Lipidapheresis

Lipid apheresis is a therapeutic blood purification procedure used in nephrology to remove LDL cholesterol from the blood (LDL apheresis). In addition to the removal of cholesterol, there is the possibility of removing other atherosclerosis (arteriosclerosis; hardening of the arteries) promoting factors such as lipoprotein (a) (LPA) and triglycerides (TG) from the blood, thus reducing the probability of developing cardiovascular disease. Due to this, lipid apheresis is used in patients suffering from the homozygous form of familial hypercholesterolemia. Familial hypercholesterolemia is a disease pattern characterized, among other things, by an early development of atherosclerosis and the occurrence of myocardial infarction (heart attack) in middle age. However, affected individuals who are homozygous (passing on the “defective” gene segment from both father and mother to the affected patient) for the lipid metabolism defect often suffer a myocardial infarction around the age of 20. The pathogenesis (cause and progression of the disease) is based on various gene mutations for the cell surface receptor of low-density lipoproteins (LDL). As a result of this receptor defect, the disease process cannot be influenced by the patient’s lifestyle, or only to a very small extent. As a result of this impaired removal of LDL from the blood, xanthomas develop already in childhood. Xanthomas are lipid deposits in the skin, which can be found especially on the eyelids and in the area of the tendon sheaths. This pathological phenomenon can also not be adequately treated by dietary and drug therapy to lower LDL cholesterol. Lipid apheresis is used in patients with severe hypercholesterolemia who could not be adequately treated with twelve months of therapy with lipostatics (lipid-lowering drugs) and an appropriate dietary lifestyle. A significant reduction in LDL cholesterol is considered a treatment success. In addition, use of lipid apheresis should be considered in patients with isolated lipoprotein (a) elevation and nonsenior LDL cholesterol and concomitant symptomatic and imaging-verified cardiovascular disease.

Indications (areas of application)

  • Severe familial hypercholesterolemia (FH) – when this condition is present and cholesterol levels are very high, affected patients develop coronary artery disease extremely early and are at high risk for myocardial infarction without this therapy.
  • Treatment can be given to both homozygous and heterozygous patients, but the indication is clearly proven in studies only in homozygous patients.
  • Isolated lipoprotein(a) elevation (Lp(a) elevation) with progressive (advancing) cardiovascular disease/cardiovascular disease.

Procedure

Lipid apheresis can be performed using a variety of procedures. Depending on the procedure used, separation (separation) of plasma from the patient’s blood may be necessary to remove lipoproteins. Examples of lipid apheresis systems that require plasma separation from blood to function include cascade filtration and heparin-induced extracorporeal LDL precipitation (HELP). Adequate removal of LDL cholesterol by lipid apheresis can only occur if the cholesterol is bound to a protein. Thus, by removing lipoproteins, lipid apheresis can contribute to the reduction of lethality (mortality) from the sequelae of familial hypercholesterolemia. Due to the fact that an increase in cholesterol levels is to be expected as a result of the receptor defect, this extracorporeal blood purification procedure must be repeated at defined intervals. Thus, this therapeutic measure is to be regarded as chronic-intermittent. Heparin-induced extracorporeal LDL precipitation (HELP).

  • The HELP procedure can remove LDL cholesterol and lipoprotein (a) as well as fibrinogen from plasma.
  • The principle of the HELP procedure is based on precipitation (precipitation) of the positively charged LDL cholesterol with the help of the negatively charged heparin. Elimination of the substances occurs at an acidic pH of 5.1 in the presence of heparin.Crucial for the function of the system is the addition of a mixture of sodium acetate buffer and heparin to the separated blood plasma. The subsequently formed heparin-protein complexes, which contain the substances to be eliminated, are then removed with a precipitation filter.
  • Before the purified plasma can be applied back into the patient’s bloodstream, it must first pass through a polyanion exchanger (DEAE cellulose) so that removal of excess heparin can be ensured. Moreover, the use of a dialyzer to remove the buffer from the purified blood plasma.
  • As a result of the reduction of fibrinogen by the procedure, blood viscosity can be reduced. This causes an improvement in blood flow, particularly in the fine capillary vessels. Randomized controlled trials (RCT) have demonstrated efficacy in cardiovascular disease and good tolerability. As a result of this blood circulation-promoting effect, the indication spectrum (scope) of the HELP procedure was extended to the treatment of acute hearing loss.
  • However, vertigo (dizziness), drops in blood pressure and burning eyes are to be cited as typical side effects. If necessary, the adverse therapeutic effects may lead to discontinuation of the therapeutic intervention.

Lipid filtration according to Monet

  • The basic principle of lipid filtration according to Monet is based on size-selective filtration of high-molecular-weight plasma components. For Monet filtration to function, and thus for lipid molecules to be removed, separation is essential. At the beginning of the process, separation of cellular components from plasma is performed with a plasma separator.
  • The plasma thus separated is now passed into the lipid filter for elimination of LDL cholesterol, lipoprotein (a), fibrinogen, and triglycerides via an upstream heater so that the substances to be removed can be retained. From this it can be concluded that filtration is dependent on size, molar mass and geometry. The diameter limit that molecules and molecular complexes must meet to be retained is 25 to 40 nm.
  • Consequently, smaller molecules such as HDL cholesterol are able to pass the filter in principle unhindered.
  • For optimal compatibility, the membrane of the filter is made of polyethylene. Polyethylene is a special plastic, which is characterized by low water absorption, good sliding properties with low wear and resistance to almost all acids, alkalis, alcohols and oils.
  • Depending on the blood flow and the given plasma volume, it can be assumed that the duration of treatment is approximately two hours. Anticoagulation can be performed with either heparin or citrate. The use of citrate is considered particularly favorable because this method of anticoagulation can almost completely prevent the calcium-dependent steps of complement activation. For better control of the anticoagulant effect, primarily short-acting substances should be used to prevent side effects such as an undesirable prolonged bleeding tendency of the affected patient.

Dextran sulfate cellulose adsorption (DSA) from plasma.

  • The principle of dextran-sulfate-cellulose adsorption differs relevantly from Monet’s lipid filtration. In DSA, the function is based on the presence of a negatively charged molecule located on a surface so that selectively positively charged molecules such as the apo-B domain of LDL or VLDL cholesterol and lipoprotein (a) can be specifically bound. As with lipid filtration, there is no retention or removal of HDL cholesterol. However, unlike lipid filtration, this is not due to the diameter, but rather to the absence of the apo-B domain.
  • Dextran-sulfate-cellulose adsorption (DSA) from plasma also begins with the separation of solid blood components using a plasma separator. This is done with the aid of two small columns containing dextran sulfate bound to cellulose beads and thus able to bind Apo-B-containing lipoproteins by adsorption. The plasma is now passed alternately over these two small columns. The change between the columns takes place after each 600 ml of treated plasma volume. While one column is active, regeneration of the second column takes place.

Immunoadsorption

  • In addition to the procedures already described, another system for the removal of lipids and lipid-like substances, immunoadsorption, finds use in lipid apheresis. Before lipid apheresis can be performed in patients, an antibody against human LDL cholesterol must first be obtained in sheep.
  • Once these antibodies have been collected, they are firmly bound to sepharose (agarose – the main component of various culture media) and are thus immobilized. Once this step has been performed, the antibody-Sepharose component can subsequently be applied to a glass container.
  • The previously separated plasma is now passed through the glass column so that the antibodies can bind the LDL cholesterol. This binding ensures that the LDL cholesterol is safely retained.
  • Once the antibodies in the column are saturated, the column is rinsed with glycerol and saline, resulting in the removal of the bound lipids.

DALI method (Direct adsorption of lipid proteins).

  • The DALI method allows direct adsorption of LDL, VLDL cholesterol and lipoprotein (a) from whole blood.
  • The single-use adsorption cartridges contain negatively charged polyacrylate ligands (special plastic) that are immobilized and bind lipoproteins by electrostatic means. Fibrinogen, on the other hand, is only slightly retained. Both via the factor “charge” and the factor “surface properties of the binding sites” can ensure selective binding of LDL cholesterol.
  • Due to the comparatively trivial setup of the system by omitting the plasma separation, a treatment time of approximately one hour is achieved. For the function of the system is only a power supply necessary.