL levels are not sufficiently lowered by drugs. LDL apheresis, direct removal of plasma LDL from circulating blood, is thought to be the most promising treatment for such refractory patients. Various techniques, such as the use of an immunoadsorbent utilizing an anti-LDL antibody, have been used in an attempt to achieve the selective removal of LDL. However, none were widely used because of complications, poor selectivity, and so forth. To establish a safe and effective LDL apheresis system, we chose a synthetic affinity adsorbent as the LDL-removing device. Synthetic polyanion compounds were used as the affinity ligands for LDL adsorbent to simulate the anion-rich sequence of LDL binding sites in the human LDL receptor. Among various polyanion compounds, those polyanions with sulfate or sulfonate groups and hydrophilic backbone were found to have strong affinity for LDL. In contrast, polyanions with carboxyl groups showed poor affinity. Dextran sulfate (DS) was selected as the affinity ligand of LDL adsorbent for its high affinity and low toxicity. The influence of its charge density and molecular weight on its affinity for LDL was suitable. The affinity rapidly increased as the charge density increased, then, reached a constant value. Little affinity was found for either the DS monomer (glucose sulfate) or DS with a molecular weight higher than 10(4) daltons whereas DS with molecular weights in the midrange showed strong affinity. DS with a midrange molecular weight was immobilized on cellulose hard gel to give LDL adsorbent clinical application. The adsorbent demonstrated an excellent selectivity for LDL and very low density lipoprotein (VLDL) in vitro. Adsorption of high-density lipoprotein and major plasma proteins was almost negligible. Additional study of the LDL-binding mechanism revealed that DS directly interacts with positively charged sites on LDL, which demonstrates that the nature of the interaction is the same as that of LDL receptor. An LDL adsorption column (Liposorber) packed with an LDL adsorbent and polysulfone hollow-fiber plasma separator (Sulflux) was developed as an efficient LDL apheresis system. Clinical investigation proved that this system is capable of intensively lowering the plasma LDL level without affecting major plasma components.

Low–Density Lipoprotein Removal Methods by Membranes and Future Perspectives

Since the application by Thompson et al. in 1975 of plasma exchange for the treatment of 2 patients with familial hyperlipidemia, plasma purification techniques for selective low-density lipoprotein (LDL) removal (i.e., LDL apheresis) have been developed and adopted for the management of this disease. Thermofiltration is one of the LDL apheresis systems that utilizes membrane techniques developed by Nose and Malchesky's group in 1985. This article reviews its rationale, in vitro studies, animal studies, and clinical investigation. Thermofiltration effectively and selectively removes LDL cholesterol while retaining in the plasma physiologically important macromolecules such as albumin and high-density lipoprotein (HDL) cholesterol. Based on the global view of the treatment of atherosclerosis by LDL apheresis, membrane techniques are as effective, safe, and simpler to apply than other methods. Additionally, these methods are effective for the removal of lipoprotein (a) and fibrinogen; thus, they can address the needs in these application areas.

A new low density lipoprotein apheresis system using two dextran sulfate cellulose columns in an automated column regenerating unit (LDL continuous apheresis)

We describe a new low density lipoprotein (LDL) apheresis system using dextran sulfate cellulose column in an automated column regenerating unit (LDL continuous apheresis). Two columns containing 150 ml of dextran sulfate cellulose were used, and the whole extracorporeal circulation was about 400 ml in volume. After 600 ml of plasma was adsorbed into the first column, the second column was used as an adsorbent and meanwhile the first column was regenerated. Thus, the 2 columns were used alternately without losing the potency of the columns. As the apparatus was automatically controlled by a computerized unit, no extra manipulation is necessary compared with the conventional single-column method. By treating 4–5 liters of plasma, non-high density lipoprotein (HDL)-cholesterol levels decreased by 63–71%, and HDL-cholesterol levels remained unchanged. Thus, this new method of LDL apheresis can safely reduce LDL-cholesterol to any desired level and will be applicable for the treatment of child and adult familial hypercholesterolemic patients with severe coronary heart disease.